BRY's Pharmacology 2nd Semester

TABLE OF CONTENTS

23. Calcium Channel Blockers (Page 1)

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

25. Diuretic Drugs (Page 8)

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

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

28. Antihypertensive Drugs (Page 20)

29. Antiarrhythmic Drugs (Page 23)

30. Drugs Used to Treat Hyperlipoproteinemia (Page 29)

31. Anticoagulatnts. Fibrinolytics. Antifibrinolytics. Antiplatelet Drugs (Page 33)

32. Drugs Affecting Hematopoiesis (Page 39)

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

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

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

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

36. Pharmacology of the Respiratory Tract (Page 61)

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

Anti-Emetics (Page 65)

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

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

Drugs Used in Cholelithiasis (Page 72)

39. Antianxiety and Hypnotic Drugs (Page 80)

40. Alcohols: Pharmacology and Toxicology (Page 86)

41. Antipsychotic Drugs (Page 90)

42. Antidepressants (Page 94)

43. General Anaesthetics (Page 99)

44. Antiepileptic Drugs (Page 105)

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

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

111)

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

Drugs, Inhalants, Ethanol (Page 116)

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

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

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

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

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

Others. COX-2 Inhibitors (Page 138)

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

A1. Drugs, 2nd Semester (Page 149)

- 1 -

23. CALCIUM CHANNEL BLOCKERS Overview

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

calcium channels (type L-calcium channels)

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

thus exhibiting use-dependence

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

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

depolarization

General Effects - 2 types

LOCATION ACTION

BLOOD VESSELS Decreased blood pressure

- arterial vasodilation

HEART Positive tropic effect

- reflex tachycardia (due to decreased blood pressure)

Negative tropic effect

- negative chronotropic effect (decreased heart rate)

- negative ionotropic effect (decreased force of contraction)

- negative bathmotropic effect (decreased myocardial excitability)

- negative dromotropic effect (decreased AV conduction)

Relevant Drugs - 3 categories

1) PHENYLALKYLAMINES (VERAPAMIL)

- primarily acts on the heart

- also has a weak action on blood vessels

- 1 type

DRUG NAME DESCRIPTION

VERAPAMIL General Description

- administered orally

- extensive first-pass metabolism

- extensively bound to plasma proteins

- not to be taken with other drugs with

negative tropic effects (eg. beta-blockers, see

21)

- 2 -

Clinical usages

- treatment of atrial fibrillation (negative

tropic effect)

- treatment of supraventricular paroxysmal

tachycardia (negative tropic effect)

- treatment of angina pectoris (negative

tropic effect and weak coronary artery

vasodilation)

- treatment of hypertension (negative tropic

effect and weak arterial vasodilation)

Side effects

- bradycardia (negative chronotropic effect)

- heart failure (negative ionotropic effect, if

symptoms of heart failure are already

present)

- supraventricular AV- junctional block

(negative dromoptropic effect)

- constipation (decreased contractility of GI

smooth muscle)

2) BENZOTHIAZEPINES (DILTIAZEM)

- acts efficaciously both on heart and blood vessels

- 1 type


DILTIAZEM General information

- same as verapamil, but less pronounced

(more reflex tachycardia)

3) DIHYDROPYRIDINES (DHP)

- primarily act on blood vessels

- also has a weak effect on the heart

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

A) SHORT/RAPIDLY-ACTING DHPS

- 4-6 hours

- 3 types


NIFEDIPINE General information

- administrated orally

- extensive first pass-metabolism

- 3 -

Clinical usages

- treatment of hypertension (strong arterial

vasodilation)

Side effects

- reflex tachycardia

- headache (cerebral artery vasodilation)

- flushing (cutaneous artery vasodilation)

- ancle edema (arterial vasodilation)

NIMODIPINE General information

- same as nifedipine

- exhibit some selectivity for cerebral

arteries

Clinical usages


vasodilation)

- treatment of cerebral vasospasms following

subarachnoid hemorrhage (then administered

IV)

Side effects


NICARDIPINE General information


- some selectivity for coronary arteries

Clinical usages


vasodilation)

- treatment of prinzmental angina pectoris

(strong coronary artery vasodilation)

