John DiepBimm118

Drug Names/Classes Used for:P

aras

ymp

ath

omim

etic

s

Indi

rect

AC

h R

Ago

nist

s

Rev

ersi

ble

Carbamates(Physostigmine)

Indicated for glaucoma. Antidote for atropine poisoning.

Quarternary Alcohol(edrophonium)

Diagnose Myasthenia Gravis

Horny Goat Weed Indicated for erectile dysfunctionIr

reve

rsib

le(O

rgan

o-P

hosp

hate

s) Insecticide (malathione)

Insects…

Nerve Gas(Sarin)

Lethal. Use atropine as antidote.

Dir

ect A

Ch

R A

goni

sts Carbachol Indicated for glaucoma

Bethanechol Indicated for urinary retention.

Pilocarpine Indicated for Glaucoma

Par

asym

pat

hol

ytic

s

mA

Ch

R B

lock

ers Atropine Causes pupil dilation, increases HR (indicated for

bradycardia), reduces bronchosecretion (for surgery)Antidote for organophosphate poisoning.

Scopolamine Indicated for motion sickness; antiemetic drug delivered transdermally

Pirenzipine Indicated for peptic ulcers; selectively blocks M1 Receptors, reduces gastric acid secretion

nAC

h R

Blo

cerk

s

Non

-D

epol

ariz

ing Tubocuraraine Poison; respiratory paralysis. Muscle relaxant.

Competitive antagonists

PancuroniumAtracurium

Muscle relaxants; competitive antagonists

Dep

ola

rizi

ng

Succinylcholine/Suxamethonium

Muscle relaxantsnACh R agonists, but has parasympatholytic effect

Cholinergic System

Direct Parasympathomimetics – drugs that mimic ACh and mostly binds mAChRIndirect Parasympathomimetics – drugs that inhibit ACh-Esterase; raises [ACh]Muscarinic Parasympatholytics – competitive antagonistsNicotinic Parasympatholytics – neuromuscular junction blockers; muscle relaxants

Non-Depolarizing – competitive antagonists; competes with ACh to prevent depolarizationDepolarizing – nACh R agonist; initially mimics ACh causing depolarization but it is not

hydrolyzed by ACh-Esterase so the depolarization is prolonged, inhibiting other signalsNicotine

Low Concentration – acts as a direct nAChR agonistHigh Concentration – has an antagonistic effect on nAChR due to channel inactivation; similar to

succinylcholine.nAChR = nicotinic acetylcholine receptor mAChR = muscarinic acetylcholine receptor

1

John DiepBimm118

Adrenergic SystemDrug Name/Class Used For:

Sym

pat

hom

imet

ics

Indi

rect

Ago

nist

s MAO Inhibitors (Tranylcypromine, Moclobemide)

Indicated for depression; inhibits metabolism of NE/E, DA, and 5HT; many side effects

Ephedrine Found in diet pills; displaces NE from storage vesicles

AmphetaminesRitalin ADDFenfluramine diet pills

Displaces NE from storage, inhibits reuptake, inhibits MAO

Dir

ect A

goni

sts

Non

-sel

ecti

ve

Epinephrine(Adrenaline) Indicated for anaphylactic shock and used as an adjuvant in local anesthetics. Dilates bronchii.

Norepinephrine (Noradrenaline)

Limited clinical use.

Sel

ecti

ve

α1 Agonists(vasoconstrictor)

Methoxamine – treats hypotensionPhenylephrine – nasal decongestantNaphazoline – nasal decongestant

α2 Agonists (sympatholytic!)ClonidineGuanfacine

Indicated for hypertension.Presynaptic α2 receptors are inhibitory, reduces sympathetic tone on cardiovascular system.

β1 Agonists Dobutamine

(+) inotropic & (+) chronotropic effect on heartUsed in Dobutamine Stress Test

β2 AgonistsAlbuterol

Indicated for asthma (inhaler). Dilates bronchii

Sym

pat

hol

ytic

s

α-re

cept

or a

ntag

onis

ts

Non-selective BlockersPhentolamine

Indicated for pheocromocytoma.Blocking α1 causes vasodilation; reducing BPBlocking α2 removes inhibition, increasing NE action on β receptors increasing HR and cardiac output

Selective α1 BlockerPrazosin, Terazosin, etc…

Indicated for hypertension and urinary retention.Side effects: Reflex tachycardia and postural hypotension.

Selective α2 Blocker (sympathomimetic!)Yohimibine

Increases sympathetic outpout. Used for male sexual dysfunction and as a weight loss drug.

β-re

cept

or a

ntag

onis

ts

Noncardioselective β blockersPropranolol

-1st gen. drug, cross reaction w/ β2 causes bronchoconstriction (side effect)-Labetalol also blocks α1 receptors (strong antihypertensive drug)-same indications as cardioselective blockers (below)

Cardioselective β blockersMetoprolol, Atenolol…

Newer drugs are more β1 selective.Indicated for angina pectoris, hypertension, cardiac dysrhythmias, myocardial infarction, heart failure, and stage fright (anxiolytic).

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John DiepBimm118

Antihypertensive Drugs

3

Drug/Class Mechanism

Sym

pat

het

ic N

ervo

us

Sys

tem

Su

pp

ress

ors

(sym

pat

hol

ytic

s)

α2 Receptor Agonists - Clonidine

Elicits α2 receptor’s inhibitory effect on the sympathetic nervous system. Less NE binding to α1 and β1 receptors.

α1 Receptor Antagonists Prazosin, Terazosin, etc…

Promotes peripheral vasodilation, reducing resistance, thereby reducing BP.

β-receptor antagonistsPropranolol, Metoprolol, Atenolol, etc

β1 receptor activation causes an increase in HR and contractility. Blocking this receptor will reduce the HR and contractility (reduces stroke volume) leading to a drop in blood pressure.

