Pharmacology

Clinical Pharmacology and Therapeutics (CPT) Revision

Notes

By Dr Garry KJ Pettet MBBS/BScRevision 2 (January 2006)

Contents

.........................................................................Preface 1

.........................................................Drug development 2

...................................................Adverse drug reactions 5

...........................................................Drug interactions 7

..............................Pharmacodynamics/pharmacokinetics 9

..................................Prescribing in renal / liver disease 12

.............................................................Rheumatology 16

.........................................................Gastroenterology 22

....................................................................Antivirals 27

...........................................................Asthma / COPD 30

..................................................................Analgesics 35

..........................................................The failing heart 38

..............................................................Endocrinology 46

.........................................................................Lipids 57

......................................................................Clotting 60

............................................................Mood disorders 68

..................................................Anti-arrhythmic drugs 74

...............................................................Hypertension 81

........................................................Antibiotic therapy 83

..................................................................Antibiotics 86

.....................................................................Diabetes 95

Copyright Dr Garry KJ Pettet 2005 - 2009

www.garrypettet.com

http://www.garrypettet.com


....................................................................Epilepsy 101

...................................................................Migraine 107

.......................................................Multiple sclerosis 109

....................................................Parkinson’s disease 110

...............................Drug-induced movement disorders 115

......................................................Myasthenia gravis 117

...................................................................Diuretics 119

........................................................Muscle relaxants 122

..............................................................Anti-emetics 124

....................................................................The eye 127

.......................................Antipsychotics (neuroleptics) 130

........................Drugs in the elderly, young or pregnant 134

.............................................Cytotoxic chemotherapy 137

............................................................Anti-malarials 141


www.garrypettet.com



Preface

I wrote these notes as a final year medical student in the UK as I found it very difficult to find a good single text to use for my CPT revision.

I used the following textbooks in writing these notes:

- British National Formulary (BNF 47 March 2004)- Clinical medicine 5th edition (Kumar, Clark)- Hands-on-guide to clinical pharmacology (Chatu, Milson & Tofield)- Medical pharmacology at a glance 4th edition (Neal)- Oxford handbook of clinical medicine 6th edition (Longmore, Wilkinson

& Rajagopalan)- Pharmacology 4th edition (Rang, Dale, Ritter)

I have made sure that everything that has been mentioned in our lectures is in these notes. We must thank the following lecturers, as some of their material may well be in these notes:

- Dr Chris Bench- Dr Neil Chapman- Dr Anton Emmanuel- Dr Michael Feher- Dr Alun Hughes- Prof Sebastian Johnston- Prof John MacDermot- Dr Janice Main- Dr Vias Markides- Dr Jamil Mayet- Dr Andrew Rice- Dr Stephen Robinson- Dr Mike Schachter- Dr Tom Sensky- Prof Peter Sever- Dr Colin Tench- Dr Simon Thom- Dr Roxaneh Zamegar

I would also like to thank Dr Wajid Hussain for proofreading the section on anti-arrhythmics.

Although every effort has been made to ensure the accuracy of these notes, I take no responsibility for errors within (but please let me know as I have to revise from these as well!).

Dr Garry Pettet


1www.garrypettet.com



Drug development

Surrogate markers:• A biological measurement which substitutes for the therapeutic end-

point• Examples:

o BP and strokeo Cholesterol and coronary disease

• Characteristics of a “good” surrogate:o Biological feasibilityo Dose-related response to interventiono Easy to measureo Reproducibleo Specific / sensitiveo High predictive valueo Acceptable by experts / regulatory authorities

Types of clinical trials:• Open:

o Subject and researcher know what they are getting• Single-blind:

o The subjects do not know what they are getting• Double-blind:

o No one knows what they are getting (during the trial)• PROBE:

o Prospectiveo Randomisedo Open-labelledo Blindedo End-pointo This is used for large, complex studies with several treatments.

It is an open trial where those who analyse the results do not know who got what treatment

The phases of a clinical trial:• Phase 1:

o Healthy volunteers (not for cancer / HIV trials)o Few subjects (< 50)o Looks at pharmacokinetics / pharmacodynamic activity / safety

• Phase 2:o Patients with the target diseaseo More subjects (100 – 200)o Usually single-blind trialso Looks again at pharmacokinetics / safety (note, these may be

different than in healthy volunteers)

• Phase 3:o Patientso Much larger (> 1000)





o Usually double-blind or PROBEo May be parallel or crossovero Multi-centreo May use either “hard” (e.g. MI) or “surrogate” end-points

• Phase 4:o Post-marketingo Surveillance for:

! Adverse drug reactions! Rare side-effects! Drug interactions

Parallel vs crossover studies:• Parallel study:

o Most randomised controlled trials (RCTs) are parallel• Crossover study:

o Need fewer subjectso Should normally be used in chronic stable diseases and the

interventions should have a rapid onset and short durationo Beware of order effects:

! Carry-over effects! Period effects:

• Changes in the patient’s disease over time

Power:• Is the study large enough to answer the study’s question?• Type 1 error (!):

o Chance of finding 2 treatments are different when they are noto Usually:

! ! = 0.05 (i.e. p < 0.05)• Type 2 error ("):

o Chance of finding 2 treatments are equal when they are noto Usually:

! " = 0.1 or 0.2 (arbitrary)• Power = 1 - " (i.e. 80 – 90% usually)• The higher we set " (i.e. the greater our power) the more expensive

the trial becomes as we need more subjects



A

B

A

B



“Intention to treat” vs “per protocol” analysis:• Intention to treat:

o Ignore whether the subjects actually take the medication (i.e. just assume they did)

• Per protocol:o Only analyse data from subjects who actually took the

medication





Adverse drug reactions

Significance:• 3 – 40% of inpatient admissions• Affects 10 – 20% of hospital patients• 4th most common cause of death in US hospital patients• Up to 30 – 60% are preventable

Types of adverse drug reaction (ADR):• Type 1:

o “Predictable” reactionso Commono Dose-relatedo A consequence of the known pharmacology of the drug

• Type 2:o “Idiosyncratic” reactionso Rareo Usually not dose-relatedo Allergieso Pharmacogenetic variations

Classification of ADRs:• Augmented pharmacological effect• Bizarre• Chronic• Delayed• End-of-treatment

Determinants of ADRs:• Drug:

o Pharmacodynamicso Pharmacokineticso Doseo Formulationo Route of administration

• Patient:o Ageo Co-morbidityo Organ dysfunctiono Genetic predisposition

• Environment:o Mistakes

Allergies vs psuedoallergies:• Allergies:

o Type I (anaphylaxis):





! Penicillins! Contrast media (anaphylactoid)

o Type II (cytotoxic antibodies – blood dyscrasias):! Haemolytic anaemia:

• Methyldopa• Penicillin• Sulphonamides

! Agranulocytosis:• Carbimazole• Clozapine

! Thrombocytopenia:• Quinidine• Heparin

o Type III (immune complex formation):! Penicillin! Sulphonamides

o Type IV (cell mediated):! Topical antibiotics

• Pseudoallergies:o Looks like an allergy but is not immune-mediatedo Examples:

! Aspirin - bronchospasm! ACE inhibitors – cough

Long-term ADRs:• Withdrawal:

o Opiateso Benzodiazepineso Corticosteroids

• Rebound:o Clonidineo "-blockers

• Adaptive:o Neuroleptics





Drug interactions

Liver enzyme inducers (cytochrome P450):• Carbamazepine• Phenobarbitone• Phenytoin• Rifampicin

Liver enzyme inhibitors (cytochrome P450):• Cimetidine• Ciprofloxacin• Grapefruit juice• Macrolide antibiotics:

o Erythromycin• Omeprazole

Important drugs metabolised by the liver (cytochrome P450):• Carbamazepine• Cyclosporin A• Combined oral contraceptive (COC) pill• Phenytoin• Theophylline• Warfarin

Some important drugs interacting with warfarin:• Drugs increasing the effect of warfarin:

o Alcoholo Amiodaroneo Antibiotics (many – reduced vitamin K absorption)o Cimetidineo Omeprazoleo Simvastatin

• Drugs decreasing the effect of warfarin:o Carbamazepineo COC pillo Rifampicin

Interactions with diuretics:• General:

o Potentiate:! ACE inhibitors! Lithium

o Metabolic:! Hypokalaemia enhances digoxin efficacy! "-blockers potentiate hypokalaemic effects of diuretics

• Loop:o Increased risk of ototoxicity with the aminoglycosides

• Potassium-sparing:





o Risk of hyperkalaemia with ACE inhibitors

Drugs affecting gastric emptying and hence drug absorption:• Increase emptying:

o Metoclopramide• Decrease emptying:

o Atropine

Impairment of drug excretion:• Probenicid:

o Competes with Penicillins for renal tubular excretion, leads to increased concentration of penicillins (can be beneficial)





Pharmacodynamics/pharmacokinetics

Half-life (t1/2):• The time taken for the concentration of drug in plasma (or blood) to

fall to half it’s original value• Drugs with a short t1/2 may have a long duration of action:

o So-called “cell-trapping”o E.g. omeprazole

Volume of distribution (Vd):• This is the apparent volume into which the drug is distributed

Vd = dose / (initial apparent plasma concentration)

• Is used to calculate the clearance of a drug• Is high for lipid-soluble drugs• Is low for water-soluble drugs• Values of Vd:

o < 5L drug retained within the vascular systemo < 15L drug is restricted to the extracellular fluid (ECF)o > 15L indicates the drug is distributed throughout the

total body water

Clearance:• The volume of plasma (or blood) cleared of drug per unit time• Depends on drug lipid solubility• Clearance (but not t1/2) provides an indication of the ability of the liver

and kidneys to dispose of the drug

First vs zero order kinetics:• First-order kinetics:

o A metabolic process that depends on the drug concentration at any given time is called a first-order process

o I.e. a non-saturable process• Zero-order kinetics:

o If any enzyme system responsible for drug metabolism becomes saturated, then the rate of elimination proceeds at a constant rate and is unaffected by an increase in the concentration of the drug

o I.e. a saturable processo Examples include:

! Phenytoin! Ethanol

o The importance of zero-order kinetics is that you could double the dose, but the plasma concentration would not double (may increase to an enormous extent)

Bioavailability:• The proportion of administered drug reaching the systemic circulation• IV drugs have 100% bioavailability





• Drugs with high bioavailability:o Ciprofloxacin (near 100%)

• Drugs with low bioavailability:o Bisphosphonates (~15%)

First-pass metabolism:• Also known as pre-systemic metabolism• This is drug metabolism that occurs before the drug reaches the

system circulation• Occurs in the liver and gut wall• Some drugs undergo extensive first-pass metabolism:

o Levodopao Lignocaineo Morphineo Nitrates (e.g. GTN)o Propranololo Verapamil

• Is generally a nuisance for two reasons:o A larger dose is needed when it is given orallyo Marked individual variations occur

Post-systemic metabolism:• The main purpose is to increase water-solubility of the drug• Phase I:

o Three types of reaction:! Oxidation:

• Most important are the P450 enzymes• Xanthine oxidase metabolises 6-mercaptopurine• Monoamine oxidase inactivates 5-HT, NA, tyramine

! Reduction / Hydrolysiso Usually produces a more reactive compound that will be acted

on by phase II componentso May activate a prodrug – examples:

! Levodopa " dopamine! Enalapril " enalaprilat! Azathioprine " 6-mercaptopurine! Methlydopa " !-methyl-noradrenaline! Carbimazole " methimazole

• Phase II:o Conjugation of a drug or phase I metabolite with an

endogenous substance to form a more polar, easily excreted, compound

o May be either:! Glucuronidation! Sulphation! Acetylation (does not alter water-solubility)





! Glutathione

Loading doses:• In practice, a steady state concentration is effectively achieved after

three plasma half-times• Faster attainment of the steady state is achieved by starting with a

larger dose – a loading dose

Therapeutic drug monitoring:• Why?

o To investigate lack of drug efficacyo Possible poor complianceo Suspected toxicityo Prevention of toxicity

• Type of drugs:o Narrow therapeutic index (TI)o Uncertain dose / concentration relationshipo Defined plasma concentrations with no active metabolites

• Examples:o Not warfarin (this measures the INR, not drug concentration!)o Antibiotics (aminoglycosides, vancomycin)o Anticonvulsants (carbamazepine, phenytoin)o Aminophylline / theophyllineo Cyclosporin Ao Digoxino Lithium





Prescribing in renal / liver disease

Important drugs whose elimination is affected by renal impairment• Half-lives are approximate ranges when renal impairment present• Amoxicillin (t1/2 2 – 14 hours):

o Applies to most penicillinso Toxic effects:

! Seizures (especially in meningitis)! Rashes are more common in renal impairment

• Atenolol (t1/2 6 – 100 hours):o Contraindicated in:

! Asthmatics! Severe heart failure! Peripheral vascular disease

o Toxic effects:! Bradycardia! Confusion! Hypotension

• Captopril (t1/2 2 – 14 hours):o Toxic effects:

! # GFR! Angioedema ! Cough:

• Probably due to a direct effect on sensory afferents• Not bradykinin

! GI disturbances! Hypotension! Taste disturbances

• Digoxin (t1/2 36 – 90 hours):o Requires therapeutic drug monitoring (TDM)o Toxic effects:

! Dysrhythmias (VT, heart block)! Gynaecomastia! Nausea (severe) / vomiting! Xanthopsia (distortion of yellow colour vision)

• Gentamicin (t1/2 2! - >50 hours):o Increased risk of toxicity when:

! Dehydrated (important as septic patients usually are)! Hyponatraemic

o Toxic effects:! Nephrotoxicity (renal tubular damage)! Ototoxicity (can be irreversible)

Vitamin D and the kidney:• Vitamin D has to undergo two hydroxylation reactions within the body

to become active





• Kidney forms the 1-hydroxy form of vitamin D and requires the enzyme 1!-hydroxylase

• In renal impairment, the above step may not happen• Bone disease caused by renal d isease is termed renal

osteodystrophy:o Loss of vitamin D activityo $ PTH activity

• Replacing vitamin D:o Alfacalcidol (the 1-hydroxylated form, thus negating need for

1!-hydroxylase)o Calcitriol (the active 1, 25-hydroxylated form) – rarely used

Nephrotoxic drugs:• ACE inhibitors:

o # GFR (if the arterial perfusion pressure is low):! Renal artery stenosis (especially bilaterally)! Coarctation of the aorta

• Cyclosporin A:o Used in renal transplantso Is a substrate for P450 (levels may be increased by other drugs)o # GFRo Damages tubular function

• Gentamicin:o Renal tubular damage

• Lithium:o Nephrogenic diabetes insipiduso Renal tubular damage

• NSAIDs:o # GFRo Papillary necrosis:

! Loss of PG-mediated vasodilatationo Na+ retention

• Others:o Urate stones:

! Anticancer drugs (tumour lysis syndrome)o Myoglobinuria:

! Alcohol! Statins

Drugs to watch when patient has impaired hepatic synthetic function:• Hypoalbuminaemia:

o Drugs which bind to albumin and are cleared by the liver:! Diazepam! Phenytoin! Tolbutamide

• A1-acidic glycoprotein deficiency:o Binds basic drugs:

! Chlorpromazine! Imipramine





! Quinidine• Reduced synthesis of clotting factors:

o Warfarin:! If the liver is synthesising even less of factors II, VII, IX

and X then warfarin’s effects will be potentiatedo Antibiotics:

! Interfere with vitamin K production in the gut by bacteria! May compound the above problem

Drugs to watch in a patient with current / recent hepatic encephalopathy:• Antidepressants:

o Tricyclic antidepressants (TCAs) are safest (but use a # dose)o Avoid monoamine oxidase inhibitors (MAOIs):

! Idiosyncratic hepatotoxicity• Anti-psychotics:

o Chlorpromazine• Anxiolytics / hypnotics:

o Oxazepam / temazepam are the safesto Avoid chlormethiazole (especially IV)

• Opiates:o Can precipitate comao Even low levels are dangerous

Drugs with a high first-pass metabolism:• These drugs will not be metabolised as much in liver impairment (if

given orally), thus the dose should be #• Chlorpromazine• Chlormethiazole• Imipramine• Morphine / pethidine• Propranolol• Verapamil

Hepatotoxic drugs:• Cholestasis:

o Chlorpromazine (reversible cholestasis)o Sulphonylureas (e.g. glibenclamide)o Carbimazole

• Hepatocellular necrosis:o Antibiotics:

! Isoniazid! Rifampicin! Nitrofurantoin

o Anticonvulsants:! Can cause liver damage at normal doses in some patients! Carbamazepine! Phenytoin! Valproate





o Anti-hypertensives:! Hydralazine:

• Also causes a SLE-like syndrome (ssDNA Abs)! Methyldopa

o Halothane (repeated exposures)o Paracetamol (overdose)





Rheumatology

Drug treatment of osteoarthritis (OA):• Simple analgesics:

o Paracetamol (as good as Ibuprofen in early disease)• Topical therapy:

o NSAIDs (e.g. ibuleve)o Capsaicin:

! Potent pain-producing agent! After a few applications, the pain-producing effect

disappears and nociceptive responses to other stimuli disappear as well – hence it’s use here

• Glucosamine• Systemic NSAIDs

Drug treatment of rheumatoid arthritis (RA):• NSAIDs• COX-II inhibitors:

o Indications:! Age >65 years! Previous history of DU / GU or GI bleed! Large doses of NSAID required to control pain

o Absolute contraindications:! Established IHD! Cerebrovascular disease! Heart failure (NYHA II – IV)

• Gastroprotection (if on NSAID / long-term steroids):o H2-receptor antagonistso Proton pump inhibitors (PPIs)o Misoprostol

• Disease modifying anti-rheumatic drug (DMARD):o Persisting synovitis >6 weekso Several may have to be tried to find the right one:

! Methotrexate! Sulphasalazine! Gold! Penicillamine! Hydroxychloroquine

• Anti-TNF! therapy:o Progressive RA after 2 DMARD failures

• Steroids are controversial but useful in acute flares

Drug treatment of osteoporosis:• Bisphosphonates:

o Are the mainstay of treatment• Calcium supplements• Vitamin D• Calcitonin (may be considered)• HRT no longer has role





Glucosamine:• Unclear mechanism of action• Probably similar efficacy to simple NSAIDs• Better tolerated than NSAIDs but not free of side-effects:

o Headacheo Rasho Drowsiness

Non-steroidal anti-inflammatory drugs (NSAIDs):• (Non- selectively) inhibit cyclo-oxygenase (COX)• COX converts arachidonic acid (derived from membrane phospholipids)

into endoperoxides• The endoperoxides are further converted into:

o Prostaglandins (PGs):! Potentiate the activity of other pain mediators! Vasodilatation

o Thromboxane A2:! Platelet aggregation! Vasoconstriction

o Prostacyclin:! Inhibits platelet aggregation! Vasodilatation

• There are 2 isoforms of COX - COX-I and COX-II:o COX-I is a constitutional enzyme and is important in the

maintenance of the protective GI mucus barrier in the stomach and of renal blood flow

o COX-II is expressed at sites of inflammation• NSAIDs are:

o Analgesico Antipyretic (inhibits the rise in brain PGs that cause pyrexia)o Anti-inflammatory (at higher doses)

• Adverse effects:o GI:

! Peptic ulceration (major adverse effect)o Renal:

! Reduced renal blood flow! Sodium retention - hypertension! Interstitial nephritis! Hyperkalaemia! Papillary necrosis (chronic use)

o Other:! Bronchospasm (especially in asthmatics)! Allergies

Aspirin as a NSAID:• Aspirin is a NSAID but the large doses required to control the

inflammation in the arthritides led to an unacceptable number of adverse effects





• It irreversibly inactivates COX – activity returns only when new enzyme is synthesised:

o Hence it’s effectiveness in platelets (cannot synthesise new enzyme)

Paracetamol as a NSAID:• Like aspirin, paracetamol is a NSAID• It’s mechanism of action is not fully understood and it has no anti-

inflammatory activity• It works, act least partly, by reducing COX tone:

o This activity is only seen in areas of low peroxide concentrationo Hence, paracetamol works best when there is little or no

leucocyte infiltration (as leucocytes produce high levels of peroxide)

Relative risk of GI toxicity with NSAIDs:• From least toxic to most toxic:

o Ibuprofeno Diclofenaco Aspirino Naproxeno Indomethacino Ketoprofen

COX-II inhibitors:• E.g. Celecoxib (Rofecoxib (Vioxx) has been withdrawn in the UK))• No better at improving symptoms of pain / inflammation than NSAIDs• 50% reduction in GI:

o Ulcerationo Perforationo Bleeds

• (Probable) increased risk of:o Myocardial infarctiono Stroke

Methotrexate:• Indications:

o Malignancyo Psoriasis (when conventional therapy fails)o Rheumatoid arthritis





• Mechanism of action:o Inhibits dihydrofolate reductaseo Leads to a reduction in the production of tetrahydrofolic acid

