BRY's Pharmacology 2nd Semester

TABLE OF CONTENTS

23. Calcium Channel Blockers (Page 1)

24. Drugs Acting on the Renin Angiotensin Aldosterone System (Page 5)

25. Diuretic Drugs (Page 8)

26. Drugs Used to Treat Congestive Heart Failure (Page 13)

27. Antianginal Drugs. Drugs That Increase Regional Blood Flow (Page 17)

28. Antihypertensive Drugs (Page 20)

29. Antiarrhythmic Drugs (Page 23)

30. Drugs Used to Treat Hyperlipoproteinemia (Page 29)

31. Anticoagulatnts. Fibrinolytics. Antifibrinolytics. Antiplatelet Drugs (3)

32. Drugs Affecting Hematopoiesis (Page 39)

33. Histamine, H1 and H2 Receptor Antagonists (Page 43)

34. Serotonin, Serotonin Receptor Agonists and Antagonists (Page 47)

35. Pharmacology of Eicosanoids. Drugs Acting on the Smooth Muscle: Smooth Muscle

Relaxants; Pharmacology of the Uterine Smooth Muscle (Page 53)

36. Pharmacology of the Respiratory Tract (Page 61)

37. Pharmacology of the Gastrointestinal Tract: Drugs in the Treatment of Peptic Ulcer; Emetics,

Anti-Emetics (Page 65)

38. Pharmacology of the Gastrointestinal Tract: Prokinetic Drugs, Laxatives, Antidiarrhoeal

Agents, Drug Treatment of Inflammatory Bowel Disease and Paralytic Ileus, Digestives,

Drugs Used in Cholelithiasis (Page 72)

39. Antianxiety and Hypnotic Drugs (Page 80)

40. Alcohols: Pharmacology and Toxicology (Page 86)

41. Antipsychotic Drugs (Page 90)

42. Antidepressants (Page 94)

43. General Anaesthetics (Page 99)

44. Antiepileptic Drugs (Page 105)

45. Central Nervous System Stimulants and Nootropic Agents (Page 109)

46. Drug Treatment of Neurodegenerative Disorders. Centrally-Acting Muscle Relaxants (Page

111)

47. Drug Abuse and Dependence: General Principles, Opioids, Anti-Anxiety and Hypnotic

Drugs, Inhalants, Ethanol (Page 116)

48. Drug Abuse and Dependence: Psychomotor Stimulants, Psychedelics, Cannabis (Page 118)

49. Opioid Analgesic Drugs: Morphine and Codeine (Page 130)

50. Opioid Analgesic Drugs: Semi-Synthetic, Synthetic Opioids; Opioid Antagonists (Page 130)

51. Cyclooxygenase Inhibitors: Aspirin, Paracetamol (Page 138)

52. Cyclooxygensae Inhibitors: Pyrazolons, Propionic Acid Derivatives, Indole Derivatives and

Others. “COX-2 Inhibitors” (Page 138)

53. Drugs Used to Treat Rheumatoid Arthritis and Gout (Page 144)

A1. Drugs, 2nd Semester (Page 149)

- 1 -

23. CALCIUM CHANNEL BLOCKERS Overview

- calcium channel blockers (“calcium antagonists”) are drugs that block voltage-sensitive

calcium channels (“type L-calcium channels”)

- the voltage-sensitive calcium channels are more susceptible to blockage in their active state,

thus exhibiting use-dependence

- voltage-sensitive calcium channels are responsible for the propagation of action potential in

unitary muscle fibers (cardiac- and smooth muscle), thus blockage of them causes decreased

depolarization

General Effects - 2 types

LOCATION ACTION

BLOOD VESSELS Decreased blood pressure

- arterial vasodilation

HEART Positive tropic effect

- reflex tachycardia (due to decreased blood pressure)

Negative tropic effect

- negative chronotropic effect (decreased heart rate)

- negative ionotropic effect (decreased force of contraction)

- negative bathmotropic effect (decreased myocardial excitability)

- negative dromotropic effect (decreased AV conduction)

Relevant Drugs

- 3 categories

1) PHENYLALKYLAMINES (VERAPAMIL)

- primarily acts on the heart

- also has a weak action on blood vessels

- 1 type

DRUG NAME DESCRIPTION

VERAPAMIL General Description

- administered orally

- extensive first-pass metabolism

- extensively bound to plasma proteins

- not to be taken with other drugs with

negative tropic effects (eg. beta-blockers, see

21)

- 2 -

Clinical usages

- treatment of atrial fibrillation (negative

tropic effect)

- treatment of supraventricular paroxysmal

tachycardia (negative tropic effect)

- treatment of angina pectoris (negative

tropic effect and weak coronary artery

vasodilation)

- treatment of hypertension (negative tropic

effect and weak arterial vasodilation)

Side effects

- bradycardia (negative chronotropic effect)

- heart failure (negative ionotropic effect, if

symptoms of heart failure are already

present)

- supraventricular AV- junctional block

(negative dromoptropic effect)

- constipation (decreased contractility of GI

smooth muscle)

2) BENZOTHIAZEPINES (DILTIAZEM)

- acts efficaciously both on heart and blood vessels

- 1 type


DILTIAZEM General information

- same as verapamil, but less pronounced

(more reflex tachycardia)

3) DIHYDROPYRIDINES (“DHP”)

- primarily act on blood vessels

- also has a weak effect on the heart

- may be subdivided in 3 groups according to duration of action

A) SHORT/RAPIDLY-ACTING DHPS

- 4-6 hours

- 3 types


NIFEDIPINE General information

- administrated orally

- extensive first pass-metabolism

- 3 -

Clinical usages

- treatment of hypertension (strong arterial

vasodilation)

Side effects

- reflex tachycardia

- headache (cerebral artery vasodilation)

- flushing (cutaneous artery vasodilation)

- ancle edema (arterial vasodilation)

NIMODIPINE General information

- same as nifedipine

- exhibit some selectivity for cerebral

arteries

Clinical usages


vasodilation)

- treatment of cerebral vasospasms following

subarachnoid hemorrhage (then administered

IV)

Side effects


NICARDIPINE General information


- some selectivity for coronary arteries

Clinical usages


vasodilation)

- treatment of prinzmental angina pectoris

(strong coronary artery vasodilation)

Side effects


B) INTERMEDIATELY-ACTING DHPS

- 8-10 hours

- 2 types


- 4 -

NITRENDIPINE General information


Clinical usages

- same as nicardipine

Side effects

- same as nifedipine, but less pronounced

reflex tachycardia

NISOLDIPINE General information

- same as nitrendipine

C) LONG/SLOWLY-ACTING DHPS

- 40-60 hours

- 1 type


AMLODIPINE General information


Clinical usages

- same as nicardipine

Side effects

- same as nitrendipine, but even less

pronounced reflex tachycardia

- 5 -

24. DRUGS ACTING ON THE RENIN ANGIOTENSIN

ALDOSTERONE SYSTEM Overview

- the renin angiotensin aldosterone system is primarily consumed with regulation of blood

pressure

- initiation of the renin angiotensin aldsterone system is done by secretion of renin from the

juxtaglomerular apparatus of the kidney nephrons in response to decreased flow rate of pre-

urine in the distal tubules of the nephrons (due to decreased blood pressure in the glomeruli

of the nephrons and following decreased glomerular filtration rate)

- activation of the renin angiotensin aldosterone system is done in 2 (3) steps

ANGIOTENSINOGEN

renin

ANGIOTENSIN I

ACE (angiotensin-converting enzyme)

ANGIOTENSIN II

ALDOSTERONE SECRETION

- the most important functions of the renin angiotensin aldosterone system include

ENZYME ACTION

ANGIOTENSIN II - arterial vasoconstriction (primarily in the kidneys, heart and

brain)

- increased sympathetic tone

- hypertrophy/hyperplasia of cardiac- and smooth muscle

- aldosterone secretion

ALDOSTERONE - sodium/water reabsorption by the kidneys

- potassium secretion by the kidneys and potassium uptake by the

cells of the body

- hydrogen ion secretion by the kidneys (pH regulation)

Relevant Drugs

- 5 categories

1) BETA-1 ADRENERGIC RECEPTOR ANTAGONISTS

- beta-1 adrenoceptors are found in macula densa cells of the juxtaglomerular

apparatus, and facilitate renin release upon activation

- beta-1 adrenoceptor antagonists thus inhibit renin release

- see 21

- 6 -

2) RENIN INHIBITORS

- renin inhibitors inhibit the enzymatic activity of renin, thus decrease the

conversion of angiotensinogen to angiotensin I

- 1 type


ENALKIREN

3) ACE INHIBITORS

- ACE inhibitors inhibit the enzymatic activity of ACE, thus decrease the

conversion of angiotensin I to angiotensin II

- 3 types


ENALAPRIL General information


- prodrug

- extensive first-pass metabolism (conversion to active

metabolites)

Medical uses

- treatment of hypertension (arterial vasodilation and

decreased sodium/water retention)

- prophylaxis of angina pectoris and AMI (coronary

artery vasodilation)

- treatment of cardiac failure (coronary arterial

vasodilation, decreased hypertrophy/hyperplasia of

cardiac muscle and decreased preload/afterload)

- treatment of chronic- and acute renal failure

(decreased workload of the kidneys)

Side effects

- hypotension

- renal failure (renal ischemia, if bilateral renal artery

stenosis is present)

- teratogenesis

- hyperkalemia (decreased potassium secretion and cell

uptake)

- respiratory mucosal edema (ACE is also responsible

for catabolizing bradykinin)

- dry cough (respiratory mucosal edema)

LISINOPRIL General information

- 7 -

- same as enalapril

RAMIPRIL General information

- same as enalapril

4) TYPE 1 ANGIOTENSIN II RECEPTOR ANTAGONISTS

- type 1 angiotensin II receptors are found in both arteries and renal tubules

and are the primary receptors for angiotensin II action

- type 1 angiotensin II receptor antagonists are competitive antagonists of

angiotensin II at type 1 angiotensin II receptors, thus decreasing their

activation

- 2 types


LOSARTAN General information


Medical uses

- treatment of hypertension (arterial vasodilation and

decreased sodium/water retention)

Side effects

- same as with enalapril (, but no respiratory mucosal

edema/dry cough)

VALSARTAN General information

- same as losartan

5) ALDOSTERONE RECEPTOR ANTAGONISTS (“POTASSIUM-SPARING

DIURETICS”)

- see 25

- 8 -

25. DIURETIC DRUGS Overview

- diuretic drugs are drugs that increase the urinary output

- all diuretics (except osmotic diuretics) are drugs that inhibit sodium reabsorption from the

renal tubules

- this results in an increased tubular oncotic pressure, decreased water reabsorption, and

following increased urinary output

Relevant Drugs

- 5 categories (listed from most- to least potent)

1) LOOP DIURETICS

- “ceiling diuretics”

- may increase urinary output to 45 liters/day (25% of glomerular filtrate)

- inhibits the 1 sodium/2 chloride/1 potassium cotransported reabsorption of

the thick ascending limb of the loop of henle

- 3 types


FUROSEMIDE General information

- administered orally or IV

- extensively bound to plasma proteins

- eliminated by the organic acid

transporter of the proximal tubule of the

kidneys

Medical uses

- treatment of severe hypertension

- treatment of systemic edema (due to

right-sided congestive heart failure)

- treatment of pulmonary edema (due to

left-sided congestive heart failure)

- treatment of ascites (due to liver

cirrhosis)

- treatment of acute- and chronic renal

failure (increased water excretion)

- treatment of hypercalcemia (inhibition

of calcium reabsorption)

Side effects

- hypotension (hypovolemia)

- hypokalemia (inhibition of potassium

reabsorption and increased tubular flow

rate)

- metabolic alkalosis (due to

- 9 -

hypokalemia)

- hypomagnesemia (increased tubular

flow rate)

- hypocalcemia (increased tubular flow

rate)

- azotemia (competition between urea

and loop diuretics at the organic acid

transporter)

ETACRYNIC ACID General information

- same as furosemide

2) THIAZIDE DIURETICS


- inhibits the sodium/chloride cotransported reabsorption of the distal tubule

- 3 types


BENDROFLUMETHAZIDE General information


- eliminated by the organic acid

transporter of the proximal tubule of the

kidneys

Medical uses

- treatment of hypertension (due to

decreased water reabsorption and

vasodilation)

- treatment of chronic resistant edema

(together with loop diuretics)

- prophylaxis of urolithiasis (increased

tubular flow rate and no inhibition of

calcium reabsorption)

- treatment of diabetes insipidus

(paradoxal decrease in urinary output)

Side effects

- hypotension (vasodilation)

- hyperglycemia (inhibition of insulin

secretion)

- hypokalemia (increased tubular flow

rate)

- metabolic alkalosis (due to

hypokalemia)

- azotemia (competition between urea

and thiazide diuretics at the organic acid

- 10 -

transporter)

- hyperlipoproteinemia

- male impotence

HYDROCHLORTHIAZIDE General information

- same as bendrofluazide

CYCLOPENTHIAZIDE General information

- same as bendrofluazide

3) CA (CARBONIC ANHYDRASE) INHIBITORS

- may increase urinary output to 10 liters/day (5% of glomerlular filtrate)

- carbonic anhydrase is the main enzyme responsible for metabolic pH

buffering

CARBONDIOXIDE + WATER

CA (carbonic anhydrase)

CARBONIC ACID

HYDROGEN ION + BICARBONATE ION

- CA inhibitors inhibit intracellular carbonic anhydrase in the tubular

epithelium of the distal tubule

- this leads to decreased intracellular hydrogen ion concentration and following

disruption of the hydrogen ion/sodium antiporter

- 1 drug


ACETAZOLAMIDE General information

- not used as a diuretic

Medical uses

- treatment of glaucoma (carbonic

anhydrase is also involved in production

of the aquous humor of the eye)

- treatment of epilepsy

Side effects

- hypokalemia (increased tubular flow

rate)

- metabolic acidosis (decreased

- 11 -

hydrogen secretion and increased loss of

bicarbonate due to no hydrogen ion in

the tubular fluid to react with to form

carbondioxide and water)

4) POTASSIUM-SPARING DIURETICS (“ALDOSTERONE RECEPTOR

ANTAGONISTS”)


- potassium-sparing diuretics antagonize the effect of aldosterone in the late

distal tubule

- 3 types


SPIRONOLACTONE General information

- direct antagonist of aldosterone at the

intracellular aldosterone receptors in the

late distal tubule, thus inhibiting

expression of aldosterone-dependent

sodium reabsorption, and potassium-

and hydrogen ion secretion


Medical uses

- coadministered with non-potassium

sparing diuretics to preserve potassium

- treatment of hyperaldosteronism

(“conn’s syndrome”)

Side effects

- hyperkalemia (decreased potassium

secretion)

- metabolic acidosis (decreased

hydrogen secretion and hyperkalemia)

- testicular atrophy

- impotence

- gynecomastia

- amenorrhea

TRIAMTERENE General information

- indirect antagonist of aldosterone by

blocking the aldosterone-dependent

sodium reabsorption and potassium

secretion


Medical uses

- 12 -

- coadministered with non-potassium

sparing diuretics to preserve potassium

Side effects

- hyperkalemia

- metabolic acidosis (due to

hyperkalemia)

AMILORIDE General information

- same as triamterene

5) OSMOTIC DIURETICS

- osmotic diuretics do not increase urinary output by the way of inhibition of

sodium reabsorption

- however, osmotic diuretics also act by increasing the tubular oncotic pressure

- the osmotic diuretics are chemical compounds that are unable to leave the

intravascular fluid space except at the large fenestrations of the glomerular

capillaries (freely filtered), and are unable to be reabsorbed by the tubular

epithelium

- this results in an increased intravascular- and tubular oncotic pressure

- 1 type


MANNITOL General information

- administered IV

Medical uses

- prophylaxis of acute renal failure

(increased tubular flow rate)

- treatment of glaucoma (increased

intravascular oncotic pressure)

- treatment of cerebral edema (increased

intravascular oncotic pressure)

Side effects

- transient expansion of the intravasular

fluid space

- 13 -

26. DRUGS USED TO TREAT CONGESTIVE HEART FAILURE Overview

- heart failure is a failure of the heart to supply the body with sufficient cardiac output

- upon occurrence of heart failure the body will initiate 2 events to try to maintain minimal

required cardiac output

EVENT CONSEQUENCE

INCREASED SYMPATHETIC TONE Positive consequences

- positive tropic effect, thus increasing heart

rate and force of contraction

Negative consequences

- vasoconstriction, and following increased

afterload (increased total peripheral

resistance for the heart to work against)

INCREASED ACTIVATION OF RAAS Positive consequences

- increased blood volume, and following

increased distribution capabilities of the

blood

Negative consequences

- increased blood pressure, and following

increased preload (increased blood volume

arriving in the atria that the heart has to

pump back out)

- congestive heart failure occurs if the negative consequences outweighs the positive

consequences, and following backwards failure symptoms occur (congestion, edema etc.)

Relevant Drugs

- 5 categories

1) CARDIAC GLYCOSIDES (“DIGITALIS”)

- affect the heart in 2 ways

A) INHIBITION OF 3 SODIUM/2 POTASSIUM ANTIPORTER

- normally consumed with maintaining normal resting membrane

potential of -90mV by continuously pumping sodium out of the cell

and potassium into the cell

- 2 consequences

CONSEQUENCE DESCRIPTION

- 14 -

POSITIVE BATHMO-

TROPIC EFFECT

- due to decreased negative

membrane potential and following

easier excitability of the myocytes

POSITIVE IONO-

TROPIC EFFECT

- due to increased intracellular

sodium and following disruption of

the sodium gradient across the

sarcolemma

- in turn, this disrupts the

sarcolemmal sodium/calcium

antiporter normally consumed with

restoring the normal intracellular

calcium balance following a

depolarization

- this leads to increased intracellular

calcium, and forces the cell to pump

more calcium into the sarcoplasmic

reticulum instead

- finally, upon the successive

depolarization more calcium will be

released from the sarcoplasmic

reticulum, thus amplifying the force

of contraction

B) INCREASED VAGAL TONE (CENTRAL STIMULATION OF

VAGAL NUCLEI)

- 2 consequences

CONSEQUENCE DESCRIPTION

NEGATIVE CHRONO-

TROPIC EFFECT

- due to depression of the SA-node

and following decreased heart rate

NEGATIVE DROMO-

TROPIC EFFECT

- due to depression of the AV-node

and following decreased AV

conduction

- 2 types


DIGOXIN General information

- found in foxgloves

- administered orally (and IV in

emergencies)

- effective dose and toxic dose has a

very small margin

- 15 -

- eliminated by the kidneys

Medical uses

- treatment of heart failure

- treatment of atrial fibrillation

(negative dromotropic effect)

Side effects

- bradycardia (negative chronotropic

effect)

- AV block (negative dromotropic

effect)

- ventricular extrasystole, ventricular

paroxysmal tachycardia and/or

ventricular fibrillation (positive

bathmotropic effect)

- vomiting (stimulation of area

postrema)

Contraindications

- kidney problems (eliminated by the

kidneys)

- hypokalemia (amplified inhibition

of the 3 sodium/2 potassium

antiporter)

- hypercalcemia (even stronger

positive ionotropic effect)

- beta-adrenergic

antagonists/verapamil (even stronger

negative chronotropic- and

dromotropic effect)

OUABAIN General information

- same as digoxin

2) DIRECT VASODILATORS

- decrease total peripheral resistance

- see 28

3) DRUGS ACTING ON THE RENIN-ANGIOTENSIN-ALDOSTERONE

SYSTEM

- decrease blood volume, decrease arterial vasoconstriction and decrease

hypertrophy/hyperplasia of cardiac muscle

- see 24

- 16 -

4) DIURETICS

- decrease blood volume

- see 25

- 17 -

27. ANTIANGINAL DRUGS. DRUGS THAT INCREASE

REGIONAL BLOOD FLOW

ANTIANGINAL DRUGS

Overview

- angina pectoris is reversible myocardial ischemia due to a coronary artery disorder

- there are 4 (5) types of angina

TYPE DESCRIPTION

SILENT MYOCARDIAL ISCHEMIA

STABLE ANGINA

- narrowed coronary artery lumen

UNSTABLE ANGINA - occluded coronary artery lumen

MIXED ANGINA - both narrowed and occluded lumen at distinct

locations

PRINZMETAL ANGINA - vasospasms of the coronary arteries

- if angina pectoris remains untreated it can progress to irreversible myocardial ischemia (acute

myocardial infarction, AMI)