Dir

ect

Vas

odil

ator

s

Calcium channel blockers (Calcium antagonists)Dihydropyridines -Nifedipine, etc…

Targets L-Type channels (no cardiac effects), blocking Ca2+ entry into the smooth muscle cell arterial vasodilation; decreases afterload reducing BPSide effects: Reflex tachycardia, postural hypotension, and peripheral edema.

Potassium Channel AgonistsMinoxidil

Increases membrane permeability to K+, K+ efflux causes membrane hyperpolarization, inhibiting voltage gated Ca2+ channels relaxation of smooth muscles vasodilation reduces BPSide effect: hair growth, marketed as RogaineLast resort for unresponsive hypertension.

Nitroprusside Delivered thru iv only and is metabolized into NO which directly activates cGMP production vasodilationReview phosphodiesterase inhibitors (Caffeine & Viagra).

Ren

in-A

ngi

oten

sin

-Ald

oste

ron

e S

yste

m

Tar

geti

ng

Dru

gs

ACE-InhibitorsCaptoprilEnalaprilBenazeprilLisinopril

By inhibiting the ACE enzyme, angiotensin I cannot be converted into the active peptide (ATII)-no aldosterone & ADH release no fluid retention-no sympathomimetic effects-no vasoconstrictionSide effect – causes coughing

Angiotensin II (ATII) Receptor Blocker -Losartan -Candesartan -etc…

Inhibits the effect of AT II by blocking the receptor-usually used if patient cannot tolerate the cough caused by ACE inhibitors

John DiepBimm118

Other Cardiovascular DiseasesAngina Pectoris – chest pain due to coronary heart disease; a symptom of myocardial ischemia (when heart doesn’t get enough oxygen)Stable Angina Predictable episodes; usually during/after physical exertion or stress

Treatment: Nitrates & β-Blockers (Propranolol, etc.)Unstable Angina Chest pain unexpected and usually occurs at rest

Treatment: NitratesVariant Angina Chest pain almost always occurs at rest and does not follow physical

exertion or stress. Due to coronary artery spasm. Treatment: Calcium channel blockers (Nifedipine, etc…)

NitratesConverted to nitric oxide (NO) guanylate cyclase cGMP smooth muscle relaxation vasodilation

Nit

rate

s

Nitroglycerine Drug of choice for angina pectoris. Reduces cardiac workload (and its oxygen demand) by reducing venous return. Causes vasodilation primarily in veins. Many different forms of administration.Do NOT combine w/ other vasodilators (Viagra…).

Isosorbide-dinitrate(ISDN)

Longer lasting effect when compared to nitroglycerine.Tolerance may occur, give lowest dose.Do NOT combine w/ other vasodilators.

Nitroprusside Promotes peripheral vasodilation.IV only; rapid onset and short duration – allows for titration

Cardiac Arrhythmias – abnormal rhythms of the heart that cause it to pump less effectively; abnormality in pacemaker cells, conduction pathway, or if other parts of the heart take over pacemaker.Class I: Sodium Channel Blockers

Slows depolarization phase of AP.Procainamide – used for atrial & ventricular arrhythmiasLidocaine – used for acute ventricular arrhythmiasFlecainide – used for chronic treatment of ventricular arrhythmias

Class II: β-Blockers

Propranolol-used for tachycardia

Class III:Potassium Channel Blockers

Prolongs repolarization by blocking potassium efflux.Bretylium & Amiodarone-used for intractable ventricular arrhythmias

Class IV:Calcium Channel Blockers

Prolongs repolarization by blocking calcium influxVerapamil – blocks both L & T Type calcium channels!Blocking T Type channels slows conduction(Blocking L Type channels coronary + arterial vasodilation)

Others Adenosine – for paroxysmal supraventricular tachycardiaDigoxin – atrial fibrillationEpinephrine - bradycardia

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John DiepBimm118

Other Cardiovascular DiseasesCongestive Heart Failure – inadequate contractility; ventricles unable to expel blood rise in venous blood pressure. Caused by blocked coronary arteries, viral infections, hypertension, leaky heart vavles, myocardial infarctions… -Right sided failure – lower limb edema -Left sided failure – pulmonary edema & respiratory distressCardiac Glycosides(Digoxin)

Slows heart rate and increases contractility.Mechanism: Inhibits Na/K ATPase, leading to an increase intracellular Na+Increased Na+ slows Na/Ca exchanger, leading to an increase intracellular Ca++Low therapeutic index.Potassium competes with digoxin in binding to Na/K ATPase -antidote for cardiac glycoside poisoning -increased potassium will reduce potency of digoxin

ACE inhibitors &ATII antagonists

Captopril & Losartan (review RAAS)Effectively reducing cardiac workload (inhibits vasoconstriction, inhibits sodium/fluid retention, inhibits NE release…)

Vasodilators Nitrates: Nitroglycerine, etc. (review Nitrates notes)Diuretics Loop Diuretics: Furosemide

Thiazides: HydrocholorothiazideK+ Sparring: Spironolactone

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John DiepBimm118

DiureticsDiuretics – increases urine output; indicated for hypertension & edema (except CA inhibitors)

Drugs Mechanism

Carbonic Anhydrase InhibitorsAzetazolamideDorzolamide

Inhibits conversion of CO2 (H+) + (HCO3-); effectively blocking reabsorption of Na+-primarily indicated for Glaucoma!Causes metabolic acidosis (lower HCO3-).