(which is essential for nucleic acid synthesis)o Prevents cells from dividing

• Administer concurrent folic acid to minimise symptoms• Adverse effects:

o Nauseao Fatigueo Pneumonitis (rare but can be life-threatening)

• Contraindications:o Renal / hepatic impairmento Pregnancy

• Interactions:o NSAIDs / probenicid:

! Reduce the excretion of methotrexate

Sulphasalazine:• Mechanism of action in RA is unknown• Adverse effects:

o Nausea / abdominal discomforto Reduced sperm counto Marrow suppression

• Contraindications:o Salicylate allergyo Renal impairment

Gold:• Adverse effects:

o Marrow suppressiono Proteinuriao Hepatitis

Penicillamine:• Adverse effects:

o Marrow suppressiono Proteinuriao Reduction in tasteo SLE

• Contraindications:o Penicillin allergyo SLE

Hydroxychloroquine:• Adverse effects:

o Rasho Retinopathy (rare)o Tinnitus

• Cautions:





o Hepatic impairment• Very toxic in overdose

Anti-TNF! therapy:• TNF! is the major mediator of inflammation• Used in RA when patient has failed to respond to >=2 DMARDs

(including methotrexate)• Can be either:

o Soluble TNF! receptors (etanercept)o Anti-TNF! receptors (infliximab)

• Reduce inflammation, inhibit progression and improve radiological Sharp score (a measure of radiological RA severity)

• Adverse effects:o Local reactionso Increased risk of infections:

! Especially tuberculosis (need to screen before therapy)o Demyelination syndromeso SLE-like syndrome:

! Avoid in SLE-suffererso Worsening of pre-existing heart failure

• Other disease indications:o Ankylosing spondylitiso Psoriatic arthritiso Crohn’s disease

Bisphosphonates:• E.g. alendronate, pamidronate• Are enzyme-resistant analogues of pyrophosphate• Bind to hydroxyapatite crystals and reduce bone resorption (via

inhibition of osteoclasts)• Indications:

o Osteoporosis (both primary and steroid-induced)o Paget’s diseaseo Malignant hypercalcaemia

• Adverse effects:o Alendronate can cause oesophagitis:

! Swallow the tablet whole with a full glass of water on an empty stomach and remain upright for at least 30 mins

Vitamin D supplementation:• Usually given as ergocalciferol (vitamin D2 – the usual dietary source

of vitamin D)• Is a fat-soluble vitamin so bile salts are necessary for absorption• Adverse effects:

o Hypercalcaemia

• Interactions:





o Some anticonvulsants (carbamazepine, phenytoin) increase the requirement of vitamin D





Gastroenterology

Drug treatment of GORD / PUD:• Antacids• Acid suppression:

o H2-receptor antagonistso Proton pump inhibitors (PPIs)

• Helicobacter pylori eradication

Drug treatment of constipation (laxatives):• Bulk laxatives• Stimulant laxatives• Osmotic agents• Stool softeners• Suppositories / enemas• Novel:

o Motilin analogues (e.g. erythromycin)o 5-HT4 antagonists (e.g. tegaserod)o Probiotics

Drug treatment of diarrhoea:• General:

o Opioids (e.g. loperamide)• Autonomic neuropathy (e.g. diabetes):

o Clonidineo Octreotide (for secretory diarrhoea)

• Bacterial overgrowth:o Treat underlying causeo Cyclical antibiotics if above fails (e.g. neuropathy)

• Pancreatic insufficiency (e.g. diabetes, chronic pancreatitis):o Pancreatin + acid-suppressant (e.g. PPI)

Drug treatment of Crohn’s disease:• Acute exacerbations:

o Steroids (oral / rectal / IV)o Elemental dieto Anti-TNF! therapy (infliximab):

! Severe (especially fistulating) disease• Maintenance:

o 5-Aminosalicylic acid (5-ASA) compoundso Azathioprine (if 5-ASA fails)o Methotrexate (if azathioprine intolerant)

Drug treatment of ulcerative colitis:• Acute exacerbations:





o Rectal 5-ASA (evidence shows benefit over steroids)o Steroids (oral / rectal / IV)

• Maintenance:o 5-ASA compounds

Antacids:• Increase gastric pH (this increases rate of emptying thus action is

short)• All antacids can interfere with drug absorption – should be taken

separately• Sodium bicarbonate:

o Only useful water-soluble antacido May cause metabolic alkalosis

• Magnesium hydroxide:o May cause diarrhoea

• Aluminium hydroxide:o May cause constipation

• Alginate-containing compounds (e.g. Gaviscon):o Form a “raft” on top of stomach contents and prevent reflux

H2-receptor antagonists:• E.g. ranitidine, cimetidine• Block histamine receptors on the gastric parietal cell membrane and

reduce acid secretion• Indications:

o GORDo PUD

• Adverse effects (mainly cimetidine):o Liver enzyme inhibitor (increases levels of):

! Anticonvulsants (carbamazepine, phenytoin, valproate)! Theophylline ! Warfarin

o Hyperprolactinaemiao Anti-androgenic activity (gynaecomastia)

Proton pump inhibitors (PPIs):• E.g. omeprazole, lansoprazole• Inactive at neutral pH but are activated in the stomach and irreversibly

inhibit the H+/K+-ATPase (proton pump)• Are more effective than H2-receptor antagonists and more cost-

effective• Indications:

o GORDo PUDo Zollinger-Ellison syndrome

• Adverse effects:o Liver enzyme inhibitor (increases levels of):





! Phenytoin! Warfarin

• Cautions:o Achlorhydria is associated with gastric cancer – unsure of long-

term effects of acid suppression

H. pylori eradication therapy:• One PPI and two antibiotics for two weeks• Usual combination (but there are many):

o Omeprazoleo Clarithromycino Amoxicillin (or metronidazole)

• Resistance to metronidazole is common

Bulk laxatives:• E.g. bran, ispaghula• Only good for mild constipation• Are usually indigestible polysaccharides• Increase the volume of the intestinal contents – thus stimulating

peristalsis by stretching mechanoreceptors• Gradual onset of action (~1 week)• Increase stool output as a function of initial stool weight:

o If stool volume is low initially then won’t see much of an increase

• Adverse effects:o Exacerbates bloating in slow-transit constipations

Stimulant laxatives:• E.g. bisacodyl, picosulphate, senna• Are inactive glycosides that are activated in the colon by bacteria• Once in colon – have direct stimulant effect on the myenteric plexus:

o Smooth muscle contraction (peristalsis)• Also increase secretion of water and electrolytes• Rapid onset of action (~8 hours) – give in evening for morning stool• Adverse effects:

o Colico Colonic atonyo Hypokalaemiao Pseudomelanosis coli (colonic pigmentation with chronic use)o Unpredictable effect

Osmotic agents:• E.g. Lactulose, magnesium salts• Poorly absorbed solutes that maintain a large stool volume by osmosis• Lactulose:

o Is a disaccharide (fructose-galactose)o Cannot be cleaved by human disaccharidases – is cleaved by

bacteria in the colon





o These sugars are poorly absorbed by the colon and act as osmotic laxatives

• Onset of action:o Salts – hourso Lactulose – 2 or 3 days

• Adverse effects:o Crampso Flatulenceo Hypermagnesaemia (especially in renal impairment) with Mg

salts

Stool softeners:• E.g. sodium docusate, arachis oil• Act like detergents in the colon and facilitate mixing of fat and water

in the stool• Adverse effects:

o Passive faecal leakage• Not effective enough to be used on their own

Suppositories / enemas:• E.g. glycerine suppositories, phosphate enemas• Probably as effective as oral osmotic laxatives

Opioids and diarrhoea:• E.g. loperamide, codeine, morphine• Stimulate µ-receptors on myenteric neurones and lead to

hyperpolarization:o Inhibits Ach release from myenteric plexus and reduces

peristalsis• Loperamide is most appropriate as it does not cross the blood-brain

barrier and is unlikely to cause dependence

Pancreatin:• Pancreatic enzyme supplement of porcine origin• Must be taken with an anti-acid drug (usually a H2-receptor

antagonist) to prevent it’s destruction in the stomach• Is inactivated by heat – caution if mixing pancreatin in with food• Indications:

o Cystic fibrosiso Chronic pancreatitiso Diabetes mellituso Pancreatectomy

• Adverse effects:o Nausea / vomitingo Abdominal discomforto Irritation of buccal / perianal mucosa

5-Aminosalicyclic acid (5-ASA) compounds:• E.g. mesalazine, olsalazine, sulphasalazine





• Unknown mechanism of action• Indications:

o Induction of remission in UC (rectal preparation)o Maintenance of remission in UC and CD:

! 1 year relapse rate (73% placebo vs 21% sulphasalazine)• Probably reduce the cancer risk associated with UC• Drug structures:

o Olsalazine:! Two 5-ASA molecules joined by an azo bond that is

cleaved by bacteria in the colono Sulphasalazine:

! 5-ASA with sulphapyridine (a sulphonamide)! The sulphapyridine carries the 5-ASA to the colon! Most of the adverse effects are caused by sulphapyridine

• Adverse effects:o Few with the newer agents (lacking sulphapyridine)

Infliximab:• An anti-TNF! monoclonal antibody• Indications:

o Crohn’s disease not controlled by steroids and a conventional immunosuppressant

o Refractory fistulating Crohn’s disease• 65% of patients initially respond to infliximab• 30% will go on to remission• Of those that respond to a single treatment – 50% maintain remission

when treated for 1 year• Infliximab closes 50% of refractory fistulas within 2 weeks and

improves healing in 65%:o However, only 30% of those who heal remain healed at 1 year

• Adverse effects:o Local reactionso Increased risk of infections:

! Especially tuberculosis (need to screen before therapy)o Demyelination syndromeso SLE-like syndrome:

! Avoid in SLE-suffererso Worsening of pre-existing heart failure





Antivirals

Treatment of herpes simplex virus (HSV) and varicella zoster virus (VZV):• Aciclovir (topical / oral / IV)• Second-line:

o Famciclovir (good for genital herpes)o Valaciclovir

Treatment of cytomegalovirus (CMV):• Ganciclovir (IV) (can cause myelosuppression)• Second-line:

o Valacicloviro Foscarnet

Treatment of human immunodeficiency virus (HIV):• Highly active anti-retroviral therapy (HAART):

o Two NRTIs plus either an NNRTI or a PI • NRTI = nucleoside reverse transcriptase inhibitor• NNRTI = non- nucleoside reverse transcriptase inhibitor• PI = protease inhibitor• Treatment of opportunistic infections

Drugs treatment of chronic hepatitis B (HBV) infection:• 40% success rate• Interferon-! (IFN-!) given as a subcutaneous injection• Lamivudine• Second-line:

o Famciclovir

Drug treatment of chronic hepatitis C (HCV) infection:• Combination therapy (most effective, up to 60% ‘cured’):

o Peginterferon-! ($ bioavailability – once weekly)o Ribavirin

• Treatment depends on HCV genotype:o Genotypes 2, 3:

! Better prognosis! Treat for 6 months

o Genotypes 1, 4:! Worse prognosis! Treat for 12 months

• If HCV RNA has not decreased after 12 weeks treatment to <1% of initial level then consider discontinuing

Drug treatment of influenza:• Influenza A only:





o Amantadine• Influenza A and B:

o Neuraminidase inhibitors:! Olseltamivir! Zanamivir

• Only used in at-risk adults who can start treatment within 48 hours of the onset of symptoms

• At-risk adults:o Chronic respiratory diseaseo Significant cardiovascular disease (excluding hypertension)o Chronic renal diseaseo Immunocompromisedo Diabetes mellitus

Aciclovir:• Is a guanosine analogue and an example of a prodrug• Aciclovir is converted to the monophosphate by thymidine kinase• Viral thymidine kinase has a much greater affinity for aciclovir than the

human enzyme• Aciclovir is therefore only activated in virally-infected cells, where it is

converted to the triphosphate:o Inhibits viral DNA polymerase and terminates the nucleotide

chain• Adverse effects:

o Rash (topical preparations)o Drip site inflammationo Renal damageo Bone marrow suppression (with parenteral administration

• Interactions:o Probenicid decreases excretion of aciclovir

Adverse effects of the NRTIs:• All of these drugs have many side-effects, only important ones for

each are listed here• Abacavir:

o Hypersensitivity (rash, Stevens-Johnson syndrome)o Hepatic impairment (lactic acidosis, hepatomegaly)

• Didanosine:o Pancreatitis

• Lamivudine:o Well toleratedo Caution in hepatic disease

• Stavudine:o Lipodystrophyo Peripheral neuropathy

• Zalcitabine:o Pancreatitiso Peripheral neuropathy





• Zidovudine (AZT):o Bone marrow suppression (initially developed as an anti-

cancer agent)

Adverse effects of the NNRTIs:• All of these drugs have many side-effects, only the important ones for

each are listed here• Efavirenz:

o Psychiatric manifestations• Nevirapine:

o Hypersensitivity (rash, Stevens-Johnson syndrome)o Many drug interactions:

! E.g. methadone is metabolised much faster

Adverse effects of the PIs:o Many side effects although an important one is lipodystrophy

• Amprenavir:o Hypersensitivity (rash, Stevens-Johnson syndrome)

• Indinavir:o Renal calculi

• Ritonavir:o Peripheral and circumoral paraesthesia

• Saquinavir:o Liver impairment

• Combination:o Kaletra (lopinavir + ritonavir):

! The ritonavir $ the concentration of the lopinavir! Diarrhoea

Lipodystrophy:• Also known as the fat redistribution syndrome• A common side effect of the PIs and stavudine• Features:

o Decreased subcutaneous fato Buffalo humpo Breast enlargemento Hyperlipidaemiao Insulin resistance - hyperglycaemia

Amantadine:• Indications:

o Influenza A in at-risk adults within 48 hours of symptomso Parkinson’s disease

• It’s anti-viral actions arise from it’s ability to inhibit a viral ion-channel• The putative mechanism in Parkinson’s disease is an increase in

dopamine release





Asthma / COPD

Severe asthma:• Unable to complete sentences• Respiratory rate >25/min• Pulse >110/min• PEFR <50% best or predicted

Life-threatening asthma:• PEFR <33% best or predicted• Bradycardia• Hypotension• Silent chest• Feeble respiratory effort• Confusion• Blood gases:

o pCO2 > 5kPao pO2 <8kPao pH <7.35

BTS guidelines for the management of acute severe asthma in adults• Initial management:

o 100% High flow oxygeno Nebulised salbutamol (5mg) or terbutaline (10mg)o Add in nebulised ipratropium bromide (0.5mg) if poor

responseo IV hydrocortisone (100mg)

• No improvement:o Consider ITU referralo Continue repeating nebulised salbutamolo IV magnesium sulphate (1.2-2g over 20 mins)o Aminophylline:

! Omit loading dose if patient is taking theophyllineo IV Salbutamol (but not with Aminophylline)

BTS 5 steps approach to the management of asthma:• Step 1 (mild intermittent asthma):

o Inhaled short-acting "2-agonist as required• Step 2 (regular preventer therapy):

o Step 1 + low dose inhaled steroid• Step 3 (add-on therapy):

o Step 2 + long-acting "2-agonist (LABA)o If partial response to LABA then:

! Continue with LABA and increase dose of inhaled steroido If no response to LABA then:

! Stop LABA and increase dose of inhaled steroid! Consider adding in leukotriene antagonist or theophylline

• Step 4 (persistent poor control):





o Step 3 + either:! High-dose inhaled steroid! Leukotriene antagonist (if not on one already)! Oral theophylline

• Step 5 (continuous or frequent use of oral steroids):o Step 4 + daily oral steroidso Refer patient for specialist care

General principles of drug treatment of COPD:• Discontinue drugs which may worsen COPD:

o E.g. "2-blockers for hypertension• Maintenance therapy:

o Inhaled bronchodilators:! "2-agonists (short-/long-acting)! Anti-muscarinics (short-/long-acting):

• These are more important than in asthmao Inhaled corticosteroids:

! If FEV1 <50% predicted! Repeated exacerbations

o Theophylline• Exacerbations:

o Oral steroidso Antibiotics (if infection suspected)

• Vaccination:o Influenza (definite benefit shown)o Pneumococcal (probable benefit)

Drug treatment of COPD by stage:• Stage 0:

o No COPD (but at risk)• Stage 1 (mild COPD):

o FEV1 <80% predictedo Short-acting "2-agonist

• Stage 2:o FEV1 50-80% predictedo Long-acting "2-agonist

• Stage 3:o FEV1 <50% predictedo Inhaled steroids (1000 - 2000µg daily)

• Stage 4:o FEV1 <30% predictedo Risk of cor pulmonaleo May need oxygen therapy if hypoxic at rest

Inhaled "2-agonists:• Short-acting (last 4-6 hours):

o Salbutamol





o Terbutaline• Long-acting (last ~12 hours):

o Salmeterol• Indications:

o Asthmao COPD with reversible component

• Mechanism of action:o Stimulate "2-receptors on airway smooth muscleo Leads to $ cAMP which # intracellular Ca2+, leading to smooth

muscle relaxation• Adverse effects:

o Tachycardiao Tremor

• Interactions (Hypokalaemia with high doses of):o Corticosteroidso Diuretics (loop and thiazide)o Theophylline

Inhaled anti-muscarinics:• Short-acting (last 3-6 hours):

o Ipratropium bromide (Atrovent)• Long-acting (once daily):

o Tiotropium (Spiriva)• Indications:

o Asthmao COPD with reversible component (especially tiotropium)

• Mechanism of action:o Inhibits the parasympathetic nervous supply of the bronchioles

by binding to muscarinic receptors• Adverse effects (uncommon as poorly absorbed systemically):

o Dry moutho Constipation

• Cautions:o Glaucomao Prostatic hypertrophy

Inhaled corticosteroids:• E.g. beclomethasone, budesonide, fluticasone• Indications:

o Asthma (from BTS step 2 onwards)• Mechanism of action:

o Decrease formation of numerous cytokines important in asthmao Inhibit generation of prostaglandins / leukotrieneso Inhibit the allergen-induced influx of eosinophils into the lungo Up-regulate "2-receptors

• Take up to 12 weeks to reach maximum efficacy• Reduce morbidity and mortality of asthma• Improve quality of life• Prevent long-term decrease in airway function





• Inhaled steroids work best at a moderate dose combined with bronchodilators

• Adverse effects (fewer than systemic corticosteroids):o High dose:

! Adrenal suppression (give patients steroid card)! Cataracts! Glaucoma! Growth suppression (probably just initial growth

velocity)! Osteoporosis

o Low dose:! Candidiasis (reduced by using a spacer device)! Hoarse voice

• Interactions:o Very few when inhaled

• Cautions:o Active or quiescent TBo Oral steroids may be required during times of high stress if on

long-term high dose inhaled steroids

Methylxanthines:• E.g. Aminophylline, theophylline• Aminophylline is a soluble form of theophylline:

o If given IV, must be by very slow IV injection• Indications:

o Asthma (BTS step 3 onwards) as theophyllineo Severe acute asthma (as aminophylline)

• Mechanism of action:o Are phosphodiesterase inhibitors and lead to an $ cAMP and

hence bronchial smooth muscle relaxationo May also increase cGMP levels and cause smooth muscle

relaxation• Adverse effects:

o Nausea / vomitingo Hypokalaemiao CNS stimulation

• Interactions (many – is metabolised by liver enzymes):o Adenosine:

! Actions of adenosine are inhibited by the methylxanthineso Plasma concentration increased by:

! COC pill! Erythromycin! Cimetidine! Verapamil

o Plasma concentration decreased by:! Carbamazepine! Phenytoin! Rifampicin

• Caution:





o Half-life is increased by:! Cardiac failure! Liver disease! Viral infections

o Half-life is decreased by:! Alcoholism! Smoking

Leukotriene antagonists:• E.g. montelukast• Taken orally• Indications:

o Asthma (BTS step 3 onwards)• Mechanism of action:

o Block the effects of cysteinyl leukotrienes (e.g. LTC4, LTD4 and LTE4) in the airways

• Advantages:o Improved compliance (oral and don’t have the steroid stigma)o Some patients respond well to themo Well tolerated

• Disadvantages:o Poor efficacy compared to inhaled steroidso Unpredictable responseo Expensive

• Adverse effects:o GI disturbanceso Drug-induced Churg-Strauss syndrome





Analgesics

Taxonomy of opioids:• Opioid:

o A compound acting at an opioid receptor• Opiate:

o An alkaloid derived from opium

Adverse effects of opioids:• CNS:

o Respiratory depression:! Decreased respiratory rate! Relief of dyspnoea

o Sedationo Euphoriao Meiosiso Anti-tussiveo Nausea / vomiting

• Non-CNS:o Pruritiso Constipationo Urinary retention

• Opiates only:o Histamine release:

! Not opioid receptor mediated

Mechanism of action of opioids:• Mimic endogenous opioids by acting on µ, % and & receptors in the:

o Dorsal horno Peri-aqueductal grey mattero Midline raphe nuclei

Contraindications to the use of strong opioids:• Severe respiratory disease (e.g. COPD)• Head injury / raised intracranial pressure:

o Interfere with neurological assessment• Hepatic failure• Acute alcohol intoxication