Relevant Drugs

- 3 categories

1) ORGANIC NITRATES

- reacts with tissue sulfhydryl (-SH) groups to form nitric oxide (NO), thus

inducing systemic vasodilation

- affects the heart in 2 ways

CAUSE CONSEQUENCE

INCREASED MYOCARDIAL

BLOOD SUPPLY

Increased myocardial oxygen supply

- general coronary artery vasodilation

(resolves prinzmetal angina)

- vasodilation of collaterals of the

coronary arteries to supply the

ischemic area of the myocardium

(resolves stable- unstable- and mixed

angina)

DECREASED MYOCARDIAL Decreased myocardial oxygen

- 18 -

WORKLOAD consumption

- decreased preload (venous

vasodilation)

- decreased afterload (arterial

vasodilation)

- 3 types


GLYCEROL TRINITRATE

(NITROGLYCERIN)

General information

- lipophilic

- administered sublingually,

transdermally or IV


Medical uses

- prophylaxis of stable angina

(administered sublingually or

transdermally)

- treatment of stable angina

(administered sublingually)

- treatment of unstable angina

(administered IV)

- treatment of acute heart failure

(administered IV)

Side effects

- postural hypotension (venous

vasodilation)

- headache (meningeal artery

vasodilation)

AMYL NITRATE General information

- same as glycerol trinitrate

ISOSORBIDE

MONONITRATE

General information


Medical uses

- prophylaxis of stable angina

- treatment of chronic heart failure

Side effects

- same as glycerol trinitrate

- 19 -

2) CALCIUM CHANNEL BLOCKERS

- causes arterial vasodilation and decreases sympathetic action on the heart,

thus both increasing myocardial blood supply and decreasing myocardial

workload

- see 23


- decreases sympathetic action on the heart, thus decreasing myocardial

workload

- contraindicated in prinzmental angina (beta-1 adrenergic receptor antagonists

are not completely selective, thus might cause coronary artery

vasoconstriction)

- see 21

DRUGS THAT INCREASE REGIONAL BLOOD FLOW

Overview - …

- 20 -

28. ANTIHYPERTENSIVE DRUGS Overview

- blood pressure is given by 2 parameters

PARAMETER DESCRIPTION

CARDIAC OUTPUT - given by the rate and stroke volume of the

heart

TOTAL PERIPHERAL RESITANCE

- given by the blood volume and the level of

vasoconstriction

- hypertension is a pathologically increased blood pressure due to an increase in any of these

parameters

Relevant Drugs

- 8 categories


- dilate the blood vessels, thus decreasing total peripheral resistance

- 4 types


MINOXIDIL General information

- activates potassium channels, thus causing

outflux of potassium

- this leads to hyperpolarization of the cell, and

following vasodilation

- strong, long acting vasodilator

- administered IV

Medical uses

- last resort in treatment of severe hypertension

Side effects

- reflex tachycardia

- increased blood volume (activation of the renin

angiotensin aldosterone system)

- hirsutism (increased facial- and body hair

growth)

HYDRALAZINE General information

- inhibits calcium release from sarcoplasmic

- 21 -

reticulum during depolarization, thus leading to

decreased vasoconstriction

- administered IV

Medical uses

- short-term treatment of hypertension

Side effects

- same as minoxidil

- SLE-like disorder (autoantibodies against own

DNA)

NITROPRUSSIDE General information

- inorganic nitrate

- administered IV

- same as organic nitrates (see 27)

DIAZOXIDE General information

- non-diuretic thiazide

- administered IV

- same as thiazide diuretics (see 25)


- cause arterial vasodilation and decrease the tropic effect of the heart, thus

causing both decreased cardiac output and total peripheral resistance

- see 23

3) ORGANIC NITRATES

- cause both arterial and venous vasoldilation, thus decrease total peripheral

resistance

- see 27

4) ALPHA-2 ADRENERGIC RECEPTOR AGONISTS

- inhibit the sympathetic vasomotor center in the brain stem and the

sympathetic- and parasympathetic ganglia, thus causing vasodilation and

following decreased total peripheral resistance

- see 19

5) ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISTS

- cause vasodilation, thus decreasing total peripheral resistance

- see 20

- 22 -


- decrease sympathetic action on the heart, thus decreasing cardiac output

- see 21

7) DRUGS ACTING ON THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM

- cause vasodilation and decreased blood volume, thus decreasing total

peripheral resistance

- see 24

8) DIURETICS

- decrease blood volume, thus decreasing total peripheral resistance

- see 25

- 23 -

29. ANTIARRHYTHMIC DRUGS Overview

- action potential in myocytes has 4 (5) phases

PHASE DESCRIPTION

PHASE 0 Rapid depolarization

- due the myocyte reaching a membrane potential

of -60 mV (critical firing threshold) and following

opening of the activation gates of voltage-gated

sodium channels

- this leads to rapid influx of sodium and

following depolarization

PHASE 1

Partial repolarization

- due to the myocyte reaching +40 mV and

following closing of the inactivation (refractory)

gates of the voltage-gated sodum channels

- partial repolarization is done by outflux of

potassium through the normal potassium-sodium

leak channels

PHASE 2 Plateau

- due to the myocyte reaching 0 mV and following

activation of voltage-gated calcium channels of

the sarcoplasmic reticulum

- this leads to release of large quantities of calcium

into the sarcoplasm, and following initiation of

muscle contraction

PHASE 3 Repolarization

- due to the myocyte reaching –10 mV and

following inactivation of the voltage-gated

calcium channels

- repolarization is done by the same mechanism as

with partial repolarization (see above)

PHASE 4 Pacemaker potential

- due to the myocyte reaching -90 mV (resting

membrane potential) and following activation of a

special sodium-potassium leak channel (only

found in SA-node, AV-node, and purkinje fibers)

that opposes the normal potassium-sodium leak

channel (found in all cells capable of depolarizing)

- this leads to a steadily increasing membrane

potential, thus initiating the successive

depolarization at -60 mV (phase 0)

- 24 -

- there are 4 types of cardiac arrhythmias

TYPE DESCRIPTION

ACTIVE ECTOPIC BEATS

(SUPRAVENTRICULAR-,

VENTRICULAR-)

General information

- “extrasystole”, “premature beat”

- 1 beat occurring before it would have been

expected originating outside the AV-node

- due to irritation of the myocardium

Causes

- excess sympathetic tone

- ischemia

- small calcified plaques

- myocardial toxins (alcohol, caffeine, nicotine,

drugs etc.)

PAROXYSMAL TACHYCARDIA

(SUPRAVENTRICULAR-,

VENTRICULAR-)

General information

- heart rate above 150 BPM

- due to successive active ectopic beats (see

above) or the presence of a reentrant circuit (see

below)

FLUTTER (ATRIAL-) General information


- due to the presence of 1 reentrant circuit

Causes

- presence of extranodal conducting pathways

(wolff-parkinson-white syndrome etc.)

- increased distance of conductance

(atrial/ventricular dilation)

- decreased velocity of conduction (ischemia,

excess parasympathetic activity etc.)

- decreased refractory period (excess sympathetic

activity etc.)

FIBRILLATION (ATRIAL-,

VENTRICULAR-)

General information


- due to the presence of multiple reentrant circuits

(see above)

- 25 -

Relevant Drugs

- antiarrhythmic drugs may be divided in 4 classes (vaughan williams’ system)

1) CLASS I ANTIARRHYTHMIC DRUGS

- blocks the voltage-gated sodium channels (phase 0), thus decrease

excitability of the myocardium

- are use-dependent, thus blocking stronger sites of the myocardium that more

frequently depolarize

- may be further subdivided in 3 groups

A) CLASS Ia ANTIARRHYTHMIC DRUGS

- cause intermediate voltage-gated sodium channel block

- also block potassium-sodium leak channels (phase 1 and phase 3), thus

increase duration of repolarization (refractory period)

- 2 types


QUINIDINE General information


- also has an atropine-like effect

Medical uses

- treatment of ventricular arrhythmias

Side effects

- ventricular paroxysmal tachycardia

(“torsade de pointes”, due to prolonged

refractory period)

- any side effect of muscarinic antagonists

(atropine-like effect, see 15)

- thrombocytopenia (autoantibodies against

platelets)

DISOPYRAMIDE General information

- same as quinidine

PROCAINAMIDE General information

- administered IV

Medical uses

- treatment of ventricular arrhythmias

Side effects


- SLE-like disorder (autoantibodies against

own DNA)

- 26 -

B) CLASS Ib ANTIARRHYTHMIC DRUGS

- cause weak voltage-gated sodium channel block

- selectively block refractory voltage-gated sodium channels

- 2 types


LIDOCAINE General information

- local anaesthetic (see 22)

- administered IV


Medical uses

- treatment of arrhythmias associated with

irreversible myocardial ischemia (AMI, due

to selective refractory blockage)

- local anaesthesia

Side effects

- see 22

PHENYTOIN General information

- antiepileptic drug (see 43)


- same as lidocaine

Medical uses


irreversible myocardial ischemia (AMI, due

to selective refractory blockage)


Side effects

- see 43

C) CLASS Ic ANTIARRHYTHMIC DRUGS

- cause strong voltage-gated sodium channel block

- 2 types


FLECAINIDE Medical uses


reentrant circuits (strong general

suppression)

- 27 -

Side effects

- heart failure (in patients with symptoms,

due to strong general suppression)

ENCAINIDE General information

- same as flecainide

2) CLASS 2 ANTIARRHYTHMIC DRUGS

- beta-adrenergic receptor antagonists

- block voltage-gated sodium- (phase 0) and calcium channels (phase 2), thus

decrease excitability and force of contraction of the myocardium

- used in treatment of arrhythmias associated with excess sympathetic tone

- see 21


- block the potassium-sodium leak channels (phase 1 and phase 3), thus

increase duration of repolarization (refractory period)

- 3 types


AMIODARONE General information

- iodine-containing compound

- accumulates in tissues


Medical uses


reentrant circuits (prolonged refractory

period)

Side effects


(prolonged refractory period)

- hypo- or hyperthyroidism (iodine, tissue

accumulation)

- photosensitivity (iodine, tissue

accumulation)

- skin discoloration (iodine, tissue

accumulation)

- visual disturbances (accumulation in the

cornea, due to iodine-content and tissue

accumulation)

- neurological disturbances (tissue

accumulation)

- 28 -

SOTALOL General information


- also a beta-adrenergic receptor antagonist

(see 21)

Medical uses


reentrant circuits


excess sympathetic activity

Side effects

- see 21


- calcium channel blockers

- block voltage-gated calcium channels, thus decrease force of contraction

- used in treatment of supraventricular/atrial arrhythmias

- see 23

- 29 -

30. DRUGS USED TO TREAT HYPERLIPOPROTEINEMIA Overview

- triglycerides and cholesterol are transported in lipoproteins in the circulation

- lipoproteins consists of 2 parts

PART DESCRIPTION

MEDULLA - hydrophobic

- consists of triglycerides and cholesterol esters

CORTEX

- hydrophilic

- consists of phospholipids, cholesterol and

apolipoproteins

- there are 5 types of lipoproteins

TYPE DESCRIPTION

CHYLOMICRON - transports triglycerides and cholesterol from the

intestines to muscle- and adipose tissue

- here, the triglycerides are split to free fatty acids by

lipoprotein lipase and the free fatty acids taken up by

these tissues

CHYLOMICRON REMNANT - transports the cholesterol and remaining triglycerides

remaining in the chylomicron to the liver

- here, the cholesterol is converted to bile salts and

secreted through the bile into the intestines for

absorption of new lipids and cholesterol

(enterohepatic bile circulation)

VLDL Very low density lipoprotein

- transports newly synthesised triglycerides and

cholesterol from the liver back to muscle- and adipose

tissue

- here, all the triglycerides are split by lipoprotein

lipase and taken up by these tissues

LDL Low density lipoprotein

- transports the remaining cholesterol either back to

the liver for conversion to bile acids, or to extrahepatic

tissues for metabolism

HDL High density lipoprotein

- a scavenger lipoprotein that adsorbs cholesterol

- 30 -

derived from cell breakdown and transfers it to vLDL

and LDL

- if VLDL and/or LDL concentration increases, there will be a higher probability of

atherosclerosis

- if HDL increases, there will be a lower probability of atherosclerosis

Relevant Drugs

- 3 categories

1) STATINS

- statins are HMG-CoA (3-hydroxy-3- methylglutaryl-coenzyme A) reductase

inhibitors

- HMG-CoA catalyzes the rate limiting step of cholesterol synthesis in the

liver, thus blocking it will lead to a relative deficiency of cholesterol for

synthesis of bile acids

- this leads to upregulation of LDL receptors, and following removal of LDL

from the circulation

- statins also reduce VLDL production

- 4 types


MEVASTATIN General information

- found in fungus


- extensive first-pass

metabolism (, though the site

of action is the liver)

Medical uses

- reduction of LDL and

VLDL

Side effects

- mild GI disturbances

- mild sleep disturbances

- mild skin rashes

LOVASTATIN General information

- same as mevastatin

SIMVASTATIN General information

- synthetic pro-drug

- same as mevastatin

- 31 -

PRAVASTATIN General information

- same as simvastatin

2) FIBRATES

- fibrates are PPAR-alpha (peroxysome proliferator-activated receptor alpha)

agonists

- PPAR-alpha is an intracellular receptor regulating gene transcription of

proteins responsible for lipid metabolism

- consequences of PPAR-alpha upregulation include

CONSEQUENCE CAUSE

DECREASED LIPID STORES - increased deliberation of

lipids from adipose tissue

DECREASED CIRCULATING LIPIDS - increased lipoprotein lipase

activity

- increased beta-oxidation

DECREASED CIRCULATING VLDL - decreased VLDL

production

DECREASED CIRCULATING LDL - increased LDL-receptor

expression

- 3 types


FENOFIBRATE Gereral information


Medical uses

- reduction of VLDL

- reduction of VLDL and

LDL

Side effects

- myositis (inflammation of

muscle)

- acute renal failure (due to

myositis and following

hemoglobinuria)

- mild GI disturbances

- 32 -

CIPROFIBRATE General information

-same as fenofibrate

BENZAFIBRATE General information

-same as fenofibrate

3) RESINS

- resins complex with bile salts in the intestines, thus inhibiting reabsorption

through the enterohepatic circulation

- this results in deficiency of bile acids, upregulation of LDL receptors, and

following removal of LDL from the circulation

- 2 types


COLESTYRAMINE Gereral information


Medical uses

- reduction of LDL

Side effects

- nausea

- vomiting

- bloating

- constipation or diarrhea

- fat-soluble vitamin

deficiency

COLESTIPIL General information

-same as colestyramine

- 33 -

31. ANTICOAGULANTS. FIBRINOLYTICS.

ANTIFIBRINOLYTICS. ANTIPLATELET DRUGS

Overview - hemostasis consists of 4 (5) mechanisms

MECHANISM DESCRIPTION

VASOCONSTRICTION - both neurally- and humorally mediated

PLATELET PLUG FORMATION - adhesion of platelets to the damaged endothelium

COAGULATION - blood clot formation by activation of fibrin

through the intrinsic- or extrinsic coagulation

cascade

PERMANENT CLOSURE - growth of fibrous tissue by conversion of smooth

muscle cells of the vessel walls to myofibroblasts

FIBRINOLYSIS - removal of the blood clot by activation of

plasmin

ANTICOAGULANTS

Overview

- anticoagulants are drugs that interfere with the coagulation factors (“serine proteases”) of the

extrinsic- and intrinsic coagulation pathways, thus inhibiting coagulation

Relevant Drugs

- 2 categories

1) INJECTABLE ANTICOAGULANTS

- injectable anticoagulants bind to the allosteric seat of antithrobin III, thus

activating it

- antithrombin III is a serine protease inhibitor responsible for inhibition of

activated coagulation factors

- , thus activation of antithrombin III leads to decreased activation of fibrin and

following inhibition of coagulation

- 2 types


HEPARIN General information

- 34 -

- endogenous compound found in the granules of mast

cells

- sulfated glycosaminoglycan (large, negatively

charged)

- extracted from bovine lung and/or hog intestine

- digested in the GI

- administered IV or subcutaneously (cause hematomas

if injected intramuscularly due to its large molecular

size)

- contains a second binding site for factor XII, XI, IX

and II (thrombin), thus accelerating their inactivation

by antithrombin III

- also accelerate inactivation of factor X

(independently of the second binding site)

Medical uses

- treatment of thrombosis, DIC and emboli

Side effects

- hemorrhage (clotting factor inhibition)

- thrombosis/DIC (autoantibodies against heparin-

platelet factor 4 complexes (and following

thrombocytopenia) and platelet factor 4-vascular

endothelium complexes)

- osteoporosis

LMWHS General information

- “low molecular weight heparins”

- fragments of heparin lacking the second binding site

- only accelerate inactivation of factor X

- administered subcutaneously

- same as heparin

2) ORAL ANTICOAGULANTS

- oral anticoagulants bind to the active site of vitamin K reductase, thus

inhibiting reduction of vitamin K to it’s active form

- reduced vitamin K is a cofactor of alpha-carboxylase, consumed with

modification of coagulation factor X, IX, VII and II (thrombin) after primary

protein translation

- only the modified coagulation factors are able to be activated, thus inhibition

of vitamin K reductase leads to decreased activation of fibrin and following

inhibition of coagulation

- 1 type


- 35 -

WARFARIN Gereral information

- also used in rat poison


- may cross the placenta

- only inhibits formation of new coagulation factors,

thus previously synthetized coagulation factors will

still be able to induce coagulation until they are

catabolized (around 48 hours)

Medical uses


Side effects

- hemorrhage (deceased clotting factor production)

- teratogenesis (may cross the placenta)

FIBRINOLYTICS

Overview

- fibrinolytics are drugs that increase activation of plasmin, thus increase fibrinolysis and

following removal of blood clots

Relevant Drugs

- 3 types


STREPTOKINASE General information

- streptococcal protein

- may only be administered once per year (antistreptococcal

antibodies will be formed within 1 week (!))