Loop Diuretics (high ceiling)FurosemideTorasemide

Inhibits Na+/K+/2Cl- symporter @ ascending limb in the Loop of Henle; effectively blocking Na, K, Cl reabsorption-most potent diuretic -for severe/moderate hypertension & edemaCauses hypokalemia

Thiazide DiureticsHydrochlorothiazideBenzthiazide

Inhibits Na+/Cl- symporter @ distal convoluted tube-for moderate hypertension & heart failure (edema)Causes hypokalemia

Potassium-Sparring DiureticsSpironolactoneAmiloride

Acts as distal portion of distal tube; enhances Na excretion & reduces K excretion (K sparring)Spironolactone – aldosterone receptor antagonist (slow)Amiloride – directly blocks Na/K channel (fast)Used in combo w/ other diurectics

Osmotic DiureticsMannitol (iv only)

Non-reabsorbable molecules that inhibit passive reabsorption of water (promoting water excretion w/ little Na excretion)-cannot cross blood-brain barrier; so water goes from brain to bloodUsed to reduce intracranial pressure

Major side effects of diuretics (except K-sparing)-Mainly Hypokalemia (loss of potassium) & hyponatremia & hypochloremia as well(may give extra potassium orally/iv)-Hypotension & dehydration

Interaction w/ Cardiac Glycosides (digoxin)-cardiac glycosides are Na/K ATPase inhibitors as a competitive K antagonist-Hypokalemia secondary to diuresis increases digoxin potency

-digoxin has a narrow therapeutic index; this may cause it to become toxic

Uricosuric AgentsIndicated for kidney stones and gouts.@ therapeutic dose: promotes excretion and inhibits reabsorption of uric acid @ sub-therapeutic dose: inhibits both excretion and reabsorption

-possibly increase uric acid concentrationProbenecid-strongly inhibits penicillin excretion!!May be beneficial when trying to elevate antibiotic plasma concentration

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John DiepBimm118

Gastrointestinal Pharmacology

Ant

acid

s

Weak BasesTums, PeptoBismol, etc..

Neutralizes stomach acid.Magnesium Hydroxide – causes diarrheaAluminum hydroxide – causes constipationThese are often combined

H2 Receptor BlockersCimetidineRanitidine

-competitively inhibits binding of histamine to H2 receptors on parietal cells; thus reducing histamine stimulated gastric acid production (there are other signals that may stimulate acid production)

Proton Pump InhibitorsOmeprazoleLansoprazole

-irreversible inhibition of H+/K+ ATPase in parietal cells-only active at low pH (activity restricted to stomach)-inhibits acid production for 1-2days Note: prevents acid replenishment; does not neutralize acid already in the stomach(GERD is primarily treated w/ PPIs)

Mucosal Protective AgentsMisoprostolSucralfate

Misoprostol – PGE analog; stimulates mucus and HCO3 production; used w/ NSAIDSSucralfate – stabilizes mucus to inhibit H+ diffusion -not absorbed

Ant

iem

etic

Dru

gs

H1 Antagonists Diphenhydramine, Meclizine, etcBlocks H1 (histamine) receptors competitively.

Muscarinic Receptor Antagonists

Scopolamine (anticholernergic)

Benzodiazepines Lorazempam; potentiates effects of GABA in CNSD2 (dopamine) AntagonistsMetoclopramideDomperidone

Competitively blocks C2 receptors in the CTZAlso increases gastric emptyingContraindicated in patients w/ Parkinson’s disease

Cannabinoids(marijuana)

Synthetic cannabinoids: Nabilone & Dronabinol -acts as an agonists at cannabinoid receptors in the CNS

Peptic Ulcers – ulcer formation in the stomach/duodenum due to insufficient mucus and/or bicarbonate and/or increased acid production (autodigestion of stomach/duodenal wall)Causes:H. pylori (majority) – breaks down mucus and triggers inflammationNSAIDS – inhibits PGE (needed for mucus/HCO3 production)Smoking – stimulates gastric acid production

Treatment of H. pylori infection and peptic ulcer:Use a combo of antibiotics and PPI (or other mucosal protectant/enhancers & antacids)Antibiotics:Bismuth/Amoxicillin – disrupts cell wallClarithromycin/Tetracyclin – inhibits protein synthesisMetronidazole – secondary agent, used when resistance develops or other agents are intolerated

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John DiepBimm118

Gastrointestinal Pharmacology

Lax

ativ

es

Bulk Laxatives – increases bowel content volume triggering stretch receptors causing reflex peristalsis

Bul

k

Carbohydrate Based-Vegetable Fibers-Bran (husk)

-insoluble/non-absorbable-expands with waterMay cause constipation if not enough water.

Osmotically Active-Epsom salt-Glauber’s salt

-partially soluble/non-absrobable-potent and fast acting

Irritant Laxatives – irritates enteric mucosa causing an increase secretion of water softening bowel content (stool); increased volume also triggers reflex peristalsis

Irri

tant

s

Ricinoleic acid (Castor Oil) -castor oil converted to ricinoleic acid-works in the small intestine

AnthraquinonesDiphenolmethanesBisacodylSodium picosulfate

-works in the large intestine

Laxative Abuse: longer interval needed to refill colon, leads to constipationLoss of water/salts in gut leads to aldosterone release; causes excretion of K+Hypokalemia reduces peristalsis

Ant

i-di

arrh

eal

Muscarinic receptor antagonists and opiates can cause constipation but are not useful for treating diarrhea because of its effect on other parts of the body.