Side effects


B) INTERMEDIATELY-ACTING DHPS

- 8-10 hours

- 2 types


- 4 -

NITRENDIPINE General information


Clinical usages

- same as nicardipine

Side effects

- same as nifedipine, but less pronounced

reflex tachycardia

NISOLDIPINE General information

- same as nitrendipine

C) LONG/SLOWLY-ACTING DHPS

- 40-60 hours

- 1 type


AMLODIPINE General information


Clinical usages

- same as nicardipine

Side effects

- same as nitrendipine, but even less

pronounced reflex tachycardia

- 5 -

24. DRUGS ACTING ON THE RENIN ANGIOTENSIN

ALDOSTERONE SYSTEM Overview

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

pressure

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

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

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

of the nephrons and following decreased glomerular filtration rate)

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

ANGIOTENSINOGEN

renin

ANGIOTENSIN I

ACE (angiotensin-converting enzyme)

ANGIOTENSIN II

ALDOSTERONE SECRETION

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

ENZYME ACTION

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

brain)

- increased sympathetic tone

- hypertrophy/hyperplasia of cardiac- and smooth muscle

- aldosterone secretion

ALDOSTERONE - sodium/water reabsorption by the kidneys

- potassium secretion by the kidneys and potassium uptake by the

cells of the body

- hydrogen ion secretion by the kidneys (pH regulation)


1) BETA-1 ADRENERGIC RECEPTOR ANTAGONISTS

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

apparatus, and facilitate renin release upon activation

- beta-1 adrenoceptor antagonists thus inhibit renin release

- see 21

- 6 -

2) RENIN INHIBITORS

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

conversion of angiotensinogen to angiotensin I

- 1 type


ENALKIREN

3) ACE INHIBITORS

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

conversion of angiotensin I to angiotensin II

- 3 types


ENALAPRIL General information


- prodrug

- extensive first-pass metabolism (conversion to active

metabolites)

Medical uses

- treatment of hypertension (arterial vasodilation and

decreased sodium/water retention)

- prophylaxis of angina pectoris and AMI (coronary

artery vasodilation)

- treatment of cardiac failure (coronary arterial

vasodilation, decreased hypertrophy/hyperplasia of

cardiac muscle and decreased preload/afterload)

- treatment of chronic- and acute renal failure

(decreased workload of the kidneys)

Side effects

- hypotension

- renal failure (renal ischemia, if bilateral renal artery

stenosis is present)

- teratogenesis

- hyperkalemia (decreased potassium secretion and cell

uptake)

- respiratory mucosal edema (ACE is also responsible

for catabolizing bradykinin)

- dry cough (respiratory mucosal edema)

LISINOPRIL General information

- 7 -

- same as enalapril

RAMIPRIL General information

- same as enalapril

4) TYPE 1 ANGIOTENSIN II RECEPTOR ANTAGONISTS

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

and are the primary receptors for angiotensin II action

- type 1 angiotensin II receptor antagonists are competitive antagonists of

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

activation

- 2 types


LOSARTAN General information


Medical uses

- treatment of hypertension (arterial vasodilation and

decreased sodium/water retention)

Side effects

- same as with enalapril (, but no respiratory mucosal

edema/dry cough)

VALSARTAN General information

- same as losartan

5) ALDOSTERONE RECEPTOR ANTAGONISTS (POTASSIUM-SPARING

DIURETICS)

- see 25

- 8 -

25. DIURETIC DRUGS Overview

- diuretic drugs are drugs that increase the urinary output

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

renal tubules

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

following increased urinary output

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

1) LOOP DIURETICS

- ceiling diuretics

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

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

the thick ascending limb of the loop of henle

- 3 types


FUROSEMIDE General information

- administered orally or IV

- extensively bound to plasma proteins

- eliminated by the organic acid

transporter of the proximal tubule of the

kidneys

Medical uses

- treatment of severe hypertension

- treatment of systemic edema (due to

right-sided congestive heart failure)

- treatment of pulmonary edema (due to

left-sided congestive heart failure)

- treatment of ascites (due to liver

cirrhosis)

- treatment of acute- and chronic renal

failure (increased water excretion)

- treatment of hypercalcemia (inhibition

of calcium reabsorption)

Side effects

- hypotension (hypovolemia)

- hypokalemia (inhibition of potassium

reabsorption and increased tubular flow

rate)

- metabolic alkalosis (due to

- 9 -

hypokalemia)

- hypomagnesemia (increased tubular

flow rate)

- hypocalcemia (increased tubular flow

rate)

- azotemia (competition between urea

and loop diuretics at the organic acid

transporter)