WHO analgesic ladder:• Step 1:

o Non-opioid analgesics:! Aspirin! Paracetamol! NSAIDs

• Step 2:o Weak opioids /partial opioid agonists:





! Codeine! Tramadol

• Step 3:o Strong opioids:

! Morphine! Diamorphine

Paracetamol (acetaminophen):• Indications:

o Mild to moderate paino Pyrexia

• Adverse effects:o Dangerous in overdose

• Overdose:o Signs / symptoms:

! None (generally)! Abdominal pain! Hypoglycaemia! Vomiting

o Investigations:! ABG, FBC, glucose, LFTs (ALT), INR, U&Es

o Treatment:! Remove the drug:

• If >12g and <1 hr since ingestion - gastric lavage• If <8 hrs since ingestion - activated charcoal

! Find the time vs paracetamol concentration graph in A&E:• If above treatment line start N-acetylcysteine

o Rule of thumb:! If PT (secs) > time since od (hrs) then bad prognosis

o Criteria for transfer to specialist liver unit:! Encephalopathy / $ ICP! INR > 2.0 at < 48 hrs or INR >3.5 at 72 hours:

• If INR is normal at 48 hours, patient can go home! Renal impairment (creatinine >200µmol/L)! Blood pH <7.3! Systolic BP <80mmHg

• Cautions:o Hepatic / renal impairmento Alcohol dependence

Codeine phosphate:• Indications:

o Cough suppressiono Diarrhoeao Mild to moderate pain

• Half-life of 3.5 hours• Adverse effects:

o Constipation (prominent)o See “adverse effects of opioids”





Tramadol:• Synthetic analogue derived from codeine• Indications:

o Moderate to severe pain• Mechanism of action:

o µ-receptor agonist (like most opioids)o Inhibits uptake of noradrenaline and 5-HT

• Advantages over other opioids:o Does not depress respiration

• Disadvantage over other opioids:o Can cause seizures

Morphine:• Indications:

o Pain:! Acute (e.g. myocardial infarction)! Chronic (e.g. chronic pancreatitis)! Terminal (e.g. malignancy)

o Acute pulmonary oedemao Intractable cough in terminal care

• Half-life of 3 hours• Tolerance to morphine occurs after about 2 weeks of continuous use• Titration of morphine dose:

o Assess individual 24 hour requirement to relieve pain at rest and on movement

o Convert to modified release morphine (MST) bd with rapid release morphine prn for breakthrough pain

o Increase the dose of MST based on the basis of breakthrough requirements





The failing heart

Heart failure:• Acute:

o Myocardial infarction (MI):! Acute! Post-MI

o Pulmonary oedema without MI• Chronic:

o Chronic stable anginao Heart failure

Drug treatment of acute myocardial infarction:• Oxygen• Aspirin 300mg (chewed) or clopidogrel (if aspirin contraindicated)• Morphine 5-10mg IV + metoclopramide 10mg IV• GTN 2 puffs or 1 tablet prn• "-blocker (e.g. atenolol 5mg IV) unless contraindicated• Thrombolysis:

o Indications:! Presentation within 12 hours of chest pain and! ST elevation >2mm in 2 or more chest leads or! ST elevation >1mm in 2 or more limb leads or! New left bundle branch block or! Posterior infarction

o Contraindications:! Bleeding! Prolonged / traumatic CPR! Trauma / surgery (within 2 weeks)! Recent haemorrhagic stroke! Severe hypertension (>200/120mmHg)! Pregnancy! Suspected aortic dissection

o Thrombolytic agent:! Streptokinase (SK):

• 1.5 million units in 100mls 0.9% saline over 1 hour• Usual first choice• Risk of allergy / anaphylaxis

! Tissue plasminogen activator (tPA):• Give if patient already received SK• Alteplase " infusion• Tenecteplase " bolus injection

• Heparin:o DVT / PE prophylaxis

Drug treatment post-myocardial infarction:• Aspirin 75mg od





• "-blocker (e.g. atenolol) or verapamil if contraindicated• ACE inhibitor (especially if evidence of heart failure)• Statin (e.g. benefit shown even if “normal” cholesterol levels)• Treat other risk factors:

o Diabetes mellituso Hypertension

• Think of the 4 A’s (Aspirin, Atenolol, ACE inhibitor and Atorvastatin)

Drug treatment of acute pulmonary oedema:• Sit patient upright• Oxygen• Furosemide (40 – 80mg slow IV)• Diamorphine (2.5 – 5mg slow IV)• GTN 2 puffs or 2x0.3mg tablets• If systolic BP >100mmHg start nitrate infusion (keep >90mmHg)• If patient worsening:

o Repeat furosemide 40 – 80mg slow IVo Consider ventilationo Consider increasing nitrate infusion

Drug treatment of chronic stable angina:• Aspirin• Nitrates:

o Relief:! GTN

o Prevention:! Long-acting nitrates

• "-blockers (e.g. atenolol 50-100mg/24 hours po)• Calcium-channel blockers:

! Caution with concomitant use of "-blocker o Dihydropyridines:

! Amlodipineo Non-dihydropyridines:

! Diltiazem! Verapamil (caution with "-blockers)

• Potassium channel activator:o Nicorandil

Drug treatment of chronic heart failure:• Diuretics:

o Furosemide (symptomatic only) ± o Spironolactone:

! Potassium-sparing! Shown to reduce mortality

o Metolazone:! Thiazide diuretic! Synergistic with furosemide for refractory oedema

• ACE inhibitors:o Shown to reduce mortality





• "-blockers:o Shown to reduce mortality (probably via # arrhythmias)o Synergistic with ACEIso “Start low, go slow” – needs careful titration

• Digoxin:o Can be used even if the patient is in sinus rhythmo No reduction in mortalityo # in hospital admissions

• Angiotensin II receptor antagonists:o Probably similar to ACEIs but little conclusive evidence

• Nitrates:o Probably reduce mortality (but less so than ACEIs)o Used in those in whom ACEIs are contraindicated

Nitrates:• All function as nitric oxide (NO) donors• Cause mainly venous dilatation (hence # preload)• Mechanism of action of NO:

o NO stimulates guanylyl cyclase which leads to an $ cGMPo $ cGMP leads to smooth muscle relaxation

• Glyceryl trinitrate (GTN):o Onset is rapid and lasts for ~30 minso Usually given sublingually

• Long-acting nitrates (isosorbide mono-/dinitrate):o More stable than GTN and last several hourso Isosorbide mononitrate is the active metabolite of isosorbide

dinitrate:! The mononitrate avoids the unpredictable first-pass

metabolism of the dinitrateo Tolerance develops after as little as 24 hours – avoid by

omitting the evening dose (permits an 8 hour drug-free interval)• Adverse effects:

o Headaches (frequently dose-limiting)o Hypotension / faintingo Reflex tachycardia (prevented by administration of a "-blocker)

• Contraindications:o Constrictive pericarditiso Hypotensiono Head traumao Hypertrophic obstructive cardiomyopathy (HOCM)o Valvular stenosis (aortic / mitral)

• Interactions:o Sildenafil (Viagra):

! Profound hypotension"-blockers:

• Non-selective:o Propranolol:

! Is a full antagonisto Pindolol / oxprenolol:





! Are partial agonistso Labetolol:

! " and ! antagonist (" > !)• “Cardio-selective” ("1-antagonists):

o Atenololo Metoprolol

• Indications:o Anginao Heart failureo Hypertensiono Post-MIo Prevention of variceal bleeding in liver disease (propranolol)o Prophylaxis of migraineo “Stress”-induced arrhythmias

• Mechanism of action:o Most do not affect resting parameters (e.g. heart rate) but

prevent the exercise-induced cardiovascular changes caused by sympathetic stimulation

o Anti-hypertensive action probably arises from an alteration in the CNS “set-point”

• Adverse effects:o Lethargy / fatigue (usually improves with use)o Bradycardiao Cold hands / feeto Hypotensiono Bronchospasm (including cardio-selective agents)o Nightmareso Worsened / precipitated heart failure

• Contraindications:o Asthma / COPDo Bradycardia / heart block

• Interactions:o Diltiazem / verapamil:

! $ risk of bradycardia / AV block o Insulin / oral anti-diabetic agents:

! "-blockers mask the signs of hypoglycaemia

Calcium-channel blockers:• Two classes:

o Dihydropyridines:! Nifedipine (short-acting)! Amlodipine (longer-acting)

o Non-dihydropyridines:! Diltiazem! Verapamil

• Indications:o All:

! Angina (especially vasospastic angina)





! Hypertensiono Nifedipine:

! Raynaud’s phenomenono Verapamil:

! Supraventricular arrhythmias:• Adenosine has largely replaced in acute situation• Can be used as prophylaxis against SVTs

• Mechanism of action:o Block L-type voltage-sensitive Ca2+ channels in:

! Arterial smooth muscle (vasodilatation):• Both classes• Can cause a reflex tachycardia

! Myocardial conduction system (negative inotropism):• Non-dihydropyridines (as they have a high

affinity for channels in the activated state• Amlodipine causes less tachycardia than nifedipine• Verapamil (and to a lesser extent diltiazem) depress the sinus node:

o Mild resting bradycardia• Verapamil slows conduction at the AVN• Diltiazem has actions in between verapamil and nifedipine:

o Popular in treatment of angina – does not cause tachycardia• Adverse effects:

o Fluid retention (ankle oedema):! Can be severe enough to merit withdrawal! Is a local effect that has nothing to do with Na+ retention

o Headacheso Hypotensiono Flushingo Gum hypertrophy

• Contraindications:o All:

! Cardiogenic shocko Dihydropyridines:

! Severe aortic stenosis / HOCM! Unstable angina

o Non-dihydropyridines:! Myocardial conduction defects (e.g. bradycardia)! Heart failure:

• Further depression of cardiac functiono Nifedipine:

! Angina (short-acting preparation may $ mortality)

o Verapamil:! Ventricular tachycardia (potentially lethal)! AF with Wolff-Parkinson-White syndrome

• Interactions:o Diltiazem:

! Digoxin:• Diltiazem $ plasma concentration of digoxin





! Carbamazepine:• Diltiazem $ plasma concentration of carbamazepine

! Phenytoin:• Diltiazem $ plasma concentration of phenytoin

o Nifedipine:! Diltiazem:

• $ plasma levels of nifedipine! Phenytoin:

• Nifedipine $ plasma levels of phenytoin! Grapefruit juice:

• $ plasma levels of nifedipine (and other dihydropyridines but not Amlodipine)

o Verapamil:! "-blockers (asystole, severe hypotension, heart failure)! Digoxin:

• Verapamil $ plasma concentration of digoxin! Cyclosporin:

• Verapamil $ plasma concentration of cyclosporin

Angiotensin converting enzyme inhibitors (ACEIs):• E.g. captopril, enalapril, lisinopril• Indications:

o Diabetic nephropathyo Hypertensiono Heart failureo Post-MI

• Inhibit ACE, thus reduce circulating angiotensin II• Actions of angiotensin II (mediated via the AT1 receptor):

o Potent vasoconstrictoro Aldosterone secretion:

! Na+ retention! K+ excretion

• Advantages:o Do not affect blood lipidso May improve cardiac remodelling

• Adverse effects:o Postural hypotension:

! Usually first-dose! More common in sodium-depleted patients

o Dry cough (Chinese are more susceptible)o Hyperkalaemiao Angioedema (in 1 – 2% of patients)

• Contraindications:o Poor renal arterial perfusion pressure:

! Renal artery stenosis / coarctation of the aorta:• Loss of renal efferent arteriole tone (caused by the

ACEI) and # afferent arteriole pressure leads to renal ischaemia





o Aortic stenosiso Pregnancy

• Interactions:o NSAIDs:

! $ risk of renal impairmento Potassium-sparing diuretics:

! $ risk of hyperkalaemiao Lithium:

! ACEIs # excretion of lithiumo Diuretics:

! $ risk of hypotension

Angiotensin II (AII) receptor antagonists:• E.g. losartan, irbesartan, candesartan• Indications:

o Diabetic nephropathyo Hypertensiono Heart failure (unlicensed indication)

• Mechanism of action:o Block the AT1 receptor, inhibiting the actions of angiotensin IIo As they do not block ACE, they do not affect the metabolism of

bradykinin – possibly why they do not cause a cough• Adverse effects/contraindications/interactions – as for ACE inhibitors

Digoxin:• Indications:

o Supraventricular dysrhythmias (esp. AF) for ventricular rate control

o Heart failure (improves symptoms not mortality)• Mechanism of action:

o Is a cardiac glycoside extracted from foxglove leaveso Inhibits cardiac membrane Na+/K+-ATPase:

! $ intracellular Na+

! Secondary $ in intracellular Ca2+

• Clinical effects:o $ force of cardiac contractiono $ cardiac vagal activity:

! # heart rate! # AV conductance! $ AVN refractory period

• Common adverse effects:o Anorexiao Nauseao Vomiting

• Toxic levels:o Digoxin requires therapeutic drug monitoringo Risk of toxicity increased with:

! Hypokalaemia (reduced competition for pump binding)! Hypercalcaemia





! Hypothyroidismo May require digoxin specific antibody fragments (Fab)o Features:

! Nausea (severe)! Dysrhythmias:

• VT• Heart block

! Xanthopsia (distortion of yellow colour vision)• Contraindications:

o Complete heart blocko HOCMo Wolff-Parkinson-White syndrome

• Caution in renal impairment:! Digoxin is excreted by the kidneys

• Drugs increasing risk of digoxin toxicity:o Anti-arrhythmics:

! Amiodarone! Quinidine

o Calcium channel blockers (non-dihydropyridines)):! Diltiazem! Verapamil

o Diuretics (loop and thiazide):! Cause hypokalaemia, thus $ risk of digoxin toxicity

Nicorandil:• Indications:

o Angina• Mechanism of action:

o Potassium channel activator with a nitrate componento Causes both arterial and venous vasodilatation

• Adverse effects:o Headacheo Flushingo Oral ulceration (rarely)

• Interactions:o Sildenafil:

! Profound hypotension – avoid concomitant use





Endocrinology

Drug treatment of hyperthyroidism:• Immediate symptom control:

o Propranolol• Long-term treatment:

o Thionamides:! Carbimazole or! Propylthiouracil

o Radioiodine (131I)• Prior to surgery to decrease thyroid vascularity:

o Lugol’s iodine solution

Immediate management of thyrotoxic storm:• IV fluids• Take blood for T3, T4 (and cultures if infection suspected)• Sedate if necessary:

o E.g. chlorpromazine• Propranolol (oral or IV if no contraindications)• Digoxin:

o May be needed to slow the heart• Anti-thyroid drugs:

o Carbimazoleo Lugol’s solution

• Corticosteroids (IV hydrocortisone or oral dexamethasone)

Drug treatment of hypothyroidism:• Hypothyroidism:

o Levothyroxine (T4)• Myxoedema coma:

o Liothyronine (T3)

Drug treatment of Addison’s:• Disease:

o Oral hydrocortisone:! 20mg in the morning! 10mg in the evening! Double during febrile illness, stress or injury

o Fludrocortisone:! Only needed if:

• Postural hypotension• # Na+, $K+ or $ renin

! Give every second day• Crisis:

o Hydrocortisone 100mg IV stato IV fluids (colloid to resuscitate then crystalloids)o Glucose IV if hypoglycaemico Antibiotics if infection present





Drug treatment of Cushing’s syndrome:• Treat the underlying cause – rarely need drug therapy long-term• Suppression of plasma cortisol level:

o Aminoglutethemideo Ketoconazoleo Metyrapone

Drug treatment of Conn’s syndrome:• Definitive treatment is with surgery• Spironolactone

Drug treatment of diabetes insipidus (DI):• Cranial DI:

o Treat the underlying causeo Intranasal desmopressin (DDAVP)

• Nephrogenic DI:o Treat the underlying causeo Bendrofluazide (paradoxically, as this is a diuretic)

Drug treatment of acromegaly:• Best treated with trans-sphenoidal surgery or irradiation• Somatostatin analogues (first line):

o Octreotide (short-acting)o Lanreotide (long-acting)

• Dopamine agonists:o Bromocriptineo Cabergoline

Drug treatment of hypopituitarism:• Need to replace what is missing• ACTH:

o Hydrocortisone• GH:

o Recombinant GH is available• FSH, LH:

o Testosterone - maleso Oestrogen (via COC pill) - females

• TSH:o Thyroxine (if hypothyroid, but can’t use to TSH to monitor)

• No need to replace prolactin

Drug treatment of hypogonadism:• Males:

o Testosterone





• Females:o COC pill

Drug treatment of hyperprolactinaemia:• Definitive treatment is surgical• Dopamine agonists:

o Bromocriptineo Cabergoline

Drug treatment of hypercalcaemia:• Treat underlying cause if possible• IV fluids• Bisphosphonates• Salmon calcitonin:

o Rarely usedo Faster onset than bisphosphonates

• Steroids:o E.g. for sarcoidosis

• Furosemide (once rehydrated)

Drug treatment of hypocalcaemia:• Mild:

o Oral calcium supplements (e.g. sandocal)• Severe:

o 10mls 10% calcium gluconate IVI over 30 minso Repeat as necessary

• Must correct magnesium levels – will never correct Ca2+ otherwise

Drug treatment of phaeochromocytoma crisis:• Control BP with IV phentolamine (short-acting !-antagonist)• When BP controlled, give phenoxybenzamine (irreversible !-

antagonist)• Give "1-blocker• Arrange for surgery within next few weeks

Thionamides:• E.g. carbimazole, propylthiouracil• Indications:

o Carbimazole:! Hyperthyroidism

o Propylthiouracil:! Usually reserved for patients intolerant to carbimazole

• Mechanism of action:o All:

! Inhibition of thyroid peroxidase! Immunosuppressive properties (controversial)





o Carbimazole:! Is a prodrug (converted to methimazole)

o Propylthiouracil:! Inhibits peripheral conversion of T4 " T3

• How to use:o Aim is to render the patient euthyroid and then give a # dose for

maintenanceo It is often possible to stop treatment after 1 or 2 years (50%

relapse rate) • Adverse effects:

o GI disturbanceso Carbimazole:

! Pruritis! Rash

o Agranulocytosis:! Carbimazole (0.1%)! Propylthiouracil (0.4%)! Patients should be told to seek medical attention if they

develop symptoms of infection (e.g. sore throat):• If neutropenia confirmed " stop treatment

• Cautions:o Pregnancy:

! Low doses should be used as carbimazole crosses the placenta and can cause neonatal hypothyroidism / goitre

! PTU is less problematic in pregnancy

Radioiodine (131I):• Treatment of choice in pts >40 years (can be used in younger pts)• Indications:

o Hyperthyroidismo Disseminated thyroid malignancy

• Mechanism of action:o The radioactive iodine is localised to the thyroid where it

destroys thyroid tissue via "-radiation• Treatment renders the pt euthyroid within 4-6 weeks, when thyroxine

replacement therapy can be undertaken (lifelong)• Adverse effects:

o Causes hypothyroidismo May precipitate thyroid storm

• Contraindications:o Childreno Pregnancy (also, pregnancy must not be allowed to occur

within 3 months)o Mothers who are unable to leave their children in others care for

at least 10 days (to avoid exposure)

Thyroxine:• May be either T4 (Levothyroxine) or T3 (liothyronine)• T3 is faster acting than T4 but with a shorter half-life





• Adverse effects (mainly in overdose):o Anginao Dysrhythmias (including AF)o MIo Tachycardiao Hyperthyroid symptoms (even when TSH in normal range)

• Cautions:o Thyroxine should be introduced slowly in those with IHD

• Interactions:o Warfarin:

! Thyroxine $ the effect of warfarin

Corticosteroids:• E.g. hydrocortisone, prednisolone, dexamethasone• Indications (many):

o Anti-inflammatory:! Topical:

• Asthma• Skin disorders (e.g. eczema)

! Systemic:• Anaphylaxis• IBD• Rheumatoid arthritis

o Immunosuppression:! Connective tissue diseases (e.g. temporal arteritis)! Leukaemia! Sarcoidosis! Transplant rejection

o Replacement:! Addison’s disease! Congenital adrenal hyperplasia

• Mechanism of action:o Bind to cytoplasmic receptor that diffuses into nucleus and binds

to steroid-response elements on DNA:! Either increases or decreases transcription with numerous

effectso Inhibits phospholipase A2 (thus # production of arachidonic acid)o # B and T cell responses to antigens

• Adverse effects (many):o CNS:

! Depression! Psychosis

o Endocrine:! Adrenal suppression! Hirsuitism





! Impotence! Oligo-/amenorrhoea! Weight gain

o Eyes:! Cataracts! Glaucoma

o Gastrointestinal:! Candidiasis! Peptic ulceration! Pancreatitis

o Immune system:! $ susceptibility to and $ severity of infections

o Metabolic:! Hyperglycaemia! Hypertension

o Musculoskeletal:! Growth suppression! Myopathy! Osteoporosis

o Skin:! Abdominal striae! Buffalo hump! Easy bruising! Poor wound healing! Thinning