Loperamide(Imodium)

-opiod derivative that selectively acts in the GI tract (w/ no CNS activity).-directly acts on the intestinal muscles reducing motility-this increases water and electrolyte reabsorptionDimethicone – anti-gas agent that is often combined with anti-diarrheal drugs

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John DiepBimm118

Metabolic Disorders (Diabetes Mellitus)At low blood glucose levels (hypoglycemia); the body will increase blood glucose by:

-Glucagon (secreted by α pancreatic cells) promotes glycogenolysis & gluconeogenesis…-epinephrine also released by adrenal medulla

β-blockers will mask symptoms of hypoglycemic shock-cortisol (anti-insulin effects) is also released by the hypothalamus

extended use of steroidal drugs may induce diabetesAt high blood glucose levels (hyperglycemia); the body will decrease blood glucose by:

-Insulin (secreted by β- pancreatic cells) promotes glucose uptake & glycolysis & glycogenesis…

Diabetes MellitusType 1 Diabetes – autoimmune disease; destruction of β pancreatic cells

Treatment requires exogenous insulin replacement to control hyperglycemiaType 2 Diabetes – hyperglycemia resulting from insulin resistance at target tissue or reduced

insulin production by β pancreatic cellsVarious levels of defect leading to resistance(receptor, signaling pathway, enzymes, glucose transporter…)

Treatment with exogenous insulin replacement or oral hypoglycemic agents

Insu

lin

The

rapy

Regular Insulin -unmodified; short acting -only insulin that can be administered thru iv

Insulin Lispro (Humalog) -rapid onset (fastest) & short acting-used before a meal

Insulin Lente(sc injection only)

-insulin + zinc micro-precipitates (delayed absorption)-long lasting (UltraLente = longest lasting)

NPH Insulin -insulin + protamine delayed absorption-long lasting

Insulin Glargine (Lantus) -synthetic insulin that is soluble at low pH, but becomes insoluble and forms precipitates at neutral pH after sc administration-long lasting (similar to Lente)

Ora

l Hyp

ogly

cem

ic A

gent

s(F

or T

ype

II o

nly)

Sulfonylureas-Tolbutamide (1st gen.)-Glimepiridide-Glipizide

Stimulates insulin release; useful for diabetes caused by low insulin levels where β- pancreatic cells are still present

Glitazones-Rosiglitazone-Pioglitazone

-Increases insulin sensitivity at target cells-Acts as a nuclear hormone receptor (PPARγ agonist) increasing transcription of insulin receptor signaling components and glucose transporters

Biguanides-Metformin

-unknown mechanism-increase glucose uptake & inhibits gluconeogenesis-lowers LDL + VLDL (bad cholesterol)-suppresses appetite-no hypoglycemic effects

Insulin and oral hypoglycemic agents may cause hypoglycemia (except Metformin)

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John DiepBimm118

Metabolic Disorders (Hyperlipidemia)“Statins”LovastatinAtorvastatin (Lipitor)

-Reversible HMG-CoA Reductase inhibitors. HMG-CoA reductase is the rate-limiting enzyme in the production of cholesterol. Inhibition effectively reduces de novo synthesis of cholesterol precursors. -Lower cholesterol levels upregulates LDL receptors in liver removing LDL from the bloodstream.

Fibrates-Clofibrate-Benzafibrate

PPARα agonists – stimulates β-oxidation of fatty acidsPromotes lipoprotein lipase activityLowers VLDL (minor effect on LDL)Increases HDL levels

Resins-Cholestyramine-Colestipol

Bile acid binding resins prevents reabsorption of bile acids in enterohepatic circulation.-The liver responds to this loss of bile acid by increasing cholesterol synthesis to make more bile acid (plasma cholesterol levels remain unchanged). -The liver will also upregulate LDL receptors to increase hepatic uptake of LDL (reducing plasma LDL). Resins are not absorbed into the blood.

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John DiepBimm118

Steroid DrugsCorticosteriods (GC) – inhibits all phases of inflammation -inhibits NFκB (a transcription regulator of proinflammatory mediators -upregulates lipocortin (lipocortin inhibits PLA2 ; no PT or LT synthesis) -promotes fetal lung development by increasing surfactantSide Effects -immune suppression

-anti-insulin effects -“steroid diabetes” -increased glucose promotes lipogenesis (fat) -increased catabolism (muscle atrophy)-salt/water retention due to cross reactivity with mineralcorticoid (aldosterone) receptors-osteoporosisProlonged use of GC therapy causes adrenal cortex atrophy, so it is important to phase out slowly to avoid flare ups due to cortisol insufficiency.

Addison’s Disease Adrenal cortex failure – low cortisol levels-hypotension-weight loss-fatigue-abnormal glucose levels-inability to cope with stress-blotchy colored skin; w/o cortisol, corticotropin is unregulated and it increases melatonin (skin pigmentation)

Cushing’s Syndrome Adrenal cortex tumor – high cortisol levels(symptoms similar to GC therapy)-hypertension-weight gain (upper body obesity, “buffalo hump”)-water retention-poor wound healing

Hydrocortison -equivalent to endogenous cortisol-indicated for adrenal insufficiency (Addison’s Disease)-mostly for topical application-cross-stimulation with mineralcorticoid receptors -have Na retaining effects

Prednisone Pro-drug; converted to active form (prednisolone)

Prednisolone Drug of choice for systemic administration-lower Na retaining effects

Triamcinolone Stronger anti-inflammatory effect, 5x more potent than cortisol-no Na retaining effects

Halogenated GC(Betamethasone)

30x more potent than cortisol-no Na or water retaining effects

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John DiepBimm118

Steroid DrugsFemale Sex Steriods

Est

roge

ns

Estradiol Primary endogenous estrogen responsible for:-breast development-improving bone density-increase HDL-promotes uterus growth & supports endometrium development

Rapidly metabolized by the liver and therefore not suitable as an oral drug

Ethinylestradiol Stable derivative of estradiolUsually found as the estrogen component of birth control pills

Mestranol Oral contraceptiveSimilar to ethinylestradiol with an extra methyl group; prodrug-cleavage of the methyl group yields ethinylestradiol

Sel

ecti

ve E

stro

gen

Rec

epto

r M

odif

ier

Raloxifene Indicated for postmenopausal osteoporosis SERM = selective estrogen receptor modifier

-anti-estrogenic effect on breast and endometrium-reduces stimulation in these tissues to avoid tumorgenesis

-estrogenic effect on bone and lipid metabolismTamoxifene(antiestrogen)

Indicated for breast cancer-anti-estrogenic effect on breast tissue-weak effect on bone and lipid metabolism

Clomiphene(antiestrogen)

Indicated for infertility-selectively inhibits estrogen binding in pituitary, effectively removing negative feedback

-this causes an increase in LH ovulation

Progesterone Rapidly metabolized by the liverStable derivatives: Hydroxy/medroxy progesterone

Testosterone derivatives: norethindrone norgestrel

Progesterone is important for the formation of secretory endometrium and the establishment of pregnancy.