ETACRYNIC ACID General information

- same as furosemide

2) THIAZIDE DIURETICS


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

- 3 types


BENDROFLUMETHAZIDE General information


- eliminated by the organic acid

transporter of the proximal tubule of the

kidneys

Medical uses

- treatment of hypertension (due to

decreased water reabsorption and

vasodilation)

- treatment of chronic resistant edema

(together with loop diuretics)

- prophylaxis of urolithiasis (increased

tubular flow rate and no inhibition of

calcium reabsorption)

- treatment of diabetes insipidus

(paradoxal decrease in urinary output)

Side effects

- hypotension (vasodilation)

- hyperglycemia (inhibition of insulin

secretion)

- hypokalemia (increased tubular flow

rate)

- metabolic alkalosis (due to

hypokalemia)

- azotemia (competition between urea

and thiazide diuretics at the organic acid

- 10 -

transporter)

- hyperlipoproteinemia

- male impotence

HYDROCHLORTHIAZIDE General information

- same as bendrofluazide

CYCLOPENTHIAZIDE General information

- same as bendrofluazide

3) CA (CARBONIC ANHYDRASE) INHIBITORS

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

- carbonic anhydrase is the main enzyme responsible for metabolic pH

buffering

CARBONDIOXIDE + WATER

CA (carbonic anhydrase)

CARBONIC ACID

HYDROGEN ION + BICARBONATE ION

- CA inhibitors inhibit intracellular carbonic anhydrase in the tubular

epithelium of the distal tubule

- this leads to decreased intracellular hydrogen ion concentration and following

disruption of the hydrogen ion/sodium antiporter

- 1 drug


ACETAZOLAMIDE General information

- not used as a diuretic

Medical uses

- treatment of glaucoma (carbonic

anhydrase is also involved in production

of the aquous humor of the eye)

- treatment of epilepsy

Side effects

- hypokalemia (increased tubular flow

rate)

- metabolic acidosis (decreased

- 11 -

hydrogen secretion and increased loss of

bicarbonate due to no hydrogen ion in

the tubular fluid to react with to form

carbondioxide and water)

4) POTASSIUM-SPARING DIURETICS (ALDOSTERONE RECEPTOR

ANTAGONISTS)


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

distal tubule

- 3 types


SPIRONOLACTONE General information

- direct antagonist of aldosterone at the

intracellular aldosterone receptors in the

late distal tubule, thus inhibiting

expression of aldosterone-dependent

sodium reabsorption, and potassium-

and hydrogen ion secretion


Medical uses

- coadministered with non-potassium

sparing diuretics to preserve potassium

- treatment of hyperaldosteronism

(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


Medical uses

- 12 -

- coadministered with non-potassium

sparing diuretics to preserve potassium

Side effects

- hyperkalemia

- metabolic acidosis (due to

hyperkalemia)

AMILORIDE General information

- same as triamterene

5) OSMOTIC DIURETICS

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

sodium reabsorption

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

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

intravascular fluid space except at the large fenestrations of the glomerular

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

epithelium

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

- 1 type


MANNITOL General information

- administered IV

Medical uses

- prophylaxis of acute renal failure

(increased tubular flow rate)

- treatment of glaucoma (increased

intravascular oncotic pressure)

- treatment of cerebral edema (increased

intravascular oncotic pressure)

Side effects

- transient expansion of the intravasular

fluid space

- 13 -

26. DRUGS USED TO TREAT CONGESTIVE HEART FAILURE Overview

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

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

required cardiac output

EVENT CONSEQUENCE

INCREASED SYMPATHETIC TONE Positive consequences

- positive tropic effect, thus increasing heart

rate and force of contraction

Negative consequences

- vasoconstriction, and following increased

afterload (increased total peripheral

resistance for the heart to work against)

INCREASED ACTIVATION OF RAAS Positive consequences

- increased blood volume, and following

increased distribution capabilities of the

blood

Negative consequences

- increased blood pressure, and following

increased preload (increased blood volume

arriving in the atria that the heart has to

pump back out)

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

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


1) CARDIAC GLYCOSIDES (DIGITALIS)