Medical uses


Side effects

- hemorrhage (fibrinolysis)

- stroke (hemorrhage)

- anaphylaxis (antistreptococcal antibodies)

ALTEPLASE General information

- recombinant tPA (“tissue plasminogen factor”, the physiological

- 36 -

protein responsible for plasmin activation)

- more active on plasminogen bound to fibrin (“clot selective”)

- very short half-life

- administered by IV infusion (very short half-life)

Medical uses


Side effects

- hemorrhage (fibrinolysis)

- stroke (hemorrhage)

RETEPLASE General information

- short half-life

- administered by IV bolus

- same as alteplase

ANTIFIBRINOLYTICS

Overview

- antifibrinolytics are drugs that inhibits activation of plasmin, thus decrease fibrinolysis and

following increase the integrity of blood clots

Relevant Drugs

- 1 type


TRANEXAMIC ACID General information


Medical uses

- treatment of severe hemorrhages

- treatment of fibrinolytic overdose

Side effects

- thrombosis

APOPROTININ General information

- inhibits proteolytic enzymes (including plasmin)

Medical uses

- 37 -

- treatment of fibrinolytic overdose

Side effects

- thrombosis

ANTIPLATELET DRUGS

Overview

- antiplatelet drugs are drugs that inhibit adhesion of platelets to the damaged endothelium,

thus inhibiting platelet plug formation

Relevant Drugs

- 4 categories

1) COX-1 INHIBITORS

- inhibits COX-1, thus inhibiting TXA2 (thromboxane A2) synthesis in platelets and

PGI2 (prostaglandin I2) synthesis in vascular endothelium

- TXA2 stimulates glycoprotein IIb/IIIa receptor expression on platelets while PGI2

inhibits it

- glycoprotein IIb/IIIa is the receptor responsible for platelet-platelet adhesion and

platelet-fibrinogen adhesion

- however, vascular endothelium is capable of syntethizing new COX-1 while platelets

are not, thus platelet plug formation is inhibited

- see 51/52

2) THIENOPYRIDINE DERIVATIVES

- inhibits ADP-mediated expression of glycoprotein IIb/IIIa, thus inbiting platelet plug

formation

- 2 types


TRICLOPIDINE General information

- pro-drug


Medical uses


Side effects

- hemorrhages

- blood dyscrasias

- diarrhea

- skin rashes

- 38 -

CLOPIDOGREL General information

- same as triclopidine

3) GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONITS

- antagonizes TXA2 and ADP, thus inhibiting platelet plug formation

- 2 types


ABCIXIMAB General information

- hybride rodent/human monoclonal antibody

- administered IV

- may only be administered once (antibodies against the

rodent part will be formed)

Medical uses


Side effects

- hemorrhages

TIROFIBRAN General information

- administered IV

Medical uses


Side effects

- hemorrhages

4) PGI2 AGONISTS

- inhibit expression of glycoprotein IIb/IIIa, thus inhibiting platelet plug formation

- 1 type


EPOPROSTENOL

- 39 -

32. DRUGS AFFECTING HEMATOPOIESIS

Overview - all blood cells originate from pluripotent stem cells of the bone marrow

- there are 5 types of blood cells

CELL TYPE DESCRIPTION

ERYTHROCYTES - RBCs

PLATELETS - cell fragments of megakaryocytes

MONOCYTES - differentiate to macrophages

GRANULOCYTES - neutrophils

- eosinophils

- basophils

LYMPHOCYTES - B lymphocytes

- T lymphocytes

- anemia is a decrease in circulating RBCs

- there are 4 types of anemia

TYPE DESCRIPTION

APLASTIC ANEMIA - due bone marrow failure

DEFICIENCY ANEMIA - normocytic, normochromic deficiency anemia (due to

erythropoietin and/or GM-CSF deficiency)

- microcytic, hypochromic deficiency anemia (due to

iron deficiency)

- macrocytic, hyperchromic anemia (due to folic acid

(vitamin B9) and/or cobolamin (vitamin B12)

deficiency)

HEMOLYTIC ANEMIA - due to increased sequestration of RBCs

HEMORRHAGIC ANEMIA - due to hemorrhages

Relevant Drugs

- 4 categories

- 40 -

1) IRON

- needed for the heme group of hemoglobin, thus deficiency leads to decreased

hemoglobin synthesis

- is utilized by the body in the ferrous (Fe2+) form

- 5 types


FERROUS SULFATE General information


Medical uses

- treatment of microcytic, hypochromic

deficiency anemia

Side effects

- nausea

- diarrhea

- abdominal cramps

FERROUS SUCCINATE General information

- same as ferrous sulfate

FERROUS GLUCONATE General information


FERROUS FUMARATE General information


IRON-DEXTRAN General information

- administered IV


2) FOLATE (“VITAMIN B9”)

- cofactor (methyl-group donor) in the synthesis of purines and pyrimidines

used for DNA- and RNA synthesis, thus deficiency leads to decreased DNA-

and RNA synthesis

- this is especially manifested in tissues with high cell turnover (bone marrow)

- is utilized by the body in the tetrahydrofolate (FH4) form

- is carried in the circulation as methyl-FH4

- the methyl group is removed by cobolamin (“vitamin B12”), thus cobolamin

is needed for it’s utilization

- 1 type


- 41 -

FOLATE Gereral information

- administered orally (parenterally in case

of malabsorption syndromes)

Medical uses

- treatment of macrocytic, hyperchromic

deficiency anemia

3) COBOLAMIN (VITAMIN B12)

- removes the methyl group of methyl-FH4, so that it can be utilized in purine

and pyrimidine synthesis

- 1 type


HYDROXYCOBOLAMIN Gereral information

- administered intramuscularly

(cobolamin deficiency is almost always

due to malabsorption syndromes)

Medical uses

- treatment of macrocytic, hyperchromic

deficiency anemia

4) CSFS (COLONY-STIMULATING FACTORS)

- CSFs are responsible for differentiating the pluripotent stem cells to all types

of commited progenitors of blood cells (except lymphocytes)

- they are also involved in final differentiation of all these cells (except

basophils)

- 2 types


GM-CSF Gereral information

- “granulocyte-macrophage colony-

stimulating factor”

- endogenous substance

- involved in differation of all cells

mentioned above

- administered IV or subcutaneously

Medical uses

- treatment of leucopenia (mainly

neutropenia)

Side effects

- 42 -

- fever

- skin rashes

- muscle pain

- muscle weakness

G-SCF Gereral information

- “granulocyte colony-stimulating factor”

- endogenous substance

- involved in differation of neutrophils

- administered IV or subcutaneously

Medical uses

- treatment of neutropenia

Side effects

- dysuria

- vasculitis

- 43 -

33. HISTAMINE, H1 AND H2 RECEPTOR ANTAGONISTS

Overview - histamine is a paracrine hormone and an inhibitory neurotransmitter

- histamine is primarily found in 3 locations

LOCATION DESCRIPTION

CNS - histaminergic neurons

SYSTEMIC CIRCULATION - granules of mast cells

- granules of basophils

GI TRACT - neuroendocrine cells in the glands of the GI

- histamine acts on histaminergic receptors

- there are 3 types of histaminergic receptors

RECEPTOR TYPE LOCATION

H1 - smooth muscle

- CNS

H2 - parietal cells of the castric glands

- heart

H3 - presynaptically in CNS neurons

General Effects

- 6 types

ORGAN DESCRIPTION

CNS - inhibition of neurotransmitter release

- nausea

HEART - positive chronotropic effect (increased heart rate)

- positive ionotropic effect (increased force of

contraction)

BLOOD VESSELS - vasodilation

- increased vascular permeability

- 44 -

RESPIRATORY TRACT - bronchoconstriction

GI TRACT - increased gastric acid secretion

- GI smooth muscle contraction

GENITO-URINARY TRACT - contraction of uterus

Relevant Drugs

- 2 categories

1) H1 RECEPTOR ANTAGONISTS (“ANTIHISTAMINES”)

- histamine acting on H1 receptors in smooth muscle is the main mediator of

the symptoms of anaphylaxis (type 1 hypersensitivity reactions)

- histamine acting on H1 receptors in the CNS is also a mediator of nausea

- H1 receptor antagonists are reversible competitive antagonists of histamine,

thus blocking it’s action

- many of the H1 receptor antagonists are not completely selective to

histaminergic receptors, thus may antagonize other types of receptors as well

(see below)

- 5 types


PROMETAZINE General information

- marked muscarinic receptor antagonist

action

- weak alpha-1 adrenergic receptor antagonist

action

- weak local anaesthetic action


- may cross the blood-brain barrier

Medical uses

- treatment of emesis (especially motion

sickness)

- treatment of insomnia (sedative)

Side effects

- diarrhea/constipation (GI smooth muscle

contraction)

- same as muscarinic receptor antagonists

(see 15)

DIPHENHYDRAMINE General information

- marked muscarinic receptor antagonist

- 45 -

action

- weak local anaesthetic action


- may cross the blood brain barrier

- same as prometazine

CYCLIZINE General information



Medical uses

- treatment of emesis (especially motion

sickness)

Side effects

- diarrhea/constipation

- sedation

CINNARIZINE General information

- same as cyclizine

MEQUITAZINE General information

- administered orally, topically and/or IV

- does not cross the blood-brain barrier

Medical uses

- treatment of anaphylactic reactions (allergic

rhinitis, urticaria (allergic skin rashes), insect

bites, drug hypersensitivities etc.)

Side effects


CENTRIZINE General information

- same as mequitazine

FEXOFENADINE General information

- same as mequitazine

2) H2 RECEPTOR ANTAGONISTS

- H2 receptor antagonists decrease histamine-mediated gastric acid secretion

- H2 receptors antagonists also inhibit the secondary messenger systems of

gastrin- and acetylcholine-mediated gastric acid secretion

- 46 -

- , thus H2 receptor antagonists may decrease basal- and pranial gastric acid

secretion by over 90%

- they also promote healing of duodenal ulcers by a separate mechanism

- 4 types


CIMETIDINE Gereral information

- minor androgen receptor antagonism

- also inhibit cytochrome P450

- administered orally, intramuscularly or IV

Medical uses

- treatment of peptic ulcer (gastric- and/or

duodenal)

- treatment of reflux esophagitis

Side effects

- hypergastrinemia

- diarrhea

- gynecomastia (androgen receptor

antagonism)

RANTIDINE General information


Medical uses

- same as cimetidine

Side effects

- same as cimetidine (but no gynecomastia)

FAMOTIDINE General information

- same as rantidine

NIZATIDINE General information


- same as rantidine

- 47 -

34. SEROTONIN, SEROTONIN RECEPTOR AGONISTS AND

ANTAGONISTS

Overview - serotonin (“5-hydroxytryptamine”, “5-HT”), like histamine, is a paracrine hormone and an

inhibitory neurotransmitter

- biosynthesis and breakdown of serotonin is done in 3 steps (similar to that of catecholamines,

see 17)

TRYPTOPHAN

tryptophan hydroxylase

5-HYDROXYTRYPTOPHAN

DOPA decarboxylase

5-HYDROXYTRYPTAMINE (5-HT, SEROTONIN)

MAO + aldehyde dehydrogenase

5 HYDROXYINDOLEACETIC ACID (5-HIAA)

- serotonin is primarily found in 3 locations

LOCATION DESCRIPTION

CNS - serotonergic neurons

SYSTEMIC CIRCULATION - platelets

GI TRACT - neuroendocrine cells in the glands of the GI

- myenteric plexus

- serotonin acts on serotonergic receptors

- there are 8 types of serotonergic receptors

RECEPTOR TYPE DESCRIPTION

5-HT 1A Location

- CNS

Effect

- CNS depression

- anxiolysis

- alertness

- 48 -

5-HT 1B Location

- CNS

- pulmonary vasculature

Effect

- CNS depression

- pulmonary vasoconstriction

5-HT 1D Location

- CNS

- cerebral vasculature

Effect

- CNS depression

- cerebral vasoconstriction

5-HT 2A Location

- CNS

- smooth muscle

- platelets

Effect

- CNS excitation

- hallucination

- arterial- and venous vasoconstriction

- arteriolar vasodilation

- bronchoconstriction

- contraction of the uterus

- platelet plug formation (platelet aggregation)

5-HT 2B Location

- stomach

Effect

- gastric smooth muscle contraction

5-HT 2C Location

- choroid plexus of the CNS

Effect

- secretion of cerebrospinal fluid

5-HT 3 Location

- 49 -

- CNS

- chemoreceptive trigger zone of area postrema in the

CNS

- spinal cord analgesic system

Effect

- CNS excitation

- nausea

- vomiting

- analgesia

5-HT 4 Location

- smooth muscle of the GI tract

Effect

- increased peristalsis

- neither selective serotonin receptor agonists nor –antagonists are completely selective, thus

may exhibit other effects on any of the other types of serotonin receptors

SEROTONIN RECEPTOR AGONISTS

Relevant Drugs

- 3 categories

1) 5-HT 1 AGONISTS

- 3 types


BUSPIRONE Medical uses

- treatment of anxiety (CNS depression)

Side effects

- restlessness (alertness)

- headache

- nausea (effect on 5-HT 3 receptors)

SUMATRIPTAN General information

- 5-HT 1D selective agonist

- do not cross the blood-brain barrier


- administered orally or subcutaneously

- 50 -

Medical uses

- treatment of migraine (vasoconstriction of

meningeal blood vessels)

Side effects

- cardiac ischemia (coronary artery

vasoconstriction)

ERGOTAMINE General information

- found in the ergot fungus

- 5-HT 1 partial agonist on blood vessels

- 5-HT 1 antagonist in all other locations

- 5-HT 2 agonist

- also an alpha-adrenergic receptor agonist (see 19)

- related to ergometrine (see 35)


- administered IV, rectally or by inhalation

Medical uses

- treatment of migraine (vasoconstriction of

meningeal blood vessels and inhibition of

nocioceptive transmission)

- treatment of postpartum hemorrhage

Side effects

- hypertension (vasoconstriction)

- coronary ischemia (vasoconstriction)

- nausea

- vomiting

2) 5-HT 2 AGONISTS

- 1 type


LSD General information

- see 48

3) 5-HT 4 AGONISTS

- 1 type


- 51 -

CISAPRIDE General information


Medical uses

- treatment of reflux esoophagitis (increased tone of

lower esophageal sphincter)

- disorders of gastric emptying (increased tone of

gastric smooth muscle)

- treatment of paralytic ileus (increased peristalsis)

Side effects

- diarrhea

- abdominal cramps

SEROTONIN RECEPTOR ANTAGONISTS

Relevant Drugs

- 2 categories

1) 5-HT 2 ANTAGONISTS

- 2 types


METHYLGLYCERGIDE General information

- also partial 5-HT 2 agonist


Medical uses

- prophylaxis of migraine (cerebral blood

vessel vasodilation)

Side effects

- nausea

- vomiting

- retroperitoneal/mediastinal fibrosis

CYPROHEPTADINE General information

- also histaminergic receptor antagonist

(see 33)


Medical uses

- 52 -

- prophylaxis of migraine (cerebral blood

vessel vasodilation)

Side effects

- sedation

- weight gain

2) 5-HT 3 ANTAGONISTS

- 2 types


ONDASETRON General information


Medical uses

- treatment of emesis (vomiting)

- treatment of anxiety

TROPISETRON General information

- same as ondasetron

- 53 -

35. PHARMACOLOGY OF EICOSANOIDS. DRUGS ACTING

ON THE SMOOTH MUSCLE: SMOOTH MUSCLE

RELAXANTS; PHARMACOLOGY OF THE UTERINE

SMOOTH MUSCLE

PHARMACOLOGY OF EICOSANOIDS

Overview - eicosanoids are autocrine- and paracrine mediator molecules of many important

physiological- and pathological processes

- there are 3 groups of eicosanoids

GROUP TYPE

PROSTAGLANDINS - PGD2

- PGE2

- PGF2-alpha

- PGI2

TROMBOXANES - TXA2

LEUKOTRIENES - LTB4

- LTC4

- LTD4

- LTE4

- they are synthesized from arachidonic acid (“5,8,11,14-eicosatetraenoic acid”) which is found

as arachidonic acid esters in phospholipids

PHOSPHOLIPIDS

phospholipase A2

ARACHIDONIC ACID

COX (“cyclooxygenase”, see 51/52) 5-lipoxygenase

PROSTAGLANDINS/ LEUKOTRIENES

TROMBOXANES

- there are 9 types of eicosanoid receptors

RECEPTOR TYPE DESCRIPTION

- 54 -

DP (PGD2) RECEPTORS Location

- blood vessels

- uterus

- GI tract

- platelets

- pituitary gland

Effect

- vasodilation

- uterine smooth muscle relaxation

- GI tract smooth muscle relaxation

- inhibition of platelet aggregation

- regulation of pituitary hormone release

EP1 (PGE2) RECEPTORS Location

- lungs

- GI tract

- CNS

- C nerve fibers

Effect


- GI tract smooth muscle contraction

- fever (increase the hypothalamic temperature set point)

- hyperalgesia (sensitization of afferent C nerve fibers, see

49)


- blood vessels

- lungs

- GI tract

Effect

- vasodilation

- bronchodilation

- GI tract smooth muscle relaxation

- intestinal fluid secretion


- uterus

- GI tract

- autonomic nervous system

- adipose tissue

- 55 -

Effect

- pregnant uterine smooth muscle contraction

- GI tract smooth muscle contraction

- inhibition of gastric acid secretion

- gastric mucous secretion

- inhibition of autonomic neurotransmitter release

- inhibition of lipolysis

FP (PGF2-alpha)

RECEPTORS

Location

- uterus

Effect

- uterine smooth muscle contraction

IP (PGI2) RECEPTORS Ligand

- PG12

Effect

- vasodilation

- inhibition of platelet aggregation

- renin release

- hyperalgesia (sensitization of afferent C nerve fibers)

TP (TXA2) RECEPTORS Location

- blood vessels

- platelets

Effect

- vasoconstriction

- platelet aggregation

BLT (LTB4) RECEPTORS Location

- neutrophils

- macrophages

- lymphocytes

Effect

- neutrophil/macrophage chemotaxis

- neutrophil degranulation

- macrophage/lymphocyte cytokine release

- macrophage/lymphocyte proliferation

- 56 -

CYSLT (LTC4, LTD4,

LTE4) RECEPTORS

Location

- blood vessels

- lungs

Effect

- vasodilation

- increase vascular permeability


- bronchial mucous secretion

SMOOTH MUSCLE RELAXANTS

Overview - …

PHARMACOLOGY OF THE UTERINE SMOOTH MUSCLE

Overview - the uterine smooth muscle, like the heart, contains pacemaker cells, thus possessing the

ability of spontaneous rhythmic contractions

- the rhythmic contractions are under hormonal control

ACTION HORMONE

FACILITATION - progesterone

- oxytocin

INHIBITION - estrogen

- the rhythmic contractions take part in several important events of the uterus, thus the

hormones controlling them partially- or completely give the outcome of these events

EVENT DESCRIPTION

MENSTURAL CYCLE Pre-ovulatory phase

- weak rhythmic contractions (estrogen)

Post-ovulatory phase

- strong rhythmic contractions (progesterone)

PREGNANCY Pregnancy

- very weak (or absent) rhythmic contractions

- 57 -

Delivery

- very strong rhythmic contractions (oxytocin)

- in addition, the uterine smooth muscle is also capable of contracting normally like any other

smooth muscle

- the normal contractions are under prostaglandin- and hormonal control

ACTION HORMONE

FACILITATION - PGE2 (EP3 receptors)

- PGF2-alpha

- histamine (H1 receptors)

- serotonin (5-HT 2A receptors)

INHIBITION - PGD2

- adrenalin (beta-2 receptors)

Relevant Drugs

- 2 categories

1) OXYTOCIC DRUGS

- facilitate uteral contraction

- 3 groups

A) OXYTOCIN RECEPTOR AGONISTS

- 1 type


OXYTOCIN General information

- endogenous hormone

- causes strong facilitation of the rhythmic

contractions of the uterus (labor)

- causes contraction of the mammary gland

(lactation)

- also causes vasodilation

- also has a weak antidiuretic effect

- administered IV or intramuscularly

Medical uses

- induction of labor (uteral contraction)

- augmentation of labor (uteral contraction)

- treatment of postpartum hemorrhage (uteral

- 58 -

contraction)

- treatment of milk congestion (mammary

gland contraction)

Side effects

- hypotension (vasodilation)

- reflex tachycardia (hypotension)

- water retention (antidiuretic effect)

B) ERGOT ALKALOIDS

- 2 types


ERGOMETRINE General information

- found in the ergot fungus

- 5-HT 2 receptor agonist

- beta-2 adrenergic receptor antagonist

- also a D2 receptor agonist

- causes strong contraction of the uterine

smooth muscle

- also causes vasoconstriction


Medical uses

- treatment of postpartum hemorrhage

Side effects


- angina (vasoconstriction)

- nausea (stimulation of the chemoreceptive

trigger zone)

- vomiting (nausea)