• Differences between the different steroids:o Hydrocortisone:

! Replacement therapy! IV in shock / status asthmaticus

o Prednisolone:! Orally for anti-inflammatory effects

o Dexamethasone:! No salt-retaining properties! Very potent! Useful when high doses required (e.g. cerebral oedema)

o Budesonide / beclomethasone:! Pass membranes very poorly! Much more active topically (e.g. aerosol, gut)

• Interactions:o Enhances activity of warfarino Live vaccines (impairs response)o Reduces activity of anticonvulsants (carbamazepine,

phenytoin)• Withdrawal of glucocorticoids – withdrawal gradually in the following:

o Course duration >3 weekso Received >40mg prednisolone (or equivalent) dailyo Been given repeated doses in the eveningo Taken a short course within 1 year of taking long-term therapy

• Notes:





o “Physiological” dose of steroid is ~7.5mg prednisoloneo Patients should be given a steroid card

Metyrapone:• Indications:

o Cushing’s syndrome:! Especially that not amenable to surgery (e.g. lung ca)

o Resistant oedema due to aldosterone secretion in:! Cirrhosis! Congestive cardiac failure

• Mechanism of action:o Competitive inhibitor of 11"-hydroxylaseo Inhibits endogenous production of cortisol (and to a lesser

extent aldosterone) by the adrenals• Contraindications:

o Adrenocortical insufficiencyo Pregnancy / breast feeding

• Adverse effects:o Hypoadrenalism

Desmopressin (DDAVP):• Synthetic vasopressin (ADH) analogue• Indications:

o Cranial diabetes insipidus (diagnosis and treatment)o Haemophiliao Persistent enuresis

• Mechanism of action:o Selectively agonises V2 receptors on renal tubular cells:

! Leads to increased reabsorption of water! Thus devoid of vasoconstrictor activity (V1)

o Also increases the plasma concentration of factor VIII• Adverse effects:

o Dilutional hyponatraemiao Fluid retention

• Contraindications:o Heart failure

Somatostatin analogues:• E.g. octreotide (given tds), lanreotide (given once monthly)• Indications:

o Acromegalyo Carcinoid syndromeo Variceal bleeding (octreotide, unlicensed indication)

• Mechanism of action in acromegaly:o Inhibits GH release from the pituitary glando 90% of patients respond and 60% have GH level normalisation





• Adverse effects:o Gallstoneso GI disturbances

• Interactions:o Anti-diabetic agents (oral and insulin):

! Octreotide may # requirements for these drugs

Dopamine agonists:• E.g. bromocriptine (short-acting), cabergoline (long-acting)• Indications:

o Acromegalyo Hyperprolactinaemiao Idiopathic Parkinson’s diseaseo Suppression of lactationo Cyclical benign breast disease

• Mechanism of action:o Directly stimulate dopamine receptors in the CNS (anti-

Parkinson’s effect)o Inhibits release of prolactin from anterior pituitaryo Inhibits the release of GH in acromegalics:

! Increases GH levels in non-acromegalics• Lead to a maximum # of GH of 7-60%:

o Only 10-15% of patients achieve GH normalisation• Adverse effects:

o Nausea / vomitingo Postural hypotensiono Drowsiness / confusiono Dyskinesiao Fibrotic reactions (rare):

! Pericardial / pulmonary and retroperitoneal fibrosis• Domperidone (D2 antagonist):

o Can be used to relieve the peripheral adverse effects of bromocriptine (does not cross the BBB so has no effect on CNS effects)

• Interactions:o Erythromycin and sympathomimetics (e.g. dobutamine):

! Increase the plasma concentration of bromocriptine

Growth hormone:• E.g. somatrophin• Indications:

o Adults:! GH deficiency

o Children:! GH deficiency! Chronic renal impairment! Turner’s syndrome

Testosterone:





• E.g. restandol (oral), sustanon (IM), andropatch (transdermal patch)• Indications:

o Male androgen deficiency• Adverse effects:

o Androgenic effects:! Fusion of epiphyses in prepubertal boys (stunted

growth)! Hirsuitism! Male pattern baldness! Acne

o Prostate abnormalities (enlargement ± malignancy)o Cholestatic jaundice

• Contraindications:o Cancers:

! Male breast! Primary liver tumour! Prostate


! Potentiates actions of warfarin

Combined oral contraceptive (COC) pill:• E.g. cilest, microgynon• Are preparations containing both an oestrogen and a progestogen• Indications:

o Contraceptiono Menstrual cycle control / menorrhagiao Mild endometriosiso Premenstrual symptoms

• Mechanism of action:o Exerts a negative feedback on the pituitary and inhibits

gonadotrophin release, and thus inhibits ovulation• Adverse effects:

o Major:! $ risk of venous thromboembolism (VTE)! $ risk of hypertension! $ risk of breast carcinoma (small)

o Minor:! Breast tenderness! Headaches! Nausea! Weight gain

• Contraindications:o Absolute:

! History of CVA / IHD / VTE! Migraine (severe / focal)! Blood clotting disorders! Active breast / endometrial cancer

o Relative:





! Age > 40 years! Obesity ! Smokers

• Interactions:o Drugs reducing the efficacy of the COC pill:

! Broad-spectrum antibiotics! P450 inducers:

• Carbamazepine• Phenytoin• Rifampicin

o Warfarin:! Oestrogens (including the COC pill) reduce the effect of

warfarin• The COC pill should be stopped several weeks prior to an elective

surgical procedure to # risk of VTE

Calcitonin:• E.g. calcitonin (porcine natural), salcatonin (synthetic salmon

calcitonin)• Indications:

o Hypercalcaemia (rarely)o Malignant bone paino Osteoporosiso Paget’s disease of bone (especially pain relief)

• Mechanism of action:o Lowers serum calcium:

! Inhibits osteoclast activity! Increases renal Ca2+ excretion

• Adverse effects:o Facial flushingo Nausea / vomitingo Tingling sensation in the handso Unpleasant taste in the mouth

!1-antagonists:• Non-selective (!1 and !2):

o Phentolamine (short-acting)o Phenoxybenzamine (irreversible, long-acting)

• !1:o Prazosino Doxazosino Tamsulosin (Flomax)

• Indications:o Non-selective !-blockers:

! Phaeochromocytomao !1-blockers:





! Hypertension! Benign Prostatic hypertrophy (doxazosin, tamsulosin)

• Mechanism of action:o Antagonism of post-synaptic !1-adrenoceptors leads to

vasodilatationo !1 blockade also leads to relaxation of the internal urethral

sphincter, resulting in $ urinary flow• Adverse effects:

o First-dose hypotension• Interactions:

o Other hypotensive agents - $ risk of hypotension





Lipids

Which patients require lipid-lowering therapy?• Primary prevention:

o Guidelines are frequently changing! Total [chol] >5mmol/L and CHD risk >30% over 10yrs or! 10yr CHD risk >=15%

• Secondary prevention:o History of CVS event (angina, MI, PVD, CVA) ± o [chol] >=5mmol/L

• Choice of drug:o First choice therapy:

! Statin o Second choice therapy:

! Fibrates! Anion exchange resins

• Note about diet:o Diet lowers [cholesterol] only by ~10% (as we endogenously

synthesise cholesterol, not just eat it)

Drugs used to treat obesity:• Orlistat• Sibutramine

Statins:• E.g. simvastatin, atorvastatin, pravastatin• Usually taken at night• Reduce incidence of all cardiovascular events and total mortality• Mechanism of action:

o Are HMG-CoA reductase inhibitors – block the rate-limiting step in hepatic cholesterol synthesis

o Due to the # concentration of cholesterol in the hepatocytes, there is an $ in the number of hepatic LDL receptors

o This leads to a # in plasma LDLo Those with homozygous familial hypercholesterolaemia do not

respond to statins (as they have no LDL receptors)• Adverse effects (all uncommon):

o Myositis:o Patients complain of weakness / aching muscles

! If CK >5x upper limit of normal discontinue! Can lead to rhabdomyolysis and renal failure! If this occurs, cannot use a statin again

o Altered LFTs• Contraindications:

o Liver diseaseo Pregnancy

• Interactions:o Drugs increasing the risk of myositis:





! Cyclosporin! Fibrates

o Warfarin:! Statins potentiate the actions of warfarin

• Patients should have their LFTs monitored regularly whilst on a statin

Fibrates:• E.g. bezafibrate, gemfibrozil• Actions:

o Unclear mechanism – possibly stimulate lipoprotein lipaseo # TGs (~30%)o # LDL (~10%)o $ HDL (10%)

• Are first line drugs in patients with hypertriglyceridaemia (who are at risk of pancreatitis and retinal vein thrombosis)

• Adverse effects:o GI disturbanceo Myositiso Gallstones

• Contraindications:o Hepatic / renal impairmento Pregnancy

• Interactions:o Statins:

! $ risk of myositiso Warfarin:

! Potentiate the actions of warfarin

Anion exchange resins:• E.g. cholestyramine, cholestipol• Mechanism of action:

o Bind bile acids in the bowelo Forces the liver to synthesise more bile acids – causes an

increase in the expression of LDL receptors and lowering of LDL• Adverse effects:

o GI disturbance:! Bloating! Constipation! Nausea / vomiting

o May aggravate hypertriglyceridaemiao Impairs the absorption of many drugso May impair the absorption of fat soluble vitamins:

! May require supplements of vitamins A, D and K

Omega-3-oils (fish oils):• Can be effective in hypertriglyceridaemia• Adverse effects:





o Fish-like odour to the patient

Orlistat:• Indications:

o Adjunct in obesity management:! BMI >30 if no diabetes! BMI >27 if diabetic

• Mechanism of action:o Pancreatic lipase inhibitoro Impairs absorption of dietary fat

• Adverse effects:o GI disturbance:

! Probably why the drug works as patients reduce their fat intake to reduce the side-effects

o May impair the absorption of fat soluble vitamins:! May require supplements of vitamins A, D and K

• Contraindications:o Cholestasiso Pregnancy


! Difficulty in controlling the INR

Sibutramine:• Indications:

o As for orlistat• Mechanism of action:

o Centrally acting anorectic o Inhibits reuptake of noradrenaline and 5-HT

• Adverse effects:o Hypertensiono Many others

• Contraindications:o Many, mainly cardiovascular





Clotting

Antiplatelet drugs:• Aspirin• Dypyridamole• Clopidogrel• GP IIb/IIIa receptor antagonists:

o Abciximab

Anticoagulants:• Oral:

o Warfarin• Parenteral:

o Unfractionated heparino Low molecular weight heparin (LMWH)

Thrombolytic agents:• Streptokinase• Tissue plasminogen activator (tPA)

Indications for antiplatelet drugs:• Acute coronary syndromes• Primary prevention of cardiovascular events:

o If 10yr CVD risk >=20% (with a controlled blood pressure)• Secondary prevention of cardiovascular events:

o CVA / TIAo IHDo PVD

• Heart valve replacements• AF (in those who cannot be anti-coagulated)

Indications for oral anti-coagulants:• AF• Prophylaxis / treatment of VTE:

o DVTo PE

• Mechanical heart valve replacements• Dilated cardiomyopathy / left ventricular aneurysm• ? TIAs

Indications for parenteral anti-coagulants:• Acute coronary syndromes• Acute arterial obstruction• Treatment of VTE:

o DVTo PE

Indications for thrombolytic agents:• Acute myocardial infarction





• Arterial thrombus• Life-threatening PE• Occluded lines / shunts

Aspirin:• Indications:

o Mild to moderate paino Pyrexiao Anti-platelet:

! Acute myocardial infarction! History of:

• Angina• Intermittent claudication• Myocardial infarction• Stroke• TIA

! AF (in patients where warfarin is contraindicated)! Kawasaki syndrome (only childhood indication)

• Mechanism of action:o Irreversibly inactivates platelet COXo Platelets cannot synthesise new COX:

! Takes 4 – 7 days for new platelets to be synthesised following a single dose (300mg)

! Reduction in production of the platelet aggregating compound thromboxane A2

• Adverse effects:o Bleedingo Bronchospasmo GI irritation / bleedingo Dangerous in overdose

• Overdose:o Signs / symptoms:

! Coma! Dehydration! Hyperventilation! Tinnitus! Seizures! Sweating! Vertigo! Vomiting

o Investigations:! Levels (salicylate and paracetamol, may have taken

both):• Levels >700mg/L are potentially fatal

! ABG, FBC, Glucose, LFTs, INR, U&Es

o Treatment:! Remove drug:

• Gastric lavage if od <1 hour ago





! Correct acidosis with 1.26% HCO3-

! >500mg/L:• Consider alkalinization of the urine

! Consider dialysis when:• Levels >700mg/L• Cardiac / renal failure• Seizures

• Cautions:o Asthmao Uncontrolled hypertension

• Contraindications:o Children <16 years (unless Kawasaki’s syndrome):

! Risk of Reye’s syndromeo Active peptic ulcerationo Bleeding disorders (e.g. haemophilia)


! Increased risk of bleedingo Methotrexate:

! Aspirin $ risk of toxic effects of methotrexate

Dipyridamole:• Indications:

o Secondary prevention of CVA / TIA:! Some synergistic benefit with aspirin! Used in those patients who have had a CVA on aspirin

o Prevention of thromboembolism from prosthetic heart valves:! Adjunct to oral anti-coagulation

• Mechanism of action:o Phosphodiesterase inhibitoro Leads to an $ in cAMP and potentiation of prostacyclin

• No increased risk of bleeding (cf aspirin)• Adverse effects:

o Headache• Contraindications:

o Myasthenia gravis (risk of exacerbation)• Interactions:

o Adenosine:! Dipyridamole prolong / enhances the effects of adenosine

Clopidogrel:• Indications:

o Secondary prevention of CVD:! Within 35 days of MI! Within 6 months of CVA

o Acute coronary syndrome (without ST elevation):! Given with aspirin! Not for >12 months

o Coronary artery stents





• Mechanisms of action:o Irreversibly blocks the action of ADP on platelets – leading to a

reduction of platelet aggregation• Adverse effects:

o Bleedingo Bone marrow suppression (rare)

• Cautions:o First few days following MI / CVA


! Increased risk of bleeding

Abciximab:• Indications:

o Patients awaiting PTCA:! Short-term prevention of MI in those with ACS

o Patients undergoing PTCA:! Adjunct to aspirin and heparin

• Mechanism of action:o Monoclonal antibody to GP IIb/IIIao Inhibit platelet aggregation

• Adverse effects:o Bleedingo Thrombocytopenia

Warfarin:• Indications:

o Prevention / treatment of VTE:! DVT! PE

o Prevention of thromboembolism:! AF! Prosthetic heart valves

• Mechanism of action:o Vitamin K antagonisto Inhibits the vitamin K-dependent synthesis of clotting factors II,

VII, IX and Xo Also inhibits formation of protein C and S:

! Has an initial procoagulant effecto Takes at least 2–3 days to work (due to the half-life of pre-

existing clotting factors in the circulation)o Prolongs the prothrombin time (PT)

• Pharmacokinetics:o Long half-life (40 hours)o Takes ~5 days after stopping treatment for INR to normaliseo Highly protein-bound (albumin)

• Dosage:o Loading:

! Warfarin therapy begins with a loading dose, usually:





• Day 1 - 10mg• Day 2 – 10mg # measure INR and adjust dose• Day 3 – 5mg (if still not target INR)

o Daily dose:! Daily maintenance is usually 3-9mg daily (taken at same

time each day)• INR (International Normalised Ratio):

o Prothrombin results can vary depending on the thromboplastin reagent used

o The INR is a conversion unit that takes into account the different sensitivities of thromboplastins

o Target INRs:! 2 – 2.5:

• Prophylaxis of DVT! 2.5:

• AF• Treatment of DVT / PE• Rheumatic mitral valve disease

! 3.5:• Recurrent DVT / PE• Mechanical prosthetic heart valves

o Monitoring the INR:! The INR should be determined daily (or alternate days) in

the early days of therapy, then at longer intervals (depending on response) then up to every 12 weeks

• Adverse effects:o Bleeding / bruisingo Skin necrosiso Alopeciao Liver damageo Pancreatitis

• Management of warfarin-induced haemorrhage:o Major bleeding:

! Stop warfarin! Give vitamin K (phytomenadione) by slow IV injection! FFP

o INR >8 (no bleeding or minor bleeding):! Stop warfarin and restart when INR <5! Vitamin K (either IV or oral)

o INR 6-8: (no bleeding or minor bleeding):! Stop warfarin and restart when INR <5

o INR <6 but >0.5 units above target value:! Reduce or stop warfarin and restart when INR <5

• Contraindications:o Pregnancy:

! Teratogenic (1st trimester)! Foetal haemorrhage (3rd trimester)

o Peptic ulcero Severe hypertension





• Interactions (many!):o Drugs that $ the efficacy of warfarin:

! Alcohol! Cimetidine! Omeprazole! Simvastatin

o Drugs that # the efficacy of warfarin:! Carbamazepine! COC pill! Rifampicin

o Drugs increasing risk of haemorrhage:! Aspirin

Heparin:• Low molecular weight heparins (LMWHs) include:

o Enoxaparino Tinzaparin

• Indications:o Treatment of VTEo Unstable anginao Acute peripheral arterial occlusiono Prophylaxis in surgeryo Extracorporeal circuits (e.g. cardiac bypass surgery)

• Mechanism of action:o Heparin potentiates the actions of antithrombin IIIo Antithrombin III inactivates factor IIa (thrombin)o Prolongs the APTT

• Structure:o Both types of heparin are extracted from bovine lung or hog

intestineo Unfractionated heparin:

! Mixture of sulphated glycosaminoglycans with a range of molecular weights up to 40,000

o LMWH:! Fragments of heparin with weights 4000 – 15,000

• Unfractionated or LMWH?o Unfractionated heparins are best used when there is a high risk

of bleeding as their effect can be terminated rapidly by stopping the infusion

o LMWHs do not require monitoring of the APTT and only need to be given once-daily

o LMWHs have a more predictable subcutaneous absorption• Adverse effects:

o Thrombocytopenia:! Immune-mediated! Develops ~6 days after starting treatment

o Hyperkalaemia:! Heparin inhibits aldosterone activity

o Haemorrhage





o Osteoporosiso Skin necrosiso Hypersensitivityo Alopecia

• Contraindications:o Bleeding disorders (e.g. haemophilia)o Thrombocytopeniao Peptic ulcero Recent cerebral haemorrhageo Severe hypertensiono Severe liver disease (especially variceal disease)o Hypersensitivity

• The effects of heparin can be reversed by IV protamine sulphate:o A strongly basic protein that forms an inactive complex with

heparin

Streptokinase (SK):• Indications:

o Acute MIo Thromboembolic events:

! PE! Thrombosed arteriovenous shunts

• Mechanism of action:o Binds circulating plasminogen and converts it to plasmino Plasmin then lyses fibrin within the thrombus and dissolves it

• Adverse effects:o Allergic reactions:

! Rash (common)! Anaphylaxis

o Hypotensiono Guillain-Barre syndrome

• Contraindications:o Bleedingo Prolonged / traumatic CPRo Trauma / surgery (within 2 weeks)o Recent haemorrhagic strokeo Severe hypertension (>200/120mmHg)o Pregnancyo Suspected aortic dissection

• Interactions:o Warfarin (increased risk of haemorrhage)

• Patients develop antibodies to streptokinase:o If a patient requires thrombolysis and has received SK in the

past – they should be given recombinant tPA

Tissue plasminogen activator (tPA):• E.g. alteplase (requires infusion), tenecteplase (bolus)





• Indications:o As for SK but in those patients who cannot receive SK

• In contrast to SK, co-administration of tPA and heparin produces added benefit (but increases the risk of stroke)





Mood disorders

Which antidepressant?• No hard and fast rules, although TCAs and SSRIs are generally first

choice• All antidepressants take 2-6 weeks to work• Antidepressants should be continued for 4-6 months after resolution

of symptoms• When to use a TCA:

o Severe depressiono When insomnia is prominent symptom

• When to use a SSRI:o Suicidal patient (safer in overdose)o Intolerance to TCAs:

! Prostatism! Dementia (TCAs can cause confusion)! Cardiac illness

• When to use a MAOI:o “Atypical” depressiono Depression refractory to first-line drugs

• When to use venlafaxine:o Severe depression with hypersomnia

Drugs used as mood stabilisers:• Lithium carbonate• Anticonvulsants:

o Carbamazepineo Valproate

Tri-Cyclic Antidepressants (TCAs):• More sedating:

o Amitriptyllineo Clomipramineo Dothiepin

• Less sedating:o Imipramine

• Indications:o Moderate to severe depressiono Neuropathic pain (amitriptylline – unlicensed indication)o Nocturnal enuresis (children)

• Mechanism of action:o Inhibit noradrenaline (NA) and serotonin (5-HT) uptake in

central nerve terminalso Most TCAs act on several other neurotransmitter receptors and

this is the reason for their large side-effect profile:! Anti-muscarinic # most TCAs! Histamine receptor blockade

