TABLE OF CONTENTS

23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. A1. Calcium Channel Blockers (Page 1) Drugs Acting on the Renin Angiotensin Aldosterone System (Page 5) Diuretic Drugs (Page 8) Drugs Used to Treat Congestive Heart Failure (Page 13) Antianginal Drugs. Drugs That Increase Regional Blood Flow (Page 17) Antihypertensive Drugs (Page 20) Antiarrhythmic Drugs (Page 23) Drugs Used to Treat Hyperlipoproteinemia (Page 29) Anticoagulatnts. Fibrinolytics. Antifibrinolytics. Antiplatelet Drugs (Page 33) Drugs Affecting Hematopoiesis (Page 39) Histamine, H1 and H2 Receptor Antagonists (Page 43) Serotonin, Serotonin Receptor Agonists and Antagonists (Page 47) Pharmacology of Eicosanoids. Drugs Acting on the Smooth Muscle: Smooth Muscle Relaxants; Pharmacology of the Uterine Smooth Muscle (Page 53) Pharmacology of the Respiratory Tract (Page 61) Pharmacology of the Gastrointestinal Tract: Drugs in the Treatment of Peptic Ulcer; Emetics, Anti-Emetics (Page 65) 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) Antianxiety and Hypnotic Drugs (Page 80) Alcohols: Pharmacology and Toxicology (Page 86) Antipsychotic Drugs (Page 90) Antidepressants (Page 94) General Anaesthetics (Page 99) Antiepileptic Drugs (Page 105) Central Nervous System Stimulants and Nootropic Agents (Page 109) Drug Treatment of Neurodegenerative Disorders. Centrally-Acting Muscle Relaxants (Page 111) Drug Abuse and Dependence: General Principles, Opioids, Anti-Anxiety and Hypnotic Drugs, Inhalants, Ethanol (Page 116) Drug Abuse and Dependence: Psychomotor Stimulants, Psychedelics, Cannabis (Page 118) Opioid Analgesic Drugs: Morphine and Codeine (Page 130) Opioid Analgesic Drugs: Semi-Synthetic, Synthetic Opioids; Opioid Antagonists (Page 130) Cyclooxygenase Inhibitors: Aspirin, Paracetamol (Page 138) Cyclooxygensae Inhibitors: Pyrazolons, Propionic Acid Derivatives, Indole Derivatives and Others. COX-2 Inhibitors (Page 138) Drugs Used to Treat Rheumatoid Arthritis and Gout (Page 144) Drugs, 2nd Semester (Page 149)

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 BLOOD VESSELS ACTION Decreased blood pressure - arterial vasodilation 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)

HEART

Relevant Drugs
3 categories 1) PHENYLALKYLAMINES (VERAPAMIL) - primarily acts on the heart - also has a weak action on blood vessels - 1 type DRUG NAME VERAPAMIL DESCRIPTION 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)

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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 DRUG NAME DILTIAZEM DESCRIPTION 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 DRUG NAME NIFEDIPINE DESCRIPTION General information - administrated orally - extensive first pass-metabolism

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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 - treatment of hypertension (strong arterial vasodilation) - treatment of cerebral vasospasms following subarachnoid hemorrhage (then administered IV) Side effects - same as nifedipine NICARDIPINE General information - same as nifedipine - some selectivity for coronary arteries Clinical usages - treatment of hypertension (strong arterial vasodilation) - treatment of prinzmental angina pectoris (strong coronary artery vasodilation) Side effects - same as nifedipine

B) INTERMEDIATELY-ACTING DHPS - 8-10 hours - 2 types DRUG NAME -3DESCRIPTION

NITRENDIPINE

General information - same as nifedipine 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 DRUG NAME AMLODIPINE DESCRIPTION General information - same as nifedipine Clinical usages - same as nicardipine Side effects - same as nitrendipine, but even less pronounced reflex tachycardia

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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 preurine 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 ANGIOTENSIN II ACTION - arterial vasoconstriction (primarily in the kidneys, heart and brain) - increased sympathetic tone - hypertrophy/hyperplasia of cardiac- and smooth muscle - aldosterone secretion - 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)

ALDOSTERONE

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 -5-

2) RENIN INHIBITORS - renin inhibitors inhibit the enzymatic activity of renin, thus decrease the conversion of angiotensinogen to angiotensin I - 1 type DRUG NAME ENALKIREN DESCRIPTION

3) ACE INHIBITORS - ACE inhibitors inhibit the enzymatic activity of ACE, thus decrease the conversion of angiotensin I to angiotensin II - 3 types DRUG NAME ENALAPRIL DESCRIPTION General information - administered orally - 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 -6-

- 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 DRUG NAME LOSARTAN DESCRIPTION General information - administered orally 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

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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 DRUG NAME FUROSEMIDE DESCRIPTION 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 -8-

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 - may increase urinary output to 10 liters/day (5% of glomerular filtrate) - inhibits the sodium/chloride cotransported reabsorption of the distal tubule - 3 types DRUG NAME BENDROFLUMETHAZIDE DESCRIPTION General information - administered orally - 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 -9-

transporter) - hyperlipoproteinemia - male impotence HYDROCHLORTHIAZIDE General information - same as bendrofluazide General information - same as bendrofluazide

CYCLOPENTHIAZIDE

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

DRUG NAME ACETAZOLAMIDE

DESCRIPTION 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

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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) may increase urinary output to 5 liters/day (3% of glomerular filtrate) potassium-sparing diuretics antagonize the effect of aldosterone in the late distal tubule 3 types DRUG NAME SPIRONOLACTONE DESCRIPTION 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 potassiumand hydrogen ion secretion - administered orally Medical uses - coadministered with non-potassium sparing diuretics to preserve potassium - treatment of hyperaldosteronism (conns 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 - administered orally Medical uses - 11 -

- 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 DRUG NAME MANNITOL DESCRIPTION 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

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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 INCREASED SYMPATHETIC TONE CONSEQUENCE 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 - 13 DESCRIPTION

POSITIVE BATHMOTROPIC EFFECT

- due to decreased negative membrane potential and following easier excitability of the myocytes - 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

POSITIVE IONOTROPIC EFFECT

B) INCREASED VAGAL TONE (CENTRAL STIMULATION OF VAGAL NUCLEI) - 2 consequences CONSEQUENCE NEGATIVE CHRONOTROPIC EFFECT NEGATIVE DROMOTROPIC EFFECT DESCRIPTION - due to depression of the SA-node and following decreased heart rate - due to depression of the AV-node and following decreased AV conduction

2 types DRUG NAME DIGOXIN DESCRIPTION General information - found in foxgloves - administered orally (and IV in emergencies) - effective dose and toxic dose has a very small margin - 14 -

- 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

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4) DIURETICS - decrease blood volume - see 25

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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 SILENT MYOCARDIAL ISCHEMIA STABLE ANGINA UNSTABLE ANGINA MIXED ANGINA DESCRIPTION

- narrowed coronary artery lumen - occluded coronary artery lumen - both narrowed and occluded lumen at distinct locations - vasospasms of the coronary arteries

PRINZMETAL ANGINA

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 INCREASED MYOCARDIAL BLOOD SUPPLY CONSEQUENCE 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 oxygen

DECREASED MYOCARDIAL - 17 -

WORKLOAD

consumption - decreased preload (venous vasodilation) - decreased afterload (arterial vasodilation)

3 types DRUG NAME GLYCEROL TRINITRATE (NITROGLYCERIN) DESCRIPTION General information - lipophilic - administered sublingually, transdermally or IV - extensive first-pass metabolism 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 General information - administered orally Medical uses - prophylaxis of stable angina - treatment of chronic heart failure Side effects - same as glycerol trinitrate

ISOSORBIDE MONONITRATE

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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 3) BETA-1 ADRENERGIC RECEPTOR ANTAGONISTS - 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

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28. ANTIHYPERTENSIVE DRUGS

Overview
blood pressure is given by 2 parameters PARAMETER CARDIAC OUTPUT DESCRIPTION - given by the rate and stroke volume of the heart - given by the blood volume and the level of vasoconstriction

TOTAL PERIPHERAL RESITANCE

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

Relevant Drugs
8 categories 1) DIRECT VASODILATORS - dilate the blood vessels, thus decreasing total peripheral resistance - 4 types DRUG NAME MINOXIDIL DESCRIPTION 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