- headache

- blurred vision

ERGOTAMINE General information

- see 34

C) PROSTAGLANDIN ANALOGUES

- 3 types


- 59 -

DINOPROST General information

- synthetic PGE2 analogue

- causes simultaneous contraction of the

uterus and relaxation of the cervix

- administered orally or intravaginally

Medical uses

- induction of labor

- 2nd trimester abortion

Side effects

- uterine pain

- nausea

- vomiting

CARBOPROST General information

- synthetic PGF2-alpha analogue


- same as dinoprostone

MISOPROSTOL General information

- see 37

2) TOCOLYTIC DRUGS

- inhibit uteral contraction

- 2 groups

A) OXYTOCIN RECEPTOR ANTAGONISTS

- 1 type


ATOSIBAN General information

- oxytocin receptor antagonist

- administered IV

Medical uses

- prevention of premature labor

Side effects


- nausea

- vomiting

- hyperglycemia

- 60 -

- skin rashes

B) SELECTIVE BETA-2 ADRENERGIC RECEPTOR AGONISTS

- inhibit uteral contraction, thus preventing premature labor

- see 19

- 61 -

36. PHARMACOLOGY OF THE RESPIRATORY TRACT

Overview - asthma is a reversible obstructive disorder of the lungs

- asthma consists of 2 phases

PHASE DESCRIPTION

ACUTE PHASE - activation of mast cells mediated by IgE and

following secretion of cytokines

LATE PHASE - chemotaxis and activation of inflammatory cells

(especially eosinophils) and following secretion of

cytokines

- secreted cytokines include

CYTOKINE DESCRIPTION

ACUTE PHASE CYTOKINES - bronchoconstrictory cytokines

- chemotactic cytokines

LATE PHASE CYTOKINES - chemotactic cytokines

- inflammatory cytokines

- vasodilatory cytokines

- growth factors

- toxic proteins

BRONCHODILATOR DRUGS

Overview - used to treat the early phase of asthma

Relevant Drugs

- 5 categories

1) BETA-2 ADRENERGIC RECEPTOR AGONISTS

- stimulates beta-2 adrenergic receptors, thus causing bronchodilation

- also inhibits release of bronchoconstrictors from activated mast cells

- administered by aerosol, orally or IV

- may pass onto the systemic circulation, thus may cause systemic side effects

- see 19

- 62 -

2) MUSCARINIC RECEPTOR ANTAGONISTS

- blocks muscarinic receptors (M3 receptors in this case), thus causing

bronchodilation and inhibition of bronchial hypersecretion

- administered by aerosol in conjunction with beta-2 adrenergic receptor

agonists

- do not pass into the systemic circulation, thus do not cause systemic side

effects

- see 15

3) HISTAMINERGIC H1 RECEPTOR ANTAGONISTS

- blocks histaminergic H1 receptors, thus causing bronchodilation and

vasoconstriction (decreased capillary permeability and following decreased

pulmonary transudation) - administered in conjunction with beta-2 adrenergic receptor agonists - see 33

4) CYSTEINYL-LEUKOTRIENE RECEPTOR ANTAGONISTS

- the bronchoconstrictory leukotrienes secreted by the activated mast cells act

on cysteinyl-leukotriene receptors - cysteinyl-leukotriene receptor antagonists block the cysteinyl-leukotriene

receptors, thus causing bronchodilation - administered in conjunction with beta-2 adrenergic receptor agonists - 2 types


MONTELUKAST General information


Medical uses

- treatment of asthma

Side effects

- headache

- constipation/diarrhea

ZAFIRLUKAST General information

- same as montelukast

5) METHYLXANTHINES

- methylxanthines inhibit adenylyl cyclase, thus leading to decreased formation

of cAMP and following broncodilation

- 63 -

- see 48

ANTI-INFLAMMATORY DRUGS

Overview - used to treat the late phase of asthma

Relevant Drugs

- 2 categories

1) GLUCOCORTICOIDS

- inhibit synthesis all the late phase cytokines (see above), thus decreasing

inflammatory cell chemotaxis, inflammation, edema (vasodilation/increased

capillary), hypertrophy/hyperplasia and bronchial epithelial damage

- see 55

2) CROMOGLICATE

- inhibits the neuronal respones of bronchial epithelial damage, thus causing

bronchodilation, decreased bronchosecretion and decreased cough

- also inhibits secretion of chemotactic cytokines by the inflammatory cells

- 2 types


CROMOGLICATE General information

- administered by aerosol in conjunction

with glucocorticoids

Medical uses


Side effects

- irritation of the upper airways

NEDOCROMIL SODIUM General information

- same as cromoglicate

ANTITUSSIVES

Overview - antitussives (“cough suppressants”) are opioid analogues that depress the brain stem

(including the cough center), thus suppressing the cough reflex

- 64 -

Relevant Drugs

- 3 types


CODEINE General information

- see 49

DEXTROMETHORPHAN General information

- analgesic opioid analogue

- same as codeine

PHOLCODINE General information

- non-analgesic opioid analogue

- 65 -

37. PHARMACOLOGY OF THE GASTROINTESTINAL TRACT:

DRUGS IN THE TREATMENT OF PEPTIC ULCER;

EMETICS, ANTI-EMETICS

DRUGS IN THE TREATMENT OF PEPTIC ULCER

Overview - the lumen of the GI tract is a very extreme environment consisting of extreme amounts of

potentially damaging substances

- to maintain the integrity of the intestinal mucosa there has to be a balance between the

protective- and the aggressive factors

- these factors include

TYPE FACTOR

PROTECTIVE FACTORS - mucin

- bicarbonate (HCO3-)

- blood flow

AGGRESSIVE FACTORS - hydrochloric acid (HCl)

- pepsin (gastric protease)

- gastric acid secretion by the parietal cells are regulated by 5 (3+2) substances

REGULATION SUBSTANCE

STIMULATION - acetylcholine

- gastrin

- histamine

INHIBITION - PGE2

- PGI2

Relevant Drugs

- 5 categories


- H2 receptor antagonists decrease histamine-mediated gastric acid secretion

- H2 receptors antagonists also inhibit the secondary messenger systems of

gastrin- and acetylcholine-mediated gastric acid secretion

- , thus H2 receptor antagonists may decrease basal- and pranial gastric acid

secretion by over 90%

- they also promote healing of duodenal ulcers by a separate mechanism

- see 33

- 66 -


- muscarinic receptor antagonists decrease acetylcholine-mediated gastric acid

secretion, thus decreasing both basal- and pranial gastric acid secretion

- see 15

3) HYDROGEN ION/POTASSIUM ANTIPORTER INHIBITORS

- hydrogen ion/potassium antiporter inhibitors irreversibly inhibit the hydrogen

ion/potassium antiporter responsible for secretion of hydrogen ions into the

parietal cell canaliculi, thus decreasing both basal- and pranial gastric acid

secretion

- 3 types


OMEPRAZOLE General information


- is degraded rapidly by the gastric

acid, thus must be administered in

enteric-coated granules for absorption

into the systemic circulation in the

small intestine

- weak base, thus, once reaching the

parietal cells through the systemic

circulation, it will be trapped in the

acidic environment of the parietal cell

canaliculi

Medical uses

- treatment of peptic ulcer


- treatment of hypergastrinemia

Side effects

- severe diarrhea

- severe headache

- mild gynecomastia

- mild impotence

- mild joint/muscle pain

LANSOPRAZOLE General information

- same as omeprazole

PANTOPRAZOLE General information

- same as omeprazole

- 67 -

4) ANTACIDS

- antacids chemically neutralize gastric acid - pepsin is only active at very low pH, thus neutralization of pH secondarily

inactivates pepsin - 4 types


MAGNESIUM HYDROXIDE General information


Medical uses

- treatment of duodenal ulcers (not

gastric-)

- treatment of dyspepsia


Side effects

- diarrhea

MAGNESIUM TRISILICATE General information

- also adsobs pepsin

- same as magnesium hydroxide

ALUMINIUM HYDROXIDE General information


- also adsorbs pepsin

Medical uses


Side effects

- constipation

SODIUM BICARBONATE General information

- very strong neutralizer (increase

gastric ph to 7,4 (!))

- deliberates carbondioxide


Medical uses


- 68 -

Side effects

- belching (deliberates carbondioxide)

- secondary hypergastrinemia

(stimulated by carbondioxide)

- metabolic alkalosis

5) MUCOPROTECTIVE DRUGS - 3 types


SUCRALFATE General information

- binds to positively charged proteins

(including glycoproteins of the gastric

mucous)

- forms a complex gel with the gastric

mucous


Medical uses

- treatment of gastric ulcer

Side effects

- constipation

- dry mouth

- nausea

MISOPROSTOL General information

- synthetic PGE1 analogue

- inhibits both basal- and pranial

gastric acid secretion

- increases secretion of bicarbonate

and mucous

- increases mucosal blood flow

- also causes simultaneous contraction

of the uterus and relaxation of the

cervix

- administered orally or intravaginally

(if used for 1st trimester abortion)

Medical uses

- treatment of peptic ulcer

- 1st trimester abortion (then

administered coherently with

mifepristone, see 57)

- 69 -

Side effects

- diarrhea

- abdominal cramps

CARBENOXOLONE General information

- found in liquorice root

- increases production of mucous

Medical uses

- treatment of gastric ulcer

EMETICS

Overview - emetics are used to induce vomiting in case of ingestion of toxic substances (poisons)

Relevant Drugs

- 1 type


IPECACUANHA General information


- contains 2 mucosal irritants (emetine and cephaeline), thus acting

peripherally to induce vomiting

ANTI-EMETICS

Overview - anti-emetics suppress one or more parts of the emetic reflex arch, thus preventing vomiting

Relevant Drugs

- 5 categories


- H1 receptor antagonists inhibit H1 receptors of the vestibular nuclei in the

CNS, thus inhibiting histamine-mediated emesis due to motion (motion

sickness)

- they also inhibit H1 receptors of the nucleus of the solitary tract (relay

nucleus for noxious stimuli of the GI tract), thus inhibiting emesis due to

ingestion of toxic substances

- see 33

- 70 -


- same as H1 receptor antagonists, though it acts on muscarinic receptors

- see 15

3) 5-HT 3 RECEPTOR ANTAGONISTS

- 5-HT 3 receptor antagonists inhibits 5-HT 3 receptors in the chemoreceptive

trigger zone, thus inhibiting emesis due to all type of noxious stimuli

(including chemotherapy-induced emesis)

- see 34

4) D2 RECEPTOR ANTAGONISTS

- D2 (dopaminergic) receptor antagonists are really antipsychotic drugs (see

41)

- D2 receptor antagonists also inhibit D2 receptors on the chemoreceptive

trigger zone, thus inhibiting emesis due to all types of noxious stimuli

- 3 groups

A) PHENOTHIAZINES

- see 41

B) BUTYROPHENONES

- see 41

C) OTHERS

- 2 types


DOMPERIDONE General information

- also increases tone of GI

smooth muscle

Medical uses

- treatment of chemotherapy-

induced emesis


(increased tone of lower

esophageal sphincter)

- treatment of disorders of

gastric emptying (increased

tone of the stomach smooth

muscle)

Side effects

- see 41

- 71 -

METOCLOPRAMIDE General information

- also increases tone if the GI

smooth muscle

- also stimulates prolactin

release

- may not cross the blood-brain

barrier, central side effects are

absent

Medical uses

- same as domperidone

Side effects

- hyperprolactinemia (increased

prolactin secretion)

5) CANABINOID RECEPTOR AGONISTS

- inhibit emesis due to substances directly stimulating the chemoreceptive

trigger zone (including chemotherapy-induced emesis)

- also decrease acetylcholine secretion of the myenteric plexus, thus decreasing

peristalsis

- 2 types


NABILONE General information

- synthetic THC derivative (see

48)


Medical uses

- conjunctive to 5-HT 3- and/or

D2 receptor antagonists in

treatment of chemotherapy-

induced emesis

- treatment of diarrhea

(decreased peristalsis)

Side effects

- see 48

DRONABINOL General information

- same as nabilone

- 72 -

38. PHARMACOLOGY OF THE GASTROINTESTINAL TRACT:

PROKINETIC DRUGS, LAXATIVES, ANTIDIARRHOEAL

AGENTS, DRUG TREATMENT OF INFLAMMATORY

BOWEL DISEASE AND PARALYTIC ILEUS, DIGESTIVES,

DRUGS USED IN CHOLELITHIASIS

Overview - peristalsis is driven by the parasympathetic nervous system (M2- and M3 muscarinic

receptors, see 14)

- the parasympathetic tone of the GI tract may be regulated in 2 ways

REGULATION RECEPTOR

STIMULATION - 5-HT 4 serotonergic receptors

INHIBITION - alpha-2 adrenergic receptors

- D2 dopaminergic receptors

- cannabinoid receptors

PROKINETIC DRUGS

Relevant Drugs

- 4 categories

1) LAXATIVES

- increase peristalsis without interfering with the normal neurohormonal

regulation

- 2 groups

A) BULK LAXATIVES (“FIBER”)

- bulk laxatives are polysaccaride polymers that are not broken down in

the GI tract

- they bind water physically in the intestinal lumen, thus increasing the

amount of feces left in the intestines

- this causes increased stretch of the wall of the GI tract, increased

activation of the cholinergic axons of the myenteric plexus, and

following increased peristalsis

- 3 types


METHYLCELLULOSE

- 73 -

BRAN

AGAR

B) OSMOTIC LAXATIVES

- osmotic laxatives are solutes that are not absorbed from the intestines

- they increase the colloid osmotic pressure of the intestinal lumen, thus

increasing the amount of water and following increased amount of

feces left in the intestines

- 3 types


LACTULOSE General information

- disaccaride of fructose and

galactose

- hydrolyzed and fermented by

bacteria to lactic- and acetic acid

which is not absorbed by the

enterocytes

Medical uses

- treatment of constipation

Side effects

- diarrhea

- flatulence

- abdominal cramps

MAGNESIUM SULFATE General information

- insoluble salt

Medical uses


Side effects

- diarrhea

MAGNESIUM HYDROXIDE General information

- same as magnesium sulfate

2) STIMULANT PURGATIVES

- 74 -

- increase GI secretion into the intestinal lumen, thus increasing the water

content and following amount of feces in the intestines

- also increase peristalsis


BISACODYL General information

- administered rectally

Medical uses


Side effects

- diarrhea

SODIUM PICOSULFATE General information


- same as bisacodyl

SENNA General information


- glycoside containing

anthracene derivatives

- hydrolyzed by bacteria to free

the antracene derivatives

- same as bisacodyl

3) PERISTALTICS

- fascilitate the parasymphatetic innervation of the intestines, thus increasing

acetylcholine release and following increased peristalsis

- 2 types

A) 5-HT 4 RECEPTOR AGONISTS

- see 34

B) D2 RECEPTOR ANTAGONISTS

- see 37

4) FECAL SOFTENERS

- decrease the surface tension of the feces, thus easing it’s transition through

the intestines

- 1 type


DOCUSATE SODIUM General information

- 75 -

- detergent

- also a weak laxative

Medical uses


ANTIDIARRHOEAL AGENTS

Relevant Drugs

- 3 categories

1) ORAL REHYDRATION

- solutions of water, sodium chloride (water follows sodium uptake), and

glucose (glucose enhances sodium uptake by the sodium/glucose

cotransporter system)

- see 33

2) ANTIMOTILITY AGENTS

- decrease peristaltic activity

- 3 groups

A) OPIOIDS

- increase the tone of smooth muscle of the GI generally and the

sphincters of the GI specially thus retarding the flow of the feces

- see 49

B) ALPHA-2 ADRENERGIC RECEPTOR AGONISTS

- presynaptically inhibit release of acetylcholine, thus decreasing

peristalsis and following retardation of the flow of the feces

- see 19

C) BISMUTH SUBSALICYLATE

- decreases GI secretions, thus decreasing the flow of the feces

- may cause tinnitus and blackening of the feces (contains bismuth)

3) ADSORBENTS

- adsorb and bind microorganisms and toxins in the GI lumen that might be

responsible for the diarrhea

- 4 types


CHARCOAL

- 76 -

CHALK

PECTIN

MAGNESIUM ALUMINIUM SILICATE

DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE

Relevant Drugs

- 3 categories

1) 5-AMINOSALICYLIC ACID

- scavenges free radicals produced by neutrophils, thus decreasing the

inflammatory response

- 3 types


SULFASALAZINE General information

- 5-aminosalicylic acid combined with

sulfonamide sulfapyridine

Medical uses

- treatment of inflammatory bowel disease

- prophylaxis of inflammatory bowel disease

- treatment of rheumatoid arthritis (see 53)

Side effects

- diarrhea

- interstitial nephritis

- headache

- skin lesions

- leucopenia

MESALAZINE General information

- 5-aminosalicylic acid itself

- same as sulfasalazine

OLSALAZINE General information

- 2 diazo-linked 5-aminosalicylic acids

- same as sulfasalazine

- 77 -

2) GLUCOCORTICOIDS

- inhibit synthesis inflammatory cytokines, thus decreasing the inflammatory

response

- administered rectally

- see 36

3) IMMUNOSUPPRESSANTS

- powerfully suppress the immune defense system, thus decreasing the


- 2 types


AZATHIOPRINE

CICLOSPORIN

DRUG TREATMENT OF PARALYTIC ILEUS

Relevant Drugs

- 3 categories

1) MUSCARINIC RECEPTOR AGONISTS

- increase activity of GI tract smooth muscle, thus increasing peristalsis

- see 14

2) CHOLINESTERASE INHIBITORS

- inhibit cholinesterase, thus increasing acetylcholine half-life, increase activity

of GI smooth muscle, and following increase peristalsis

- see 14

3) 5-HT 4 RECEPTOR AGONISTS

- see above

DIGESTIVES

Overview - digestives are supplements to normal substances of the GI preoccupied with digestion

- digestives are administered in case of maldigestions due to deficiency of any of these

substances

Relevant Drugs

- 3 categories

- 78 -

1) GASTRIC ACID SUPPLEMENTS

- 2 types


HYDROCHLORIC ACID General information

- given alone or together with pepsin

2) BILE SUPPLEMENTS

- 1 type


DIHYDROCHOLIC ACID General information

- increases production of bile

3) PANCREATIC ENZYME SUPPLEMENTS

- 3 types


LIPASE

TRYPSIN

AMYLASE

DRUGS USED IN CHOLELITHIASIS

Relevant Drugs

- 3 categories

1) BILE ACIDS

- form micelles around free cholesterol in the bile, thus preventing further

aggregation

- 2 types


CDCA

(CHENODEOXYCHOLIC ACID)

Medical uses

- treatment of cholesterol

cholelithiasis

UDCA General information

- 79 -

(URSODEOXYCHOLIC ACID) - same as CDCA


- decrease release of acetylcholine, thus decreasing cholic spasms

- see 15

3) OPIOIDS

- decrease pain associated with cholic spasms

- see above

- 80 -

39. ANTIANXIETY AND HYPNOTIC DRUGS

Overview - anxiety is a fear response due to an appropriate stimulus

- the fear response is executed in the body by an extensive increase in noradrenalin release

- the fear response consists of 2 components

COMPONENT LOCATION

CENTRAL COMPONENT - locus ceruleus of the CNS

PERIPHERAL COMPONENT - the sympathetic nervous system

- anxiety disorder is a pathological fear response due to an inappropriate stimulus

- there are 3 main types of anxiety disorders

DISORDER DESCRIPTION

GENERALIZED ANXIETY DISORDER - chronic fear response without any

definite stimulus

PANIC DISORDER - extensive repeating attacks of fear

response

PHOBIA - fear response due to an inappropriate

stimulus

Relevant Drugs

- anxiety and sleep disorders are pharmacologically interconnected, thus normally (but not

necessary) drugs treating one may also be used in treating the other

- 4 categories

1) BENZODIAZEPINES

- bind to the allosteric seat of presynaptic GABA A receptors, thus facilitate

increased responsiveness to GABA

- GABA is an inhibitory neurotransmitter of the CNS, thus increased

responsiveness to GABA leads to increased inhibition of neuronal

transmission

- effects of benzodiazepines include

EFFECT DESCRIPTION

ANXIOLYTIC/

ANTIAGGRESSIVE

- inhibit adrenergic neurons of

locus ceruleus

- 81 -

SEDATIVE - decrease time to fall asleep

- increase duration of sleep

- decrease REM sleep

- decrease slow wave sleep

ANTICONVULSIVE - decrease chemically induced

convulsions by convulsants

inhibiting GABA A receptors

ANTEROGRADE AMNESIC - obliterate memory of events

during their influence

MUSCLE TONE/

COORDINATION DEPRESSANT

- unknown mechanism

- benzodiazepines cause dependence by 2 out of the 4 mechanisms of

dependence of abuse-drugs (see 47)

MECHANISM CAUSE

TOLERANCE - downregulation of GABA A

receptors

NEGATIVE REINFORCEMENT - anxiety

- dizziness

- loss of appetite

- tremor

- convulsions

- the shorter-acting the benzodiazepines are, the more pronounced dependence

will occur

- 3 groups

A) SHORT-ACTING

- 12-18 hours

- 2 types


LORAZEPAM General information


- lipophilic, thus accumulate in fat over time

Medical uses

- treatment of insomnia (sleeping pills)

- 82 -


Side effects

- drowsiness

- sedation

- confusion

- amnesia

- impaired coordination

TEMAZEPAM General information

- same as lorazepam

B) INTERMEDIATELY-ACTING

- 18-24 hours

- 2 types


NITRAZEPAM General information

- same as lorazepam

ALPRAZOLAM General information

- same as lorazepam

- has an active metabolite, thus prolonging it’s

effect

- also has an antidepressive action

Medical uses


- treatment of depression (antidepressive

action)