- affect the heart in 2 ways

A) INHIBITION OF 3 SODIUM/2 POTASSIUM ANTIPORTER

- normally consumed with maintaining normal resting membrane

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

and potassium into the cell

- 2 consequences

CONSEQUENCE DESCRIPTION

- 14 -

POSITIVE BATHMO-

TROPIC EFFECT

- due to decreased negative

membrane potential and following

easier excitability of the myocytes

POSITIVE IONO-

TROPIC EFFECT

- due to increased intracellular

sodium and following disruption of

the sodium gradient across the

sarcolemma

- in turn, this disrupts the

sarcolemmal sodium/calcium

antiporter normally consumed with

restoring the normal intracellular

calcium balance following a

depolarization

- this leads to increased intracellular

calcium, and forces the cell to pump

more calcium into the sarcoplasmic

reticulum instead

- finally, upon the successive

depolarization more calcium will be

released from the sarcoplasmic

reticulum, thus amplifying the force

of contraction

B) INCREASED VAGAL TONE (CENTRAL STIMULATION OF

VAGAL NUCLEI)

- 2 consequences

CONSEQUENCE DESCRIPTION

NEGATIVE CHRONO-

TROPIC EFFECT

- due to depression of the SA-node

and following decreased heart rate

NEGATIVE DROMO-

TROPIC EFFECT

- due to depression of the AV-node

and following decreased AV

conduction

- 2 types


DIGOXIN General information

- found in foxgloves

- administered orally (and IV in

emergencies)

- effective dose and toxic dose has a

very small margin

- 15 -

- eliminated by the kidneys

Medical uses

- treatment of heart failure

- treatment of atrial fibrillation

(negative dromotropic effect)

Side effects

- bradycardia (negative chronotropic

effect)

- AV block (negative dromotropic

effect)

- ventricular extrasystole, ventricular

paroxysmal tachycardia and/or

ventricular fibrillation (positive

bathmotropic effect)

- vomiting (stimulation of area

postrema)

Contraindications

- kidney problems (eliminated by the

kidneys)

- hypokalemia (amplified inhibition

of the 3 sodium/2 potassium

antiporter)

- hypercalcemia (even stronger

positive ionotropic effect)

- beta-adrenergic

antagonists/verapamil (even stronger

negative chronotropic- and

dromotropic effect)

OUABAIN General information

- same as digoxin

2) DIRECT VASODILATORS

- decrease total peripheral resistance

- see 28

3) DRUGS ACTING ON THE RENIN-ANGIOTENSIN-ALDOSTERONE

SYSTEM

- decrease blood volume, decrease arterial vasoconstriction and decrease

hypertrophy/hyperplasia of cardiac muscle

- see 24

- 16 -

4) DIURETICS

- decrease blood volume

- see 25

- 17 -

27. ANTIANGINAL DRUGS. DRUGS THAT INCREASE

REGIONAL BLOOD FLOW

ANTIANGINAL DRUGS

Overview

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

- there are 4 (5) types of angina

TYPE DESCRIPTION

SILENT MYOCARDIAL ISCHEMIA

STABLE ANGINA

- narrowed coronary artery lumen

UNSTABLE ANGINA - occluded coronary artery lumen

MIXED ANGINA - both narrowed and occluded lumen at distinct

locations

PRINZMETAL ANGINA - vasospasms of the coronary arteries

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

myocardial infarction, AMI)


1) ORGANIC NITRATES

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

inducing systemic vasodilation

- affects the heart in 2 ways

CAUSE CONSEQUENCE

INCREASED MYOCARDIAL

BLOOD SUPPLY

Increased myocardial oxygen supply

- general coronary artery vasodilation

(resolves prinzmetal angina)

- vasodilation of collaterals of the

coronary arteries to supply the

ischemic area of the myocardium

(resolves stable- unstable- and mixed

angina)

DECREASED MYOCARDIAL Decreased myocardial oxygen

- 18 -

WORKLOAD consumption

- decreased preload (venous

vasodilation)

- decreased afterload (arterial

vasodilation)

- 3 types


GLYCEROL TRINITRATE

(NITROGLYCERIN)

General information

- lipophilic

- administered sublingually,

transdermally or IV


Medical uses

- prophylaxis of stable angina

(administered sublingually or

transdermally)

- treatment of stable angina

(administered sublingually)

- treatment of unstable angina

(administered IV)

- treatment of acute heart failure

(administered IV)

Side effects

- postural hypotension (venous

vasodilation)

- headache (meningeal artery

vasodilation)