• Adverse effects:





o Sedation (some more than others)o Confusiono Seizures (# seizure threshold)o Blurred vision (loss of accommodation)o Dry mouth (can lead to # dental hygiene)o Heart blocko Postural hypotensiono Constipationo Impotence

• Contraindications:o Dysrhythmias (especially heart block)o Epilepsyo Severe coronary heart diseaseo Suicidal patient (danger in overdose)

• TCA overdose:o Clinical features:

! Tachycardia! Mydriasis! Convulsions! Arrhythmias! Hypotension

o Management:! Treat convulsions with diazepam! Treat SVT / VT with sodium bicarbonate (even in absence

of acidosis)• Interactions:

o MAOIs:! Danger of potentially fatal hyperthermia syndrome

o Anti-arrhythmics:! Increased risk of ventricular dysrhythmias

o Anticonvulsants:! TCAs lower the seizure threshold and thus antagonise the

effect of anticonvulsantso Antipsychotics:

! Increased risk of ventricular dysrhythmias

Selective Serotonin Reuptake Inhibitors (SSRIs):• E.g. fluoxetine (prozac), paroxetine (seroxat), citalopram• Indications:

o Depression:! High suicide risk! Those intolerant to TCAs (e.g. Prostatism)

o Obsessive compulsive disorder (OCD)o Eating disorders

• Mechanism of action:o “Selectively” block the uptake of 5-HT by central nerve terminal,

thus increasing it’s concentration





o Fewer side-effects than the TCAs:! Less anti-muscarinic effects! Safer in overdose

• Adverse effects:o Nausea / anorexiao Insomniao Sexual dysfunction:

! Loss of libido! Failure of orgasm

• Contraindications:o Children <18 years of age:

! $ risk of self-harm / suicidal behaviouro Mania

• Interactions:o MAOIs:

! Do not start an SSRI until at least 2 weeks after stopping a MAOI

! Risk of hyperthermia syndrome:• Hyperthermia• Tremor• Collapse

o Anticonvulsants (e.g. carbamazepine, phenytoin):! SSRIs $ plasma levels of these drugs

o Haloperidol:! SSRIs $ plasma levels of haloperidol

Monoamine Oxidase Inhibitors (MAOIs):• Non-selective (inhibit MAO-A and MAO-B):

o Phenelzine• MAO-AIs (reversible):

o Moclobemide• MAO-BIs:

o Selegiline• Indications:

o “Atypical” depression (especially in young patients):! Weight gain! Hypersomnia

o Second-line use in depression (after TCA / SSRI)• Mechanism of action:

o MAO is found throughout body tissues (including the gut)o There are 2 isoforms of MAO - A and Bo MAO-A has a preference for 5-HT (this is seen to be beneficial in

depression)o MAO-B has a preference for dopamine (hence an anti-Parkinson

effect with selegiline)o MAO regulates intra-neuronal concentration of it’s substrates (it

is not involved in the inactivation of released transmitter)• Adverse effects:

o Hypotension





o Weight gaino Sedationo Anti-muscarinic effects

• Contraindications:o Hepatic impairmento Phaeochromocytomao Non-compliant patients (unable to monitor diet)

• Interactions:o Main hazard is with foods – the “cheese reaction”:

! Caused by foods containing high levels of tyramine:• Hard cheeses• Yeast extracts (e.g. marmite)• Red wine / beer

! MAO in the gut wall usually metabolises tyramine, thus preventing it reaching the systemic circulation

! In the presence of a MAOI, tyramine reaches the circulation and acts as a sympathomimetic (triggers the release of NA) and can lead to severe hypertension

! Treat with:• !1-antagonist (e.g. phentolamine) or• Nifedipine

o Antidepressants (TCAs, SSRIs):! Avoid concomitant use (allow washout period in between)! Potentiation of all side-effects and risk of hyperthermia

syndromeo Pethidine:

! Hyperthermia! CNS depression or excitement

o Carbamazepine:! MAOIs can # the plasma levels of carbamazepine

• The selective MAO-AIs have a much smaller risk of the “cheese reaction”

Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs):• E.g. venlafaxine• Indications:

o Severe / refractory depressiono Anxiety disorders

• Adverse effects:o Nauseao Insomniao Hypertension (at high doses)o Withdrawal problems common

• Interactions:o MAOIs:

! Risk of hyperthermia syndrome• Fewer side-effects than the TCAs but no more efficacious





Noradrenaline and Specific Serotenergic Antidepressants (NaSSAs):• E.g. mirtazapine• Indications:

o Depression (especially with insomnia)• Adverse effects:

o Drowsiness (even at low doses)o $ appetite / weight gaino Blood dyscrasias (rarely)

• Interactions:o Other sedatives (including alcohol)o MAOIs

• Safe in overdose• Minimal effects on sexual function

Lithium carbonate:• Indications:

o Acute maniao Prophylaxis of bipolar disordero Recurrent depressiono Aggressive / self-mutilating behaviour

• Toxicity:o Lithium requires therapeutic drug monitoring:

! Normal range is 0.4 – 1.0mmol/L• Adverse effects:

o 0.4 – 1.0mmol/L:! Nausea! Diarrhoea! Polyuria / polydipsia (nephrogenic DI)! Weight gain

o 1.0 – 2.0mmol/L:! Blurred vision! Anorexia / vomiting! Ataxia / dysarthria / tremor! Drowsiness

o >2.0mmol/L:! Convulsions! Hyperreflexia! Oliguria! Circulatory failure - death

• Long-term effects:o Can cause renal tubular damage and hypothyroidism

• Contraindications:o Pregnancy (although consider relative risks of drug cessation)o Renal impairmento Thyroid diseaseo Sick sinus syndromeo Poor compliance

• Interactions:o Lithium levels increased by:





! Diuretics (thiazides > loop)! ACEIs! NSAIDs! Alcohol

o Lithium levels decreased by:! Xanthines (e.g. theophylline)! Antacids! Acetazolamide





Anti-arrhythmic drugs

Vaughan-Williams classification:• Class I:

o Are all Na+ channel blockers (local anaesthetics)o Ib only works in the ventricleso Ia (A, SAN, AVN, V):

! E.g. quinidine, disopyramide, procainamide! $ AP duration! Hardly ever used in the UK (but used in the USA)

o Ib (V only):! E.g. lidocaine (lignocaine)! AP duration unaffected or slightly #

o Ic (A, SAN, AVN, V):! E.g. flecainide! AP duration slightly $! Primarily act by slowing conduction

• Class II (A, SAN, AVN, V):o "-blockers (e.g. propranolol)o # automaticityo # AP duration acutely (may prolong it with prolonged use)o # refractory period

• Class III (A, SAN, AVN, V):o E.g. amiodarone, sotalol (a "-blocker)o All have effects on various K+ channelso $ AP durationo $ refractory period

• Class IV (SAN, AVN):o Ca2+ channel blockers (e.g. verapamil)o Dihydropyridines (e.g. amlodipine) have no role in arrhythmias

• Unclassified:o Digoxin (AVN)o Adenosine (AVN)

Supraventricular arrhythmias:• Supraventricular tachycardias (SVTs) are often due to re-entry:

o SNRT (sinus node re-entry tachycardia)o AVNRT (atrioventricular node re-entry tachycardia)o AVRT (atrioventricular re-entry tachycardia):

! Caused by an accessory pathway• Atrial arrhythmias:

o Atrial tachycardiao Atrial flutter

o Atrial fibrillation (AF):! Paroxysmal! Persistent





! Permanent

Treatment of SVTs:• Vagal manoeuvres• Adenosine:

o 6mg " 12mg " 12mg• If adenosine fails:

o Cardiovascular instability:! Synchronised cardioversion

o No cardiovascular instability:! Verapamil or! Digoxin or! Amiodarone

• Prophylaxis:o "-blockerso Flecainide (AVRT)o Verapamil (AVNRT)

• Wolff-Parkinson-White (WPW) syndrome:o If pt with WPW has AF and fast ventricular rate:

! Adenosine, digoxin and verapamil are absolutely contraindicated

! Use Flecainide

Treatment of atrial tachycardia:• Treat underlying coronary / structural heart disease if present• Exclude digoxin toxicity• "-blockers• Verapamil• Often refractory to drug treatment – treat with radiofrequency

ablation (RFA)

Treatment of atrial flutter:• Drugs are generally ineffective, but can try:

o Amiodarone:! Drug most likely to work

o Digoxin:! Rate control only

o "-blockers:! Rate control! Chance of return to sinus rhythm (SR)

o Verapamil:! Rate control! Chance of return to SR

• DC cardioversion ± anticoagulation can work• RFA is the treatment of choice

Treatment of atrial fibrillation (AF):• Acute:

o Treat underlying cause (e.g. pneumonia)o DC cardioversion (first-line choice):





! Anticoagulation is not essential if AF is of recent onset (<48 hours) with a structurally normal heart (but most people do)

! If required, give warfarin for at least 3 weeks before and at least 4 weeks after

o Control ventricular rate:! Digoxin! If ventricular rate still too fast:

• "-blocker (can return patient to sinus rhythm)o Chemical cardioversion:

! Amiodarone or! Flecainide (if haemodynamically stable) or! "-blocker

• Chronic:o Control ventricular rate:

! Digoxin! If rate still too fast consider:

• (Cautiously) $ digoxin dose• "-blocker• Amiodarone

o Anticoagulation:! > 65 years:

• Warfarin (INR 2.5 – 3.5)! <65 years with no risk factors or > 65 years and unable

to be warfarinised:• Aspirin

Treatment of ventricular tachycardia (VT):• Acute:

o Haemodynamically stable:! Amiodarone or! Lidocaine

o Not haemodynamically stable:! Synchronised DC cardioversion! Amiodarone

• Recurrent / paroxysmal:o Drugs:

! Amiodarone! "-blocker (works synergistically with amiodarone)! Sotalol

o Implantable defibrillator:! # mortality

Drug treatment of Torsade de Pointes:• Often associated with prolongation of the QT interval• Causes of QT prolongation:

o Electrolyte disturbances:! Hypokalaemia





! Hypocalcaemiao Congenital long QT syndromeso Drugs:

! Class Ic and III anti-arrhythmics! TCAs

o Ischaemia• Treatment:

o IV MgSO4

Treatment of bradyarrhythmias:• Haemodynamically compromised:

o Drugs:! Atropine ±! Isoprenaline / adrenaline

o Pacing:! External! Temporary transvenous

• Stable:o Withdraw any negatively chronotropic drugs (e.g. "-blockers)o Exclude secondary causes:

! ACS! Hypothyroidism

o Assess need for permanent pacemaker

Adenosine:• Indications:

o Paroxysmal SVTo To aid diagnosis of broad complex SVTs

• Mechanism of action:o Binds to adenosine (A1) receptors in the cardiac conduction

system:! Opens ACh-sensitive K+ channels

o Slows conduction in the heart by prolonging the refractory period in the AVN / bundle of His

• Adverse effects:o All are short-lived (half-life of 8 – 10secs)o Bronchospasmo Chest paino Flushingo Severe bradycardia (rare)

• Contraindications:o Asthmao 2nd or 3rd degree heart block (unless pacemaker in-situ)

• Interactions:o Dipyridamole:

! Prolongs / enhances action of adenosineo Theophylline:

! Inhibits adenosine





Amiodarone:• Indications:

o Paroxysmal:! SVT! Nodal tachycardia! VT

o Atrial fluttero AFo VF

• Amiodarone is generally used when other drugs have been ineffective or are contraindicated

• Mechanism of action:o Not fully understoodo Blocks several channels:

! !-adrenoceptors, "-adrenoceptors, Na+ and Ca2+

o Generally slows conduction through the heart• Pharmacokinetics:

o Very long half-life:! 10 – 100 days (average 36 days)

o Requires a loading dose in life-threatening arrhythmias:! Central vein (causes phlebitis in peripheral veins)

o This means that drug interactions can occur long after amiodarone has been stopped

• Adverse effects:o Common:

! Corneal microdeposits (reversible):• Can cause driver headlight dazzling at night

! Photosensitive rasho Less common:

! Thyroid dysfunction (hyper- or hypo-)! Pulmonary fibrosis! Grey skin colour! Peripheral neuropathy! Ataxia

• Special notes:o Thyroid function must be checked before treatment and every 6

months:! If hyperthyroidism develops, this can be very refractory

and may require cessation of amiodaroneo Shortness of breath suggests development of pulmonary fibrosis

• Contraindications:o Thyroid diseaseo Pregnancyo Iodine allergy (as amiodarone contains iodine)

• Interactions:o "-blockers / non-dihydropyridines (e.g. diltiazem, verapamil):

! $ risk bradycardia, AV block and myocardial depression





o Digoxin:! Amiodarone $ plasma levels of digoxin

o Class Ia drugs:! $ QT interval

o Phenytoin:! Amiodarone $ plasma levels of phenytoin

o Warfarin:! Amiodarone $ plasma levels of warfarin

Lidocaine (lignocaine):• Indications:

o Ventricular arrhythmias (especially after MI):! Stops VT and # risk of VF! Does not # mortality when used prophylactically

o Local anaesthesia• Mechanism of action:

o Class Ib anti-arrhythmic agento Not active orally (massive 1st-pass metabolism)o Blocks fast Na+ channels:

! Slows conduction in the heart (only ventricles)! Inhibits AP propagation in nerve axons

• Adverse effects:o Uncommon:

! Convulsions! Drowsiness! Bradycardia! Cardiac arrest

• Contraindications:o AV node block (all degrees)o Severe heart failureo Hypovolaemia

• Interactions:o Cimetidine:

! $ plasma levels of lidocaine

Flecainide:• Indications:

o AVRTo WPW syndrome associated arrhythmiaso Paroxysmal AF (chemical cardioversion)

• Mechanism of action:o Class Ic anti-arrhythmic agento Na+ channel blocker

• Contraindications:





o Previous MIo Haemodynamically significant valvular disease





Hypertension

British hypertension society (BHS) classification of BP levels:• Optimal:

o <120 / <80 mmHg• Normal:

o <130 / <85 mmHg• High normal:

o 130-139 / 85-89 mmHg• Hypertension:

o Grade 1 (mild):! 140-159 / 90-99 mmHg

o Grade 2 (moderate):! >160 – 179 / 100-109 mmHg

o Grade 3 (severe):! >=180 / >=110 mmHg

o Isolated systolic:! Systolic BP is more important than diastolic! Grade 1:

• 140-159 / <90 mmHg! Grade 2:

• >=160 / <90 mmHg

Complications of hypertension:• Cerebral:

o Encephalopathyo Haemorrhageo Thromboembolismo TIA

• Other:o MI (hypertension accounts for 25% of MIs)o Heart failureo Dissecting aneurysmo Renovascular diseaseo Peripheral vascular disease

When to treat patients with anti-hypertensive agents:• Definitely treat:

o >=160 / >=100 mmHg (i.e. grade II hypertension)• Treat if

o >=140 / >=90 mmHg and (i.e. grade I hypertension)o Target organ damage oro CVS complications oro Diabetes oro CV event risk >=2%/year (>=20% at 10 years)

Target blood pressure for patients on anti-hypertensive medication:





• There is evidence for these systolic values but the diastolic is arbitrary• Patients with diabetes, renal impairment or CVS disease:

o <=130 / <=80 mmHg• Other patients:

o <=140 / <=85 mmHg

The BHS ABCD approach to the treatment of hypertension:• Key:

o ACE inhibitoro Beta blockero Calcium channel blockero Diuretic (thiazide)

• Step 1:o Young (<55 yrs) and non-black:

! A (or B*)o Older (>55 yrs) or black:

! C or D• Step 2:

o A (or B*) + C or D• Step 3:

o A (or B*) + C + D• Step 4 (resistant hypertension):

o Add either:! !-blocker! Spironolactone

• *"-blockers will probably be removed from this algorithm as they may induce new onset diabetes mellitus





Antibiotic therapy

Below are empirical treatments only – the correct antibiotic will depend upon sensitivities determined by bacteriological culture

Treating pneumonia:• Community acquired:

o Mild (streptococcus, haemophilus, mycoplasma):! Amoxicillin po ±! Erythromycin po (if penicillin sensitive or atypicals)

o Severe (same bugs as for mild):! Co-amoxiclav IV or! Cefuroxime IV and! Erythromycin IV

o Atypical:! Legionella:

• Clarithromycin ± rifampicin! Chlamydia:

• Tetracycline! Pneumocystis carinii:

• Co-trimoxazole• Hospital acquired (Gram (–ve), pseudomonas, anaerobes):

o Aminoglycoside IV ando 3rd generation cephalosporin IV ±o Anti-pseudomonal penicillin IV

• Aspiration:o Cefuroxime IV ando Metronidazole IV

Treating meningitis:• Immediate treatment:

o Outside hospital:! Benzylpenicillin 1.2g IV/IM

o Inside hospital:! Cefotaxime 2g IV

• Subsequent treatment:o Depends on sensitivitieso Generally cefotaximeo Benzylpenicillin and rifampicin for meningococcal meningitis

• Contacts – eradicate carriage:o Rifampicin (2 days)o Ciprofloxacin (single dose)

Treating tuberculosis:• Initial phase (8 weeks on 3–4 drugs):





o Rifampicino Isoniazido Pyrazinamideo Ethambutol (if isoniazid resistance is possible)

• Continuation phase (4–10 months on 2–3 drugs, depends on site):o Rifampicino Isoniazid ±o Ethambutol

• Give pyridoxine throughout treatment (prevents isoniazid neuropathy)

Treating septicaemia – source unknown:• Take blood cultures first!• Anti-pseudomonal penicillin (e.g. ticarcillin) and• Cefuroxime IV or• Gentamicin IV

Treating Neutropenic sepsis:• Take blood cultures first!• First-line:

o Piperacillin + Gentamicin• Second-line:

o Ceftazidime + vancomycin• Third-line:

o Add amphotericin B

Treating a UTI:• Depends on sensitivities• Cystitis:

o Mild:! Trimethoprim

o More severe:! Co-amoxiclav! Ciprofloxacin

• Acute pyelonephritis:o Cefuroxime

Treating MRSA infection:• Vancomycin or• Teicoplanin

Treating clostridium difficile:• Metronidazole po or• Vancomycin po

Treating cellulitis:• Depends on the organism, but a good start would be:

o Benzylpenicillin and





o Flucloxacillin

Prophylactic antibiotics and surgery:• Single bolus as good as prolonged therapy:

o Metronidazole IV ando Cefuroxime IV

Helicobacter pylori eradication therapy:• One PPI and two antibiotics for two weeks• Usual combination (but there are many):

o Omeprazoleo Clarithromycino Amoxicillin (or metronidazole)

• Resistance to metronidazole is common





Antibiotics

Antibiotics that inhibit cell wall synthesis:• "-lactams:

o Penicillinso Cephalosporins

• Glycopeptides:o Vancomycino Teicoplanin

• Carbapenems:o Imipenem

• Monobactams:o Aztreonam

Antibiotics that inhibit protein synthesis:• 30S ribosome:

o Aminoglycosides:! Gentamicin! Amikacin

o Tetracyclines:! Tetracycline! Doxycycline

• 50S ribosome:o Macrolides:

! Erythromycin! Clarithromycin

o Chloramphenicolo Fusidic acid

Antibiotics that inhibit nucleic acid synthesis:• Quinolones:

o Ciprofloxacin• Metronidazole• Trimethoprim• Rifampicin• Sulphonamides

Antibiotics that do not accumulate in renal impairment:• Chloramphenicol• Co-trimoxazole• Doxycycline• Isoniazid• Macrolides• Quinolones• Rifampicin

Penicillins:• Are all active against Gram +ve bugs (some against Gram –ve bugs)





• A common mechanism of resistance is the production of an enzyme ("-lactamase) that degrades the drug

• Penicillin:o Benzylpenicillin (penicillin G):

! Parenteral (is destroyed by gastric acids)o Phenoxymethylpenicillin (penicillin V):

! Oral (but poor bioavailability)! Used for prophylaxis in:

• Splenectomy patients• Sickle cell anaemia patients

o Indications:! Pneumococcus! Streptococcus! Meningococcus! Leptospiral infections

• Broad-spectrum (activity against some Gram –ve bugs as well):o Amoxicillin (oral or parenteral)o Indications:

! (As for penicillin)! Escherichia coli! Haemophilus influenzae (resistance is increasing ~15%)! Salmonella

• "-lactamase resistant:o Flucloxacillin:

! Indications:• "-lactamase-producing staphylococci

o Co-amoxiclav (Augmentin):! Amoxicillin + ! Clavulanic acid ("-lactamase inhibitor)! Indications:

• Amoxicillin resistant URTIs and UTIs• Anti-pseudomonal:

o Ticarcillino Pipericillin:

! Combined with Tazobactam (a "-lactamase inhibitor) as Tazocin

• Adverse effects:o Rash:

! Common to all penicillins! Maculopapular rash in glandular fever if given amoxicillin

o Nausea / vomitingo Uncommon:

! Anaphylactic shock! Convulsions

• Contraindications:o Penicillin hypersensitivity

• Interactions:





o COC pill:! Penicillins reduce the efficacy of the pill

o Probenicid:! Probenicid # excretion of the penicillins! Allows for a # dose of penicillin to be used or for

prolonged high plasma levels to be attained

Cephalosporins:• Have a similar range of activity to amoxicillin but are more "-

lactamase stable• Are 3 “generations” of parenteral cephalosporins:

o As the generations progress, the cephalosporins become more effective against Gram –ve bugs

o First generation have pretty much been supersededo Second:

! Cefuroxime:• Similar spectrum to amoxicillin

o Third:! All are a common cause of C. difficile diarrhoea! Cefotaxime:

• Important drug in the treatment of meningitis! Ceftazidime:

• Pseudomonas and others! Ceftriaxone:

• Long-half life (once daily administration)• Effective in serious infections:

o Pneumoniao Septicaemia

• Are 2 “generations” of orally active cephalosporins:o Both have similar spectrums of action:

! URTIs! Refractory cystitis! Otitis media

o First (e.g. cefalexin)o Second (e.g. cefaclor)

• Adverse effects:o Bleedingo Diarrhoeao Nausea / vomitingo Thrombophlebitis (parental cephalosporins)

• Contraindications:o Hypersensitivity:

! There is also a 10% cross-reactivity with penicillins

• Interactions:o Probenicid:

! Probenicid # excretion of the cephalosporins! Allows for a # dose of cephalosporin to be used





Glycopeptides:• E.g. vancomycin, teicoplanin• Active against aerobic and anaerobic Gram +ve bacteria• Vancomycin (oral or IV):

o Indications:! IV:

• Infective endocarditis• MRSA

! Oral:• Clostridium difficile (pseudomembranous colitis)

• Teicoplanin:o Indications (IV or IM):

! Used for serious Gram +ve infections• IV Vancomycin requires therapeutic drug monitoring• Adverse effects:

o Ototoxicity (tinnitus and deafness)o Nephrotoxicity (less so with teicoplanin)o Neutropenia

• Interactions:o Increased risk of ototoxicity with:

! Loop diureticso Increased risk of nephrotoxicity with:

! Aminoglycosides! Cyclosporin

Carbapenems:• E.g. imipenem, meropenem• Incredibly broad spectrum:

o Active against both Gram +ve and –ve bacteriao "-lactamase stableo Is effective against MRSA and anaerobeso Best single agent choice for nosocomial infection

• Imipenem:o Rapidly degraded by renal dipeptidaseo Must be given in conjunction with cilastatin (a dipeptidase

inhibitor)• Meropenem:

o Similar to imipenem but is stable to renal dipeptidase, does not need to be given with cilastatin

• Adverse effects:o Nausea / vomiting / diarrhoea (3–4% of patients)o Cross-reactivity with "-lactam antibioticso Seizures (imipenem >> meropenem)

Aminoglycosides:• E.g. Gentamicin, amikacin, streptomycin• Active against many Gram –ve and some Gram +ve bacteria





• Indications:o Second line treatment for severe Gram –ve infection:

! Infective endocarditis! Septicaemia! Acute pyelonephritis

o Topical:! Eye! Ear

o Streptomycin is reserved for resistant tuberculosis• Mechanism of action:

o Bactericidalo Inhibit bacterial protein synthesis by binding to the 30S

ribosome• Pharmacokinetics:

o Inactive orally (must be given IV / topically)o Excreted unchanged by the kidneys:

! Use with caution in renal impairment (adjust dose)o Therapeutic drug monitoring is required:

! Peak plasma levels should be measured (~1 hour after administration)

• Adverse effects:o Nephrotoxicity (renal tubular damage)o Ototoxicity (damage to CN VIII):

! “Deaf and dizzy”! Can be irreversible

• Contraindications:o Myasthenia gravis:

! Aminoglycosides can impair neuromuscular transmission by inhibiting Ca2+-influx into nerve terminal and preventing release of ACh

o Pregnancy• Interactions:

o Drugs potentiating the nephrotoxicity of aminoglycosides:! Cyclosporin! Loop diuretics:

• Also potentiate ototoxicityo Anticholinesterases (e.g. neostigmine):

! Aminoglycosides antagonise the effects of these drugs• Notes:

o Neomycin is very poorly absorbed:! Often used dermatologically or as part of bowel prep

o Tobramycin:! Can be inhaled (good in CF patients)! Can precipitate acute airway obstruction

Tetracyclines:• E.g. tetracycline, doxycycline• Indications:





o Good for some intracellular organisms (as they penetrate macrophages):

! Chlamydia (STD) # doxycycline! Rickettsia (Q-fever)! Borrelia burgdorferi (Lyme disease)

o Acneo Anthrax (doxycycline)

• Pharmacokinetics:o Were the first orally-active broad-spectrum antibiotics (can be

given IV)o Bacteriostatico Absorption from gut is variable - # by:

! Ca2+ (milk)! Mg2+ (antacids)! Iron preparations

o Excreted unchanged in the urine (except doxycycline)• Adverse effects:

o Deposited in growing bones / teeth:! Causes staining and (occasionally) dental hypoplasia! Do not use in children <12 years or in pregnancy

o Renal impairment (except doxycycline)• Contraindications:

o Renal impairment (except doxycycline)

Fusidic acid:• Potent narrow-spectrum anti-staphylococcal antibiotic• Always used in combination to prevent resistance • Indications:

o Infections caused by penicillin-resistant staphylococcio Especially:

! Osteomyelitis (well concentrated in bone)! Staphylococcal endocarditis

o Can be used topically• Adverse effects:

o Reversible jaundiceo Acute renal failure (monitor renal function)o Liver impairment (monitor LFTs)

Macrolides:• E.g. erythromycin, clarithromycin• Indications:

o Erythromycin:





! Active against Gram +ve bacteria (e.g. staphylococci, streptococci) and the atypicals (e.g. mycoplasma, chlamydia, legionella)

! A good “respiratory” antibiotic! A substitute for penicillin in those with hypersensitivity

o Clarithromycin:! More potent than erythromycin (except H. influenzae)! Part of helicobacter pylori eradication therapy

• Do not cross the blood-brain-barrier (no good for meningitis)• Adverse effects:

o Erythromycin causes nausea / vomiting / diarrhoea:! Is an agonist at the motilin receptor in the gut

o Phlebitis• Interactions:

o Inhibit cytochrome P450:! $ levels of warfarin, theophylline, cyclosporin A (and

many others)o Digoxin:

! $ plasma levels of digoxino Terfenadine (non-sedating antihistamine):

! $ risk of arrhythmias

Quinolones:• E.g. ciprofloxacin, ofloxacin• Active against many Gram –ve and some Gram +ve bacteria:

o Campylobactero Escherichia colio Pseudomonaso Salmonella

• Indications:o UTIo Salmonella infectiono Cystic fibrosis lung infectionso Gonorrhoeao Tuberculosis (3rd-line drug)o Anthrax

• Pharmacokinetics:o Ciprofloxacin has a near 100% bioavailability when taken

orally• Adverse effects:

o GI disturbanceo Tendon damage (including rupture)o Seizures (lowers seizure threshold)

• Cautions:o Epilepsyo Myasthenia graviso History of tendon damage

• Interactions:





o Inhibits cytochrome P450 (many interactions):! $ levels of warfarin, theophylline, cyclosporin A

Metronidazole:• Indications:

o Anaerobeso Protozoal infections:

! Entamoeba histolytica! Giardia lamblia! Trichomonas vaginalis

o Part of helicobacter eradication therapyo Pseudomembranous colitis (C. difficile)

• Pharmacokinetics:o Oral, IV or rectalo Clinical / laboratory monitoring if treatment > 10 days

• Adverse effects:o GI disturbances (uncommon and well tolerated)

• Cautions:o Hepatic impairment

• Interactions:o Disulfiram (Antabuse)-like reaction with alcohol:

! Flushing! Hypotension! Abdominal pain

o Phenytoin:! $ plasma levels of phenytoin

o Warfarin:! $ plasma levels of warfarin

Rifampicin:• Indications:

o Tuberculosiso Leprosyo Meningitis contact prophylaxiso MRSA

• Adverse effects:o Deranged LFTs (usually mild but can be serious)o Stains secretions pink / orange:

! Saliva! Tears! Urine

• Contraindications:o Jaundice

• Interactions:o Potent cytochrome P450 inducer (many reactions):

! # efficacy of:• Carbamazepine• COC pill• Corticosteroids





• Phenytoin• Warfarin

Isoniazid:• Indications:

o Tuberculosis• Adverse effects:

o Peripheral neuropathy (more likely in):! Alcoholism! Chronic renal failure! Diabetics! HIV! Malnutrition! Can be prevented by pyridoxine (vitamin B6)

o Hepatitiso Psychosis

• Contraindications:o Hepatic impairment

• Interactions: o Anticonvulsants (carbamazepine, phenytoin):

! Isoniazid $ plasma levels of these drugs

Pyrazinamide:• Indications:

o Tuberculosis• Pharmacokinetics:

o Good CSF penetration (good in TB meningitis)• Adverse effects:

o Hepatocellular toxicity• Contraindications:

o Gout (avoid in acute attack)o Hepatic impairmento Porphyria

Ethambutol:• Indications:

o Tuberculosis (if isoniazid resistance is suspected)• Adverse effects:

o Visual disturbances (reversible if drug stopped early):! Caused by a retorbulbar neuritis! Not too much of a problem with only 8 weeks of therapy

• Contraindications:o Renal impairment ($ risk of visual damage)





Diabetes

Treatment of diabetes:• Both types:

o Diet:! # weight (as this # insulin resistance)! # simple sugars! $ complex carbohydrates! $ fibre intake

o Address associated risk factors:! Hyperlipidaemia! Hypertension (<=130 / <=80 mmHg)! Smoking

• Type I:o All require insulin

• Type II:o BMI < 25:

! Sulphonyureao BMI > 25:

! Meformin (a biguanide)o If not controlled on a sulphonylurea, add metformino If not controlled on metformin, add a sulphonylureao If not controlled on 2 drugs or intolerant consider adding:

! A glitazone! Acarbose

o Insulin if poor glycaemic control with oral agents:! 50% of pts will require insulin within 6 years of diagnosis

What to check at a diabetic’s annual review:• Blood glucose record• BP• HbA1c• Lipids• Renal function• Urine (protein / glucose)

Treatment of diabetic ketoacidosis (DKA):• Only occurs in type I diabetes• IV fluids:

o Patients may be 5–10L fluid depleteo Use 0.9% saline (first bag usually ran in stat)

• Monitor (initially hourly):o Creatinine (to look for pre-renal failure)o Glucose o HCO3- / pHo K+ (Initially plasma levels $ - masks body wide K+ depletion)

• Insulin:o Aim for a glucose fall of 5mmol/h





o Initial bolus of soluble insulin then insulin infusion• Potassium replacement (monitor plasma levels):

o Has been lost due to the diuresiso Don’t give more than 20mmols/L in each bag

• If acidosis severe (pH <7.0) consider bicarbonate:o Severe acidosis can impair insulin binding to its receptoro Comes in 50ml bottles (8.4% = 1mg / ml)

• Identify the cause of the DKA (e.g. infection)• LMWH (to prevent thrombosis) until mobile

Treatment of hyperglycaemic hyper-osmotic non-ketotic (HHONK) coma• Only occurs in type II diabetes• No acidosis (as ketosis is suppressed by endogenous insulin)• IV fluids• Insulin (small doses):

o Wait until 1 hour after fluids (may not be needed)• Full heparin anticoagulation

Treatment of hypoglycaemia:• If able to take oral treatment:

o Lucozade (or other high sugar drink / sweet)• Else:

o 20–30mg dextrose IV (e.g. 200–300mls 10% dextrose):! high concentrations (e.g. 50%) can be irritative and can

even cause stroke!)o Glucagon 1mg IV/IM:

! Almost as fast as IV dextrose! Doesn’t work when given repeatedly or if given to

patients with no or poor glycogen reserves (e.g. alcoholics)

• Once conscious:o Give the patient a meal

• When to admit:o If patient is hypoglycaemia following oral anti-diabetics (as

they can be very long-acting)

Sulphonylureas:• E.g. tolbutamide (very short-acting), glicazide (short-acting),

glibenclamide (once daily)• Mechanism of action:

o Are insulin secretagogues (thus require some functional "-cells)

o Reduce the K+ permeability of "-cells by blocking ATP-sensitive K+ channels:

! Causes depolarisation and Ca2+ entry! Thus causing insulin secretion

• Pharmacokinetics:o All bind strongly to albumin (several drug interactions)






o Weight gain (largely due to $ appetite)o Hypoglycaemia (can be severe / fatal):

! Admit (as the hypoglycaemia can persist for up to 24 hrs)! Much greater risk than with metformin

o GI disturbances (~3% of patients)o Bone marrow suppression (rare)

• Cautions:o Elderly ± renal impairment:

! $$ risk of hypoglycaemia (mainly glibenclamide)o Breast-feeding

• Interactions:o Drugs potentiating the hypoglycaemic effect:

! Sulphonamides (including co-trimoxazole)! Chloramphenicol

Metformin:• Usually given twice daily• A biguanide (the only available one!)• Mechanism of action:

o Is an insulin-sensitizero # gluconeogenesiso $ peripheral utilization of insulino # LDL / VLDL

• Does not cause hypoglycaemia• Adverse effects:

o GI disturbances:! Start at ~1g / daily! Nausea / anorexia / vomiting / diarrhoea

o Lactic acidosis (uncommon):! Caused by a build-up of pyruvate

o # absorption of vitamin B12• Contraindications:

o Conditions predisposing to metformin-induced lactic acidosis:! Mild renal impairment! Severe hepatic impairment! Severe heart failure

o Pregnancy / breast-feeding• Interactions:

o Alcohol:! $ risk of lactic acidosis

Glitazones (thiazolidinediones):• E.g. pioglitazone, rosiglitazone• Indications:

o Type II diabetes:





! Pa t i en t s who canno t t o l e r a t e ( o r t he r e a r e contraindications to) combination therapy with metformin and a sulphonylurea

! In such cases, the glitazone should replace whichever drug in the combination is poorly tolerated / contraindicated

• Mechanism of action:o Interact with a nuclear receptor (peroxisome proliferator-

activator receptor gamma " PPAR-')o PPAR-' regulates genes involved in lipid metabolism and insulin

actiono Reduce insulin resistanceo # circulating insulin relative to plasma glucose but do not #

glucose levels to normal• Adverse effects:

o Hepatotoxicity:! Monitor LFTs before and during treatment

o Weight gaino Anaemia (uncommon)

• Contraindications:o Hepatic impairmento Combination with insulin (risk of heart failure)

Acarbose:• Mechanism of action:

o Intestinal !-glucosidase inhibitoro Delays the digestion of starch and sucroseo Is taken with meals and lowers the post-prandial increase in

blood glucose (~1-2mmol/L)• Adverse effects:

o Abdominal pain / bloatingo Flatulence

• Contraindications:o IBDo History of abdominal surgeryo Pregnancy

Insulin:• N.B. normal individuals require ~60U of endogenous insulin daily• Indications:

o All T1DMo T2DM where control / symptoms / complications pooro Hyperkalaemia (with glucose)

• Pharmacokinetics:o Physical state:

! Short-acting soluble insulins (rapid onset):• E.g. Actrapid, insulin lispro, insulin asparte• Inject 15–30 mins before meals





• Onset in 30–60 mins• Maximum effect 2–4 hours• Duration up to 8 hours

! Intermediate-acting (isophane insulins):• Are insulin with protamine preparations• E.g. insulatard

! Long-acting:• Either insulin zinc suspensions (e.g. ultratard) or

synthetics (e.g. insulin glargine)! Mixed-insulins:

• E.g. mixtardo Human insulin absorbed faster than porcine / bovine insulino Porcine / bovine insulin may cause less hypoglycaemiao Factors affecting absorption:

! Temperature! Exercise

• Insulin effects:o Adipose tissue:

! $ lipoprotein lipase activity:• # TGs

! $ GLUT-4 activity:• $ glucose storage as fat

! # lipolysis:o Liver:

! # glycogenolysis! # gluconeogenesis! Inhibition of ketogenesis

o Muscle:! # proteolysis! $ GLUT-4 activity:

• # plasma glucose levels• Insulin regimes:

o Twice daily mixed insulins:! Possibly better for children or older T2DM

o Basal bolus (qds) regime:! More “physiological”! Involves more injections! Best regimen for # diabetic complications

• Problems with Actrapid (short-acting human insulin):o Needs to be given 15 minutes before mealso Can cause a late post-prandial hypoglycaemia:

! Leads to post-prandial hyperglycaemia (as patients don’t give enough as they fear the hypoglycaemia)

• Problems with insulin glargine (long-acting human insulin analogue):o Nocturnal hypoglycaemia (can be dangerous)o Uniform action (not physiological)

• Adverse effects:o Hypoglycaemia:

! 30% of T1DM ever (10%/year, 3% frequent episodes)





! Sweating! Tachycardia! Tremor! Aggression! Confusion! Coma

o Fat hypertrophy / atrophy at injection site (rotate site to avoid this)

o Weight gain:! As blood [glucose] is # you get hungry!





Epilepsy

Classification of epilepsy:• Generalised:

o Implies bilateral abnormal electrical activity in the brain with bilateral motor manifestations

o Consciousness is impairedo Types:

! Tonic-clonic (grand-mal)! Absence (petit-mal)! Myoclonic

• Partial:o A localised seizure that may be either:

! Simple (without loss of consciousness):• Jacksonian seizure

! Complex (with loss of awareness)o May progress to a generalised seizure

Management of status epilepticus:• Remember 25% of status turns out to be pseudostatus• ABC (need to maintain airway)• Oxygen• If alcoholism / malnutrition give thiamine• If hypoglycaemic give glucose• Stop the seizure:

o Lorazapam (slow IV bolus) if failso Phenytoin (IV infusion) if failso Phenobarbital IV if failso Anaesthetise with thiopentone / propofol

Drug treatment of epilepsy (NICE recommendations):• Generalised seizures:

o First-line (all):! Valproate

o Second-line (tonic-clonic):! Carbamazepine! Phenytoin

o Second-line (absence):! Ethosuximide

o Second-line (myoclonic):! Ethosuximide! Lamotrigine

• Partial seizures:o First-line:

! Carbamazepine! Valproate

o Second-line:! Lamotrigine





! Gabapentin! Vigabatrin

o Third-line:! Phenytoin

Carbamazepine:• Indications:

o Partial seizures (first-line)o Tonic-clonic seizures (second-line)o Trigeminal neuralgiao Bipolar disorder

• Mechanism of action:o Related to the tri-cyclic antidepressantso Induces a use-dependent block of neuronal Na+ channels

• Pharmacokinetics:o Has an active metabolite (produced in the liver)o t! of 10–20 hourso Is an enzyme inducer (even of it’s own metabolism)o Requires therapeutic drug monitoring

• Adverse effects:o Ataxiao Nauseao Neutropeniao Sedationo SIADHo Teratogenic:

! Foetal neural tube defects• Contraindications:

o AV conduction abnormalities (unless paced)o History of bone marrow depressiono Porphyria

• Interactions (many as is an enzyme inducer):o Carbamazepine # the efficacy of:

! COC pill! Corticosteroids! Cyclosporin! Phenytoin! Warfarin

o Drugs that $ the level of carbamazepine:! Cimetidine! Erythromycin

Phenytoin:• Indications:





o All types of epilepsy (except absence seizures) but not first-line

o Status epilepticuso Trigeminal neuralgia

• Mechanism of action:o Related to the barbiturateso Induces a use-dependent block of neuronal Na+ channels

• Pharmacokinetics:o t! of 20–60 hourso Has a saturable metabolism (zero-order kinetics):

! This means that over the therapeutic plasma concentration range, the rate of inactivation does not $ in proportion to the plasma concentration

! This means that the t! $ as the dose is $o ~90% protein bound:

! Some drugs (e.g. valproate, salicyclates) inhibit this binding competitively

! This $ the free [phenytoin] but also $ the hepatic clearance of phenytoin

! The net result is unpredictableo Is a potent enzyme inducero Once daily dosage (should be nocte)o Requires therapeutic drug monitoring

• Adverse effects:o Ataxiao Sedationo Acneo Folate deficiencyo Gum hypertrophyo Hirsuitismo Lymphadenopathyo Osteomalacia (vitamin D resistance)o Photosensitivity

• Cautions:o Hepatic impairment (# dose) # commono Pregnancy:

! Cleft palate• Interactions (many):

o Phenytoin # the efficacy of:! COC pill! Rifampicin! Warfarin

o Drugs that $ the level of phenytoin:! Aspirin! Cimetidine

Sodium valproate:• Indications:

o All types of epilepsy (first-line)





• Mechanism of action:o Not fully understoodo Causes a significant $ in brain [GABA]