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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) General information - non-diuretic thiazide - administered IV - same as thiazide diuretics (see 25)

DIAZOXIDE

2) CALCIUM CHANNEL BLOCKERS - 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

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6) BETA-1 ADRENERGIC RECEPTOR ANTAGONISTS - 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

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29. ANTIARRHYTHMIC DRUGS

Overview
action potential in myocytes has 4 (5) phases PHASE PHASE 0 DESCRIPTION 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 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 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 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) 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) - 23 -

PHASE 1

PHASE 2

PHASE 3

PHASE 4

there are 4 types of cardiac arrhythmias TYPE ACTIVE ECTOPIC BEATS (SUPRAVENTRICULAR-, VENTRICULAR-) DESCRIPTION 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) General information - heart rate above 250 BPM - 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 - heart rate above 350 BPM - due to the presence of multiple reentrant circuits (see above)

FLUTTER (ATRIAL-)

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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 DRUG NAME QUINIDINE DESCRIPTION General information - administered orally - 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 General information - administered IV Medical uses - treatment of ventricular arrhythmias Side effects - ventricular paroxysmal tachycardia - SLE-like disorder (autoantibodies against own DNA)

PROCAINAMIDE

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B) CLASS Ib ANTIARRHYTHMIC DRUGS - cause weak voltage-gated sodium channel block - selectively block refractory voltage-gated sodium channels - 2 types DRUG NAME LIDOCAINE DESCRIPTION General information - local anaesthetic (see 22) - administered IV - extensive first-pass metabolism 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) - administered orally - same as lidocaine Medical uses - treatment of arrhythmias associated with irreversible myocardial ischemia (AMI, due to selective refractory blockage) - treatment of epilepsy Side effects - see 43

C) CLASS Ic ANTIARRHYTHMIC DRUGS - cause strong voltage-gated sodium channel block - 2 types DRUG NAME FLECAINIDE DESCRIPTION Medical uses - treatment of arrhythmias associated with reentrant circuits (strong general suppression)

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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 3) CLASS 3 ANTIARRHYTHMIC DRUGS - block the potassium-sodium leak channels (phase 1 and phase 3), thus increase duration of repolarization (refractory period) - 3 types DRUG NAME AMIODARONE DESCRIPTION General information - iodine-containing compound - accumulates in tissues - administered orally Medical uses - treatment of arrhythmias associated with reentrant circuits (prolonged refractory period) Side effects - ventricular paroxysmal tachycardia (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) - 27 -

SOTALOL

General information - administered orally - also a beta-adrenergic receptor antagonist (see 21) Medical uses - treatment of arrhythmias associated with reentrant circuits - treatment of arrhythmias associated with excess sympathetic activity Side effects - see 21

4) CLASS 4 ANTIARRHYTHMIC DRUGS - calcium channel blockers - block voltage-gated calcium channels, thus decrease force of contraction - used in treatment of supraventricular/atrial arrhythmias - see 23

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30. DRUGS USED TO TREAT HYPERLIPOPROTEINEMIA

Overview
triglycerides and cholesterol are transported in lipoproteins in the circulation lipoproteins consists of 2 parts PART MEDULLA DESCRIPTION - hydrophobic - consists of triglycerides and cholesterol esters - hydrophilic - consists of phospholipids, cholesterol and apolipoproteins

CORTEX

there are 5 types of lipoproteins TYPE CHYLOMICRON DESCRIPTION - 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 - 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) 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 Low density lipoprotein - transports the remaining cholesterol either back to the liver for conversion to bile acids, or to extrahepatic tissues for metabolism High density lipoprotein - a scavenger lipoprotein that adsorbs cholesterol - 29 -

CHYLOMICRON REMNANT

VLDL

LDL

HDL

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 DRUG NAME MEVASTATIN DESCRIPTION General information - found in fungus - administered orally - 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 General information - synthetic pro-drug - same as mevastatin

SIMVASTATIN

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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 DECREASED LIPID STORES CAUSE - increased deliberation of lipids from adipose tissue - increased lipoprotein lipase activity - increased beta-oxidation - decreased VLDL production - increased LDL-receptor expression

DECREASED CIRCULATING LIPIDS

DECREASED CIRCULATING VLDL

DECREASED CIRCULATING LDL

3 types DRUG NAME FENOFIBRATE DESCRIPTION Gereral information - administered orally 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 - 31 -

CIPROFIBRATE

General information -same as fenofibrate General information -same as fenofibrate

BENZAFIBRATE

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 DRUG NAME COLESTYRAMINE DESCRIPTION Gereral information - administered orally Medical uses - reduction of LDL Side effects - nausea - vomiting - bloating - constipation or diarrhea - fat-soluble vitamin deficiency COLESTIPIL General information -same as colestyramine

- 32 -

31. ANTICOAGULANTS. FIBRINOLYTICS. ANTIFIBRINOLYTICS. ANTIPLATELET DRUGS

Overview
hemostasis consists of 4 (5) mechanisms MECHANISM VASOCONSTRICTION PLATELET PLUG FORMATION COAGULATION DESCRIPTION - both neurally- and humorally mediated - adhesion of platelets to the damaged endothelium - blood clot formation by activation of fibrin through the intrinsic- or extrinsic coagulation cascade - growth of fibrous tissue by conversion of smooth muscle cells of the vessel walls to myofibroblasts - removal of the blood clot by activation of plasmin

PERMANENT CLOSURE

FIBRINOLYSIS

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 DRUG NAME HEPARIN DESCRIPTION General information - 33 -

- 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 heparinplatelet 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 its 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 DRUG NAME DESCRIPTION - 34 -

WARFARIN

Gereral information - also used in rat poison - administered orally - 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 - treatment of thrombosis, DIC and emboli 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 DRUG NAME STREPTOKINASE DESCRIPTION General information - streptococcal protein - may only be administered once per year (antistreptococcal antibodies will be formed within 1 week (!)) Medical uses - treatment of thrombosis, DIC and emboli Side effects - hemorrhage (fibrinolysis) - stroke (hemorrhage) - anaphylaxis (antistreptococcal antibodies) ALTEPLASE General information - recombinant tPA (tissue plasminogen factor, the physiological - 35 -

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 - treatment of thrombosis, DIC and emboli 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 DRUG NAME TRANEXAMIC ACID DESCRIPTION General information - administered orally or IV Medical uses - treatment of severe hemorrhages - treatment of fibrinolytic overdose Side effects - thrombosis APOPROTININ General information - inhibits proteolytic enzymes (including plasmin) Medical uses - 36 -

- 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 DRUG NAME TRICLOPIDINE DESCRIPTION General information - pro-drug - administered orally Medical uses - treatment of thrombosis, DIC and emboli Side effects - hemorrhages - blood dyscrasias - diarrhea - skin rashes

- 37 -

CLOPIDOGREL

General information - same as triclopidine

3) GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONITS - antagonizes TXA2 and ADP, thus inhibiting platelet plug formation - 2 types DRUG NAME ABCIXIMAB DESCRIPTION General information - hybride rodent/human monoclonal antibody - administered IV - may only be administered once (antibodies against the rodent part will be formed) Medical uses - treatment of thrombosis, DIC and emboli Side effects - hemorrhages TIROFIBRAN General information - administered IV Medical uses - treatment of thrombosis, DIC and emboli Side effects - hemorrhages

4) PGI2 AGONISTS - inhibit expression of glycoprotein IIb/IIIa, thus inhibiting platelet plug formation - 1 type DRUG NAME EPOPROSTENOL DESCRIPTION

- 38 -

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 ERYTHROCYTES PLATELETS MONOCYTES GRANULOCYTES DESCRIPTION - RBCs - cell fragments of megakaryocytes - differentiate to macrophages - neutrophils - eosinophils - basophils - B lymphocytes - T lymphocytes

LYMPHOCYTES

anemia is a decrease in circulating RBCs there are 4 types of anemia TYPE APLASTIC ANEMIA DEFICIENCY ANEMIA DESCRIPTION - due bone marrow failure - 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) - due to increased sequestration of RBCs - due to hemorrhages