AMYL NITRATE General information

- same as glycerol trinitrate

ISOSORBIDE

MONONITRATE

General information


Medical uses

- prophylaxis of stable angina

- treatment of chronic heart failure

Side effects

- same as glycerol trinitrate

- 19 -

2) CALCIUM CHANNEL BLOCKERS

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

thus both increasing myocardial blood supply and decreasing myocardial

workload

- see 23


- decreases sympathetic action on the heart, thus decreasing myocardial

workload

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

are not completely selective, thus might cause coronary artery

vasoconstriction)

- see 21

DRUGS THAT INCREASE REGIONAL BLOOD FLOW

Overview -

- 20 -

28. ANTIHYPERTENSIVE DRUGS Overview

- blood pressure is given by 2 parameters

PARAMETER DESCRIPTION

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

heart

TOTAL PERIPHERAL RESITANCE

- given by the blood volume and the level of

vasoconstriction

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

parameters


1) DIRECT VASODILATORS

- dilate the blood vessels, thus decreasing total peripheral resistance

- 4 types


MINOXIDIL General information

- activates potassium channels, thus causing

outflux of potassium

- this leads to hyperpolarization of the cell, and

following vasodilation

- strong, long acting vasodilator

- administered IV

Medical uses

- last resort in treatment of severe hypertension

Side effects

- reflex tachycardia

- increased blood volume (activation of the renin

angiotensin aldosterone system)

- hirsutism (increased facial- and body hair

growth)

HYDRALAZINE General information

- inhibits calcium release from sarcoplasmic

- 21 -

reticulum during depolarization, thus leading to

decreased vasoconstriction

- administered IV

Medical uses

- short-term treatment of hypertension

Side effects

- same as minoxidil

- SLE-like disorder (autoantibodies against own

DNA)

NITROPRUSSIDE General information

- inorganic nitrate

- administered IV

- same as organic nitrates (see 27)

DIAZOXIDE General information

- non-diuretic thiazide

- administered IV

- same as thiazide diuretics (see 25)

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

- 22 -


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

- see 21

7) DRUGS ACTING ON THE RENIN ANGIOTENSIN ALDOSTERONE SYSTEM

- cause vasodilation and decreased blood volume, thus decreasing total

peripheral resistance

- see 24

8) DIURETICS

- decrease blood volume, thus decreasing total peripheral resistance

- see 25

- 23 -

29. ANTIARRHYTHMIC DRUGS Overview

- action potential in myocytes has 4 (5) phases

PHASE DESCRIPTION

PHASE 0 Rapid depolarization

- due the myocyte reaching a membrane potential

of -60 mV (critical firing threshold) and following

opening of the activation gates of voltage-gated

sodium channels

- this leads to rapid influx of sodium and

following depolarization

PHASE 1

Partial repolarization

- due to the myocyte reaching +40 mV and

following closing of the inactivation (refractory)

gates of the voltage-gated sodum channels

- partial repolarization is done by outflux of

potassium through the normal potassium-sodium

leak channels

PHASE 2 Plateau

- due to the myocyte reaching 0 mV and following

activation of voltage-gated calcium channels of

the sarcoplasmic reticulum

- this leads to release of large quantities of calcium

into the sarcoplasm, and following initiation of

muscle contraction

PHASE 3 Repolarization

- due to the myocyte reaching 10 mV and

following inactivation of the voltage-gated

calcium channels

- repolarization is done by the same mechanism as

with partial repolarization (see above)

PHASE 4 Pacemaker potential

- due to the myocyte reaching -90 mV (resting

membrane potential) and following activation of a

special sodium-potassium leak channel (only

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

that opposes the normal potassium-sodium leak

channel (found in all cells capable of depolarizing)

- this leads to a steadily increasing membrane

potential, thus initiating the successive

depolarization at -60 mV (phase 0)

- 24 -

- there are 4 types of cardiac arrhythmias

TYPE DESCRIPTION

ACTIVE ECTOPIC BEATS

(SUPRAVENTRICULAR-,

VENTRICULAR-)

General information

- extrasystole, premature beat

- 1 beat occurring before it would have been

expected originating outside the AV-node

- due to irritation of the myocardium

Causes

- excess sympathetic tone

- ischemia

- small calcified plaques

- myocardial toxins (alcohol, caffeine, nicotine,

drugs etc.)

PAROXYSMAL TACHYCARDIA

(SUPRAVENTRICULAR-,

VENTRICULAR-)

General information

- heart rate above 150 BPM

- due to successive active ectopic beats (see

above) or the presence of a reentrant circuit (see

below)

FLUTTER (ATRIAL-) General information


- due to the presence of 1 reentrant circuit

Causes

- presence of extranodal conducting pathways

(wolff-parkinson-white syndrome etc.)