• Pharmacokinetics:o t! of 8–15 hourso Metabolised by the liver but not an enzyme inducer (may be an

enzyme inhibitor)• Adverse effects (fewer severe effects than most anticonvulsants):

o Hepatotoxicity:! Need to monitor LFTs

o Teratogenicity:! Neural tube defects! Probably the safest anticonvulsant to use in pregnancy

o Thinning / curling of the hairo Thrombocytopeniao Tremoro Sedationo Weight gain

• Contraindications:o Severe liver disease

• Interactions:o Drugs that # the efficacy of valproate:

! Neuroleptics! Tri-cyclic antidepressants

Phenobarbital:• Indications:

o All types of epilepsy (except absence seizures) but not first-lineo Status epilepticus

• Mechanism of action:o Is a barbiturateo Binds to the GABA receptor and enhances actions of GABA

• Pharmacokinetics:o Well absorbedo 50% protein boundo t! 36–120 hourso Enzyme inducer

• Adverse effects:o Sedation with impairment of intellectual and motor

performanceo Ataxiao Osteomalaciao Folate deficiency

• Cautions:o Elderlyo Respiratory depressiono Impaired hepatic / renal function





• Interactions (many more than shown below):o Phenobarbital # the efficacy of:

! COC pill! Warfarin

Vigabatrin:• Indications:

o Epilepsy (usually second- or third-line)• Mechanism of action:

o Was the first “designer” drug in the field of epilepsyo Is a irreversible GABA-transaminase inhibitor:

! $ [GABA] in the CSF• Pharmacokinetics:

o t! 5 hours (although duration of action is long)o Is not an enzyme inducer

• Adverse effects:o Depressiono Psychotic disturbanceso Visual field defects (~30% of patients)

• Contraindications:o Those with visual field defects

Lamotrigine:• Indications:

o Can be used as monotherapy of:! Generalised seizures (especially absence seizures)! Partial seizures

• Pharmacokinetics:o t! 15–70 hours

• Adverse effects:o Rashes (very common):

! Can be as severe as Stevens-Johnson syndromeo Drowsinesso Tremor

• Interactions:o Valproate:

! Valproate $ the plasma levels of lamotrigine

Primidone:• Is a pro-drug of phenobarbital• ? an anticonvulsant in it’s own right• Adverse effects:

o As for phenobarbital

Ethosuximide:• Indications:

o Absence seizures (second-line)• Pharmacokinetics:

o t! of 30–70 hours





o Is not an enzyme inducer• Adverse effects:

o Nausea / anorexiao Sedationo Ataxiao Hypersensitivity (rare)

Gabapentin:• Indications:

o Adjunctive treatment of partial seizureso Neuropathic paino It’s role is likely to increase in the future

• Pharmacokinetics:o t! of 5–7 hourso Not metabolisedo Few (if any) interactions

• Adverse effects:o Ataxiao Drowsiness





Migraine

Prophylaxis against migraine:• Avoid precipitating factors (if possible):

o Foods (mainly tyramine containing food)o Irregular meals / sleeping patternso Alcoholo “Weekend” migraines are probably caused by caffeine

withdrawal• 5-HT antagonists:

o E.g. pizotifeno Methysergide:

! Only prescribed by those experience in its use! Good for cluster headaches! Fibrotic side effects:

• Cardiac fibrosis• Pulmonary fibrosis• Retroperitoneal fibrosis

• "-blockers:o E.g. propranolol, atenolol, metoprololo High doses often needed

• Amitriptylline:o Unrelated to it’s antidepressant effect

• Sodium valproate:o Refractory migraines

Treatment of migraine:• Simple analgesics:

o E.g. paracetamol / aspirin / NSAIDso Give with metoclopramide:

! Anti-emetic and $ gastric emptying (thus $ absorption of the analgesic)

o Must be given early in an attack• 5-HT1D agonists:

o E.g. sumatriptano Can be given oral / sc / intranasallyo Is a (relatively) selective vasoconstrictoro ~70% efficacy:

! Best if taken at onset to abort the migraineo Adverse effects:

! Dizziness! Flushing

o Avoid:! In patients with IHD or uncontrolled hypertension:

• Can cause angina-like pain (discontinue)! With SSRIs and MAOIs

• Ergotamine:o Rarely used now





o Primarily a vasoconstrictoro Adverse effects:

! Nausea / vomiting! Peripheral /coronary vasoconstriction





Multiple sclerosis

Drug treatment of an acute relapse of MS:• IV methylprednisolone:

o High doseo Short course (3–5 days)o Does not alter the long-term prognosis

• No other approaches have shown any benefit

Prevention of relapse in MS:• Interferon-"1 (IFN-"1a and IFN-"1b):

o Given SC / IMo Trials have shown a 30%# in relapses (only in relapsing /

remitting disease)o Probably does not alter the natural historyo Expensive:

! ~£10,000/person/yearo Adverse effects:

! ‘Flu-like symptoms! Depression

• Glatiramer:o May prevent relapsing as for IFN-" but does not alter the long-

term prognosis

Symptomatic treatment of MS:• Spasticity / painful spasms:

o Baclofen:! Inhibits nerve transmission at the spinal level! Adverse effects:

• Sedation• Hypotonia• Urinary disturbance

! Serious side effects can occur on abrupt withdrawal:• Convulsions• Hyperthermia• Psychiatric reactions

o Dantrolene:! Inhibits muscle contraction:

• Prevents Ca2+ release from sarcoplasmic reticulum! Adverse effects:

• Aggravates weakness• Hepatotoxic

• Detrusor instability:o Anticholinergics (e.g. oxybutynin, TCAs)

• Paroxysmal pain:o Anticonvulsants / TCAs





Parkinson’s disease

Features of Parkinson’s disease:• Bradykinesia• Rigidity (“lead-pipe”)• Tremor (4–7 Hz, “pill-rolling”)• Festinant gait• Loss of arm swinging• Monotonous speech• Loss of facial expression• Micrographia

Drug treatment of Parkinson’s disease (PD):• Treatment should not be started before it is necessary because of

delayed unwanted effects• Levodopa (L-dopa):

o First-line therapy• Direct dopamine agonists:

o E.g. apomorphine, bromocriptine, lisuride, pergolideo Used as an alternative or adjunct to L-dopa

• Amantadine:o Useful in mild / moderate PDo May have a use in late disease with marked dyskinesia

• Anticholinergics:o E.g. benzhexolo Most useful in mild PD with tremor in younger patientso Also good for controlling dribbling

• Monoamine oxidase B inhibitors (MAO-BIs):o E.g. selegilineo Used as an adjunct to L-dopa to allow a # in dose:

! Can also # dose-related response fluctuations• Catechol – O – methyl transferase (COMT) inhibitors:

o E.g. entacaponeo May be useful in # end-of-dose fluctuations with L-dopa

Levodopa:• An example of a prodrug• Must be combined with a peripheral dopa-decarboxylase inhibitor:

o E.g. carbidopa, benserazideo Prevents L-dopa metabolism in the peripheryo Do not cross the blood-brain barrier (BBB)o Thus # dose (by about 10 fold)o # adverse effects

• Pharmacokinetics:o t! of 2 hourso There is a large individual variation in kinetics, thus slow

titration is essential• Mechanism of action:





o Is a pro-drug of dopamineo (Dopamine is not used as it cannot cross the BBB)o L-dopa crosses the BBB and is rapidly converted to dopamine

by dopa-decarboxylase in the braino This dopamine replaces the deficiency in the basal ganglia

• With L-dopa, ~80% show improvement in rigidity and hypokinesia and ~20% are restored to near-normal function (for a period)

• Adverse effects:o Short-term:

! Nausea / vomiting:• Treat with domperidone (dopamine antagonist)

! GI disturbances! Postural hypotension! Cardiac dysrhythmias! Haemolytic anaemia (rarely)

o Long-term:! Neuropsychiatric syndromes:

• Delirium• Hallucinations (patient maintains insight)• Psychosis• Treatment:

o Dose #o Atypical neuroleptics (e.g. clozapine)

! Response fluctuations:• Akinesia:

o End-of-dose• Dyskinesia:

o Peak doseo Onset / end-of-dose

• Unpredictable on-off responses (“yo-yo”-ing)• Treatment:

o Careful regulation of plasma L-dopa levelso Use modified-release preparationso Try:

! COMT inhibitor! MAO-BI! Dopamine agonist

! Loss of response:• Usually within 2–5 years• ~50% are back to pre-treatment status after 5 yrs• Treatment:

o Try dopamine agonist• Contraindications:

o Closed angle glaucoma

• Interactions:o Non-selective MAOIs:





! Risk of hyperthermia syndrome with concomitant use! Withdraw MAOIs 2 weeks before starting L-dopa

o Anti-hypertensives:! Enhanced hypotensive effect

o Neuroleptics:! Neuroleptics antagonise the action of L-dopa (and vice-

versa)

Apomorphine:• PD indications:

o Advanced disease with “on-off” periods with L-dopa• Pharmacokinetics:

o Must be given parenterally (SC)• Mechanism of action:

o Very potent dopamine D1 and D2 agonist• Adverse effects:

o Profound nausea / vomitingo As for L-dopa

• Contraindications:o Respiratory / CNS depressiono Neuropsychiatric problems / dementia

Dopamine agonists:• Older compounds (ergot derivatives):

o Bromocriptine, cabergoline, lisuride, pergolide• Recent compounds (synthetic):

o Pramipexole, ropiniroleo Side-effects are less than the older agents

• Indications:o Can be used as an alternative to L-dopa but are usually used as

adjuncts• Pharmacology:

o Duration of action:! Pergolide = cabergoline > bromocriptine > lisuride

o Potency:! Pergolide = lisuride > cabergoline > bromocriptine

• Are less effective than L-dopa but are associated with fewer late unwanted dyskinetic effects

• Adverse effects:o Nausea / vomitingo Hypotension

Amantadine:• Mechanism of action:

o Unknown





o May cause release of dopamineo May be a weak anticholinergic

• Is less effective than L-dopa or even bromocriptine but it’s use may be revived for late onset dyskinesia

• Adverse effects:o Dizzinesso Insomniao Livedo reticulariso Peripheral oedema

Anticholinergics:• E.g. benzhexol, procyclidine• Until L-dopa was discovered, anti-muscarinic agents were the only

available treatment for PD• Mechanism of action:

o As the nigrostriatal neurones progressively degenerate in PD, the release of (inhibitory) dopamine # and the excitatory cholinergic interneurones in the striatum become relatively overactive

o Blocking these mACh receptors “resets” this balanceo Only really reduce the tremor of PD (little effect on rigidity

and Bradykinesia)• Use is declining rapidly (especially in the elderly) largely due to

their unwanted effects on memory• Adverse effects:

o CNS:! Confusion! Hallucinations! Memory impairment

o Other:! Blurred vision! Dry mouth! Postural hypotension! Constipation

Monoamine oxidase B inhibitors (MAO-BIs):• E.g. selegiline• Indications:

o May allow L-dopa dose #o # end-of-dose deteriorations in advanced PDo Can be used alone to delay need for L-dopa for a few months

• Adverse effects (reasonably well tolerated):o No “cheese reaction” (does not affect MAO-A)o Potentiates L-dopa related symptomso Insomnia

Catechol-O-methyl transferase (COMT) inhibitors:• E.g. entacapone• Mechanism of action:

o Prolongs the action of a single dose of L-dopa





o Has no anti-PD activity when used alone but # the “off” time in late disease when used with L-dopa

• Adverse effects:o GI disturbanceso Dyskinesiaso Urine may be coloured reddish-brown





Drug-induced movement disorders

The most commonly implicated drugs in this section are the antipsychotics (but also more common drugs such as metoclopramide)

To be covered:• Acute dystonias• Akathisia• Parkinsonism• Tardive dyskinesia• Neuroleptic malignant syndrome

Acute dystonias:• Dystonia is a syndrome of sustained muscle contractions that produce

twisting and repetitive movements or abnormal postures• Presentation:

o Most common in young maleso Occurs within hours / days of starting the implicated drugo Usually oculogyric:

! Spasm of the extra-ocular muscles, forcing the eyes into upward or lateral gaze

• Treatment:o IV anticholinergics (e.g. procyclidine)o ? continue oral anticholinergics for ~48 hours

Akathisia:• This is a restless, repetitive and irresistible need to move• Can culminate in suicide• Occurs within days or months of starting the implicated drug• Equal sex incidence• May persist even after drug is stopped• Treatment:

o Often ineffectiveo May respond to:

! Amantadine! Anticholinergics! "-blockers

Parkinsonism:• Bradykinesia and rigidity but little tremor





• Affects up to 20% of patients on antipsychotics• Presentation:

o Usually in first few months of starting the drugo More common in the elderly

• Treatment:o Withdraw / # dose of drug if possibleo Anticholinergics / Amantadine may be effective:

! Do not use L-dopao May persist even after drug is stopped

Tardive dyskinesia (TD):• Are involuntary movements of the tongue, lips, face, trunk and

extremities• Presentation:

o Occurs after many months / years of using the drugo Affects up to ~20% of patientso More common in women and the elderly

• Treatment:o Some neuroleptics are less likely to cause TD:

! Clozapine, risperidone, sulpirideo A change of neuroleptic may help

Malignant hyperthermia syndrome:• Is a rare idiosyncratic drug reaction that is unpredictable• Commonly implicated drugs:

o Antipsychoticso Suxamethonium

• Presentation:o Often a young maleo Extreme rigidityo Hyperthermiao Fluctuating conscious level

• There is a very high mortality if the syndrome goes unrecognised• Treatment:

o Stop the causative drugo Dantrolene:

! Stops Ca2+ release in muscle! Thus stopping the excessive muscle contractions





Myasthenia gravis

The Tensilon (edrophonium) test:• Give edrophonium IV as a bolus dose• Positive test:

o Improvement of weakness occurs within seconds and the response lasts for 2–3 minutes

• To be certain, the test should be preceded by a bolus of saline to act as a control

Drug treatment of myasthenia gravis (MG):• Oral anticholinesterases:

o Provide symptomatic improvement (complete relief is rare)• Corticosteroids:

o Lead to a rapid improvement in most patientso Can produce total remissiono High doses are usually needed (60mg on alternate days)

• Immunosuppressants:o E.g. azathioprine, cyclophosphamide, cyclosporino Lead to an improvement in most patientso Are steroid-sparing agentso More effective in older patients

• Thymectomy:o Improves prognosis (especially in women <40 years with

positive AChR antibodies and a history of <10 years)o Must always remove a thymoma if presento Complete remission is rare

• Plasmapheresis:o Useful during exacerbationso Effects may last up to 3 months

Anticholinesterases:• E.g. neostigmine, pyridostigmine• Indications:

o Myasthenia gravis (oral)o Reversal of non-depolarising muscle relaxants (IV)

• Mechanism of action:o Inhibit acetylcholinesterase, thus $ the concentration of ACh

in the synaptic clefto Myasthenia gravis:

! The $ concentration of ACh has an $ probability of binding to a receptor at the neuromuscular junction

o Reversal of muscle relaxants:! The $ concentration of ACh overcomes the competitive

blockade of the muscle relaxant

• Adverse effects:o Abdominal cramps





o Bradycardiao Hypersalivationo Nausea / vomitingo Sweating

• Interactions:o Aminoglycosides:

! # the action of anticholinesterases





Diuretics

Loop diuretics:• E.g. furosemide• Indications:

o Acute pulmonary oedemao Chronic heart failureo Oliguria secondary to acute renal failure

• Mechanism of action:o Inhibit NaCl reabsorption in the thick segment of the

ascending loop of Henle:! Inhibit the Na+/K+/2Cl- pump

o This section has a high capacity for absorbing NaCl and so loop diuretics produce the most profound diuresis

o The $ Na+ that reaches the distal tubule also leads to an osmotic effect, drawing yet more water into the lumen

o Also possess venodilator properties that are independent of their diuretic effect

• Adverse effects:o Hypokalaemiao Hypocalcaemiao Hypomagnesaemiao Hyperuricaemia (can cause gout)o Deafness (high doses – effects on the endolymph)o Postural hypotension

• Contraindications:o Renal failure with anuria

• Interactions:o Aminoglycosides:

! $ risk of ototoxicity and nephrotoxicityo Digoxin:

! Hypokalaemia caused by furosemide $ risk of digoxin toxicity

o Lithium:! # excretion of lithium - $ plasma levels

Thiazide diuretics:• E.g. bendrofluazide, metolazone• Indications:

o Hypertensiono Heart failure

• Mechanism of action:o Moderately powerful diuretics (metolazone > bendrofluazide)o # reabsorption of Na+ in the distal tubuleo The $ Na+ load in the distal tubule stimulates Na+ exchange

with K+ and H+ ions thus $ their excretion and tending towards hypokalaemia and a metabolic alkalosis






o Hypokalaemiao Hyponatraemiao Hyperglycaemiao Hypercalcaemiao Hyperlipidaemiao Hyperuricaemiao Postural hypotensiono Impotence

• Contraindications:o Severe hepatic / renal impairmento Gout

• Interactions:o Digoxin:

! Hypokalaemia caused by thiazides $ risk of digoxin toxicity


Spironolactone (a potassium-sparing diuretic):• Indications:

o Chronic heart failure (shown to # mortality)o Refractory hypertension (BHS step 4)o Ascites / oedema caused by cirrhosiso Conn’s syndrome (primary hyperaldosteronism)o Potassium conservation with thiazide and loop diuretics

• Mechanism of action:o Is a competitive aldosterone antagonisto Aldosterone causes Na+ reabsorption and K+ excretion in the

distal tubuleo Inhibition of this action leads to a mild diuresis and retention of

K+

o It is a weak diuretic because only 2% of the total Na+ reabsorption is under aldosterone control

• Adverse effects:o Hyperkalaemiao Gynaecomastiao Impotence

• Contraindications:o Hyperkalaemiao Addison’s disease

• Interactions:o $ risk of hyperkalaemia:

! ACE inhibitors / AII receptor antagonists! NSAIDs


o Potassium salts ($ risk of hyperkalaemia)

Other potassium-sparing diuretics:





• E.g. amiloride, triamterene• Indications:

o Potassium conservation with thiazide and loop diuretics• Mechanism of action:

o Block Na+ channels in the distal tubuleo $ Na+ excretion (thus causing a diuresis) and # K+ excretion

• Adverse effects:o Hyperkalaemia

• Contraindications:o Renal impairment

• Interactions:o $ risk of hyperkalaemia:

! ACE inhibitors / AII receptor antagonists! NSAIDs


o Potassium salts ($ risk of hyperkalaemia)

Osmotic diuretics:• E.g. mannitol• Indications:

o Cerebral oedema• Mechanism of action:

o Mannitol is a compound that is filtered by the kidneys but is not reabsorbed

o Is given in amount such that it significantly contributes to plasma osmolarity

o The $ plasma osmolarity (by compounds which cannot cross the blood-brain barrier) leads to extraction of water from the brain

• Adverse effects:o Chillso Fever

• Contraindications:o Congestive cardiac failureo Pulmonary oedema





Muscle relaxants

Types of muscle relaxants:• Depolarizing:

o Suxamethonium• Non-depolarizing (competitive):

o Can be reversed with an antichol inesterase (unlike suxamethonium)

o Pancuronium:! Long-duration of action! Atropine-like effects

o Vecuronium:! No cardiovascular effects! Short duration of action

o Atracurium:! Decomposes spontaneously in plasma:! Does not depend on liver / kidneys for excretion

o Rocuronium:! Rapid onset (almost as fast as Suxamethonium)

Suxamethonium:• Pharmacokinetics:

o Is 2 ACh molecules linked by their acetyl groupso Rapid onset (1–1.5 minutes) o Very short duration of action (3–7 minutes):

! Metabolised by plasma pseudocholinesterase• Mechanism of action:

o Suxamethonium diffuses slowly to the motor endplate and persist for long enough to cause loss of electrical excitability

o Before paralysis occurs, the muscle fibres are activated causing twitching (fasciculation)

• Adverse effects:o Muscle aches (caused by the fasciculation)o Prolonged block:

! ~1 in 2000 people have a deficiency of plasma pseudocholinesterase and paralysis may last several hours

o Bradycardiao K+ release (from muscle)o Malignant hyperthermia:

! Very high mortality (~65%)! Treated with dantrolene

• Contraindications:o Family history of malignant hyperthermiao Hyperkalaemia

• Interactions:o Drugs $ action of Suxamethonium (many):





! Aminoglycosides! Metoclopramide! Verapamil

Non-depolarizing muscle relaxants:• E.g. pancuronium, vecuronium, atracurium, rocuronium• Mechanism of action:

o Do not cross the BBB or the placentao Block the nicotinic ACh receptor at the motor endplate,

thus inhibiting muscle contraction• Adverse effects:

o These vary between the various drugs (see above)o Hypotensiono Anaphylactoid reactions