HEMOLYTIC ANEMIA HEMORRHAGIC ANEMIA

Relevant Drugs
4 categories - 39 -

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 DRUG NAME FERROUS SULFATE DESCRIPTION General information - administered orally Medical uses - treatment of microcytic, hypochromic deficiency anemia Side effects - nausea - diarrhea - abdominal cramps FERROUS SUCCINATE General information - same as ferrous sulfate General information - same as ferrous sulfate General information - same as ferrous sulfate General information - administered IV - same as ferrous sulfate

FERROUS GLUCONATE

FERROUS FUMARATE

IRON-DEXTRAN

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 DNAand 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 its utilization - 1 type DRUG NAME - 40 DESCRIPTION

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 DRUG NAME HYDROXYCOBOLAMIN DESCRIPTION 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 DRUG NAME GM-CSF DESCRIPTION Gereral information - granulocyte-macrophage colonystimulating factor - endogenous substance - involved in differation of all cells mentioned above - administered IV or subcutaneously Medical uses - treatment of leucopenia (mainly neutropenia) Side effects - 41 -

- 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

- 42 -

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 CNS SYSTEMIC CIRCULATION DESCRIPTION - histaminergic neurons - granules of mast cells - granules of basophils - neuroendocrine cells in the glands of the GI

GI TRACT

histamine acts on histaminergic receptors there are 3 types of histaminergic receptors RECEPTOR TYPE H1 LOCATION - smooth muscle - CNS - parietal cells of the castric glands - heart - presynaptically in CNS neurons

H2

H3

General Effects
6 types ORGAN CNS DESCRIPTION - inhibition of neurotransmitter release - nausea - positive chronotropic effect (increased heart rate) - positive ionotropic effect (increased force of contraction) - vasodilation - increased vascular permeability

HEART

BLOOD VESSELS

- 43 -

RESPIRATORY TRACT GI TRACT

- bronchoconstriction - increased gastric acid secretion - GI smooth muscle contraction - contraction of uterus

GENITO-URINARY TRACT

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 its 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 DRUG NAME PROMETAZINE DESCRIPTION General information - marked muscarinic receptor antagonist action - weak alpha-1 adrenergic receptor antagonist action - weak local anaesthetic action - administered orally - 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

- 44 -

action - weak local anaesthetic action - administered orally - may cross the blood brain barrier - same as prometazine CYCLIZINE General information - administered orally - may cross the blood-brain barrier Medical uses - treatment of emesis (especially motion sickness) Side effects - diarrhea/constipation - sedation CINNARIZINE General information - same as cyclizine 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 - diarrhea/constipation CENTRIZINE General information - same as mequitazine General information - same as mequitazine

MEQUITAZINE

FEXOFENADINE

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 - 45 -

, 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 DRUG NAME CIMETIDINE DESCRIPTION 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 - administered orally, intramuscularly or IV Medical uses - same as cimetidine Side effects - same as cimetidine (but no gynecomastia) FAMOTIDINE General information - same as rantidine General information - administered orally - same as rantidine

NIZATIDINE

- 46 -

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 CNS SYSTEMIC CIRCULATION GI TRACT DESCRIPTION - serotonergic neurons - platelets - neuroendocrine cells in the glands of the GI - myenteric plexus

serotonin acts on serotonergic receptors there are 8 types of serotonergic receptors RECEPTOR TYPE 5-HT 1A DESCRIPTION Location - CNS Effect - CNS depression - anxiolysis - alertness

- 47 -

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 - 48 -

- 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 DRUG NAME BUSPIRONE DESCRIPTION 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 - extensive first-pass metabolism - administered orally or subcutaneously

- 49 -

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) - may cross the blood-brain barrier - 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 DRUG NAME LSD DESCRIPTION General information - see 48

3) 5-HT 4 AGONISTS - 1 type DRUG NAME - 50 DESCRIPTION

CISAPRIDE

General information - administered orally 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 DRUG NAME METHYLGLYCERGIDE DESCRIPTION General information - also partial 5-HT 2 agonist - administered orally 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) - administered orally Medical uses

- 51 -

- prophylaxis of migraine (cerebral blood vessel vasodilation) Side effects - sedation - weight gain

2) 5-HT 3 ANTAGONISTS - 2 types DRUG NAME ONDASETRON DESCRIPTION General information - administered orally Medical uses - treatment of emesis (vomiting) - treatment of anxiety TROPISETRON General information - same as ondasetron

- 52 -

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 PROSTAGLANDINS TYPE - PGD2 - PGE2 - PGF2-alpha - PGI2 - TXA2 - LTB4 - LTC4 - LTD4 - LTE4

TROMBOXANES LEUKOTRIENES

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/ TROMBOXANES there are 9 types of eicosanoid receptors RECEPTOR TYPE DESCRIPTION - 53 LEUKOTRIENES

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 - bronchoconstriction - GI tract smooth muscle contraction - fever (increase the hypothalamic temperature set point) - hyperalgesia (sensitization of afferent C nerve fibers, see 49)

EP2 (PGE2) RECEPTORS

Location - blood vessels - lungs - GI tract Effect - vasodilation - bronchodilation - GI tract smooth muscle relaxation - intestinal fluid secretion

EP3 (PGE2) RECEPTORS

Location - uterus - GI tract - autonomic nervous system - adipose tissue - 54 -

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

- 55 -

CYSLT (LTC4, LTD4, LTE4) RECEPTORS

Location - blood vessels - lungs Effect - vasodilation - increase vascular permeability - bronchoconstriction - 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 FACILITATION HORMONE - progesterone - oxytocin - estrogen

INHIBITION

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 MENSTURAL CYCLE DESCRIPTION Pre-ovulatory phase - weak rhythmic contractions (estrogen) Post-ovulatory phase - strong rhythmic contractions (progesterone) PREGNANCY Pregnancy - very weak (or absent) rhythmic contractions - 56 -

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 FACILITATION HORMONE - PGE2 (EP3 receptors) - PGF2-alpha - histamine (H1 receptors) - serotonin (5-HT 2A receptors) - PGD2 - adrenalin (beta-2 receptors)

INHIBITION

Relevant Drugs
2 categories 1) OXYTOCIC DRUGS - facilitate uteral contraction - 3 groups A) OXYTOCIN RECEPTOR AGONISTS - 1 type DRUG NAME OXYTOCIN DESCRIPTION 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 - 57 -

contraction) - treatment of milk congestion (mammary gland contraction) Side effects - hypotension (vasodilation) - reflex tachycardia (hypotension) - water retention (antidiuretic effect)

B) ERGOT ALKALOIDS - 2 types DRUG NAME DESCRIPTION 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 - administered orally, intramuscularly or IV Medical uses - treatment of postpartum hemorrhage Side effects - hypertension (vasoconstriction) - angina (vasoconstriction) - nausea (stimulation of the chemoreceptive trigger zone) - vomiting (nausea) - headache - blurred vision ERGOTAMINE General information - see 34

C) PROSTAGLANDIN ANALOGUES - 3 types DRUG NAME - 58 DESCRIPTION

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 - administered intramuscularly - same as dinoprostone General information - see 37

MISOPROSTOL

2) TOCOLYTIC DRUGS - inhibit uteral contraction - 2 groups A) OXYTOCIN RECEPTOR ANTAGONISTS - 1 type DRUG NAME ATOSIBAN DESCRIPTION General information - oxytocin receptor antagonist - administered IV Medical uses - prevention of premature labor Side effects - hypertension (vasoconstriction) - nausea - vomiting - hyperglycemia - 59 -

- skin rashes

B) SELECTIVE BETA-2 ADRENERGIC RECEPTOR AGONISTS - inhibit uteral contraction, thus preventing premature labor - see 19

- 60 -

36. PHARMACOLOGY OF THE RESPIRATORY TRACT

Overview
asthma is a reversible obstructive disorder of the lungs asthma consists of 2 phases PHASE ACUTE PHASE DESCRIPTION - activation of mast cells mediated by IgE and following secretion of cytokines - chemotaxis and activation of inflammatory cells (especially eosinophils) and following secretion of cytokines

LATE PHASE

secreted cytokines include CYTOKINE ACUTE PHASE CYTOKINES DESCRIPTION - bronchoconstrictory cytokines - chemotactic cytokines - chemotactic cytokines - inflammatory cytokines - vasodilatory cytokines - growth factors - toxic proteins