Mifepristone (RU486)(anti-progesterone)

Induce medical abortions (<49days)Combine w/ PG analogue (Misoprostol) to increase uterine contraction

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John DiepBimm118

Steroid DrugsMale Sex Steroids/Others

And

roge

ns

Testosterone Responsible for both anabolic and androgenic effectsRapidly metabolized by the liver.

-ester derivatives increases its half-lifeNandrolone(banned)

Strong anabolic effects.Injection only.

Stanozolol(banned)

Strong anabolic effects. (Not a β blocker despite “-olol” ending)Oral.

DHEA Dehydroepiandrosterone. Marketed as an anabolic steroid.This is misleading because it’s a precursor for both testosterone and estrogen.High levels of DHEA may lead to elevated levels of testosterone as well as estrogen.

Ant

i-A

ndro

gens

Flutamide Indicated for prostate cancerCompetitive androgen receptor antagonist -blocks testosterone’s stimulating effects

Finasteride Indicated for prostate gland enlargement and baldness-blocks the conversion of testosterone to DHT -DHT is a testosterone metabolite that is much more potentNote: bald men have elevated levels of DHT

GnR

H M

odif

iers

/Ana

logu

s

Danazol Indicated for endometriosis (growth of endometrium outside of the uterus)Inhibits GnRH release (no LH/FSH production) and consequently no steroid production

Synthetic GnRH-Gonadorelin-Buserelin

Given in pulses (s.c.) induced ovulation (stimulates LH/FSH)Given continuously medical castration (desensitize GnRH receptors)

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John DiepBimm118

Steroid Drugs“Oral Contraceptives”General Mechanism -Estrogen inhibits FSH; suppressing follicle development

-Progesterone inhibits LH; inhibiting ovulation & increases mucus viscosity (prevents sperm penetration)-Both steroids alter endometrium, preventing implantation

Combination Pills Highly effectiveEstrogen component: EthinylestradiolProgesterone component: varies29 day cycle (includes 7 day break to induce withdrawal bleeding)Biphasic preparation – includes progesterone break after 7 day breakMonophasic preparation – no progesterone break (but [progesterone] varies through-out cycle)

Mini Pill Less reliable than combination pillsContains only progesterone (used when estrogen is contraindicated)Contraception mechanism relies mainly on increased mucus viscosity.-mucolytic agents (usually found in cough medications) may cause contraception failure

Morning After Pill-Levonorgestrel

High dose of progesteroneMust be taken within 72 hours.

Oral contraception failures:1. Mucolytic agents2. Barbituates. Barbituates or other P450 inducing drugs may cause failure because steroids are metabolized by P450 enzymes3. Diarrhea or laxatives. Due to poor absorption of the drug.

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John DiepBimm118

Allergy DrugsAllergy MediatorsAllergen activates mast cells

1. Mast cell degranulation. Rapid release of histamine and other inflammatory agents2. Activation of PLA2; producing leukotrienes and prostaglandins. Late stage response.3. Stimulates cytokine transcription. Late stage inflammatory response.

Review histamine and leukotriene actions (receptor specific) from lecture slides.

H1

Rec

ptor

Ant

agon

ists

1st G

ener

atio

n D

rugs

(S

edat

ing)

Eth

anol

amin

es

Dephenhydramine(Benadryl)

Indicated for seasonal and skin allergies

Dimenhydrinate(Dramamine)

Used as an anti-emetic (for motion sickness)Also blocks mAChRs.

Doxyamine(Nyquil)

Most potent OTC sedative (better than barbiturates)Same efficacy as diphenhydramine in terms of anti-allergies.

Chlorpheniramine Anti-allergyAnti-depressant (also blocks serotonin re-uptake)(Alklyamines)

Pip

eraz

ines

Meclizine (Dramamine II)

Anti-emetic (but less drowsy)

Hydroxyzine (Atarax)

Pro-Drug, anti-allergy effect from metabolite Certirizine

2nd

Gen

. (N

on-

Sed

atin

g)

Certirizine(Zyrtec)

Hydroxyzine metabolite.(also a Piperazine)

Pip

erid

ines

Loratadine (Claritin) No drowsiness.Active metabolite = desloratadine

Desloratadine (Clarinex) Long half-life

Fexofenadine (Allegra) Highly selective for H1-receptor

Mast Cell Stabilizers-Cromolyn-Nedcromil

Only preventative; acts by preventing mediator release from mast cells.Useless if histamine or other mediators are already released.Prophylactic agent for asthma and other allergy symptoms

Leukotriene Receptor Blockers-Montelukast (Singulair)

Prevents exercise and aspirin-induced asthmaAntagonist of LTD4 at cysteinyl LT receptor

5-Lipoxygenase Inhibitor-Zileuton (Zyflo)

Prevents production of all leukotrienes Not useful for treatment of attacks.

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John DiepBimm118

CNS DrugsHypnotics/AnxiolyticsBarbiturates

-phenobarbital(long acting)

-thiopental(short acting)

General inhibition of the CNS w/ sedative-hypnotic actions.

Mechanism: Augments GABA responses (by potentiating GABA signal) and mimics GABA (by opening Cl-channels in the absence of GABA). Keeps Cl channels open longer, hyperpolarizing the cell preventing further excitation. Also blocks excitatory glutamate receptors.