- increased distance of conductance

(atrial/ventricular dilation)

- decreased velocity of conduction (ischemia,

excess parasympathetic activity etc.)

- decreased refractory period (excess sympathetic

activity etc.)

FIBRILLATION (ATRIAL-,

VENTRICULAR-)

General information


- due to the presence of multiple reentrant circuits

(see above)

- 25 -

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

1) CLASS I ANTIARRHYTHMIC DRUGS

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

excitability of the myocardium

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

frequently depolarize

- may be further subdivided in 3 groups

A) CLASS Ia ANTIARRHYTHMIC DRUGS

- cause intermediate voltage-gated sodium channel block

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

increase duration of repolarization (refractory period)

- 2 types


QUINIDINE General information


- also has an atropine-like effect

Medical uses

- treatment of ventricular arrhythmias

Side effects

- ventricular paroxysmal tachycardia

(torsade de pointes, due to prolonged

refractory period)

- any side effect of muscarinic antagonists

(atropine-like effect, see 15)

- thrombocytopenia (autoantibodies against

platelets)

DISOPYRAMIDE General information

- same as quinidine

PROCAINAMIDE General information

- administered IV

Medical uses

- treatment of ventricular arrhythmias

Side effects


- SLE-like disorder (autoantibodies against

own DNA)

- 26 -

B) CLASS Ib ANTIARRHYTHMIC DRUGS

- cause weak voltage-gated sodium channel block

- selectively block refractory voltage-gated sodium channels

- 2 types


LIDOCAINE General information

- local anaesthetic (see 22)

- administered IV


Medical uses

- treatment of arrhythmias associated with

irreversible myocardial ischemia (AMI, due

to selective refractory blockage)

- local anaesthesia

Side effects

- see 22

PHENYTOIN General information

- antiepileptic drug (see 43)


- same as lidocaine

Medical uses


irreversible myocardial ischemia (AMI, due

to selective refractory blockage)

- treatment of epilepsy

Side effects

- see 43

C) CLASS Ic ANTIARRHYTHMIC DRUGS

- cause strong voltage-gated sodium channel block

- 2 types


FLECAINIDE Medical uses


reentrant circuits (strong general

suppression)

- 27 -

Side effects

- heart failure (in patients with symptoms,

due to strong general suppression)

ENCAINIDE General information

- same as flecainide

2) CLASS 2 ANTIARRHYTHMIC DRUGS

- beta-adrenergic receptor antagonists

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

decrease excitability and force of contraction of the myocardium

- used in treatment of arrhythmias associated with excess sympathetic tone

- see 21


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

increase duration of repolarization (refractory period)

- 3 types


AMIODARONE General information

- iodine-containing compound

- accumulates in tissues


Medical uses


reentrant circuits (prolonged refractory

period)

Side effects


(prolonged refractory period)

- hypo- or hyperthyroidism (iodine, tissue

accumulation)

- photosensitivity (iodine, tissue

accumulation)

- skin discoloration (iodine, tissue

accumulation)

- visual disturbances (accumulation in the

cornea, due to iodine-content and tissue

accumulation)

- neurological disturbances (tissue

accumulation)

- 28 -

SOTALOL General information


- also a beta-adrenergic receptor antagonist

(see 21)

Medical uses


reentrant circuits


excess sympathetic activity

Side effects

- see 21


- calcium channel blockers

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

- used in treatment of supraventricular/atrial arrhythmias

- see 23

- 29 -

30. DRUGS USED TO TREAT HYPERLIPOPROTEINEMIA Overview

- triglycerides and cholesterol are transported in lipoproteins in the circulation

- lipoproteins consists of 2 parts

PART DESCRIPTION

MEDULLA - hydrophobic

- consists of triglycerides and cholesterol esters

CORTEX

- hydrophilic

- consists of phospholipids, cholesterol and

apolipoproteins

- there are 5 types of lipoproteins

TYPE DESCRIPTION

CHYLOMICRON - transports triglycerides and cholesterol from the

intestines to muscle- and adipose tissue

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

lipoprotein lipase and the free fatty acids taken up by

these tissues

CHYLOMICRON REMNANT - transports the cholesterol and remaining triglycerides

remaining in the chylomicron to the liver

- here, the cholesterol is converted to bile salts and

secreted through the bile into the intestines for

absorption of new lipids and cholesterol

(enterohepatic bile circulation)