LATE PHASE CYTOKINES

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 - 61 -

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 DRUG NAME MONTELUKAST DESCRIPTION General information - administered orally 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 - 62 -

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 DRUG NAME CROMOGLICATE DESCRIPTION General information - administered by aerosol in conjunction with glucocorticoids Medical uses - treatment of asthma 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

- 63 -

Relevant Drugs
3 types DRUG NAME CODEINE DESCRIPTION General information - see 49 General information - analgesic opioid analogue - same as codeine General information - non-analgesic opioid analogue

DEXTROMETHORPHAN

PHOLCODINE

- 64 -

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 PROTECTIVE FACTORS FACTOR - mucin - bicarbonate (HCO3-) - blood flow - hydrochloric acid (HCl) - pepsin (gastric protease)

AGGRESSIVE FACTORS

gastric acid secretion by the parietal cells are regulated by 5 (3+2) substances REGULATION STIMULATION SUBSTANCE - acetylcholine - gastrin - histamine - PGE2 - PGI2

INHIBITION

Relevant Drugs
5 categories 1) 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 - , 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 - 65 -

2) MUSCARINIC RECEPTOR ANTAGONISTS - 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 DRUG NAME OMEPRAZOLE DESCRIPTION General information - administered orally - 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 reflux esophagitis - treatment of hypergastrinemia Side effects - severe diarrhea - severe headache - mild gynecomastia - mild impotence - mild joint/muscle pain LANSOPRAZOLE General information - same as omeprazole General information - same as omeprazole

PANTOPRAZOLE

- 66 -

4) ANTACIDS - antacids chemically neutralize gastric acid - pepsin is only active at very low pH, thus neutralization of pH secondarily inactivates pepsin - 4 types DRUG NAME MAGNESIUM HYDROXIDE DESCRIPTION General information - administered orally Medical uses - treatment of duodenal ulcers (not gastric-) - treatment of dyspepsia - treatment of reflux esophagitis Side effects - diarrhea MAGNESIUM TRISILICATE General information - also adsobs pepsin - same as magnesium hydroxide General information - administered orally - also adsorbs pepsin Medical uses - same as magnesium hydroxide Side effects - constipation SODIUM BICARBONATE General information - very strong neutralizer (increase gastric ph to 7,4 (!)) - deliberates carbondioxide - administered orally Medical uses - same as magnesium hydroxide

ALUMINIUM HYDROXIDE

- 67 -

Side effects - belching (deliberates carbondioxide) - secondary hypergastrinemia (stimulated by carbondioxide) - metabolic alkalosis

5) MUCOPROTECTIVE DRUGS - 3 types DRUG NAME SUCRALFATE DESCRIPTION General information - binds to positively charged proteins (including glycoproteins of the gastric mucous) - forms a complex gel with the gastric mucous - administered orally 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) - 68 -

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 DRUG NAME IPECACUANHA DESCRIPTION General information - administered orally - 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 1) H1 RECEPTOR ANTAGONISTS - 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 - 69 -

2) MUSCARINIC RECEPTOR ANTAGONISTS - 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 DRUG NAME DOMPERIDONE DESCRIPTION General information - also increases tone of GI smooth muscle Medical uses - treatment of chemotherapyinduced emesis - treatment of reflux esophagitis (increased tone of lower esophageal sphincter) - treatment of disorders of gastric emptying (increased tone of the stomach smooth muscle) Side effects - see 41

- 70 -

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 DRUG NAME NABILONE DESCRIPTION General information - synthetic THC derivative (see 48) - administered orally Medical uses - conjunctive to 5-HT 3- and/or D2 receptor antagonists in treatment of chemotherapyinduced emesis - treatment of diarrhea (decreased peristalsis) Side effects - see 48 DRONABINOL General information - same as nabilone

- 71 -

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 STIMULATION INHIBITION RECEPTOR - 5-HT 4 serotonergic receptors - 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 DRUG NAME METHYLCELLULOSE DESCRIPTION

- 72 -

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 DRUG NAME LACTULOSE DESCRIPTION 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 - treatment of constipation Side effects - diarrhea MAGNESIUM HYDROXIDE General information - same as magnesium sulfate

2) STIMULANT PURGATIVES

- 73 -

increase GI secretion into the intestinal lumen, thus increasing the water content and following amount of feces in the intestines also increase peristalsis DRUG NAME BISACODYL DESCRIPTION General information - administered rectally Medical uses - treatment of constipation Side effects - diarrhea SODIUM PICOSULFATE General information - administered orally - same as bisacodyl General information - administered orally - glycoside containing anthracene derivatives - hydrolyzed by bacteria to free the antracene derivatives - same as bisacodyl

SENNA

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 its transition through the intestines - 1 type DRUG NAME DOCUSATE SODIUM - 74 DESCRIPTION General information

- detergent - also a weak laxative Medical uses - treatment of constipation

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 DRUG NAME CHARCOAL DESCRIPTION

- 75 -

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 DRUG NAME SULFASALAZINE DESCRIPTION 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 General information - 2 diazo-linked 5-aminosalicylic acids - same as sulfasalazine

OLSALAZINE

- 76 -

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 inflammatory response - 2 types DRUG NAME AZATHIOPRINE CICLOSPORIN DESCRIPTION

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 - 77 -

1) GASTRIC ACID SUPPLEMENTS - 2 types DRUG NAME HYDROCHLORIC ACID DESCRIPTION General information - given alone or together with pepsin

2) BILE SUPPLEMENTS - 1 type DRUG NAME DIHYDROCHOLIC ACID DESCRIPTION General information - increases production of bile

3) PANCREATIC ENZYME SUPPLEMENTS - 3 types DRUG NAME LIPASE TRYPSIN AMYLASE DESCRIPTION

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 DRUG NAME CDCA (CHENODEOXYCHOLIC ACID) DESCRIPTION Medical uses - treatment of cholesterol cholelithiasis General information - 78 -

UDCA

(URSODEOXYCHOLIC ACID)

- same as CDCA

2) MUSCARINIC RECEPTOR ANTAGONISTS - decrease release of acetylcholine, thus decreasing cholic spasms - see 15 3) OPIOIDS - decrease pain associated with cholic spasms - see above

- 79 -

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 CENTRAL COMPONENT PERIPHERAL COMPONENT LOCATION - locus ceruleus of the CNS - 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 GENERALIZED ANXIETY DISORDER DESCRIPTION - chronic fear response without any definite stimulus - extensive repeating attacks of fear response - fear response due to an inappropriate stimulus

PANIC DISORDER

PHOBIA

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 ANXIOLYTIC/ ANTIAGGRESSIVE - 80 DESCRIPTION - inhibit adrenergic neurons of locus ceruleus

SEDATIVE

- decrease time to fall asleep - increase duration of sleep - decrease REM sleep - decrease slow wave sleep - decrease chemically induced convulsions by convulsants inhibiting GABA A receptors - obliterate memory of events during their influence - unknown mechanism

ANTICONVULSIVE

ANTEROGRADE AMNESIC

MUSCLE TONE/ COORDINATION DEPRESSANT -

benzodiazepines cause dependence by 2 out of the 4 mechanisms of dependence of abuse-drugs (see 47) MECHANISM TOLERANCE CAUSE - downregulation of GABA A receptors - anxiety - dizziness - loss of appetite - tremor - convulsions

NEGATIVE REINFORCEMENT

the shorter-acting the benzodiazepines are, the more pronounced dependence will occur 3 groups A) SHORT-ACTING - 12-18 hours - 2 types DRUG NAME LORAZEPAM DESCRIPTION General information - administered orally - lipophilic, thus accumulate in fat over time Medical uses - treatment of insomnia (sleeping pills) - 81 -

- treatment of anxiety Side effects - drowsiness - sedation - confusion - amnesia - impaired coordination TEMAZEPAM General information - same as lorazepam

B) INTERMEDIATELY-ACTING - 18-24 hours - 2 types DRUG NAME NITRAZEPAM DESCRIPTION General information - same as lorazepam General information - same as lorazepam - has an active metabolite, thus prolonging its effect - also has an antidepressive action Medical uses - treatment of anxiety - treatment of depression (antidepressive action) Side effects - same as lorazepam

ALPRAZOLAM

B) LONG-ACTING - 24-48 hours - 2 types DRUG NAME DIAZEPAM DESCRIPTION General information - same as lorazepam - administered orally or IV