Side effects

- same as lorazepam

B) LONG-ACTING

- 24-48 hours

- 2 types


DIAZEPAM General information

- same as lorazepam


- 83 -

- has an active metabolite (nordazepam)

- nordazepam has yet another active

metabolite (oxazepam), thus prolonging it’s

action even further

Medical uses



- treatment of excessive muscle tension

- treatment of status epilepticus (, then

administered IV)

Side effects

- same as lorazepam

CLONAZEPAM General information

- same as lorazepam

Medical uses



Side effects

- same as lorazepam

2) BARBITURATES

- general depressants of the CNS

- largely obsolete as anxiolytic- and hypnotic drugs

- are also abuse-drugs

- like any other abuse-drug they have 4 mechanisms by which they cause

dependence (see 47)

MECHANISM TYPE

POSITIVE REINFORCEMENT - see 47

CONDITIONING - see 47

TOLERANCE - upregulation of the hepatic

cytochrome P450 system (the

enzyme system by which they are

metabolized)

NEGATIVE REINFORCEMENT - hallucinations

- same as benzodiazepines

- 84 -

- 3 groups

A) SHORT-ACTING

- less than 1 hour

- 2 types


METOHEXITAL General information

- administered IV

- lipophilic, thus accumulate in adipose

tissue over time

Medical uses

- induction of general anaesthesia

Side effects

- euphoria

- drowsiness (sedation)

- respiratory depression

- cardiovascular depression

- death (if overdosed)

THIOPENTAL General information

- same as metohexital


- 1-6 hours

- 2 types


PENTOBARBITAL General information


- not especially lipophilic, thus will not

accumulate in adipose tissue

Medical uses

- treatment of insomnia


Side effects


- 85 -

BUTOBARBITAL General information

- same as pentobarbital

B) LONG-ACTING

- 6-12 hours

- 1 type


PHENOBARBITAL General information

- same as pentobarbital

Medical uses

- treatment of epileptic convulsions

Side effects


3) 5-HT 1 AGONISTS

- bind to presynaptic 5-HT 1 receptors, thus increasing inhibition of neuronal

transmission (including locus ceruleus) and following anxiolysis

- their effect takes weeks to develop, thus are ineffective in panic

- also have an arousing effect, thus are ineffective in sedation

- see 34

3) NON-SELECTIVE BETA ADRENERGIC RECEPTOR ANTAGONISTS

- inhibit the systemic sympathetic response to anxiety

- see 21

- 86 -

40. ALCOHOLS: PHARMACOLOGY AND TOXICOLOGY

ETHANOL

Overview - ethanol is a low potency abuse-drug

- it has 3 effects on CNS neuronal transmission

EFFECT DESCRIPTION

FACILITATION OF GABA-A RECEPTORS - facilitation of GABA-mediated

neuronal inhibition

INHIBITION OF NMDA RECEPTORS - inhibition of glutamate-mediated

neuronal excitation

INHIBITION OF VOLTAGE-GATED

CALCIUM CHANNELS

- presynaptic inhibition of

neurotransmitter release

- the effects of ethanol consumption are classified according to the circulating amount of

ethanol

QUANTITY EFFECT

50 MG/100 ML - decreased intellectual function

- decreased motor coordination

- increased self-confidence

- euphoria

150 MG/100 ML - all of the effects above

- melancholy

- aggression

- submission

300 MG/100 ML - coma

500 MG/100 ML - cessation of respiration

- death

- , thus the overall effect closely resembles that of general anaesthetics (see 43)

- like any other abuse-drug it has 4 mechanisms by which it causes dependence (see 47)

- 87 -

MECHANISM CAUSE

POSITIVE REINFORCEMENT - inhibition of voltage-gated calcium

channels, thus inhibiting release of

inhibitory neurotrasmitters that

regulate the mesolimbic-mesocortical

dopaminergic pathway


TOLERANCE - downregulation of GABA-A

receptors

- upregulation of NMDA receptors

- upregulation of voltage-gated

calcium channels

NEGATIVE REINFORCEMENT - tremor

- nausea

- sweating

- fever

- epilepsy-like seizures

- hallucinations

- confusion

- agitation

- aggression

- it is used orally and is absorbed by the mucosa of the stomach and the small intestine

- 90% is metabolized in the liver, while the remaining 10% is excreted unchanged by the

kidneys and lungs

- metabolism of ethanol is done in 2 steps

ETHANOL

alcohol dehydrogenase

ACETALDEHYDE

aldehyde dehydrogenase

ACETIC ACID

- both of the enzymes envolved in is dependent on NAD+ as a cofactor for its enzymatic

action, thus the availability of NAD+ is the rate-limiting factor of ethanol metabolism

- 88 -

- for the same reason hepatic metabolism of ethanol exhibit early saturation kinetics, thus if

high amounts of alcohol is absorbed (eg. if empty stomach) most of it will escape first-pass

metabolism

- consequences of ethanol consumption include

LOCATION EFFECT

CNS - ventricular enlargement

- cerebellar neuronal degeneration

- dementia

PERIPHERAL NERVOUS SYSTEM - periphral neuropathy

BLOOD VESSELS - cutaneous vasodilation (gives the

perception of being warm though a

great heat loss is occurring)

LIVER - alcoholic hepatitis

- jaundice/cirrhosis

GI TRACT - increased gastic acid secretion by

the parietal cells of the stomach

- peptic ulcer

- gastritis

ENDOCRINE SYSTEM - increased ACTH secretion by the

pituitary gland

- secondary adrenocortical

hyperactivity

- immunosuppression

- decreased ADH secretion by the

pituitary gland

- increased urinary output

- decreased oxytocin secretion by the

pituitary gland (females)

- delayed labor at term

- decreased testosterone production in

the testes (males)

- impotence

- femininization

GENITO-URINARY TRACT - severe teratogenesis

- alcohol-related neurodevelopmental

disorder (decreased brain size,

- 89 -

decreased intellectual function,

decreased motor coordination)

- fetal alcohol syndrome (mental

retardation, hyperactivity, decreased

brain size, retardation of growth,

abnormal facial development)

METHANOL

Overview - methanol is metabolized by the same enzymes as ethanol

METHANOL

alcohol dehydrogenase

FORMALDEHYDE


FORMIC ACID

- formaldehyde is extremely reactive binding covalently to proteins, especially enzymes of the

citric acid cycle, thus inactivating them

- this leads to severe lactic acidosis

- methanol may also be converted to formaldehyde by retinol dehydrogenase in the retina, thus

causing blindness

- 90 -

41. ANTIPSYCHOTIC DRUGS

Overview - there are 3 main D2 dopaminergic pathways of the CNS

PATHWAY DESCRIPTION

MESOLIMBIC-MESOCORTICAL

PATHWAY

- between the midbrain, hippocampus and

cerebral cortex

- “reward center”

NIGROSTRIATAL PATHWAY - between substantia nigra and corpus

striatum

- facilitates voluntary movement

TUBEROINFUNDIBULAR PATHWAY - between hypothalamus and pituitary

gland

- inhibits pituitary secretion of prolactin

and GH

- schizophrenia is the major type of psychosis

- it is due to hyperactivity of the mesolimbic-mesocortical pathway

- there are 4 groups of symptoms of schizophrenia

GROUP DESCRIPTION

POSITIVE SYMPTOMS General information

- mental processes absent in well

individuals, but present in schizophrenia

Symptoms

- delusion

- hallucination

- disturbance of thinking

- aggression

NEGATIVE SYMPTOMS General information

- mental processes present in well

individuals, but absent in schizophrenia

Symptoms

- isolation

- apathy/anhedonia

- memory impairment

- 91 -

- intellectual impairment

- speech impairment

ANXIETY General information

- see 39

BIPOLAR DEPRESSION General information

- see 42

Relevant Drugs

- antipsychotic drugs are D2 receptor antagonists

- they work by decreasing the activity of the mesolimbic-mesocortical pathway, thus

decreasing the positive symptoms of schizophrenia

- however, the negative symptoms remain unaffected

- their antipsychotic effect takes weeks to develop

- they are effective in 70% of the cases, while ineffective in the last 30% (treatment-resistant

schizophrenia, the cause is unknown)

- the effective dose is also highly variable, thus administration must be adjusted on a trial-and-

error basis

- antipsychotic drugs are administered orally or intramuscularly (, then esterified with

heptanoic or decanoic acid to increase lipophilicity)

- they also cause upregulation of D2 receptor expression, thus decreasing their effectiveness

over time

- they are also partial muscarinic-, alpha-adrenergic-, H1-, and 5-HT 2 antagonists to varying

degree

- general side effects of antipsychotic drugs include

SIDE EFFECTS DESCRIPTION

MESOLIMBIC-MESOCORTICAL SIDE EFFECTS - sedation

- confusion

- coma (if overdosed)

NIGROSTRIATAL SIDE EFFECTS - acute dystonias (acute

reversible involuntary

movements including muscle

spasms, torticollis and

protruding tongue due to

antagonism of the nigrostriatal

pathway)

- tardive dyskinesia (delayed

irreversible involuntary

movements of the face and

tongue due to upregulation of

D2 receptors in the nigrostratal

pathway)

- convulsions (if overdosed)

- 92 -

TUBEROINFUNDIBULAR SIDE EFFECTS - hyperprolactinemia

- lactation (even in males (!))

- gynecomastia

- amenorrhea

- impotence (males)

- infertility (females)

MUSCARINIC RECEPTOR SIDE EFFECTS - see 15

ALPHA-ADRENERGIC SIDE EFFECTS - see 20

5-HT 2 SIDE EFFECTS - see 34

OTHER SIDE EFFECTS - cholestatic jaundice

- skin photosensitivity

- 2 categories

1) CLASSIC ANTIPSYCHOTIC DRUGS

- exhibit most (if not all) of the side effects of antipsychotic drugs

- 2 groups

A) PHENOTHIAZINES

- 2 types


CHLOROPROMAZINE Medical uses

- treatment of schizophrenia

- treatment of huntington’s

disease (see 46)

- treatment of chemotherapy-

indiced emesis (see 37)

Side effects

- see above

THIORIDAZINE General information

- same as chloropromazine

B) BUTYROPHENONES

- 2 types

- 93 -


HALOPERIDOL General information


DROPERIDOL General information


2) ATYPICAL ANTIPSYCHOTIC DRUGS

- have increased muscarinic receptor antagonist activity, thus magnifying this

side effect

- however, this also counteracts the nigrastriatal side effects

- 4 types


SULPIRIDE

RISPERIDONE

CLOZAPINE General information

- also shows a tendency to treat

negative symptoms and

treatment-resistant

schizophrenia

OLANZAPINE General information

- same as clozapine

- 94 -

42. ANTIDEPRESSANTS

Overview - there are 3 types of monoamine neurotransmitters

TYPE DESCRIPTION

SEROTONIN - see 34

NORADRENALINE - see 18

DOPAMINE - see 41

- not relevant in depression

- depression is a disorder of mood due to functional deficit of monoamine neurotransmitters

(primarily serotonin)

- there are 2 types of depression

TYPE DESCRIPTION

UNIPOLAR DEPRESSION

BIPOLAR DEPRESSION - “manic depression”

- alteration between depression and mania every 2-3

weeks

- there are 2 groups of symptoms of depression

GROUP DESCRIPTION

EMOTIONAL SYMPTOMS - misery

- apathy

- pessimism

- low self esteem

- loss of motivation

- indecisiveness

BIOLOGICAL SYMPTOMS - retardation of thought

- loss of libido

- loss of appetite

- sleep disturbance

- 95 -

Relevant Drugs

- 3 categories

1) TRICYCLIC ANTIDEPRESSANS (TCAS)

- TCAs are competitive non-selective monoamine uptake 1 inhibitors, thus

inhibiting reuptake of monoamines released into the synaptic cleft (see 17)

- they have active metabolites, thus increasing their effectiveness and duration

of action

- they also downregulate presynaptic autoreceptors, thus further increasing their

effectiveness

- their antidepressive effect takes weeks to develop due to latency in receptor

downregulation

- they are administered orally

- they are lipophilic, thus accumulate in adipose tissue over time

- they are also partial muscarinic receptor antagonists, thus having atropine-like

side effects

- general side effects of TCAs may be divided in 2 groups

SIDE EFFECT DESCRIPTION

CNS SIDE EFFECTS Therapeutic dose

- sedation

- confusion

- orthostatic hypotension

(hyperactivity of the vasomotor center

of the CNS)

Overdose

- excitement

- delirium

- convulsions


- coma

PERIPHERAL SIDE EFFECTS Therapeutic dose

- muscarinic receptor antagonist side

effects (see 15)

- ECG disorders (prolongation of QT

interval)

- impotence

Overdose

- ventricular fibrillation (prolongation

of QT interval

- death (ventricular fibrillation)

- 96 -

- 2 groups

A) NON-SELECTIVE TCAS

- 2 types


IMIPRAMINE

AMITRIPTYLINE

B) NORADRENALINE-SELECTIVE TCAS

- 2 types


DESIPRAMINE

CLOMIPRAMINE

2) SEROTONIN-SELECTIVE UPTAKE 1 INHIBITORS

- inhibits serotonin reuptake by monoamine uptake 1 specifically

- like TCAs, their antidepressive effect takes weeks to develop

- 4 types


FLUOXETINE General information


Medical uses

- treatment of depression


- treatment of obsessive-compulsive

disorders

Side effects

- nausea

- anorexia

- insomnia

- decreased libido

- failure of orgasm

FLUVOXAMINE General information

- 97 -

- same as fluoxetine

PAROXETINE General information


SERTALINE General information


3) MONOAMINE OXIDASE INHIBITORS (MAOIS)

- MAOIs allosterically inhibit enzymatic catabolism of monoamines by

monoamine oxidase in the presynaptic neuronal cytoplasm

- this increases cytoplasmic concentration of monoamines, and following

passive diffusion of monoamines into the synaptic cleft (see 17)

- like TCAs, they also downregulate presynaptic autoreceptors, thus increasing

their effectiveness

- their antidepressive effect takes weeks to develop due to latency in receptor

downregulation

- 2 groups

A) IRREVERSIBLE MAOIS

- 3 types


PHENELZINE General information


Medical uses

- treatment of depression

Side effects

- excitement

- insomnia

- tremor

- convulsions (if overdose)

- increased appetite

- weight gain

- atropine-like side effects

- severe hypertension (if simultaneous

administration of indirectly acting

sympatomimetics (see 17))

IPRONIAZID General information

- same as phenelzine

- 98 -

TRANYLCYPROMINE General information


B) REVERSIBLE MAOIS

- 1 type


MOCLOBEMIDE General information


- 99 -

43. GENERAL ANAESTHETICS

Overview - general anaesthetics act by decreasing excitatory neurotransmitter release and decreasing the

postsynaptic excitability in response to those excitatory neurotransmitters

- this is done by binding to the hydrophobic domains of ligand-gated ion channels of neurons,

thus inhibiting their depolarization

- there are 4 stages of anaesthesia

STAGE DESCRIPTION

STAGE I “Analgesia”

- conscious

- drowsy

- amnesic

- voluntary movement is still present

- coherent speech is still present

- reduced reaction to stimuli

STAGE II “Excitement”

- loss of consciousness

- delirious

- involuntary movement

- incoherent speech

- loss of reaction to non-painful stimuli

- reflex reactions to painful stimuli

- exaggerated reflexes

- irregular respiration

- irregular heart rate

STAGE III “Surgical anaesthesia”

- loss of movement

- loss of speech

- regular respiration

- regular heart rate

- muscle tone is still present

STAGE IV “Overdose”

- medullary paralysis

- cessation of respiration

- cardiovascular collapse

- cessation of muscle tone

- death

- 100 -

Relevant Drugs

- 2 categories

1) INHALATION ANAESTHETICS

- inhalation anaesthetics are volatile gasses

- they enter and leave the systemic circulation through the pulmonary capillaries

- the pharmacokinetic aspects of inhalation anaesthetics are primarily given by

2 parameters

PARAMETER DESCRIPTION

OIL/GAS PARTITION

COEFFICIENT

General information

- the oil/gas partition coefficient describes

the solubility of the gas in oil (ie. the

lipophilicity of the inhalation anaesthetic)

- partially or completely determines 2 of

the characteristics of the inhalation

anaesthetics

Potency

- the higher the oil/gas partition

coefficient is, the more efficacious it can

bind to the hydrophobic domains of the

ligand-gated ion channels to produce

general anaesthesia

- , thus the higher the oil/gas partition

coefficient is, the smaller alveolar partial

pressure of the inhalation anaesthetics is

needed to produce general anaesthesia

Recovery

- however, higher oil/gas partial pressure

also results in higher amounts of gas to be

redistributed to adipose tissue by

secondary distribution

- , thus the higher the oil/gas partition

coefficient is, the longer time is needed

for it’s elimination

BLOOD/GAS PARTITION

COEFFICIENT

General information

- the blood/gas partition coefficient

describe the solubility of the gas in blood

(ie. the hydrophilicity of the inhalation

anaesthetic)

- partially or completely determines 2 of

the characteristics of the inhalation

anaesthetics

- 101 -

Induction

- the higher the blood/gas partition

coefficient is, the more gas is needed to be

dissolved in blood before it can diffuse out

of the blood stream and into the neurons

to produce general anaesthesia

- , thus the higher the blood/gas partition

coefficient is, the longer time is needed to

produce general anaesthesia

Recovery

- also, the higher the blood/gas partition

coefficient is, the more gas is dissolved in

blood

- , thus the higher the blood/gas partition

coefficient is, the longer time is needed

for it’s elimination

- , thus inhalation anaesthetics ideally need to exhibit of moderate oil/gas

partition coefficient (for as little alveolar partial pressure of inhalation

anaesthetic as possible needed, with as little redistribution to adipose tissue as

possible) and of small blood/gas partition coefficient (for as little solubility in

blood as possible)

- inhalation anaesthetics are usually used for maintenance of general anaesthesia

- 6 types (listed from high potency with slow induction and slow recovery to

low potency with fast induction and fast recovery)


ETHER General information

- has paralytic properties

- has analgesic properties

- large blood/gas partition coefficient

(slow induction and slow recovery)

- large oil/gas partition coefficient (high

potency, but even slower recovery)

- highly explosive

Side effects

- irritation of the respiratory tract

- postoperative nausea and vomiting (long

recovery)

HALOTHANE General information

- intermediate blood/gas partition

coefficient (intermediate induction and

- 102 -

intermediate recovery)

- high oil/gas partition coefficient (high

potency and slower recovery)

- is the only inhalation anaesthetic that is

notably metabolized by the liver (30%)

- metabolites (mainly trifluoroacetic acid)

binds covalently to proteins of the liver

Side effects

- hypotension (vasodilation and

myocardial depression)

- ventricular extrasystoles (myocardial

sensitization to adrenaline)

- malignant hyperthermia (excessive

calcium release from skeletal muscle

sarcoplasmic reticulum)

- hepatic failure (immune reaction to

trifluoroacetic acid-bound proteins)


recovery)

ENFLURANE General information

- intermediate blood/gas partition

coefficient (intermediate induction and

intermediate recovery)

- intermediate oil/gas partition coefficient

(intermediate potency and intermediate

recovery)

Side effects

- hypotension

- ventricular extrasystoles

- malignant hyperthermia

- seizures

ISOFLURANE General information

- irritate the respiratory tract

- same as eflurane (but no seizures)

SEVOFLURANE General information

- low blood/gas partition coefficient (fast

induction and fast recovery)

- low oil/gas partition coefficient (low

potency and fast recovery)

- same as isoflurane (but no irritation of

the respiratory tract)

- 103 -

NITROUS OXIDE General information


- low blood/gas partition coefficient (fast

induction and fast recovery)

- very low oil/gas partition coefficient

(very low potency and fast recovery)

- can only be used as an adjunct to other

general anaesthetics (very low potency)

- inhibits methionine synthase if

administered for more than 6 hours, thus

decreasing DNA- and protein synthesis

Side effects

- anemia (bone marrow depression due to

decreased DNA synthesis)

- leucopenia (bone marrow depression)

2) INTRAVENOUS ANAESTHETICS

- causes much faster induction of general anaesthesia than inhalation

anaesthetics (less that 20 seconds) due to their direct introduction into the

circulatory system

- however, they also are very short-acting (5-10 minutes) due to their high

lipophilicity and following rapid redistribution to adipose tissue

- from this point on, recovery is solely given by hepatic metabolism

- , thus intravenous anaesthetics are usually used for induction of anaesthesia

- 5 types (listed from fast induction and slow recovery to slow induction and

fast recovery)


METOHEXITAL General information

- slowly metabolized (slow recovery)

- a short-acting barbiturate (see 39)

THIOPENTAL General information


ETOMIDATE General information

- intermediately metabolized

(intermediate recovery)

Side effects


recovery)

- adrenal cortical suppression

- 104 -

FENTADYL General information


- rapidly metabolized (fast recovery)

- synthetic opioid derivative (see 50)

- may be used as a general anaesthetic

alone by continuous infusion

- also used for analgesia

Side effects

- see 50

KETAMINE General information

- phencyclidine analogue (see 48)

- produces dissociative anaesthesia

(analgesia, amnesia, paralysis, and

relative sensory loss, without loss of

consciousness (!))