Indications:-epilepsy (phenobarbital) and anesthesia induction (thiopental)(not a first line drug due to many side effects)

Side effects/Risks-high risk of dependence (severe/lethal withdrawal symptoms)-may lead to cardio-respiratory depression-potent inducers of P450 enzymes; drug interactions (contraceptives, etc.)

Benzodiazepines

-Diazepam (Valium)-Lorazepam- Alprazolam- Midazolam

Mechanism: Benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor (by selectively binding to benzodiazepine receptors which are coupled to the GABA receptors). While barbiturates increase the length of time Cl channels stay open, benzodiazepines increases the frequency of GABA binding (opening of Cl channels).

Indications: Anxiolytic, anticonvulsant (anti-epilepsy), anesthesia induction, etc…-all forms of anxieties -epilepsy (Clonazepam)-depression (Alprazolam)-anesthesia induction (Midazolam)

Side effects/Risks:-anterogade amnesia (date rape drug)-much fewer side effects than barbiturates

Both barbiturates and benzodiazepines have an inhibitory effect on the CNS by modulating GABA signals (hyperpolarizing cells to prevent further excitation). While both classes of drugs enhance GABA signals, barbiturates can also open Cl channels even in the absence of GABA.

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John DiepBimm118

CNS DrugsAntidepressants

“Amine hypothesis of depression” – functional decrease in NE or serotonin causes depression (over-simplified…)MAO Inhibitors

-Tranylcypramine

Mechanism: Inhibits the metabolism of serotonin (as well as NE/E and dopamine); effectively increasing serotonin levels.

Side Effects:-may cause fatal hypertension (due to increase sympathetic input (NE))-Food-Drug interaction: “cheese-reaction”

Increased levels of tyramine which is usually metabolized by MAO may displace NE from storage vesicles, further increasing NE signals hypertensive crisis

Only used if resistant to all other treatments.Tricyclic Antidepressants (TCAs)

-Imipramine-Amitriptyline

Mechanism: Prevents reuptake of NE and serotonin into pre-synaptic terminal thereby potentiating the effect of the neurotransmitters at the post-synaptic neurons.

Side Effects-sedation (also binds H1 receptors)-strong interaction with alcohol

Selective Serotonin Reuptake Inhibitors(SSRIs)

-Fluoxetine (Prozac)-Paroxetine (Paxil)-Sertraline (Zoloft)

Mechanism: Specifically prevents serotonin reuptake thereby potentiating its effect on post-synaptic neurons

Same efficacy as TCAs but fewer side effects possibly due to its specificity for serotonin

Side Effects-rare: may cause violence and aggression-inhibits sexual climax

These antidepressants produce a functional increase in serotonin levels in the CNS. Supports the “amine hypothesis of depression.”

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John DiepBimm118

CNS DrugsNeuroleptics (anti-psychotics)

“Dopamine hypothesis of schizophrenia” – functional increase in CNS dopamine causes schizophrenia. Serotonin may also be involved in modulating dopamine responses. (over-simplified)

Typ

ical

/Cla

ssic

al N

euro

lept

ics

Phenothiazines-Chlorpromazine

Butyrophenones-haloperidol

Mechanism: Blocks D2 receptors on post-synaptic neuron preventing receptor activation by dopamine.

Side EffectsExtrapyramidal Effects: Due to dopamine blockage in striatum

-Acute dystonia: motor impairment (around face, neck); -immediate onset, reversible

-Akatheisa: “pseudo-Parkinsonism,” tremor/rigidity -occurs days/months after treatment, reversible

-Tardive Dyskinesia: involuntary movements of most body parts -occurs after extended treatment; irreversible-Sedation (blocks H1 receptor)-Dry mouth, constipation, and urinary retention -blocks mACh receptors and α-adrenergic receptors-lactation (dopamine is needed to inhibit prolactin)-strong interaction with alcohol

Aty

pica

l Ner

uole

ptic

s ClozapineOlanzapineRisperidone

Mechanism: Blocks both dopamine and serotonin receptors preventing receptor activation by dopamine and serotonin. Acts more specifically in the limbic system (fewer extrapyramidal effects)

Clozapine – causes agranulocytosis (decrease in white blood cells)

Note: Cocaine and amphetamines both causes an increase in dopamine levels in the CNS, which mimics schizophrenia symptoms.

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John DiepBimm118

CNS DrugsParkinson’s Disease

Pathology-Loss of dopaminergic suppression of excitatory cholinergic neurons in the striatum -Cholinergic neurons causes an increase in GABA output suppressing the thalamus which reduces signaling to the motor cortex…causing movement disorderRefer to lecture slide.

Dop

amin

e R

epla

cem

ent

L-Dopa & Carbidopa

L-Dopa – dopamine precursor that can cross the blood brain barrier (dopamine cannot cross the blood brain barrier)-L-Dopa can be converted to dopamine in the periphery leading to many side effects…

Combine with Carbidopa!Carbidopa – dopamine decarboxylase inhibitor-Since it cannot cross the blood brain barrier, it exerts its effect in the periphery by inhibiting the conversion of L-dopa to dopamine-this means more L-dopa will reach the CNS

Dop

amin

e A

goni

st

Bromocriptine Actions similar to L-Dopa.Potent agonist of D2 receptor.(suppresses prolactin; was used to treat galactorrhoea)

Selegiline Indirect agonist. Specifically inhibits MAO-B in the CNS, extending dopamine’s half-life. MAO-B is responsible for the metabolism of dopamine.

Atropine Muscarinic acetylcholine receptor antagonist.Reduces cholinergic signals in the CNS which is responsible for stimulating GABA output suppressing the thalamus.

No longer used for Parkinson’s disease.Antipsychotics used to treat schizophrenia may induce symptoms similar to Parkinson’s disease due to its dopamine lowering effect.