- 82 -

- has an active metabolite (nordazepam) - nordazepam has yet another active metabolite (oxazepam), thus prolonging its action even further Medical uses - treatment of anxiety - treatment of epilepsy - 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 - treatment of anxiety - treatment of epilepsy 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 POSITIVE REINFORCEMENT CONDITIONING TOLERANCE TYPE - see 47 - see 47 - upregulation of the hepatic cytochrome P450 system (the enzyme system by which they are metabolized) - hallucinations - same as benzodiazepines

NEGATIVE REINFORCEMENT

- 83 -

3 groups A) SHORT-ACTING - less than 1 hour - 2 types DRUG NAME METOHEXITAL DESCRIPTION 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

B) INTERMEDIATELY-ACTING - 1-6 hours - 2 types DRUG NAME PENTOBARBITAL DESCRIPTION General information - administered orally - not especially lipophilic, thus will not accumulate in adipose tissue Medical uses - treatment of insomnia - treatment of anxiety Side effects - same as metohexital - 84 -

BUTOBARBITAL

General information - same as pentobarbital

B) LONG-ACTING - 6-12 hours - 1 type DRUG NAME PHENOBARBITAL DESCRIPTION General information - same as pentobarbital Medical uses - treatment of epileptic convulsions Side effects - same as metohexital

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

- 85 -

40. ALCOHOLS: PHARMACOLOGY AND TOXICOLOGY

ETHANOL
Overview
ethanol is a low potency abuse-drug it has 3 effects on CNS neuronal transmission EFFECT FACILITATION OF GABA-A RECEPTORS DESCRIPTION - facilitation of GABA-mediated neuronal inhibition - inhibition of glutamate-mediated neuronal excitation - presynaptic inhibition of neurotransmitter release

INHIBITION OF NMDA RECEPTORS

INHIBITION OF VOLTAGE-GATED CALCIUM CHANNELS

the effects of ethanol consumption are classified according to the circulating amount of ethanol QUANTITY 50 MG/100 ML EFFECT - decreased intellectual function - decreased motor coordination - increased self-confidence - euphoria - all of the effects above - melancholy - aggression - submission - coma - cessation of respiration - death

150 MG/100 ML

300 MG/100 ML 500 MG/100 ML

, 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)

- 86 -

MECHANISM POSITIVE REINFORCEMENT

CAUSE - inhibition of voltage-gated calcium channels, thus inhibiting release of inhibitory neurotrasmitters that regulate the mesolimbic-mesocortical dopaminergic pathway - see 47 - downregulation of GABA-A receptors - upregulation of NMDA receptors - upregulation of voltage-gated calcium channels - tremor - nausea - sweating - fever - epilepsy-like seizures - hallucinations - confusion - agitation - aggression

CONDITIONING TOLERANCE

NEGATIVE REINFORCEMENT

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

- 87 -

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 CNS EFFECT - ventricular enlargement - cerebellar neuronal degeneration - dementia - periphral neuropathy - cutaneous vasodilation (gives the perception of being warm though a great heat loss is occurring) - alcoholic hepatitis - jaundice/cirrhosis - increased gastic acid secretion by the parietal cells of the stomach - peptic ulcer - gastritis - 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, - 88 -

PERIPHERAL NERVOUS SYSTEM BLOOD VESSELS

LIVER

GI TRACT

ENDOCRINE SYSTEM

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 aldehyde dehydrogenase 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

- 89 -

41. ANTIPSYCHOTIC DRUGS

Overview
there are 3 main D2 dopaminergic pathways of the CNS PATHWAY MESOLIMBIC-MESOCORTICAL PATHWAY DESCRIPTION - between the midbrain, hippocampus and cerebral cortex - reward center - between substantia nigra and corpus striatum - facilitates voluntary movement - between hypothalamus and pituitary gland - inhibits pituitary secretion of prolactin and GH

NIGROSTRIATAL PATHWAY

TUBEROINFUNDIBULAR PATHWAY

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 POSITIVE SYMPTOMS DESCRIPTION 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 - 90 -

- intellectual impairment - speech impairment ANXIETY General information - see 39 General information - see 42

BIPOLAR DEPRESSION

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-anderror 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 MESOLIMBIC-MESOCORTICAL SIDE EFFECTS DESCRIPTION - sedation - confusion - coma (if overdosed) - 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)

NIGROSTRIATAL SIDE EFFECTS

- 91 -

TUBEROINFUNDIBULAR SIDE EFFECTS

- hyperprolactinemia - lactation (even in males (!)) - gynecomastia - amenorrhea - impotence (males) - infertility (females) - see 15 - see 20 - see 34 - cholestatic jaundice - skin photosensitivity

MUSCARINIC RECEPTOR SIDE EFFECTS ALPHA-ADRENERGIC SIDE EFFECTS 5-HT 2 SIDE EFFECTS OTHER SIDE EFFECTS

2 categories 1) CLASSIC ANTIPSYCHOTIC DRUGS - exhibit most (if not all) of the side effects of antipsychotic drugs - 2 groups A) PHENOTHIAZINES - 2 types DRUG NAME CHLOROPROMAZINE DESCRIPTION Medical uses - treatment of schizophrenia - treatment of huntingtons disease (see 46) - treatment of chemotherapyindiced emesis (see 37) Side effects - see above THIORIDAZINE General information - same as chloropromazine

B) BUTYROPHENONES - 2 types - 92 -

DRUG NAME HALOPERIDOL

DESCRIPTION General information - same as chloropromazine General information - same as chloropromazine

DROPERIDOL

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 DRUG NAME SULPIRIDE RISPERIDONE CLOZAPINE General information - also shows a tendency to treat negative symptoms and treatment-resistant schizophrenia General information - same as clozapine DESCRIPTION

OLANZAPINE

- 93 -

42. ANTIDEPRESSANTS
Overview
there are 3 types of monoamine neurotransmitters TYPE SEROTONIN NORADRENALINE DOPAMINE DESCRIPTION - see 34 - see 18 - 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 UNIPOLAR DEPRESSION BIPOLAR DEPRESSION DESCRIPTION

- manic depression - alteration between depression and mania every 2-3 weeks

there are 2 groups of symptoms of depression GROUP EMOTIONAL SYMPTOMS DESCRIPTION - misery - apathy - pessimism - low self esteem - loss of motivation - indecisiveness - retardation of thought - loss of libido - loss of appetite - sleep disturbance

BIOLOGICAL SYMPTOMS

- 94 -

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 CNS SIDE EFFECTS DESCRIPTION Therapeutic dose - sedation - confusion - orthostatic hypotension (hyperactivity of the vasomotor center of the CNS) Overdose - excitement - delirium - convulsions - respiratory depression - 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)

- 95 -

2 groups A) NON-SELECTIVE TCAS - 2 types DRUG NAME IMIPRAMINE AMITRIPTYLINE DESCRIPTION

B) NORADRENALINE-SELECTIVE TCAS - 2 types DRUG NAME DESIPRAMINE CLOMIPRAMINE DESCRIPTION

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 DRUG NAME FLUOXETINE DESCRIPTION General information - administered orally Medical uses - treatment of depression - treatment of anxiety - treatment of obsessive-compulsive disorders Side effects - nausea - anorexia - insomnia - decreased libido - failure of orgasm FLUVOXAMINE General information

- 96 -

- same as fluoxetine PAROXETINE General information - same as fluoxetine General information - same as fluoxetine

SERTALINE

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 DRUG NAME PHENELZINE DESCRIPTION General information - administered orally 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

- 97 -

TRANYLCYPROMINE

General information - same as phenelzine

B) REVERSIBLE MAOIS - 1 type DRUG NAME MOCLOBEMIDE DESCRIPTION General information - same as phenelzine

- 98 -

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 STAGE I DESCRIPTION Analgesia - conscious - drowsy - amnesic - voluntary movement is still present - coherent speech is still present - reduced reaction to stimuli 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 Surgical anaesthesia - loss of movement - loss of speech - regular respiration - regular heart rate - muscle tone is still present Overdose - medullary paralysis - cessation of respiration - cardiovascular collapse - cessation of muscle tone - death

STAGE II

STAGE III

STAGE IV

- 99 -

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 OIL/GAS PARTITION COEFFICIENT DESCRIPTION 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 its 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