- may be used as a general anaesthetic

agent alone by continuous infusion

Side effects

- see 48

- 105 -

44. ANTIEPILEPTIC DRUGS

Overview - epilepsy is a neurologic disorder characterized by epileptic seizures

- epileptic seizures are sudden high frequency neuronal discharges (hyperactivity) in the CNS

- there are 2 groups of epileptic seizures

TYPE DESCRIPTION

PARTIAL SEIZURES General information

- localized seizure not exceeding the cerebral

hemisphere from which it originates

- 2 types

Simple Seizure

- the seizure stays in it’s location of origin

- no loss of consciousness

- symptoms depend on where the seizure is located

(motor seizure, sensory seizure, autonomic seizure,

psychomotor seizure etc.)

Complex seizure

- the seizure spreads from it’s location of origin to other

areas of the CNS, including the reticular formation

- loss of consciousness (hyperactivity of the reticular

formation)

- symptoms depend on where the seizure originates

from and where it spreads

GERERALISED SEIZURES General information

- global seizure involving both hemispheres

- 2 types

Grand mal seizures

- “tonic-clonic seizures”


- rigid extensor spasm

- cessation of respiration

- micturition

- defecation

- salivation

- all of this is followed by series of violent synchronous

jerks that gradually dies out

- 106 -

Petit mal seizures

- “absence seizures”

- rhythmic oscillating seizure of thalamic relay neurons


- vacant stare

- no motor abnormalities

- the exact pathophysiological origin of epilepsy is unknown, and the same applies to the

pharmacological mechanisms of the drugs used to treat it

Relevant Drugs

- 3 categories

1) DRUGS AFFECTING PARTIAL- AND GRAND MAL SEIZURES

- 3 types


PHENYTOIN General information

- inhibits sodium channels, thus blocking the

initiation and propagation of action potentials

- use dependent, thus inhibiting more efficacious

sodium channels that more frequently open (eg.

sodium channels of seizure-affected neurons)


- metabolized by the liver

- causes induction of hepatic enzymes, thus

causing increased metabolism of itself and

following tolerance over time

Medical uses

- treatment of partial- and grand mal epileptic

seizures

- treatment of cardiac arrhythmias (see 29)

Side effects

- vertigo

- ataxia

- nystagmus

- headache

- confusion

- intellectual deterioration

- gum hypertrophy

- hirsutism (abnormal growth of body hair, due

to increased androgen secretion)

- macrocytic, hyperchromic anemia (disorder of

- 107 -

folate metabolism)

- skin rashes

- teratogenesis

CARBAMAZEPINE General information

- also mood-stabilizing

- same as phenytoin

Medical uses

- treatment of partial- and grand mal epileptic

seizures

- treatment of manic depression (mood

stabilizer)

Side effects

- sedation

- ataxia

- mental deterioration

- water retention

- leucopenia (bone marrow depression)

- skin rashes

PHENOBARBITAL General information

- a barbiturate

- also facilitates increased sensitivity of GABA

A receptors, thus increasing inhibition of

excitatory neurotransmission

- see 39

2) DRUGS AFFECTING PETIT MAL SEIZURES

- 1 type


ETHOSUXIMIDE General information

- inhibits T-type calcium channels, thus

blocking rhythmic oscillations of thalamic relay

neurons


Medical uses

- treatment of petit mal seizure

Side effects

- 108 -

- vertigo

- nausea

- apathy

- anorexia

3) DRUGS AFFECTING ALL TYPES OF EPILEPTIC SEIZURES

- 2 types


VALPROATE General information

- fascilitates increased sensitivity of GABA A

receptors, thus increasing inhibition of

excitatory neurotransmission

- also inhibits GABA transaminase, thus

decreasing inactivation of GABA in the

neuromuscular junction and following even

stronger inhibition of excitatory

neurotransmission

- also inhibits sodium channels, thus blocking

the initiation and propagation of action

potentials

- also mood-stabilizing

Medical uses

- administered in conjunction with other

antiepileptic drugs in treatment of all types of

epilepsy

- treatment of manic depression (mood

stabilizer)

Side effects

- hair loss

- liver damage

- teratogenesis

LONG-ACTING

BENZODIAZEPINES

General information

- see 39

- 109 -

45. CENTRAL NERVOUS SYSTEM STIMULANTS AND

NOOTROPIC AGENTS

CENTRAL NERVOUS SYSTEM STIMULANTS

Overview - see 48

NOOTROPIC AGENTS

Overview - nootropic drugs are drugs that enhance the intellectual capacity

- they act by one or more of 4 mechanisms

MECHANISM DESCRIPTION

ENHANCEMENT OF CEREBRAL

MICROCIRCULATION

- increasing cerebral blood flow (vasodilation)

- increasing RBC plasticity

- inhibiting platelet aggregation

- reducing blood viscosity


METABOLISM

- increasing cerebral energy supply

- enhancing cerebral energy utilization


NEUROTRANSMISSION

- increasing availability and/or effect of

acetylcholine

- increasing availability and/or effect of

monoamines (see 42)

NEUROPROTECTION - neutralizing free radicals (“antioxidation”)

Relevant Drugs

- 3 types


PIRACETAM General information

- enhances cerebral microcirculation

- enhances cerebral metabolism

- enhances cerebral neurotransmission (acetylcholine)

- neuroprotective


- 110 -

Medical uses

- treatment of stroke

- treatment of dementia (including alzheimer’s disease, see 46)

Side effects

- hyperactivity

- insomnia

VINPOCETINE General information


- enhances cerebral metabolism

- administered IV

Medical uses


- treatment of perfusion disorders of the eye and the inner ear

(including tinnitus)

Side effects

- hypotension

- tachycardia

PENTOXYFILLINE General information

- theobromine derivative (see 48)


Medical uses


- treatment of perfusion disorders of the eye and the inner ear

Side effects

- hypotension

- cardiac arrythmias

- dizziness

- 111 -

46. DRUG TREATMENT OF NEURODEGENERATIVE

DISORDERS. CENTRALLY-ACTING MUSCLE

RELAXANTS

DRUG TREATMENT OF NEURODEGENERATIVE DISORDERS

Overview - there are 3 main types of neurodegenerative disorders

TYPE

ALZHEIMER’S DISEASE

PARKINSON’S DISEASE

HUNTINGTON’S DISEASE

ALZHEIMER’S DISEASE

Overview - alzheimer’s disease is a progressive dementia of idiopathic origin

- it occurs primarily due to loss of neurons in 2 locations of the CNS

LOCATION NEURONS AFFECTED

HIPPOCAMPUS - unselective neuronal loss

BASAL FOREBRAIN - cholinergic neuronal loss

Relevant Drugs

- 2 categories

1) CHOLINESTERASE INHIBITORS

- cholinesterase inhibitors inhibit cholinesterase in the cholinergic synapses,

thus inhibiting acetylcholine breakdown and following increased acetylcholine

concentration in those synapses (see 14)

- however, different cholinesterase inhibitors are used centrally to treat

alzheimer’s disease than those used peripherally to treat peripheral disorders

- 4 types


- 112 -

TACRINE Side effects

- cholinergic side effects (see 14)

- hepatotoxicity

DONEPEZIL Side effects

- cholinergic side-effects

RIVASTIGMINE General information

- selective for the CNS

GALANTHAMINE General information

- also an nicotinic acetylcholine receptor allosteric

activator (see 14)

Side effects

- cholinergic side-effects

2) NOOTROPIC DRUGS

- enhances the intellectual capacity, thus counteracting the dementia

- see 45

PARKINSON’S DISEASE

Overview - parkinson’s disease is a progressive motility disorder

- it occurs primarily due to loss of dopaminergic neurons running from substantia nigra to

corpus striatum (“nigrostriatal tract”, see 41)

- these dopaminergic neurons are inhibitory neurons that act on D2 receptors of cholinergic

neurons in the corpus striatum, thus loss of inhibition causes hyperactivity of these

cholinergic neurons

- parkinson’s disease is characterized by 3 (4) symptoms

SYMPTOM DESCRIPTION

HYPOKINESIA - voluntary movement is hard to initiate and -to stop

- due to loss of dopaminergic neurons

TREMOR - at rest

- due to hyperactivity of cholinergic neurons

RIGIDITY - increased resistance to voluntary movement

- due to loss of dopaminergic neurons and hyperactivity of

cholinergic neurons

- 113 -

(DEMENTIA) - decreased mental capacity

- due to loss of other types of neurons elsewhere in the CNS

- biosynthesis and breakdown of dopamine is done in 5 steps (similar to that of

catecholamines, see 17)

TYROSINE

tyrosine hydroxylase

L-DOPA

DOPA decarboxylase

DOPAMINE

MAO (MAO-A peripherally, MAO-B centrally)

3,4-DIHYDROXYPHENYLACETALDEHYDE


3,4-DIHYDROXYPHENYLACETIC ACID

COMT

HOMOVANILLIC ACID

Relevant Drugs

- 2 categories

1) DOPAMINE REPLENISHERS

- 4 types


L-DOPA General information

- precursor of dopamine

- increases dopamine biosynthesis


- coadministered with carbidopa (a peripheral

DOPA decarboxylase inhibitor, see 17) to inibit

peripheral use of dopamine

- causes downregulation of dopamine receptors,

thus tolerance will develop over time

Side effects

- dyskinesia (involuntary movements of face and

limbs)

- on-off effect (rapid fluctuations of symptoms)

- schizophrenia-like syndrome (see 41)

- nausea

- 114 -

- anorexia

SELEGILINE General information

- selective MAO-B inhibitor (, thus only acts in

the CNS, see 17)

- decreases central monoamine breakdown

ENTACAPONE General information

- COMT inhibitor

- decreases central- and peripheral monoamine

breakdown

AMANTIDINE General information

- antiviral drug

- increases presynaptic dopamine release and

decreases presynaptic dopamine reuptake

2) D2 RECEPTOR AGONISTS

- 3 types


BROMOCRIPTINE Medical uses

- treatment of galactorrhea

- treatment of gynecomastia

- treatment of parkinson’s disease

LISURIDE

PERGOLIDE


- block muscarinic receptors, thus inhibiting the effect of the hyperactive

cholinergic neurons in the corpus striatum

- see 15

HUNTINGTON’S DISEASE

Overview - huntington’s disease is, like parkinson’s disease, a progressive motility disorder

- 115 -

- however, huntington’s disease is due to loss of GABA neurons running in opposite direction

to that of the dopaminergic neurons affected in parkinson’s disease (from corpus striatum to

substantia nigra)

- these GABA neurons are inhibitory neurons of the dopaminergic neurons in the substantia

nigra, thus loss of inhibition causes hyperactivity of these dopaminergic neurons

- , thus huntington’s disease exhibit opposite symptoms to that of parkinson’s disease

Relevant Drugs

- 2 categories

1) GABA AGONISTS

- 1 type


BACLOFEN

2) D2 RECEPTOR ANTAGONISTS

- “antipsychotic drugs”

- block D2 receptors, thus inhibiting the effect of the hyperactive dopaminergic

neurons

- see 41

CENTRALLY-ACTING MUSCLE RELAXANTS

Overview - …

- 116 -

47. DRUG ABUSE AND DEPENDENCE: GENERAL

PRINCIPLES, OPIOIDS, ANTI-ANXIETY AND HYPNOTIC

DRUGS, INHALANTS, ETHANOL

Overview - drug abuse is recurrent use of drugs that are illegal and/or cause harm to the subject of

interest

- drug dependence is the state of mind when drug use becomes compulsory (rather than

voluntarily) and takes precedence over other needs of the subject of interest

- drug dependence has 2 components

COMPONENT TYPE

PSYCHOLOGICAL DEPENDENCE Positive reinforcement

- occurs when the abuse-drug is used

- stimulation of the mesolimbic-

mesocortical dopaminergic pathway of the

CNS (reward center, see 41) and following

feeling of reward

Conditioning

- occurs when the abuse-drug is withdrawed

- the association of items, locations or

people with the abuse-drug induced feeling

of reward

PHYSIOLOGICAL DEPENDENCE Tolerance

- occurs when the abuse-drug is used

- physiological opposition of the

biochemical responses of the abuse-drug

over time, thus decreasing its effectiveness

- see 6

Negative reinforcement

- occurs when the abuse-drug is withdrawed

- the physiological result of the

physiological contradiction of the

biochemical responses of the abuse-drug,

when the abuse-drug is not used

OPIOIDS

Overview

- 117 -

- see 49

ANTI-ANXIETY AND HYPNOTIC DRUGS

Overview - see 39

INHALANTS

Overview - …

ETHANOL

Overview - see 40

- 118 -

48. DRUG ABUSE AND DEPENDENCE: PSYCHOMOTOR

STIMULANTS, PSYCHEDELICS, CANNABIS

PSYCHOMOTOR STIMULANTS

Overview - psychomotor stimulants are abuse-drugs that exhibit both physical- and psychological effects

in the subject of interest

Relevant Drugs

- 3 categories

1) AMPHETAMINE ANALOGUES

- amphetamines are abuse-drugs that fascilitate secretion of monoamines

(dopamine, noradrenaline and serotonin) into the synaptic cleft

- they are taken up by the neuron by way of the uptake 1 monoamine transporter

in exchange for cytoplasmic monoamines, thus facilitating the release of

monoamines

- further, they are taken up by the cytoplasmic neurotransmitter vesicles by the

way of VMAT in exchange for monoamines, thus displacing monoamines

from the neurotransmitter vesicles and into the cytoplasm

- the effects of amphetamines are classified according to the monoamines

released

MONOAMINE EFFECT

DOPAMINE Abuse dose

- euphoria

- pleasure

- excitement

- increased confidence

- increased sex drive

- increased mental performance

- increased physical performance

- insomnia

Overdose

- hallucinations

- paranoia

- aggression

NORADRENALINE - increased motor activity

SEROTONIN - anorexia

- 119 -

- like any other abuse-drug they have 4 mechanisms by which they cause

dependence (see 47)

MECHANISM CAUSE

POSITIVE REINFORCEMENT - release of dopamine, and following

stimulation of the mesolimbic-

mesocortical dopaminergic pathway


TOLERANCE - depletion of dopamine

- depletion on noradrenaline

(- depletion of serotonin)

NEGATIVE REINFORCEMENT - apathy

- axiety

- depression

- suicidality

- consequences of amphetamine consumption include

ORGAN EFFECT

HEART - tachycardia

- cardiac arrhythmias

BLOOD VESSELS - vasoconstriction

- hypertension

SKELETAL MUSCLE - tremor

- hyperthermia

ENDOCRINE SYSTEM - increased ADH secretion by the

pituitary gland

- hypotonic hypervolemia

UPON OVERDOSE - sudden death (even from just a

single moderate dose (!))

- 120 -

- they are used orally or nasally and absorbed from the nasal- and/or small

intestinal mucosa

- 6 types


AMPHETAMINE General information

- abuse-drug

Medical uses

- treatment of narcolepsy

- treatment of obesity

METHAMPHETAMINE General information

- “speed”

- abuse-drug

METHYLENEDIOXY-

METHAMPHETAMINE

General information

- “ecstasy”

- abuse-drug

MESACAINE General information

- abuse-drug

METHYLPHENIDATE Medical uses

- treatment of ADHD (paradoxically

(!))

FENFLURAMINE General information

- has a stronger action of serotonin

release, thus producing more

pronounced anorexia

2) COCAINE ANALOGUES

- cocaine is an abuse-drug found in coca leaves

- it inhibits presynaptic reuptake of monoamines uptake 1, thus increasing

monoamine concentration (dopamine and noradrenaline) in the synaptic cleft

- it also blocks sodium channels, thus is clinically used as a local surface

anaesthetic (see 22)

- the effects of cocaine are classified according to the monoamines increased in

the synaptic cleft

MONOAMINE EFFECT

DOPAMINE - euphoria

- pleasure

- 121 -

- garrulity

NORADRENALINE Abuse Dose

- increased motor activity

- hyperthermia

- tachycardia

- vasoconstriction

- hypertension

Overdose

- tremor

- convulsions


- vasomotor depression

- like any other abuse-drug it has 4 mechanisms by which it causes dependence

(see 47)

MECHANISM CAUSE

POSITIVE REINFORCEMENT - inhibition of presynaptic dopamine

reuptake, and following stimulation

of the mesolimbic-mesocortical

dopaminergic pathway


TOLERANCE - downregulation of dopaminergic

receptors

- downregulation of adrenergic

receptors

NEGATIVE REINFORCEMENT - dysphoria

- depression

- decreased mental performance

- decreased physical performance

- consequences of cocaine consumption include

ORGAN EFFECT

HEART - tachycardia

- cardiac arrhythmias

- 122 -

- myocardial damage

BLOOD VESSELS - vasoconstriction

- hypertension

- coronary- and/or cerebral artery

thrombosis

SKELETAL MUSCLE - tremor

- hyperthermia

UPON OVERDOSE - convulsions



- death

- 2 types


HYDROCHLORIDE SALT

COCAINE

General information

- “snow”

- abuse-drug

- used nasally or IV

FREE BASE COCAINE General information

- “crack”

- abuse-drug

- used by inhalation, nasally or IV

3) NICOTINE

- nicotine is an abuse-drug found in nicotiana (“tobacco”)

- tobacco is a compound substance consisting of several pharmacologically

active components

- the pharmacologically active components of tobacco are divided in 2 groups

according to the chemical phase of the components

A) SOLID PHASE COMPONENTS

- “particular phase components”

- include

TYPE DESCRIPTION

NICOTINE

- 123 -

POLYCYCLIC

AROMATIC

HYDROCARBONS

(TAR)

B) GASSEOUS PHASE COMPONENTS

- include

TYPE DESCRIPTION

CARBON MONOXIDE

NITROGEN DIOXIDE

HYDROGEN CYANIDE

AMMONIA

FORMALDEHYDE

NITROSAMIDES

- of these, nicotine is the most pharmacologically active component causing

both ALL the immediate effects and the ALL the mechanisms of dependence

of tobacco (see below)

- nicotine is a nicotinergic receptor agonist, thus causing excitation of

nicotinergic cholinergic receptors (see 14)

- the effects of nicotine are classified according to the nicotinergic receptor it

acts on

TYPE EFFECT

CNS TYPE - satiety

- analgesia

- sedation

- alertness


- increased physical performance

- decreased skeletal muscle tone

GANGLION TYPE - positive chronotropic effect

(increased heart rate)

- positive ionotropic effect

(increased force of heart contraction)

- vasoconstriction

- increased circulating free fatty

- 124 -

acids

- decreased glomerular filtration

- decreased peristalsis

- sweating

MUSCLE TYPE - increased skeletal muscle tone

(completely overridden by the

decreased skeletal muscle tone of the

CNS type nicotinergic receptors (see

above))

- like any other abuse-drug it has 4 mechanisms by which it causes dependence

(see 47)

MECHANISM CAUSE

POSITIVE REINFORCEMENT - stimulation of the mesolimbic-

mesocortical dopaminergic pathway


TOLERANCE - desensitization of nicotinic

receptors (partly opposed by a

simultaneous upregulation of the

same nicotinic receptors (!))