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John DiepBimm118

CNS DrugsEpilepsy (seizures)PathologyExcessive excitability of neurons in the CNS, causing seizuresEnhancement of GABA: Augment inhibitory effect of GABA to counter excessive excitation.Only useful for generalized and partial convulsive disorders (not for absence seizures)Carbamazepine(benzodiazepine)

Increases Cl- influx in response to GABA, counteracts depolarization, (elevating seizure threshold.)

Tiagabin Prevents GABA reuptake.

Phenytoin Mechanism: Blocks voltage gated Na channels that are in the inactivated state, preferentially blocks high frequency discharges. “use-dependent inhibition”

(does not elevate seizure threshold, but rather, limits the propagation and spread of seizure.)

-eliminated by 0th order kinetics-Indicated for convulsive seizures, not absence seizures

Side Effect: hyperplasia (gum enlargement)Ethosuximide Mechanism: Blocks T-type calcium channels; (elevates seizure

threshold thru depression of nerve transmission)

-good for absence seizuresValproate Mechanism: unknown; thought to be GABA-mediated

-useful for both convulsive and absence seizures

Side Effects-hepatotoxicity-teratogenic

Strychnine – a toxin that induces strong convulsions by blocking Glycine receptors-Glycine is an inhibitor NT that is similar to GABA-Glycine also binds NMDA receptor as a co-activator (with Glutamate) where it has excitatory functions (not strychnine sensitive)

Antedotes: anticonvulsants (benzodiazepines) and muscle relaxants (nACh R blockers)

AlcoholismReview lecture slides on effects of alcohol.Disulfuram – inhibits aldehyde dehydrogenase; leading to acetylaldehyde accumulation causing “hang-over”

-also blocks the conversion of dopamine to NE, rise in dopamine levels causes schizophrenic symptoms Naltrexone – opiod receptor antagonist; inhibiting the reward response that normally results for alcohol consumption

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John DiepBimm118

Pain KillersGeneral Anesthesia-unconciousness, analgesia, amnesia, and muscle relaxation-induced by intravenous anesthetics and maintained by inhalation anesthetics-inhalation anesthetics are generally removed simply by exhalation of unchanged gas

Intr

aven

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Ane

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Thiopental(barbiturate)

Rapid onset with high lipid solubility (accumulates in fat); slow recoveryNarrow therapeutic range No analgesic effect

Propofol Rapidly metabolized for quick recovery.Used for same-day surgery

Ketamine Phencyclidine (PCP) analogue; may cause hallucinations during recoveryHave both anesthetic and analgesic properties-often used in veterinarian medicine and in tranqulizers

Midazolam Benzodiazepine. Very short-acting.Have all benzodiazepine properties, often used for anesthesia induction

Inha

lati

on A

nest

heti

cs

Speed and PotencySolubility in blood – speed of onset is inversely correlated w/ degree of solubility in blood

-blood acts as a drug reservoir (need to saturate the blood first, to achieve effect)-more soluble = slower onset

Solubility in lipid – potency is directly correlated w/ lipid solubility-more lipophillic = more potent

Ether Obsolete. Slow onset and recovery.

Nitrous Oxide Low potency (must be combined with other agents to achieve anesthesia)Rapid induction and recoveryHave both anesthetic and analgesic properties.

Haloethanes High potency anesthetic; combined w/ N2ONo analgesic properties.Some hepatic metabolism occurs; repeated use causes hepatoxicityAlso causes hypotension (thru vasodilation and cardiac suppression)

-Enfluran-Isofluran-Desfluran

High potency anesthetic; similar to haloethanesFewer side effects because less metabolized by liver.

Exa

mpl

e

1. Pre-medication -Diazepam (anxiolytic, benzodiazepam)-Fantanyl (analgesis, opiod)-Atropine (autonomic stabilization, mACh R blocker)

2. Anesthesia Induction

-Midazolam (benzodiazepine) or Thiopental (barbiturate)-Succinylcholine (muscle relaxant, nACh R blocker)

3. Anesthesia Maintenance

-Haloethane (anesthesia)-Nitrous Oxide (analgesia & anesthesia)-Pancuronium (muscle relaxant, nACh R blocker)

4. Recovery -Neostygmine (reversing neuromuscular block) ACh R agonist)

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John DiepBimm118

Pain KillersOpioid AnalgesicsAnalgesic Mechanisms1. Spinal Analgesia – Activation of pre-synaptic opioid receptors decreases Substance P release

-Decreasing pain signal transmission from nocireceptors2. Supraspinal Analgesia – Activation of post-synaptic opioid receptors causes hyperpolarization

-Inhibition of neurons in the pain pathway Morphine CNS – sedation, nausea, and cough suppression

Respiratory System – reducing frequency and depth of breathingGI Tract – increases segmentation and decreases peristalsis (constipation)Eyes – papillary constriction (due to parasympathetic activation)Withdrawal symptoms-autonomic hyperactivity due to tolerance (elevated levels of cAMP in response to adenylyl cyclase upregulation)

-diarrhea, vomiting, pain, etc…Codeine Pro-drug, that is converted into morphine by CYP2D6.

-CYP2D6 inhibitors (like Fluoxetine) may reduce codeine efficacy-Genetic polymorphism may also explain codeine resistance

(lacking this enzyme)Little euphoric effect, so low risk for addiction.Used as an anti-tussive (cough suppressant)-may still cause constipation and respiratory suppression

Dextromethrophan Synthetic morphine derivative that does not act thru opioid receptors.Same efficacy as codeine-no GI or analgesic effect

Heroin Diamorphine; diacylated-morphine is more lipophilic than morphine so it crosses the blood-brain barrier more rapidly producing a greater rush.-2x more potent than morphine

Hydrocodone Vicodin; often combined w/ NSAIDs for synergistic effect

Oxycodone Indicated for chronic pain.-Addicts chew thru the slow release formulation to obtain immediate release to mimic heroin rush

Meperidine Similar to morphine, but shorter duration.Used during labor.