- 100 -

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 its 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) DRUG NAME ETHER DESCRIPTION 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 - 101 -

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) - postoperative nausea and vomiting (long 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) 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)

SEVOFLURANE

- 102 -

NITROUS OXIDE

General information - has analgesic properties - 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) DRUG NAME METOHEXITAL DESCRIPTION General information - slowly metabolized (slow recovery) - a short-acting barbiturate (see 39) General information - same as metohexital General information - intermediately metabolized (intermediate recovery) Side effects - postoperative nausea and vomiting (long recovery) - adrenal cortical suppression - 103 -

THIOPENTAL

ETOMIDATE

FENTADYL

General information - has analgesic properties - 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

- 104 -

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 PARTIAL SEIZURES DESCRIPTION General information - localized seizure not exceeding the cerebral hemisphere from which it originates - 2 types Simple Seizure - the seizure stays in its 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 its 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 - loss of consciousness - rigid extensor spasm - cessation of respiration - micturition - defecation - salivation - all of this is followed by series of violent synchronous jerks that gradually dies out

- 105 -

Petit mal seizures - absence seizures - rhythmic oscillating seizure of thalamic relay neurons - loss of consciousness - 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 DRUG NAME PHENYTOIN DESCRIPTION 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) - administered orally - 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 - 106 -

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 DRUG NAME ETHOSUXIMIDE DESCRIPTION General information - inhibits T-type calcium channels, thus blocking rhythmic oscillations of thalamic relay neurons - administered orally Medical uses - treatment of petit mal seizure Side effects - 107 -

- vertigo - nausea - apathy - anorexia

3) DRUGS AFFECTING ALL TYPES OF EPILEPTIC SEIZURES - 2 types DRUG NAME VALPROATE DESCRIPTION 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

- 108 -

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 ENHANCEMENT OF CEREBRAL MICROCIRCULATION DESCRIPTION - increasing cerebral blood flow (vasodilation) - increasing RBC plasticity - inhibiting platelet aggregation - reducing blood viscosity - increasing cerebral energy supply - enhancing cerebral energy utilization - increasing availability and/or effect of acetylcholine - increasing availability and/or effect of monoamines (see 42) - neutralizing free radicals (antioxidation)

ENHANCEMENT OF CEREBRAL METABOLISM ENHANCEMENT OF CEREBRAL NEUROTRANSMISSION

NEUROPROTECTION

Relevant Drugs
3 types DRUG NAME PIRACETAM DESCRIPTION General information - enhances cerebral microcirculation - enhances cerebral metabolism - enhances cerebral neurotransmission (acetylcholine) - neuroprotective - administered orally or IV

- 109 -

Medical uses - treatment of stroke - treatment of dementia (including alzheimers disease, see 46) Side effects - hyperactivity - insomnia VINPOCETINE General information - enhances cerebral microcirculation - enhances cerebral metabolism - administered IV Medical uses - treatment of stroke - treatment of perfusion disorders of the eye and the inner ear (including tinnitus) Side effects - hypotension - tachycardia PENTOXYFILLINE General information - theobromine derivative (see 48) - enhances cerebral microcirculation Medical uses - treatment of stroke - treatment of perfusion disorders of the eye and the inner ear Side effects - hypotension - cardiac arrythmias - dizziness

- 110 -

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 ALZHEIMERS DISEASE PARKINSONS DISEASE HUNTINGTONS DISEASE

ALZHEIMERS DISEASE
Overview
alzheimers disease is a progressive dementia of idiopathic origin it occurs primarily due to loss of neurons in 2 locations of the CNS LOCATION HIPPOCAMPUS BASAL FOREBRAIN NEURONS AFFECTED - unselective neuronal loss - 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 alzheimers disease than those used peripherally to treat peripheral disorders - 4 types DRUG NAME - 111 DESCRIPTION

TACRINE

Side effects - cholinergic side effects (see 14) - hepatotoxicity Side effects - cholinergic side-effects General information - selective for the CNS General information - also an nicotinic acetylcholine receptor allosteric activator (see 14) Side effects - cholinergic side-effects

DONEPEZIL

RIVASTIGMINE

GALANTHAMINE

2) NOOTROPIC DRUGS - enhances the intellectual capacity, thus counteracting the dementia - see 45

PARKINSONS DISEASE
Overview
parkinsons 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 parkinsons disease is characterized by 3 (4) symptoms SYMPTOM HYPOKINESIA DESCRIPTION - voluntary movement is hard to initiate and -to stop - due to loss of dopaminergic neurons - at rest - due to hyperactivity of cholinergic neurons - increased resistance to voluntary movement - due to loss of dopaminergic neurons and hyperactivity of cholinergic neurons

TREMOR

RIGIDITY

- 112 -

(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 aldehyde dehydrogenase 3,4-DIHYDROXYPHENYLACETIC ACID COMT HOMOVANILLIC ACID

Relevant Drugs
2 categories 1) DOPAMINE REPLENISHERS - 4 types DRUG NAME L-DOPA DESCRIPTION General information - precursor of dopamine - increases dopamine biosynthesis - administered orally - 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 - 113 -

- anorexia SELEGILINE General information - selective MAO-B inhibitor (, thus only acts in the CNS, see 17) - decreases central monoamine breakdown General information - COMT inhibitor - decreases central- and peripheral monoamine breakdown General information - antiviral drug - increases presynaptic dopamine release and decreases presynaptic dopamine reuptake

ENTACAPONE

AMANTIDINE

2) D2 RECEPTOR AGONISTS - 3 types DRUG NAME BROMOCRIPTINE DESCRIPTION Medical uses - treatment of galactorrhea - treatment of gynecomastia - treatment of parkinsons disease

LISURIDE PERGOLIDE

3) MUSCARINIC RECEPTOR ANTAGONISTS - block muscarinic receptors, thus inhibiting the effect of the hyperactive cholinergic neurons in the corpus striatum - see 15

HUNTINGTONS DISEASE
Overview
huntingtons disease is, like parkinsons disease, a progressive motility disorder

- 114 -

however, huntingtons disease is due to loss of GABA neurons running in opposite direction to that of the dopaminergic neurons affected in parkinsons 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 huntingtons disease exhibit opposite symptoms to that of parkinsons disease

Relevant Drugs
2 categories 1) GABA AGONISTS - 1 type DRUG NAME BACLOFEN DESCRIPTION

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

- 115 -

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 PSYCHOLOGICAL DEPENDENCE TYPE Positive reinforcement - occurs when the abuse-drug is used - stimulation of the mesolimbicmesocortical 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
- 116 -

see 49

ANTI-ANXIETY AND HYPNOTIC DRUGS

Overview
see 39

INHALANTS
Overview

ETHANOL
Overview
see 40

- 117 -

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 DOPAMINE EFFECT Abuse dose - euphoria - pleasure - excitement - increased confidence - increased sex drive - increased mental performance - increased physical performance - insomnia Overdose - hallucinations - paranoia - aggression NORADRENALINE SEROTONIN - 118 - increased motor activity - anorexia

like any other abuse-drug they have 4 mechanisms by which they cause dependence (see 47) MECHANISM POSITIVE REINFORCEMENT CAUSE - release of dopamine, and following stimulation of the mesolimbicmesocortical dopaminergic pathway - see 47 - depletion of dopamine - depletion on noradrenaline (- depletion of serotonin) - apathy - axiety - depression - suicidality

CONDITIONING TOLERANCE

NEGATIVE REINFORCEMENT

consequences of amphetamine consumption include ORGAN HEART EFFECT - tachycardia - cardiac arrhythmias - vasoconstriction - hypertension - tremor - hyperthermia - increased ADH secretion by the pituitary gland - hypotonic hypervolemia - sudden death (even from just a single moderate dose (!))