NEGATIVE REINFORCEMENT - irritability

- insomnia


- decreased physical performance

- consequences of tobacco consumption may be divided in 2 groups according

to the causative agents

A) CONSEQUENCES OF NICOTINE AND CARBON MONOXIDE

- include

TYPE CONSEQUENCE

CARDIOVASCULAR

DISORDERS

- hypertension

- hyperlipoproteinemia

- coronary- and/or cerebral artery

thrombosis

- gangrene

- 125 -

FETAL DISORDERS - spontaneous abortion

- placenta praevia (obstruction of the

cervical canal by the placenta)

- premature delivery

- increased perinatal death

- decreased birth weight

B) CONSEQUENCES OF TAR AND ALL OTHER GASSEOUS STATE

COMPONENTS

- include

TYPE CONSEQUENCE

PULMONARY

DISORDERS

- chronic obstructive pulmonary

disorders (COPD)

CANCERS - respiratory tract cancers

- oesophageal cancers

- pancreatic cancers

- urinary bladder cancers

4) CANNABIS

- cannabis is an abuse drug found in cannabis sativa (“hemp”)

- the pharmacologically active components of cannabis are cannabinoids

- there are 3 main types of cannabinoids

TYPE DESCRIPTION

THC - “delta-9 tetrahydrocannabinol”

- the only pharmacologically active

cannabinoid

CANNABIDOL - THC precursor

CANNABINOL - THC metabolite

- cannabinoids are cannabinoid receptor agonists

- there are 2 types of cannabinoid receptors

RECEPTOR TYPE LOCATION

CB1 RECEPTOR - mesolimbic-mesocortical pathway

- hippocampus

- substantia nigra

- crebellum

- 126 -

CB2 RECEPTOR - lymphoid system

- cannabinoid receptors inhibit adenylyl cyclase, thus leading to decreased

formation of cAMP

- cannabinoid receptors also activate potassium channels and inhibit calcium

channels, thus inhibiting neuronal depolarization and inhibiting release of

neurotransmitters respectively and following inhibition of neuronal

transmission

- the effects of cannabinoids include

ORGAN EFFECT

CNS - euphoria

- sensory amplification (visual-,

auditory- and tactile-)

- sedation


(with subjective perception of

increased mental performance)

- decreased motor coordination

- catalepsy

- analgesia

- antiemesis

- increased appetite

HEART - tachycardia

BLOOD VESSELS - vasodilation

EYES - decreased intraocular pressure

- blood-shot eyes (conjunctival

blood vessel vasodilation)

BRONCHI - bronchoconstriction

LYMPHOID SYSTEM - decreased immune function

GENITO-URINARY TRACT - teratogenesis

- decreased testosterone production

- decreased sperm production

- it causes little or no dependence

- 127 -

- it is used by inhalation, orally or IV

- it is lipophilic, thus will accumulate in adipose tissue over time

- 2 types

TYPE DESCRIPTION

MARIJUANA General information

- dried leaves and flowers of

cannabis sativa

HASHISH - resin of cannabis sativa

5) METHYLXANTHINES

- methylxanthines inhibit adenylyl cyclase, thus leading to decreased formation

of cAMP - effects of xanthines include

ORGAN EFFECT

CNS - CNS excitation

- insomnia


- nervousness

- increased motor activity

- tremor

- increased respiration

HEART - increased heart rate

- increased force of contraction

BLOOD VESSELS - systemic vasodilation

- cerebral vasoconstricion

BRONCHI - bronchodilation

KIDNEYS - increased glomerular filtration

- decreased reabsorption

- increased diuresis

- they cause little or no dependence

- 4 types


- 128 -

THEOPHYLLINE General information

- found in tea (and coffee)


Medical uses


Side effects

- any other effect of xanthines (see

above)

AMINOPHYLLINE General information

- administered IV

- same as theophylline

CAFFEINE General information

- found in coffee (and tea) and cola

nuts (coca cola)

THEOBROMINE General information

- found in cocoa

PSYCHEDELICS (PSYCHOMIMETIC DRUGS)

Overview - psychedelics are abuse-drugs that exhibit only psychological effects in the subject of interest

Relevant Drugs

- 3 categories

1) LSD ANALOGUES

- LSD is an extremely potent abuse-drug

- it is a 5-HT 2 receptor agonist in the CNS and –antagonist in the periphery

- the CNS effects of LSD are classified according to dose

DOSE EFFECT

ABUSE DOSE - hallucinations (visual-, auditory-,

olfactory-, tactile-, and cross-

connections (eg. auditory stimuli

are perceived as visual stimuli (!)))

- illogical mental performance

- 129 -

OVERDOSE - “bad trip”

- horrific halucinations

- paranoia

- suicide

- homicide

- it causes little or no dependence (!)

- consequences of LSD, see 34

- 2 types


LSD General information

- “lysergic acid diethylamide”

- abuse-drug

- semisynthetic compound

synthesized from ergot alkaloids

(found in fungus)

PSILOCYBIN General information

- found in fungus

2) PHENCYCLIDINE

- phencyclidine is an abuse-drug with 2 effects in the CNS

EFFECT CONSEQUENCE

FACILITATION OF SIGMA NON-

OPIOID RECEPTORS

INHIBITION OF NMDA

RECEPTORS

- inhibition of glutamate-mediated

neuronal excitation

- it causes little or no dependence

- the effects of phencyclidine are divided according to dose

MONOAMINE EFFECT

ABUSE DOSE - analgesia

- same as LSD

OVERDOSE - same as LSD

- 130 -

49. OPIOID ANALGESIC DRUGS: MORPHINE AND CODEINE

50. OPIOID ANALGESIC DRUGS: SEMI-SYNTHETIC,

SYNTHETIC OPIOIDS; OPIOID ANTAGONISTS

Overview - there are 2 types of pain

TYPE DESCRIPTION

ACUTE PAIN - excited by mechanical- and/or thermal stimuli

- conveys surface pain

- transmitted by A-delta nerve fibers from the

dorsal horns of the spinal cord through the

neospinothalamic tract to the basal ganglia and the

somatosensory cortex

- the main neurotransmitter is glutamate

CHRONIC PAIN - excited by mechanical-, thermal- and/or chemical

stimuli

- conveys both surface- and visceral pain

- transmitted by C nerve fibers from the dorsal

horns of the spinal cord through the

paleospinothalamic tract to the brain stem

(including the periaqueductal grey area)

- the main neurotransmitter is substance P

- the endogenous analgesic system is a CNS reflex arch that inhibit the excitation of A-delta-

and C nerve fibers

- it originates in the periaqueductal grey area in response to chronic pain afferens and transmit

efferent excitatory signals down to nucleus raphe magnus and nucleus reticularis

paragigantocellularis of the brain stem

- these nuclei transmit the efferent signal through the dorsolateral column to the dorsal horn of

the spinal tract where they secrete serotonin (see 34) and enkephalins, respectively

- both serotonin and enkephalins inhibit excitation of A-delta- and C nerve fibers by action on

5-HT 3- and opioid receptors respectively, thus inhibiting spinal pain transmission

- there are 5 types of endogenous opioids classified according to their location of action

LOCATION TYPE

SPINAL CORD - met-enkephalin

- leu-enkephalin

CNS - beta-endorphin

- dynorphin A

- nociceptin

- 131 -

- opioids act on opioid receptors

- there are 3 types of opioid receptors

RECEPTOR TYPE EFFECT

MY OPIOID RECEPTOR - supraspinal analgesia (fascilitation of the

periaqueductal grey area and nucleus

paragigantocellularis)

- spinal analgesia (inhibition of the A-delta- and C

nerve fibers)

- peripheral analgesia (inhibition of neural

transmission from nocioceptors)

- euphoria

- pleasure

- sedation

- emesis

- vomiting



- increased tone of GI smooth muscle (spincters

especially)

- myosis

KAPPA OPIOID RECEPTOR - spinal analgesia

- peripheral analgesia

- dysphoria

- sedation

- myosis (pupillary constriction)


especially)

DELTA OPIOID RECEPTOR - spinal analgesia




especially)

- 132 -

- the opioid receptors are G-protein coupled receptors, thus inhibiting adenylate cyclase and

following decreased cAMP formation

- they also activate potassium channels and inhibit calcium channels, thus inhibiting

depolarization and inhibiting release of neurotransmitters respectively and following

inhibition of neuronal transmission

- many (but not all) exogenous opioid analgesic drugs are also abuse-drugs

- like any other abuse-drug they have 4 mechanisms by which they cause dependence (see 47)

MECHANISM CAUSE

POSITIVE REINFORCEMENT - see 47


TOLERANCE - substantially increased activity of adenylyl

cyclase (!)

NEGATIVE REINFORCEMENT - distress

- insomnia

- nausea

- diarrhea

- sweating

- fever

- midriasis (pupillary dilatation)

- piloerection (“cold turkey”)

- they may cause coma if overdosed

Relevant Drugs

- 3 categories

1) MORPHINE ANALOGUES

- include morphine and semisynthetic morphine derivatives

- 3 types


MORPHINE General information

- strong agonist of all opioid

receptor types

- administered orally, IV or

intrathecally

- causes dependence (see above)

Medical uses

- treatment of acute- and chronic

- 133 -

pain


Side effects

- see above

DIAMORPHINE General information

- “heroin”

- strong agonist of all opioid

receptor types

- metabolized to morphine

- very high lipid solubility, thus

crossing the blood- brain barrier

very rapidly


- causes dependence

- same as morphine

3-METHOXYMORPHINE General information

- “codeine”

- weak agonist of all opioid

receptor types


- does not cause dependence

Medical uses

- treatment of mild pain


- treatment of cough (antitussive)

Side effects

- inhibition of bronchial

secretions and bronchial ciliary

activity, thus shoud not be

administered as a treatment of

asthmatic cough

- same as morphine

2) SYNTHETIC OPIOID DERIVATIVES

- 4 groups

A) PHENYLPIPERIDINE ANALOGUES

- 2 types


- 134 -

FENTANYL General information

- strong my opioid receptor

agonist

- administered IV, transdermally

or intravenously

- causes dependence

Medical uses

- treatment of acute pain

- general anaesthesia (, then

administered intravenously)

Side effects

- same as morphine

PENTHIDINE General information


agonist

- metabolized to the active

metabolite norpentidine

- also has muscarinic antagonist

activity

- administered orally or

intramuscularly

- causes dependence

Medical uses


Side effects

- excitement (norpentidine)

- hallucinations (norpentidine)

- convulsions (norpentidine)

- muscarinic antagonist side

effects (see 15)

- same as morphine

B) METHADONE DERIVATIVES

- 2 types


METHADONE General information


agonist

- 135 -


- binds extensively to the

extravascular compartment and is

slowly released from there, thus

may accumulate in the body over

time

- also causes less euphoria and

dependence for the same reason

Medical uses

- treatment of chronic pain

- treatment of morphine/heroin

addiction

Side effects

- same as morphine (but less

euphoria or dependence)

DEXTROPROPOXYPHENE General information

- weak agonist of all opioid

receptor types

- metabolized to the active

metabolite norpropoxyphene


- does not cause dependence

Medical uses

- treatment of mild pain

Side effects

- convulsions (norpropoxyphene)

- same as morphine

C) BENZOMORPHAN DERIVATIVES

- 1 type


PENTAZOCINE General information

- kappa opioid receptor agonist

and my opioid receptor antagonist


- causes dysphoria (kappa opioid

receptor agonist)

- 136 -

Medical uses


Side effects

- see above

D) THEBAINE DERIVATIVES

- 1 type


BUPRENORPHINE General information

- my opioid receptor agonist and

kappa opioid receptor antagonist

- administered sublingually, IV or

intrathecally

Medical uses

- treatment of acute- and chronic

pain

Side effects

- same as morphine

E) OTHERS

- 1 type


LOPERAMIDE General information

- does not cross the blood-brain

barrier

- selective for the GI tract

- also decrease intestinal

secretions

Medical uses


Side effects

- constipation

- abdominal cramps

- 137 -

3) OPIOID ANTAGONISTS

- 2 types


NAXOLONE General information

- antagonizes all opioid receptor

types

- short-acting

- administered IV

Medical uses

- treatment of opioid receptor

agonist induced respiratory

depression

NALTREXONE General information

- long-acting

- same as naxolone

- 138 -

51. CYCLOOXYGENASE INHIBITORS: ASPIRIN,

PARACETAMOL

52. CYCLOOXYGENASE INHIBITORS: PYRAZOLONS,

PROPIONIC ACID DERIVATIVES, INDOLE DERIVATIVES

AND OTHERS. “COX-2 INHIBITORS”

Overview - cyclooxygenase inhibitors (“non-steroidal anti-inflammatory drugs”, “NSAIDs”) inhibit

cyclooxygenase (“COX”), thus inhibiting the formation of prostaglandins and thromboxanes

(see 35)

- there are 3 types of COX

TYPE DESCRIPTION

COX-1 Location

- most tissues

Effect

- normal tissue homeostasis

COX-2 Location

- inflammatory cells

Effect

- edema (vasodilation and potentiation of the

effect of the inflammatory mediators that

cause increased capillary permeability)

- pain (potentiation of the effect of the

inflammatory mediators that cause irritation of

afferent C nerve fibers)

- fever (increase in the hypothalamic

temperature set point in response to bacterial

endotoxins)

COX-3 Location

- CNS

Effect

- pain (cerebral vasodilation)

- induction of fever (see above)

- COX inhibitors are primarily administered to obliterate the effects of COX-2 and COX-3

- 139 -

- , thus the general medical uses of COX inhibitors include

MEDICAL USE

TREATMENT OF INFLAMMATION

TREATMENT OF PAIN

TREATMENT OF FEVER

- however, most COX inhibitors are non-selective reversible inhibitors of COX, thus also

inhibiting COX-1

- the effects of COX-1 inhibition are usually considered side effects, and include

ORGAN SIDE EFFECT

GI TRACT Increased gastric acid production and

decreased mucous production

- dyspepsia


- nausea

- vomiting

- peptic ulcers

KIDNEYS Vasoconstriction and following renal ischemia

- acute renal insufficiency

- chronic nephritis

- renal papillary necrosis

SKIN Increased arachidonic acid available for 5-

lipoxygenase and following increased

leukotriene production (see 35)

- rashes

- urticaria (“hives”)

- photosensitivity

Relevant Drugs

- 6 categories

1) SALICYLIC ACID DERIVATIVES

- salicylic acid derivatives are non-selective irreversible COX inhibitors

- 1 type


- 140 -

ASPIRIN General information

- “acetylsalicylic acid”


- severe side effects (irreversible COX

inhibition)

Medical uses

- see above


(inhibition of platelet aggregation, due to

irreversible COX-1 inhibition)

- treatment of radiation-induced diarrhea

- prophylaxis of colonic- and rectal cancer

- prophylaxis of alzheimer’s disease

Side effects

- see above

- hemorrhages (inhibition of platelet

aggregation)

- salicylism (deafness, tinnitus and vertigo, due

to repeated administration of large doses of

aspirin)

- salicylate poisoning (respiratory acidosis (due

to respiratory center depression), metabolic

acidosis (due to uncoupling of oxidative

phosphorylation), hyperpyrexia (due to

uncoupling of oxidative phosphorylation and

following increased metabolic rate) and finally

coma, due to aspirin overdose)

- reye’s syndrome (hepatic insufficiency and

encephalopathy in children, due to aspirin

administration during a viral infection)

2) ACETIC ACID DERIVATIVES

- “indole derivatives”

- 3 types


INDOMETACIN General information

- potent COX inhibitor

- has severe side effects (potent COX

inhibitor)

- also inhibits phagocytosis of urate crystals by

neutrophils


- 141 -

Medical uses

- see above

- treatment of gout (inhibition of urate crystal

phagocytosis)

SULINDAC General information

- pro-drug


DICLOFENAC General information

- accumulates in synovial fluid


Medical uses

- see above

- treatment of rheumatoid arthritis

(accumulates in synovial fluid)

3) PROPIONIC ACID DERIVATIVES

- 3 types


IBUPROFEN General information

- weak COX inhibitor

- has little or no side effects (weak COX

inhibitor)

KETOPROFEN

FENOPROFEN General information

- pro-drug

4) ENOLIC ACID DERIVATIVES

- “pyrazolon derivatives”

- 1 type


PHENYLBUTAZONE General information

- potent COX inhibitor

- has severe side effects (potent COX

inhibitor)

- 142 -

5) COXIBS

- “COX-2 inhibitors”

- coxibs are selective reversible COX-2 inhibitors

- 3 types


CELECOXIB General information

- has little or no side effects (selective COX-2

inhibitor)


ROFECOXIB General information

- same as celecoxib

PARECOXIB General information

- same as celecoxib

- administered orally or parenterally

6) ANILINE DERIVATIVES

- “COX-3 inhibitors”

- aniline derivatives are selective reversible COX-3 inhibitors

- 1 type


PARACETAMOL General information

- “acetaminophen”

- has little or no anti-inflammatory effect

(selective COX-3 inhibitor)

- has little or no side effects in therapeutic

doses (selective COX-3 inhibitor)


- metabolized by the liver by glucoronidation

and/or sulfation

Medical uses

- treatment of pain

- treatment of fever

Side effects

- paracetamol overdose (nausea and vomiting

followed by hepatic- and renal tubular

necrosis, due to saturation of the hepatic

- 143 -

enzymes responsible for it’s metabolism and

following metabolism by the cytochrome P450

enzyme system leading to the formation of a

toxic metabolite (n-acetyl-p-benzoquinone

imine))

- 144 -

53. DRUGS USED TO TREAT RHEUMATOID ARTHRITIS

AND GOUT

DRUGS USED TO TREAT RHEUMATOID ARTHRITIS

Overview - rheumatoid arthritis is an autoimmune disorder leading to inflammation of the joints and

following erosion of the joint cartilage and –bone

Relevant Drugs

- 5 categories

1) DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS

- “DMARDs”

- act by unknown mechanisms in treating rheumatoid arthritis

- have very slow onsets (months (!))