Anti-emetics

Causes of nausea and vomiting:• Drugs:

o Antibiotics (e.g. erythromycin)o Cytotoxic agentso Digoxino Opioids

• Vestibular disease (e.g. labyrinthitis)• Provocative movement (e.g. seasickness)• Migraine• Abdominal disease• Pregnancy

Physiology of nausea:• Emesis is coordinated by the vomiting centre (medulla oblongata)• An important input to the vomiting centre is the chemoreceptor

trigger zone (CTZ) in the area postrema:o The CTZ is not protected by the BBB, therefore circulating

toxins/drugs can stimulate ito Possesses the following receptors:

! Dopamine (D2)! Serotonin (5HT3)

• The vomiting centre also receives cholinergic (muscarinic) and histamine input

• Thus the following drug classes are helpful anti-emetics:o D2 receptor antagonistso 5-HT3 receptor antagonistso Anti-muscarinic agentso Antihistamines (H1)

• Dexamethasone is a useful anti-emetic following cancer chemotherapy

• Vomiting is easier to prevent than it is to stop

D2 receptor antagonist anti-emetics:• E.g. metoclopramide, domperidone• Indications:

o Nausea and vomiting due to:! Abdominal disease! Drugs (especially opioids)! Migraine! Post-operative nausea / vomiting

• Mechanism of action:o Blocks D2 receptors in the CTZo Prokinetic actions on the gut ($ absorption of many drugs):

! Can be an advantage (e.g. analgesics in migraine with vomiting)






o Acute dystonia (especially if age <20 years and female)o Hyperprolactinaemia

• Domperidone does not readily cross the BBB and is much less likely to cause central reactions (e.g. dystonic reactions)

• Contraindications:o GI obstruction / perforation / haemorrhage o Recent (3–4 days) GI surgery

• Interactions:o NSAIDs:

! $ absorption of NSAIDs $ their beneficial (and toxic) effects

5-HT3 antagonist anti-emetics:• E.g. ondansetron, granisetron• Indications:

o Nausea and vomiting due to:! Cytotoxic agents! Radiotherapy! Post-operative nausea / vomiting

• Adverse effects:o Headacheo Constipation

Anti-muscarinic anti-emetics:• E.g. hyoscine• Indications:

o Prophylaxis against motion sickness• Adverse effects:

o Blurred visiono Dry moutho Drowsiness

• Contraindications:o Prostatic enlargemento Glaucomao Myasthenia graviso Paralytic ileus

• Interactions:o Alcohol:

! Sedative effects of hyoscine are enhanced by alcohol

Antihistamine anti-emetics:• E.g. cinnarizine, cyclizine• Indications:

o Nausea and vomiting due to:





! Vestibular disease! Drugs

• Adverse effects:o Drowsinesso Anti-muscarinic effects, e.g.:

! Blurred vision! Dry mouth

• Contraindications:o Prostatic enlargemento Glaucomao Urinary retention





The eye

Maintenance of intraocular pressure (IOP):• The IOP is determined by aqueous humour volume• Production:

o Aqueous humour is produced by the highly vascularised processes of the ciliary body

o The ciliary epithelial cells (which contain ATPase and carbonic anhydrase) absorb Na+ from the stroma and transport it to the intercellular clefts (which open on the aqueous humour side)

o The hyperosmolality in the clefts leads to water flow from the stroma, producing a continuous flow of aqueous

o The ciliary epithelium is also leaky and ~30% of aqueous is formed by ultrafiltration

• Drainage:o Pupil " trabecular meshwork " canal of Schlemm " episcleral

veins

Treatment of acute narrow-angle glaucoma:• This must be treated quickly to prevent permanent retinal damage• # aqueous production:

o Acetazolamide IV stat• $ aqueous outflow:

o Pilocarpine eye drops statso Mannitol IV stat:

! To draw water out of the eye• Prevent recurrence:

o Surgery (Peripheral iridotomy)

Drug treatment of chronic open-angle glaucoma:• All of the following treatments are given topically (eye drops)• # aqueous production:

o "-blockerso !-agonistso Carbonic anhydrase inhibitors

• $ aqueous outflow:o Muscarinic agonists

Age-related macular degeneration (AMD):• Most common cause of blindness in the UK• New blood vessels form under the retina and leakage of fluid and blood

from the vascular complexes causes severe loss of vision within a few years

• Treatment (relatively new):o Verteporfin (photodynamic therapy):





! Is a light-sensitive dye that is given IV and is taken up by vascular endothelium

! A laser is then applied to the eye and this activates the dye, which releases free radicals that destroy the new vessels

Mydriatic drugs:• Muscarinic antagonists:

o Also cause cycloplegia (paralysis of the ciliary muscle)o Tropicamideo Cyclopentolate

• !-agonists:o Do not affect the pupillary light reflex or accommodationo Phenylephrine

"-blockers and glaucoma:• E.g. timolol• Drugs of choice in chronic open-angle glaucoma• Mechanism of action:

o Block "2 receptors on the ciliary processes and # aqueous secretion

o May also block "-receptors on afferent blood vessels to the ciliary processes (this vasoconstriction # ultrafiltration)

• Adverse effects (may be absorbed systemically):o Bradycardiao Bronchospasm

• Contraindications:o Asthmao Heart blocko Heart failure

!-agonists in glaucoma:• E.g. adrenaline, phenylephrine• # IOP by vasoconstriction of the ciliary body afferent blood vessels• Interestingly, !-antagonists and "-agonists also # IOP:

o $ aqueous outflow rather than #productiono Dilatation of the aqueous / episcleral veins

Carbonic anhydrase inhibitors:• E.g. Acetazolamide (IV / IM / oral), dorzolamide (topical)• Inhibition of carbonic anhydrase prevents HCO3- formation• Since HCO3- and Na+ transport are linked, this leads to a # in aqueous

formation• Dorzolamide can be used alone in those in whom "-blockers are

contraindicated• Dorzolamide is a sulphonamide and systemic side effects can occur:

o Rasheso Bronchospasm





Muscarinic agonists:• E.g. pilocarpine• # IOP by contracting the ciliary muscle• This pulls the scleral spur and results in the trabecular meshwork

being stretched and separated• The fluid pathways are opened up and aqueous outflow is increased• Adverse effects:

o Miosis:! Causes near-sightedness (blurred distance vision)! Brow ache! Headache! Poor night vision





Antipsychotics (neuroleptics)

The dopamine hypothesis of psychosis:• Psychotic symptoms result from $ dopamine neurotransmission• Dopamine receptors:

o D1-like:! D1 and D5! Are post-synaptic! Stimulate adenylate cyclase and $ cAMP

o D2-like:! D2, D3 and D4! Are both pre- and post-synaptic! Inhibit adenylate cyclase and # cAMP

• Dopaminergic pathways:o Mesolimbic / mesocortical:

! Concerned with mood and emotional stability! Ventral tegmental area:

• Ventral striatum and the frontal cortexo Nigrostriatal:

! Concerned with movement! Substantia nigra and the dorsal striatum

• Neuroleptics block D2 receptors:o Explains why they cause movement disorders as a side effect

Clinical classification of neuroleptics:• Typical:

o Produce extrapyramidal symptoms (EPS)• Atypical:

o So-called because they have a low incidence of EPSo However, all apart from clozapine can cause EPS at high doses

Chemical classification of neuroleptics:• Typical:

o Phenothiazines:! Propylamines (chlorpromazine):

• Sedation ++• Anticholinergic ++• EPS ++

! Piperidines (thioridazine):• Sedation ++• Anticholinergic ++• EPS +• Can cause torsade de pointes

! Piperazines (fluphenazine):• Sedation +• Anticholinergic +• EPS +++

o Thioxanthines (flupenthixole):! Sedation +





! Anticholinergic +! EPS ++

o Butyrophenones (haloperidol):! Sedation -! Anticholinergic -! EPS +++

• Atypical:o “True”:

! Clozapine:• Sedation ++• Anticholinergic +• EPS -

o “Apparent”:! Sulpiride:

• Sedation +• Anticholinergic –• EPS +

! Risperidone:• Sedation ++• Anticholinergic +• EPS +

General effects of the neuroleptics:• Early (hours):

o Desired:! Sedation (histamine / !-receptor blockade)! Tranquilisation (dopamine blockade)

o Unwanted:! Acute dystonic reactions

• Medium (days–weeks):o Desired:

! Suppression of:• Delusions• Disordered thinking• Hallucinations

o Unwanted:! Akathisia! Parkinsonism

• Late (months–years):o Desired:

! Prevention of relapseo Unwanted:

! Tardive dyskinesia• Any time:

o Neuroleptic malignant syndromeChlorpromazine:

• Indications:o Psychotic disorders (e.g. schizophrenia / mania)o Labyrinthine disorders / vertigo





o Nausea / vomitingo Chronic hiccups


! Sedation! Anticholinergic effects:

• Blurred vision• Dry mouth• Postural hypotension• Constipation• Urinary retention

! Extrapyramidal effects:• Acute dystonia• Akathisia• Parkinsonism• Tardive dyskinesia

! Hyperprolactinaemia:• Amenorrhoea• Galactorrhoea• Impotence

o Uncommon:! Neuroleptic malignant syndrome! Agranulocytosis! Cholestatic jaundice

• Interactions:o ACE inhibitors:

! Can cause severe hypotension

Haloperidol:• Indications:

o Psychosiso Motor tics


! Extrapyramidal effects:• Acute dystonia• Akathisia• Parkinsonism

! Postural hypotensiono Uncommon:

! Convulsions! Neuroleptic malignant syndrome! Tardive dyskinesia! Weight loss

• Interactions:o Amiodarone:

! $ risk of ventricular arrhythmiaso Carbamazepine:

! # plasma levels of haloperidol (metabolism accelerated)





o Fluoxetine:! $ plasma levels of haloperidol

Clozapine:• Regarded by many as the only “true” atypical neuroleptic:

o EPS is not evident even at high doseso Effective in patients refractory to other neurolepticso Can treat the negative symptoms of schizophrenia

• Mechanism of action:o Blocks D4 and 5-HT2 receptorso Weak blockade of striatal D2 receptors

• Adverse effects:o Agranulocytosis (requires regular blood monitoring)o Myocarditis / cardiomyopathyo Ileus

• Contraindications:o Severe cardiac disorderso History of neutropenia / agranulocytosis

• Interactions:o Avoid concomitant use with drugs that have a high risk of

causing agranulocytosis (e.g. carbimazole)





Drugs in the elderly, young or pregnant

Pharmacokinetics in the elderly:• Distribution:

o # body water:! Thus water soluble drugs have a # volume of distribution

(Vd)! Thus $ [water soluble drugs]

o $ body fat:! Lipid soluble drugs have an $ Vd! Thus # [fat soluble drugs]

o # plasma albumin:! # drug protein binding! Thus $ levels of drugs that usually bind to protein

o # weight (no longer a 70kg man!):! Thus standard dose will lead to $ [drug]

• Metabolism:o # oxidationo # first-pass metabolismo # induction of liver enzymeso Warfarin is more effective

• Excretion:o # GFRo # tubular secretion

Altered end-organ sensitivity in the elderly:• Autonomic nervous system:

o Defective compensatory mechanisms:! E.g. antihypertensives " postural hypotension

o "-receptors (# density)• Brain:

o $ sensitivity to anxiolytics and hypnotics (may lead to confusion)• Heart (failing):

o # perfusion of liver / kidneys " # function of these organs

Two groups of drugs in the elderly cause 2/3 of all adverse drug reactions:• Drugs acting on the:• Brain:

o Antidepressantso Anti-Parkinson’s drugso Hypnotics

• Circulation:o Antihypertensiveso Digoxino Diuretics

Compliance issues in the elderly:• Living alone / unsupervised





• Confusion because of change in tablet shape / colour• Impaired vision• Arthritic hands

Pharmacokinetics in neonates:• Absorption:

o # gastric motilityo Variable peripheral perfusion (care with IM injections)

• Distribution:o Blood brain barrier is immatureo $ body water:

! Thus # [water soluble drugs]o # body fat:

! Thus $ [fat soluble drugs]o Protein binding low (adult levels at 1 year of age)

• Metabolism:o # P450 activityo # conjugation:

! E.g. chloramphenicol " grey baby syndrome• Excretion:

o # GFR:! The neonate has 30% of adult GFR and 20% of adult

tubular secretion! This $ to 50% at 1 week of age! $ to 100% at 6 months of age

Drugs with adverse effects on foetal development:• ACE inhibitors• Alcohol• Androgens• Anticonvulsants• Folate antagonists (e.g. methotrexate)• Tetracyclines• Thalidomide• Warfarin

Drugs to avoid in later pregnancy:• Aspirin:

o Haemorrhageo Kernicterus

• Aminoglycosides:o CN VIII damage

• Anti-thyroid drugs (e.g. carbimazole):o Goitreo Hypothyroidism

• Benzodiazepines:o “Floppy baby” syndrome

• Chloramphenicol:o Grey baby syndrome





• Warfarin:o Haemorrhage

• Sulphonylureas:o Kernicterus





Cytotoxic chemotherapy

Classification of anti-cancer drugs:• Alkylating agents:

o Cyclophosphamideo Chlorambucilo Cisplatino Dacarbazineo Ifosfamideo Mitomycin C

• Anti-metabolites:o Folate antagonists:

! Methotrexateo Pyrimidine analogues:

! 5-Fluorouracil (5-FU)! Cytarabine (cytosine arabinoside)! Gemcitabine

o Purine analogues:! Azathioprine

• Cytotoxic antibiotics:o Anthracyclines:

! Doxorubicin (adriamycin)o Bleomycin

• Plant derivatives:o Taxanes:

! Paclitaxelo Vinca alkaloids:

! Vincristine! Vinblastine

• Epipodophyllotoxins:o Etoposide

• Hormonal:o Antagonists:

! Anti-androgens:• Cyproterone

! Anti-oestrogens:• Tamoxifen

o Corticosteroidso GnRH analogues:

! Goserelino Somatostatin analogues:

! Octreotide• Miscellaneous compounds:

o Hydroxyurea

Some example chemotherapy regimens:• BEP:

o Bleomycin





o Etoposideo Cisplatinumo Testicular teratoma

• CHOP:o Cyclophosphamideo Hydroxydaunomycin (doxorubicin) o Oncovin (vincristine)o Prednisoloneo Radical treatment of non-Hodgkin’s lymphoma (NHL)

• ABVD:o Adriamycin (doxorubicin)o Bleomycino Vinblastineo Dacarbazineo Hodgkin’s lymphoma

• FEC:o 5-Fluorouracilo Etoposideo Cyclophosphamideo Breast cancer

General adverse effects of cytotoxic agents:• Nausea / vomiting• Alopecia• Oral / intestinal ulceration• Diarrhoea• Bone marrow suppression:

o Anaemiao Leucopeniao Thrombocytopenia

• Teratogenicity• Carcinogenesis

Emesis-risk:• High risk:

o Treat with granisetron + dexamethasone + domperidone)o Cisplatinum (high dose)o Etoposide (high dose)o Dacarbazineo Ifosfamide

• Moderate risk:o Cisplatinum (low dose)o Cyclophosphamideo Doxorubicino Methotrexate (high dose)

• Low risk:o Treat with domperidone ± dexamethasoneo Bleomycino Methotrexate (low dose)



patient’s biggest concern

physician’s biggest concern



o Mitomycino Vincristine

Prevention of nausea / vomiting:• Acute:

o 5-HT3 antagonist (e.g. granisetron) +o Dexamethasone

• Delayed:o Domperidone / metoclopramideo Dexamethasone

Alkylating agents:• E.g. cyclophosphamide, chlorambucil, cisplatin, dacarbazine,

ifosfamide, mitomycin• Mechanism of action:

o Readily form covalent bonds with the bases in DNAo Prevent cell division by cross-linking the two strands of the

double helixo Their main action occurs during replication (i.e. during S phase

with a block at G2)o Results in apoptotic cell death

• Cyclophosphamide:o Indications:

! Malignancy! Autoimmune disease (e.g. SLE, rheumatoid arthritis)! Nephritic syndrome! Vasculitis

o Adverse effects (in addition to the general ones above):! Haemorrhagic cystitis:

• Due to the metabolite acrolein• Can be ameliorated by:

o $ fluid intakeo Mesna (a sulphydryl donor)

! Infertility in men:• Long-term use• May be irreversible

• Cisplatin:o A platinum containing alkylating agento Revolutionised the treatment of tumours of the testes / ovaryo Adverse effects:

! Nephrotoxicity! Very severe nausea / vomiting! Peripheral neuropathy! Ototoxicity! Anaphylactoid reactions

Pyrimidine analogues:• E.g. 5-FU, cytarabine, gemcitabine• 5-FU:





o Mechanism of action:! Interferes with thymidylate synthetase (essential for

the production of thymidylic acid)! Impairs DNA synthesis (but not RNA or protein

synthesis)• Cytarabine:

o Mechanism of action:! Incorporated into DNA and RNA! Inhibits DNA replication and (to a lesser extent) DNA

repair• Gemcitabine:

o An analogue of cytarabineo Has fewer unwanted effects:

! ‘Flu-like symptoms! Mild myelotoxicity

Purine analogues:• E.g. 6-mercaptopurine (6-MP), azathioprine (a pro-drug of 6-MP)• Indications:

o Autoimmune diseases (e.g. rheumatoid arthritis, SLE)o Prevention of transplant rejectiono Steroid-sparing agent

• Mechanism of action:o 6-MP is converted to a “fraudulent” nucleotideo Is incorporated into and interferes with replicating DNAo Also impairs the de novo pathway of purine synthesis

• Adverse effects:o Nausea / vomitingo Bone marrow suppressiono Alopeciao Jaundice

• Interactions:o Allopurinol:

! Allopurinol inhibits the metabolism of azathioprine, thus $ it’s toxicity

Cytotoxic antibiotics:• E.g. doxorubicin• Mechanism of action:

o Inserts itself between base pairs (intercalation):! Alters the topography of DNA! Causes unwinding of DNA

o Causes topoisomerase II-associated DNA strand breakso Causes free-radical formation:

! Responsible for cardiac toxicity (as the heart cannot inactivate them due to a lack of catalase activity)

• Adverse effects:o Cardiac toxicity:

! Acute Myocarditis / pericarditis





! Late onset cardiac failure:• 5% of patients after high dose therapy

Taxanes:• E.g. paclitaxel (taxol)• Derived from Yew tree bark• Mechanism of action:

o Stabilise cell microtubules (in effect “freezing” them)o Prevents spindle formation in mitotic cells and causing cell cycle

arrest in metaphase• Adverse effects:

o Bone marrow suppressiono Hypersensitivity:

! Must pre-treat the patient with:• Antihistamines• Corticosteroids

o Neurotoxicity

Vinca alkaloids:• E.g. vincristine, vinblastine• Extracts of the periwinkle plant• Mechanism of action:

o Bind to tubulin and inhibit it’s polymerisation into microtubules

o This prevents spindle formationo Leads to cell cycle arrest in metaphase

• Adverse effects:o Relatively non-toxico Neurotoxicity:

! Paraesthesia! Neuromuscular abnormalities

o Fatal if given intrathecally

Hydroxyurea:• Indications:

o Malignancyo Sickle cell anaemia ($ production of fetal Hb)

• Mechanism of action:o A urea analogueo Inhibits ribonucleotide reductaseo Interferes with the conversion of ribonucleotides to

deoxyribonucleotides

Anti-malarialsMain signs / symptoms of malaria:

• ‘Flu-like symptoms:o Headacheo Malaiseo Myalgia





• Fever ± chills• Anaemia• Jaundice• Hepatosplenomegaly• No lymphadenopathy / rash

Poor prognostic signs:• Young (< 3 years)• Pregnant• Hyperparisitaemia (> 5% of RBCs)• CNS:

o Fitso Coma

• Renal:o Blackwater fever (haemoglobinuria)o Oliguriao Acure renal failure

• Hypoglycaemia (< 2.2 mmol/L)• Acidosis ($ [lactate])

Treatment of malaria:• If species unknown or mixed infection then treat as for falciparum• P. Falciparum:

o Quinine ando Tetracycline or doxycycline or clindamycino Alternatives:

! Malarone or! Fansidar

• Non-falciparum:o Chloroquine ±o Primaquine (if P.ovale / P.vivax):

! Improves liver clearance of the parasite

Prophylaxis against malaria:• Avoid getting bitten if possible• High risk of P.falciparum:

o Mefloquineo Malaroneo Doxycycline

• No / low risk of P.falciparum:o Chloroquine and proguanil

Quinine:• Adverse effects:

o Tinnituso Nausea

Chloroquine:• Adverse effects:

o Retinopathy





o Psychosis

Fansidar:• Adverse effects:

o Stevens-Johnson syndromeo Blood dyscrasiaso Deranged LFTs

Primaquine:• Adverse effects:

o Haemolytic anaemia (G6PD-deficiency)o Methaemoglobinaemia

Mefloquine:• Adverse effects:

o Severe psychiatric reactions:! More common in young women with a previous history of

psychiatric illness• Has a long t! (needs to be started 2–3 weeks before travelling)





Pharmacology

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