Methadone Similar to morphine, but much longer duration.Used to treat morphine/heroin addiction

Fentanyl High potency. Can be used transdermally.Short-lasting. Used in anesthesia and patient controlled infusions.

Opi

ate

Ant

agon

ists

Naloxone Short-acting competitive antagonist used to rapidly reverse opioid induced analgesia and respiratory suppression.

Naltrexone Long-acting competitive antagonistUsed to protect detoxified addicts from relapsing.

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John DiepBimm118

Pain KillersLocal AnestheticsMechanismReversibly inhibits Na channels (cytoplasmic side) that are activated to block generation of action potentials. “Use dependent”Note: Phenytoin (antiepileptic) specifically blocks inactivated Na channelsAll are weak bases that exist mainly in its ionized form.Passes thru the plasma membrane in its unionized form, but exerts its effect in its ionized form intracellularly.Cocaine -contains ester bond; rapidly metabolized by non-specific esterases in

the plasma-cocaine’s CNS effects are independent from its analgesic effect

(blocks reuptake of DA, 5-HT, NE)

Lidocaine -contains amide bond; longer acting compared to local anesthetics w/ ester bonds

Local anesthetics often combined with vasoconstrictors (epinephrine) to extend duration of action and to minimize bleeding.

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John DiepBimm118

Pain KillersNSAIDS (non-steroidal anti-inflammatory drugs)Mechanism:Inhibits cyclooxygenase (COX), preventing prostaglandin synthesis.Prostaglandins do not cause pain themselves, but sensitize nocireceptors to painNote:COX1 – constitutively expressed; “house-keeping functions”COX2 – induced by pro-inflammatory factors (TNF & IL-1…)Classical NSAIDs – inhibits both COX1 and COX2

-inhibition of COX1 reduces overall “house-keeping” PGs side effects (gastric ulcers)Aspirin The only known irreversible COX inhibitor

-have cardioprotective effects (low dose aspirin)PGIs – anticoagulating effects; found in endothelial cells w/

nucleus. They can renew COX transcriptionally after aspirin is elminated

TXa – coagulating effect; found in thrombocytes w/o nucleus. They cannot renew COX even after aspirin is elminated.

Low dose aspirin shifts PG synthesis to PGI.Side Effects-Reyes syndrome in children, do not use in children!-high doses may cause tinnitus and nausea

Acetaminophen(Tylenol)

Indicated for analgesic and antipyretic property.Easily crosses blood-brain barrier.Have little side effects but a very narrow therapeutic index.Overdose fatal hepatoxicity Acetaminophen can be converted into a toxic metabolite that requires glutathione conjugation. OD of acetaminophen will deplete glutathione and lead to accumulation of the toxic metabolite hepatic necrosis

COX-2 Specific NSAIDs – inhibits only COX 2-supposedly fewer side effects -recent studies show that they increase the risk of cardiovascular diseases!!!

-Reofecoxib (Vioxx)-Celecoxib (Celebrex)

Antibiotics (overview)

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John DiepBimm118

Cel

l Wal

l Syn

thes

is I

nh

ibit

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β- L

acta

m A

nti

bio

tics

General Mechanism: Inhibit transpeptidase required for cross-linking of peptidoglycan chains for bacterial cell wall synthesis. Also inactivates autolytic enzyme inhibitor.Penicillins Classifications:

-Narrow Spectrum: active against gram (+) only-Broad or Extended Spectrum: active against gram (+) & gram (-) & some others-increased range is due to the addition of amino or carboxy group-β-Lactamase sensitive vs. β-Lactamase resistant-antibiotics that are inactivated by β-Lactamase are said to be β-Lactamase sensitve

β-Lactamase Inhibitor -Clavulanic Acid -sulbactam

-inhibits β-Lactamase produced by the bacteria-allows β-Lactamase sensitive antibiotics to become resistant

Cephalosporins Same mechanism as penicillinsThere are 4 generations. The newer generations have:broader spectrum, increased resistance to β-Lactamase, and increased ability to reach CSF.

Vancomycin (polypeptides)Bacitracin (polypeptides)

Other cell wall inhibitors that operate thru a different mechanism (different than β- Lactam Antibiotics)

Pro

tein

Syn

thes

is I

nh

ibit

ors General Mechanism – Inhibit either 30s or 50s ribosomal subunit (which differ from

mammalian cells). Since they operate intracellularly, they must be able to penetrate the cell wall and/or membrane. Entry inhibition would be a point of drug resistance.Aminoglycosides -Gentamycin

-O2 dependent transport to enter cells -ineffective against anaerobes

Tetracyclines -oral absorption impaired by Ca2+ and Mg2+Macrolides -Azithromycin (long t1/2)

-good alternative to penicillin-once daily dosing of Azithromycin increases compliance

Chloramphenicol -very broad spectrum-reserved for resistant cases; severe side effects

Clindamycin -used to treat penicillin-resistant cocci

Fol

ate

An

tago

n General Mechanism – block folate synthesis (folate is required for nucleotide synthesis)Bacteria cannot take up folic acid and must make it from PABA.Folate Metabolism: PABA Folate Tetrathydrofolate DNASulfonamides -structurally similar to PABA; competes with PABA in

the folate pathway (interferes with PABA folate)Trimethoprim -interferes with the folate tetrahydrofolate step

-often combined with sulfonamides

Qu

inol

ones Ciprofloxain

LevofloxainEtc…

Mechanism – inhibitor of bacterial DNA gyrase (enzyme that is involved in the winding/unwinding of DNA. This results in inhibition of DNA synthesis/transcription-very broad spectrum

-Focus on knowing the general mechanism and the classifications (cell wall synthesis inhibitors, protein synthesis inhibitors, folate antagonists, and quinolones).

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