- 5 types


SODIUM AUROTHIOMALATE General information

- gold-containing compound


Side effects

- blood dyscrasias

- proteinuria

- skin rashes

- stomatitis

- hepatitis

- encephalopathy

- peripheral neuropathy

AURANOFIN General information

- gold-containing compound


- same as sodium aurothiomalate

D-PENICILLAMIDE General information

- hydrolysate of penicillin

- may celate metals


Side effects

- 145 -

- blood dyscrasias

- proteinuria

- skin rashes

- stomatitis

- anorexia

- nausea

- vomiting

- taste disturbance (celation of zinc)

CHLOROQUINE General information

- also an antimalarial drug (see 71)

- may accumulate in the retina


Medical uses

- treatment of malaria

- treatment of SLE


Side effects

- visual disturbance (accumulates in

the retina)

METHOTREXATE General information

- folic acid antagonist

Medical uses


Side effects

- pulmonary fibrosis

2) NON-STEREOIDAL ANTI-INFLAMMATORY DRUGS

- inhibit COX, thus inhibiting formation of inflammatory cytokines and

following inhibition of inflammation

- see 51/52

3) IMMUNOSUPPRESSANTS

- powerfully suppress the immune defense system, thus decreasing the


- see 36

- 146 -

4) GLUCOCORTICOIDS

- inhibit synthesis inflammatory cytokines, thus decreasing the inflammatory

response

- see 36

5) 5-AMINOSALICYLIC ACID

- scavenges free radicals produced by neutrophils, thus decreasing the


- see 38

DRUGS USED TO TREAT GOUT

Overview - gout is a deposition of urate crystals in the synovia of joints due to excess formation of urate

- this leads to phagocytosis of the urate crystals by neutrophils and following initiation of

inflammation (“gouty arthritis”)

- urate formation is done in 2 steps

HYPOXANTHINE

xanthine oxidase

XANTHINE

xanthine oxidase

URATE

Relevant Drugs

- 4 categories

1) XANTHINE OXIDASE INHIBITORS

- xanthine oxidase inhibitors inhibit xanthine oxidase, thus decreasing

formation of urate

- 1 type


ALLOPURINOL General information

- hypoxanthine analogue

- binds to the active seat of xanthine oxidase,

thus inhibiting it

- is converted by xanthine oxidase to

alloxanthine

- alloxanthine binds to the allosteric seat of

xanthine oxidase, thus further inhibiting it

- may cause gout when first administered (!),

thus may not be used for treatment of gout

- 147 -


Medical uses

- prophylaxis of gout

Side effects

- gastrointestinal disturbances

- skin rashes

2) URICOSURIC DRUGS

- uricosuric drugs inhibit reabsorption of urate, thus increasing urate excretion

- 2 types


PROBENECID General information

- may cause gout when first administered (!),

thus may not be used for treatment of gout

Medical uses


Side effects

- uolithiasis

SULFINPYRAZOLE General information

- same as probenecid

3) ANTI-INFLAMMATORY DRUGS

- 1 type


COLCHICINE General information

- binds to tubulin leading to depolymerization

of microtubules and following decreased

motility of neutrophils


Medical uses


- treatment of gout

Side effects

- 148 -

- nausea

- vomiting

- severe diarrhea

- abdominal pain

- gastrointestinal hemorrhage

- renal tubular necrosis

- peripheral neuropathy

- skin rashes

4) NON-STEREOIDAL ANTI-INFLAMMATORY DRUGS

- NSAIDS inhibit COX-2, thus inhibiting production of inflammatory

prostaglandins and thromboxanes and following inhibition of inflammation

(see 51/52)

- used in prophylaxis and treatment of gout

- 149 -

A1. DRUGS, 2ND SEMESTER

23. CALCIUM CHANNEL BLOCKERS

1) PHENYLALKYLAMINES

- Verapamil

2) BENZOTHIAZEPINES

- Diltiazem

3) DIHYDROPYRIDINES (“DHP”)

A) SHORT/RAPIDLY-ACTING

- Nifedipine

- Nimodipine

- Nicardipine

B) INTERMEDiATELY-ACTING

- Nintrendipine

- Nisoldipine

C) LONG/SLOWLY-ACTING

- Amlodipine

24. DRUGS ACTING ON THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM


2) RENIN INHIBITORS

- Enalkiren

3) ACE INHIBITORS

- Enalapril

- Lisinopril

- Ramipril

4) TYPE 1 ANGIOTENSIN II RECEPTOR ANTAGONISTS

- Losartan

- Valsartan

5) ALDOSTERONE RECEPTOR ANTAGONISTS (“POTASSIUM-SPARING

DIURETICS”)

25. DIURETIC DRUGS

1) LOOP DIURETICS

- Furosemide

- Etacrynic Acid

- 150 -

2) THIAZIDE DIURETICS

- Berndroflumethazide

- Hydrochlorthiazide

- Cyclopenthiazide

3) CARBONIC ANHYDRASE INHIBITORS

- Acetazolamide

4) POTASSIUM-SPARING DIURETICS

- Spironolactone

- Triamterene

- Amiloride

5) OSMOTIC DIURETICS

- Mannitol

26. DRUGS USED TO TREAT CONGESTIVE HEART FAILURE

1) CARDIAC GLYCOSIDES (“DIGITALIS”)

- Digoxin

- Ouabain

2) DIRECT VASOLDILATORS

3) DRUGS ACTING ON THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

4) DIURETICS

26. ANTIANGINAL DRUGS. DRUGS THAT INCREASE REGIONAL BLOOD FLOW

1) ORGANIC NITRATES

- Glycerol Trinitrate (“Nitroglycerin”)

- Amyl Nitrate

- Isosorbide Mononitrate



27. ANTIHYPERTENSIVE DRUGS


- Minoxidil

- Hydralazine

- Nitroprusside

- Diazoxide


3) ORGANIC NITRATES

- 151 -

4) ALPHA-2 ADRENERGIC RECEPTOR AGONISTS

5) ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISTS


7) DRUGS ACTING ON THE RENIN-ANGIOTENSIN-ALDOSTERONE. SYSTEM

8) DIURETICS

28. ANTIARRYTHMIC DRUGS

1) CLASS I ANTIARRYTHMIC DRUGS

A) CLASS Ia ANTIARRYTHMIC DRUGS

- Quinidine

- Disopyramide

- Procainamide

B) CLASS Ib ANTIARRYTHMIC DRUGS

- Lidocaine

- Phenytoin

C) CLASS Ic ANTIARRYTHMIC DRUGS

- Flecainide

- Encainide

2) CLASS 2 ANTIARRYTHMIC DRUGS (“BETA-ADRENERGIC RECEPTOR

ANTAGONISTS”)

3) CLASS 3 ANTIARRYTHMIC DRUGS

- Amiodarone

- Sotalol

4) CLASS 4 ANTIARRYTHMIC DRUGS (“CALCIUM CHANNEL BLOCKERS”)

30. DRUGS USED TO TREAT HYPERLIPOPROTEINEMIA

1) STATINS

- Mevastatin

- Lovastatin

- Simvastatin

- Pravastatin

2) FIBRATES

- Fenofibrate

- Ciprofibrate

- Benzafibrate

3) RESINS

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- Colestyramine

- Colestipil

31. ANTICOAGULANTS. FIBRINOLYTICS. ANTIFIBRINOLYTICS. ANTIPLATELET DRUGS

1) ANTICOAGULANTS

A) INJECTABLE ANTICOAGULANTS

- Heparin

- LMWHS (“Low Molecular Weight Heparins”)

B) ORAL ANTICOAGULANTS

- Warfarin

2) FIBRINOLYTICS

- Streptokinase

- Alteplase

- Reteplase

3) ANTIFIBRINOLYTICS

- Tranexamic Acid

- Apoprotinin

4) ANTIPLATELET DRUGS

A) COX-1 INHIBITORS

B) THIENOPYRIDINE DERIVATIVES

- Triclopidine

- Clopidogrel

C) GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONISTS

- Abciximab

- Tirofibran

D) PGI2 AGINISTS

- Epoprostenol

32. DRUGS AFFECTING HEMATOPOIESIS

1) IRON

- Ferrous Sulfate

- Ferrous Succinate

- Ferrous Gluconate

- Ferrous Fumarate

- Iron-Dextran

2) FOLIC ACID (“VITAMIN B6”)

- Folic Acid

3) COBOLAMIN (“VITAMIN B12”)

- 153 -

- Hydroxycobolamin

4) CSFS (“COLONY-STIMULATING FACTORS”)

- GM-CSF

- G-CSF

33. HISTAMINE, H1 AND H2 RECEPTOR ANTAGONISTS

1) H1 RECEPTOR ANTAGONISTS (“ANTIHISTAMINES”)

- Prometazine

- Diphenhydramine

- Cyclicine

- Cinnarizine

- Mequitazine

- Centrizine

- Fexofenadine


- Cimetidine

- Rantidine

- Famotidine

- Nizatidine

34. SEROTONIN, SEROTONIN RECEPTOR AGONISTS AND ANTAGONISTS

1) SEROTONIN RECEPTOR AGONISTS

A) 5-HT 1 AGONISTS

- Buspirone

- Sumatriptan

- Ergotamine

B) 5-HT 2 AGONISTS

- LSD

C) 5-HT 4 AGONISTS

- Cisapride

2) SEROTONIN RECEPTOR ANTAGONISTS

A) 5-HT 2 ANTAGONISTS

- Methylglyceride

- Cyproheptadine

B) 5-HT 3 ANTAGONISTS

- Ondasetron

- Tropisetron

35. PHARMACOLOGY OF EICOSANOIDS. DRUGS ACTING ON THE SMOOTH MUSCLE:

SMOOTH MUSCLE RELAXANTS; PHARMACOLOGY OF THE UTERINE SMOOTH

- 154 -

MUSCLE

1) PHARMACOLOGY OF EICOSANOIDS

A) PROSTAGLANDINS

- PGD2

- PGE2

- PGF2-alpha

- PGI2

B) TROMBOXANES

- TXA2

C) LEUKOTRIENES

- LTB4

- LTC4

- LTD4

- LTE4

2) SMOOTH MUSCLE RELAXANTS

- …

3) PHARMACOLOGY OF UTERINE SMOOTH MUSCLE

A) OXYTOCIC DRUGS

I) OXYTOCIN RECEPTOR AGONISTS

- Oxytocin

II) ERGOT ALKALOIDS

- Ergometrine

- Ergotamine

III) PROSTAGLANDIN ANALOGUES

- Dinoprost

- Carboprost

- Misoprostol

B) TOCOLYTIC DRUGS

I) OXYTOCIN RECEPTOR ANTAGONISTS

- Atosiban

II) SELECTIVE BETA-2 ADRENERGIC RECEPTOR AGONISTS

36. PHARMACOLOGY OF THE RESPIRATORY TRACT

1) BRONCHODILATOR DRUGS

A) BETA-2 ADRENERGIC RECEPTOR AGONISTS

B) MUSCARINIC RECEPTOR ANTAGONISTS

- 155 -

C) HISTAMINERGIC H1 RECEPTOR ANTAGONISTS

D) CYSTEINYL-LEUKOTRIENE RECEPTOR ANTAGONISTS

- Montelukast

- Zafirlukast

2) ANTI-INFLAMMATORY DRUGS

A) GLUCOCORTICOIDS

B) CROMOGLICATE

- Cromoglicate

- Neddocromil Sodium

3) ANTITUSSIVES

- Codeine

- Dextromethorphan

- Pholcodine

37. PHARMACOLOGY OF THE GASTROINTESTINAL TRACT: DRUGS IN THE

TREATMENT OF PEPTIC ULCER; EMETICS, ANTI-EMETICS

1) DRUGS IN THE TREATMENT OF PEPTIC ULCER

A) H2 RECEPTOR ANTAGONISTS


C) HYDROGEN ION/POTASSIUM ANTIPORTER INHIBITORS

- Omeprazole

- Lansoprazole

- Pantoprazole

D) ANTACIDS

- Magnesium Hydroxide

- Magnesium Trisilicate

- Aluminium Hydroxide

- Sodium Bicarbonate

E) MUCOPROTECTIVE DRUGS

- Sucralfate

- Misoprostol

- Carbenoxolone

2) EMETICS

- Ipecacuanha

3) ANTI-EMETICS

A) H1 RECEPTOR ANTAGONISTS

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C) 5-HT 3 RECEPTOR ANTAGONISTS

D) D2 RECEPTOR ANTAGONISTS

I) PHENOTHIAZINES

II) BUTYRPHENONES

III) OTHERS

- Domperidone

- Metoclopramide

E) CANABINOID RECEPTOR AGONISTS

- Nabilone

- Dronabinol

38. PHARMACOLOGY OF THE GASTROINTESTINAL TRACT: PROKINETIC DRUGS,

LAXATIVES, ANTIDIARRHOEAL AGENTS, DRUG TREATMENT OF INFLAMMATORY

BOWEL DISEASE AND PARALYTIC ILEUS, DIGESTIVES, DRUGS USED IN

CHOLELITHIASIS

1) PROKINETIC DRUGS

A) LAXATIVES

I) BULK LAXATIVES

- Methylcellulose

- Bran

- Agar

II) OSMOTIC LAXATIVES

- Lactulose

- Magnesium Sulfate

- Magnesium Hydroxide

B) STIMULANT PURGATIVES

- Bisacodyl

- Sodium Picosulfate

- Senna

C) PERISTALTICS

I) 5-HT 4 RECEPTOR AGONISTS

II) D2 RECEPTOR ANTAGONISTS

D) FECAL SOFTENERS

- Docusate Sodium

2) ANTIDIARRHOEAL AGENTS

- 157 -

A) ORAL REHYDRATION

B) ANTIMOTILITY AGENTS

I) OPIOIDS

II) ALPHA-2 ADRENERGIC RECEPTOR AGONISTS

III) BISMUTH SUBSALICYLATE

C) ADSORBENTS

- Charcoal

- Chalk

- Pectin

- Magnesium Aluminium Silicate

3) DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE

A) 5-AMINOSALICYLIC ACID

- Sulfosalazine

- Mesalazine

- Olasalazine

B) GLUCOCORTICOIDS

C) IMMUNOSUPPRESSANTS

- Azathioprine

- Ciclosporin

4) DRUG TREATMENT OF PARALYTIC ILEUS

A) MUSCARINIC RECEPTOR AGONISTS

B) CHOLINESTERASE INHIBITORS

C) 5-HT 4 RECEPTOR AGONISTS

5) DIGESTIVES

A) GASTIC ACID SUPPLEMENTS

- Hydrochloric Acid

B) BILE SUPPLEMENTS

- Dihydrocholic Acid

C) PANCREATIC ENZYME SUPPLEMENTS

- Lipase

- Trypsin

- Amylase

6) DRUGS USED IN CHOLELITHIASIS

- 158 -

A) BILE ACIDS

- CDCA (“Chenodeoxycholic Acid”)

- UDCA (“Ursodeoxycholic Acid”)


C) OPIOIDS

39. ANTIANXIETY AND HYPNOTIC DRUGS

1) BENZODIAZEPINES

A) SHORT-ACTING

- Lorazepam

- Temazepam


- Nitrazepam

- Alprazolam

C) LONG-ACTING

- Diazepam

- Clonazepam

2) BARBITURATES

A) SHORT-ACTING

- Metohexital

- Thiopental


- Pentobarbital

- Butobarbital

C) LONG-ACTING

- Phenobarbital

3) 5-HT 1 AGONISTS

4) NON-SELECTIVE BETA ADRENERGIC RECEPTOR ANTAGONISTS

40. ALCOHOLS: PHARMACOLOGY AND TOXICOLOGY

1) ETHANOL

2) METHANOL

41. ANTIPSYCHOTIC DRUGS

1) CLASSIC ANTIPSYCHOTIC DRUGS

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A) PHENOTHIAZINES

- Chloropromazine

- Thioridazine

B) BUTYROPHENONES

- Haloperidol

- Droperidol

2) ATYPICAL ANTIPSYCHOTIC DRUGS

- Sulpiride

- Risperidone

- Clozapine

- Olanzapine

42. ANTIDEPRESSANTS

1) TCAS (“TRICYCLIC ANTIDEPRESSANTS”)

A) NON-SELECTIVE TCAS

- Imipramine

- Amitriptyline

B) NORADRENALINE-SELECTIVE TCAS

- Desipramine

- Clomipramine

2) SEROTONIN-SELECTIVE INHIBITORS

- Fluoxetine

- Fluvoxamine

- Paroxetine

- Sertaline

3) MAOIS (“MONOAMINE OXIDASE INHIBITORS”)

A) IRREVERSIBLE MAOIS

- Phenelzine

- Iproniazid

- Tranylcypromine

B) REVERSIBLE MAOIS

- Moclobemide

43. GENERAL ANAESTHETICS

1) INHALATION ANAESTHETIC

- Ether

- Halothane

- Enflurane

- Isoflurane

- Sevoflurane

- 160 -

- Nitrous Oxide

2) INTRAVENOUS ANAESTHETICS

- Metohexital

- Thiopental

- Etomidate

- Fentadyl

- Ketamine

44. ANTIEPILEPTIC DRUGS

1) DRUGS AFFECTING PARTIAL- AND GRAND MAL SEIZURES

- Phenytoin

- Carbamazepine

- Phenobarbital

2) DRUGS AFFECTING PETIT MAL SEIZURES

- Ethosuximide

3) DRUGS AFFECTING ALL TYPES OF EPILEPTIC SEIZURES

A) VALPROATE

B) LONG-ACTING BENZODIAZEPINES

45. CENTRAL NERVOUS SYSTEM STIMULANT AND NOOTROPIC AGENTS

1) CENTRAL NERVOUS SYSTEM STIMULANTS

2) NOOTROPIC AGENTS

- Piracetam

- Vinpocetine

- Pentoxyfilline

46. DRUG TREATMENT OF NEURODEGENERATIVE DISORDERS. CENTRALLY ACTING

MUSCLE RELAXANTS

1) DRUG TREATMENT OF NEURODEGENERATIVE DISORDERS

A) ALZHEIMER’S DISEASE

I) CHOLINESTERASE INHIBITORS

- Tacrine

- Donepezil

- Rivastigmine

- Galanthamine

II) NOOTROPIC DRUGS

B) PARKINSON’S DISEASE

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I) DOPAMINE REPLENISHERS

- L-DOPA

- Selegiline

- Entacapone

- Amantidine

II) D2 RECEPTOR AGONISTS

- Bromocriptine

- Lisuride

- Pergolide

III) MUSCARINIC RECEPTOR ANTAGONISTS

C) HUNTINGTON’S DISEASE

I) GABA AGONISTS

- Baclofen

II) D2 RECEPTOR ANTAGONIST

2) CENTRALLY-ACTING MUSCLE RELAXANTS

- …

47. DRUG ABUSE AND DEPENDENCE: GENERAL PRINCIPLES, OPIOIDS, ANTIANXIETY

AND HYPNOTIC DRUGS, INHALANTS, ETHANOL

1) OPIOIDS

2) ANTI-ANXIETY AND HYPNOTIC DRUGS

3) INHALANTS

- …

4) ETHANOL

48. DRUG ABUSE AND DEPENDENCE: PSYCHOMOTOR STIMULANTS, PSYCHEDELICS,

CANNABIS

1) PSYCHOMOTOR STIMULANTS

A) AMPHETAMINE ANALOGUES

- Amphetamine

- Metamphetamine (“Speed”)

- Methylenedioxymethamphetamine (“Ecstasy”)

- Mesacaine

- Methylphenidate

- Fenfluramine

B) COCAINE ANALOGUES

- Hydrochloride Salt Cocaine (“Snow”)

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- Free Base Cocaine (“Crack”)

C) METHYLXANTHINES

- Theophylline

- Aminophylline

- Caffeine

- Theobromine

2) PSYCHEDELICS (“PSYCHOMIMETIC DRUGS”)

A) LSD ANALOGUES

- LSD

- Psilocybin

B) PHENCYCLIDINE

C) CANNABIS

- Marijuana

- Hashish

49./50. OPIOID ANALGESIC DRUGS: MORPHINE AND CODEINE. OPIOID ANALGESIC

DRUGS: SEMI-SYNTHETIC, SYNTHETIC OPIOIDS; OPIOID ANTAGONISTS

1) MORPHINE ANALOGUES

- Morphine

- Diamorphine (“Heroin”)

- 3- Methoxymorphine

2) SYNTHETIC OPIOID DERIVATIVES

A) PHENYLPIPERIDINE ANALOGUES

- Fentadyl

- Penthidine

B) METHADONE DERIVATIVES

- Methadone

- Dextropropoxyphene

C) BENZOMORPHAN DERIVATIVES

- Pentazocine

D) THEBAINE DERIVATIVES

- Buprenorphine

E) OTHERS

- Loperamide

3) OPIOID ANTAGONISTS

- Naxolone

- Naltrexone

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51./52. CYCLOOXYGENASE INHIBITORS: ASPIRIN. PARACETAMOL.

CYCLOOXYGENASE INHIBITORS: PYRAZOLONS, PROPIONIC ACID

DERIVATIVES, INDOLE DERIVATIVES AND OTHERS. “COX-2 INHIBITORS”

1) SALICYLIC ACID DERIVATIVES

- Aspirin (“Acetylsalicylic Acid”)

2) ACETIC ACID DERIVATIVES (“INDOLE DERIVATIVES”)

- Indometacin

- Sulindac

- Diclofenac

3) PROPIONIC ACID DERIVATIVES

- Ibuprofen

- Ketoprofen

- Fenoprofen

4) ENOLIC ACID DERIVATIVES (“PYRAZOLON DERIVATIVES”)

- Phenylbutazone

5) COXIBS (“COX-2 INHIBITORS”)

- Celecoxib

- Rofecoxib

- Parecoxib

6) ANILINE DERIVATIVES (“COX-3 INHIBITORS”)

- Paracetamol

53. DRUGS USED TO TREAT RHEUMATOID ARTHRITIS AND GOUT

1) DRUGS USED TO TREAT RHEUMATOID ARTHRITIS

A) DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS

- Sodium Aurothiomalate

- Auranofin

- D-Penicillamide

- Chloroquine

- Methotrexate

B) NON-STEREOIDAL ANTI-INFLAMMATORY DRUGS (“NSAIDS”)

C) IMMUNOSUPPRESSANTS

D) GLUCOCORTICOIDS

E) 5-AMINOSALICYLIC ACID

2) DRUGS USED TO TREAT GOUT

A) XANTHINE OXIDASE INHIBITORS

- Allopurinol

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B) URICOSURIC DRUGS

- Probenecid

- Sulfinpyrazole

C) ANTI-INFLAMMATORY DRUGS

- Colchicine

D) NON-STEREOIDAL ANTI-INFLAMMATORY DRUGS (“NSAIDS”)

BRY's Pharmacology 2nd Semester

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