BLOOD VESSELS

SKELETAL MUSCLE

ENDOCRINE SYSTEM

UPON OVERDOSE

- 119 -

they are used orally or nasally and absorbed from the nasal- and/or small intestinal mucosa 6 types DRUG NAME AMPHETAMINE DESCRIPTION General information - abuse-drug Medical uses - treatment of narcolepsy - treatment of obesity METHAMPHETAMINE General information - speed - abuse-drug General information - ecstasy - abuse-drug General information - abuse-drug Medical uses - treatment of ADHD (paradoxically (!)) General information - has a stronger action of serotonin release, thus producing more pronounced anorexia

METHYLENEDIOXYMETHAMPHETAMINE

MESACAINE

METHYLPHENIDATE

FENFLURAMINE

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 DOPAMINE EFFECT - euphoria - pleasure - 120 -

- garrulity NORADRENALINE Abuse Dose - increased motor activity - hyperthermia - tachycardia - vasoconstriction - hypertension Overdose - tremor - convulsions - respiratory depression - vasomotor depression

like any other abuse-drug it has 4 mechanisms by which it causes dependence (see 47) MECHANISM POSITIVE REINFORCEMENT CAUSE - inhibition of presynaptic dopamine reuptake, and following stimulation of the mesolimbic-mesocortical dopaminergic pathway - see 47 - downregulation of dopaminergic receptors - downregulation of adrenergic receptors - dysphoria - depression - decreased mental performance - decreased physical performance

CONDITIONING TOLERANCE

NEGATIVE REINFORCEMENT

consequences of cocaine consumption include ORGAN HEART EFFECT - tachycardia - cardiac arrhythmias - 121 -

- myocardial damage BLOOD VESSELS - vasoconstriction - hypertension - coronary- and/or cerebral artery thrombosis - tremor - hyperthermia - convulsions - vasomotor depression - respiratory depression - death

SKELETAL MUSCLE

UPON OVERDOSE

2 types DRUG NAME HYDROCHLORIDE SALT COCAINE DESCRIPTION General information - snow - abuse-drug - used nasally or IV General information - crack - abuse-drug - used by inhalation, nasally or IV

FREE BASE COCAINE

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 NICOTINE DESCRIPTION

- 122 -

POLYCYCLIC AROMATIC HYDROCARBONS (TAR) B) GASSEOUS PHASE COMPONENTS - include TYPE CARBON MONOXIDE NITROGEN DIOXIDE HYDROGEN CYANIDE AMMONIA FORMALDEHYDE NITROSAMIDES DESCRIPTION

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 CNS TYPE EFFECT - satiety - analgesia - sedation - alertness - increased mental performance - increased physical performance - decreased skeletal muscle tone - positive chronotropic effect (increased heart rate) - positive ionotropic effect (increased force of heart contraction) - vasoconstriction - increased circulating free fatty

GANGLION TYPE

- 123 -

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 POSITIVE REINFORCEMENT CAUSE - stimulation of the mesolimbicmesocortical dopaminergic pathway - see 47 - desensitization of nicotinic receptors (partly opposed by a simultaneous upregulation of the same nicotinic receptors (!)) - irritability - insomnia - decreased mental performance - decreased physical performance

CONDITIONING TOLERANCE

NEGATIVE REINFORCEMENT

consequences of tobacco consumption may be divided in 2 groups according to the causative agents A) CONSEQUENCES OF NICOTINE AND CARBON MONOXIDE - include TYPE CARDIOVASCULAR DISORDERS CONSEQUENCE - hypertension - hyperlipoproteinemia - coronary- and/or cerebral artery thrombosis - gangrene

- 124 -

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 PULMONARY DISORDERS CANCERS CONSEQUENCE - chronic obstructive pulmonary disorders (COPD) - 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 THC DESCRIPTION - delta-9 tetrahydrocannabinol - the only pharmacologically active cannabinoid - THC precursor - THC metabolite

CANNABIDOL CANNABINOL

cannabinoids are cannabinoid receptor agonists there are 2 types of cannabinoid receptors RECEPTOR TYPE CB1 RECEPTOR LOCATION - mesolimbic-mesocortical pathway - hippocampus - substantia nigra - crebellum

- 125 -

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 CNS EFFECT - euphoria - sensory amplification (visual-, auditory- and tactile-) - sedation - decreased mental performance (with subjective perception of increased mental performance) - decreased motor coordination - catalepsy - analgesia - antiemesis - increased appetite - tachycardia - vasodilation - decreased intraocular pressure - blood-shot eyes (conjunctival blood vessel vasodilation) - bronchoconstriction - decreased immune function - teratogenesis - decreased testosterone production - decreased sperm production

HEART BLOOD VESSELS EYES

BRONCHI LYMPHOID SYSTEM GENITO-URINARY TRACT

it causes little or no dependence - 126 -

it is used by inhalation, orally or IV it is lipophilic, thus will accumulate in adipose tissue over time 2 types TYPE MARIJUANA DESCRIPTION General information - dried leaves and flowers of cannabis sativa - resin of cannabis sativa

HASHISH

5) METHYLXANTHINES - methylxanthines inhibit adenylyl cyclase, thus leading to decreased formation of cAMP - effects of xanthines include ORGAN CNS EFFECT - CNS excitation - insomnia - increased mental performance - nervousness - increased motor activity - tremor - increased respiration - increased heart rate - increased force of contraction - systemic vasodilation - cerebral vasoconstricion - bronchodilation - increased glomerular filtration - decreased reabsorption - increased diuresis

HEART

BLOOD VESSELS

BRONCHI KIDNEYS

they cause little or no dependence 4 types DRUG NAME - 127 DESCRIPTION

THEOPHYLLINE

General information - found in tea (and coffee) - administered orally Medical uses - treatment of asthma Side effects - any other effect of xanthines (see above)

AMINOPHYLLINE

General information - administered IV - same as theophylline General information - found in coffee (and tea) and cola nuts (coca cola) General information - found in cocoa

CAFFEINE

THEOBROMINE

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 ABUSE DOSE EFFECT - hallucinations (visual-, auditory-, olfactory-, tactile-, and crossconnections (eg. auditory stimuli are perceived as visual stimuli (!))) - illogical mental performance

- 128 -

OVERDOSE

- bad trip - horrific halucinations - paranoia - suicide - homicide

it causes little or no dependence (!) consequences of LSD, see 34 2 types DRUG NAME LSD DESCRIPTION General information - lysergic acid diethylamide - abuse-drug - semisynthetic compound synthesized from ergot alkaloids (found in fungus) General information - found in fungus

PSILOCYBIN

2) PHENCYCLIDINE - phencyclidine is an abuse-drug with 2 effects in the CNS EFFECT FACILITATION OF SIGMA NONOPIOID RECEPTORS INHIBITION OF NMDA RECEPTORS CONSEQUENCE

- inhibition of glutamate-mediated neuronal excitation

it causes little or no dependence the effects of phencyclidine are divided according to dose MONOAMINE ABUSE DOSE EFFECT - analgesia - same as LSD - same as LSD

OVERDOSE

- 129 -

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 ACUTE PAIN DESCRIPTION - 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 - 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

CHRONIC PAIN

the endogenous analgesic system is a CNS reflex arch that inhibit the excitation of A-deltaand 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 SPINAL CORD TYPE - met-enkephalin - leu-enkephalin - beta-endorphin - dynorphin A - nociceptin - 130 -

CNS

opioids act on opioid receptors there are 3 types of opioid receptors RECEPTOR TYPE MY OPIOID RECEPTOR EFFECT - 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 - respiratory depression - vasomotor depression - increased tone of GI smooth muscle (spincters especially) - myosis KAPPA OPIOID RECEPTOR - spinal analgesia - peripheral analgesia - dysphoria - sedation - myosis (pupillary constriction) - increased tone of GI smooth muscle (spincters especially) DELTA OPIOID RECEPTOR - spinal analgesia - respiratory depression - vasomotor depression - increased tone of GI smooth muscle (spincters especially)

- 131 -

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 POSITIVE REINFORCEMENT CONDITIONING TOLERANCE CAUSE - see 47 - see 47 - substantially increased activity of adenylyl cyclase (!) - distress - insomnia - nausea - diarrhea - sweating - fever - midriasis (pupillary dilatation) - piloerection (cold turkey)

NEGATIVE REINFORCEMENT

they may cause coma if overdosed

Relevant Drugs
3 categories 1) MORPHINE ANALOGUES - include morphine and semisynthetic morphine derivatives - 3 types DRUG NAME MORPHINE DESCRIPTION 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 - 132 -

pain - treatment of diarrhea 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 - administered orally or IV - causes dependence - same as morphine General information - codeine - weak agonist of all opioid receptor types - administered orally - does not cause dependence Medical uses - treatment of mild pain - treatment of diarrhea - 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

3-METHOXYMORPHINE

2) SYNTHETIC OPIOID DERIVATIVES - 4 groups A) PHENYLPIPERIDINE ANALOGUES - 2 types DRUG NAME - 133 DESCRIPTION

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 - strong my opioid receptor agonist - metabolized to the active metabolite norpentidine - also has muscarinic antagonist activity - administered orally or intramuscularly - causes dependence Medical uses - treatment of acute pain Side effects - excitement (norpentidine) - hallucinations (norpentidine) - convulsions (norpentidine) - muscarinic antagonist side effects (see 15) - same as morphine

B) METHADONE DERIVATIVES - 2 types DRUG NAME METHADONE DESCRIPTION General information - strong my opioid receptor agonist

- 134 -

- administered orally or IV - 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 - administered orally - does not cause dependence Medical uses - treatment of mild pain Side effects - convulsions (norpropoxyphene) - same as morphine

C) BENZOMORPHAN DERIVATIVES - 1 type DRUG NAME PENTAZOCINE DESCRIPTION General information - kappa opioid receptor agonist and my opioid receptor antagonist - administered orally or IV - causes dysphoria (kappa opioid receptor agonist)

- 135 -

Medical uses - treatment of acute pain Side effects - see above

D) THEBAINE DERIVATIVES - 1 type DRUG NAME BUPRENORPHINE DESCRIPTION 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 DRUG NAME LOPERAMIDE DESCRIPTION General information - does not cross the blood-brain barrier - selective for the GI tract - also decrease intestinal secretions Medical uses - treatment of diarrhea Side effects - constipation - abdominal cramps

- 136 -

3) OPIOID ANTAGONISTS - 2 types DRUG NAME NAXOLONE DESCRIPTION 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

- 137 -

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 COX-1 DESCRIPTION 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 - 138 -

, 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 GI TRACT SIDE EFFECT Increased gastric acid production and decreased mucous production - dyspepsia - diarrhea/constipation - nausea - vomiting - peptic ulcers Vasoconstriction and following renal ischemia - acute renal insufficiency - chronic nephritis - renal papillary necrosis Increased arachidonic acid available for 5lipoxygenase and following increased leukotriene production (see 35) - rashes - urticaria (hives) - photosensitivity

KIDNEYS

SKIN

Relevant Drugs
6 categories 1) SALICYLIC ACID DERIVATIVES - salicylic acid derivatives are non-selective irreversible COX inhibitors - 1 type DRUG NAME DESCRIPTION

- 139 -

ASPIRIN

General information - acetylsalicylic acid - administered orally - severe side effects (irreversible COX inhibition) Medical uses - see above - treatment of thrombosis, DIC and emboli (inhibition of platelet aggregation, due to irreversible COX-1 inhibition) - treatment of radiation-induced diarrhea - prophylaxis of colonic- and rectal cancer - prophylaxis of alzheimers 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) - reyes syndrome (hepatic insufficiency and encephalopathy in children, due to aspirin administration during a viral infection)

2) ACETIC ACID DERIVATIVES - indole derivatives - 3 types DRUG NAME INDOMETACIN DESCRIPTION General information - potent COX inhibitor - has severe side effects (potent COX inhibitor) - also inhibits phagocytosis of urate crystals by neutrophils - administered orally

- 140 -

Medical uses - see above - treatment of gout (inhibition of urate crystal phagocytosis) SULINDAC General information - pro-drug - administered orally General information - accumulates in synovial fluid - administered orally or IV Medical uses - see above - treatment of rheumatoid arthritis (accumulates in synovial fluid)

DICLOFENAC

3) PROPIONIC ACID DERIVATIVES - 3 types DRUG NAME IBUPROFEN DESCRIPTION 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 DRUG NAME PHENYLBUTAZONE DESCRIPTION General information - potent COX inhibitor - has severe side effects (potent COX inhibitor)

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5) COXIBS - COX-2 inhibitors - coxibs are selective reversible COX-2 inhibitors - 3 types DRUG NAME CELECOXIB DESCRIPTION General information - has little or no side effects (selective COX-2 inhibitor) - administered orally General information - same as celecoxib General information - same as celecoxib - administered orally or parenterally

ROFECOXIB

PARECOXIB

6) ANILINE DERIVATIVES - COX-3 inhibitors - aniline derivatives are selective reversible COX-3 inhibitors - 1 type DRUG NAME PARACETAMOL DESCRIPTION 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) - administered orally - 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 - 142 -

enzymes responsible for its metabolism and following metabolism by the cytochrome P450 enzyme system leading to the formation of a toxic metabolite (n-acetyl-p-benzoquinone imine))

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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 DRUG NAME SODIUM AUROTHIOMALATE DESCRIPTION General information - gold-containing compound - administered intramuscularly Side effects - blood dyscrasias - proteinuria - skin rashes - stomatitis - hepatitis - encephalopathy - peripheral neuropathy AURANOFIN General information - gold-containing compound - administered orally - same as sodium aurothiomalate General information - hydrolysate of penicillin - may celate metals - administered orally Side effects - 144 -

D-PENICILLAMIDE

- 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 - administered orally Medical uses - treatment of malaria - treatment of SLE - treatment of rheumatoid arthritis Side effects - visual disturbance (accumulates in the retina) METHOTREXATE General information - folic acid antagonist Medical uses - treatment of rheumatoid arthritis 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 inflammatory response - see 36

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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 inflammatory response - 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 DRUG NAME ALLOPURINOL DESCRIPTION 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

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- administered orally 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 DRUG NAME PROBENECID DESCRIPTION General information - may cause gout when first administered (!), thus may not be used for treatment of gout Medical uses - prophylaxis of gout Side effects - uolithiasis SULFINPYRAZOLE General information - same as probenecid

3) ANTI-INFLAMMATORY DRUGS - 1 type DRUG NAME COLCHICINE DESCRIPTION General information - binds to tubulin leading to depolymerization of microtubules and following decreased motility of neutrophils - administered orally Medical uses - prophylaxis of gout - treatment of gout Side effects - 147 -

- 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

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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 1) BETA-1 ADRENERGIC RECEPTOR ANTAGONISTS 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

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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 2) CALCIUM CHANNEL BLOCKERS 3) BETA-1 ADRENERGIC RECEPTOR ANTAGONISTS 27. ANTIHYPERTENSIVE DRUGS 1) DIRECT VASODILATORS - Minoxidil - Hydralazine - Nitroprusside - Diazoxide 2) CALCIUM CHANNEL BLOCKERS 3) ORGANIC NITRATES - 150 -

4) ALPHA-2 ADRENERGIC RECEPTOR AGONISTS 5) ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISTS 6) BETA-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 - 151 -

- 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) - 152 -

- 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 2) H2 RECEPTOR ANTAGONISTS - 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 - 153 -

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 - 154 -

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 B) MUSCARINIC 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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B) MUSCARINIC RECEPTOR ANTAGONISTS 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 - 156 -

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

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A) BILE ACIDS - CDCA (Chenodeoxycholic Acid) - UDCA (Ursodeoxycholic Acid) B) MUSCARINIC RECEPTOR ANTAGONISTS C) OPIOIDS 39. ANTIANXIETY AND HYPNOTIC DRUGS 1) BENZODIAZEPINES A) SHORT-ACTING - Lorazepam - Temazepam B) INTERMEDIATELY-ACTING - Nitrazepam - Alprazolam C) LONG-ACTING - Diazepam - Clonazepam 2) BARBITURATES A) SHORT-ACTING - Metohexital - Thiopental B) INTERMEDIATELY-ACTING - 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 - 158 -

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 - 159 -

- 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) ALZHEIMERS DISEASE I) CHOLINESTERASE INHIBITORS - Tacrine - Donepezil - Rivastigmine - Galanthamine II) NOOTROPIC DRUGS B) PARKINSONS DISEASE - 160 -

I) DOPAMINE REPLENISHERS - L-DOPA - Selegiline - Entacapone - Amantidine II) D2 RECEPTOR AGONISTS - Bromocriptine - Lisuride - Pergolide III) MUSCARINIC RECEPTOR ANTAGONISTS C) HUNTINGTONS 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) - 161 -

- 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)

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