VLDL Very low density lipoprotein

- transports newly synthesised triglycerides and

cholesterol from the liver back to muscle- and adipose

tissue

- here, all the triglycerides are split by lipoprotein

lipase and taken up by these tissues

LDL Low density lipoprotein

- transports the remaining cholesterol either back to

the liver for conversion to bile acids, or to extrahepatic

tissues for metabolism

HDL High density lipoprotein

- a scavenger lipoprotein that adsorbs cholesterol

- 30 -

derived from cell breakdown and transfers it to vLDL

and LDL

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

atherosclerosis

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


1) STATINS

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

inhibitors

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

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

synthesis of bile acids

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

from the circulation

- statins also reduce VLDL production

- 4 types


MEVASTATIN General information

- found in fungus


- extensive first-pass

metabolism (, though the site

of action is the liver)

Medical uses

- reduction of LDL and

VLDL

Side effects

- mild GI disturbances

- mild sleep disturbances

- mild skin rashes

LOVASTATIN General information

- same as mevastatin

SIMVASTATIN General information

- synthetic pro-drug

- same as mevastatin

- 31 -

PRAVASTATIN General information

- same as simvastatin

2) FIBRATES

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

agonists

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

proteins responsible for lipid metabolism

- consequences of PPAR-alpha upregulation include

CONSEQUENCE CAUSE

DECREASED LIPID STORES - increased deliberation of

lipids from adipose tissue

DECREASED CIRCULATING LIPIDS - increased lipoprotein lipase

activity

- increased beta-oxidation

DECREASED CIRCULATING VLDL - decreased VLDL

production

DECREASED CIRCULATING LDL - increased LDL-receptor

expression

- 3 types


FENOFIBRATE Gereral information


Medical uses

- reduction of VLDL

- reduction of VLDL and

LDL

Side effects

- myositis (inflammation of

muscle)

- acute renal failure (due to

myositis and following

hemoglobinuria)

- mild GI disturbances

- 32 -

CIPROFIBRATE General information

-same as fenofibrate

BENZAFIBRATE General information

-same as fenofibrate

3) RESINS

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

through the enterohepatic circulation

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

following removal of LDL from the circulation

- 2 types


COLESTYRAMINE Gereral information


Medical uses

- reduction of LDL

Side effects

- nausea

- vomiting

- bloating

- constipation or diarrhea

- fat-soluble vitamin

deficiency

COLESTIPIL General information

-same as colestyramine

- 33 -

31. ANTICOAGULANTS. FIBRINOLYTICS.

ANTIFIBRINOLYTICS. ANTIPLATELET DRUGS

Overview - hemostasis consists of 4 (5) mechanisms

MECHANISM DESCRIPTION

VASOCONSTRICTION - both neurally- and humorally mediated

PLATELET PLUG FORMATION - adhesion of platelets to the damaged endothelium

COAGULATION - blood clot formation by activation of fibrin

through the intrinsic- or extrinsic coagulation

cascade

PERMANENT CLOSURE - growth of fibrous tissue by conversion of smooth

muscle cells of the vessel walls to myofibroblasts

FIBRINOLYSIS - removal of the blood clot by activation of

plasmin

ANTICOAGULANTS

Overview

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

extrinsic- and intrinsic coagulation pathways, thus inhibiting coagulation


1) INJECTABLE ANTICOAGULANTS

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

activating it

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

activated coagulation factors

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

following inhibition of coagulation

- 2 types


HEPARIN General information

- 34 -

- endogenous compound found in the granules of mast

cells

- sulfated glycosaminoglycan (large, negatively

charged)

- extracted from bovine lung and/or hog intestine

- digested in the GI

- administered IV or subcutaneously (cause hematomas

if injected intramuscularly due to its large molecular

size)

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

and II (thrombin), thus accelerating their inactivation

by antithrombin III

- also accelerate inactivation of factor X

(independently of the second binding site)

Medical uses

- treatment of thrombosis, DIC and emboli

Side effects

- hemorrhage (clotting factor inhibition)

- thrombosis/DIC (autoantibodies against heparin-

platelet factor 4 complexes (and following

thrombocytopenia) and platelet factor 4-vascular

endothelium complexes)

- osteoporosis

LMWHS General information

- low molecular weight heparins

- fragments of heparin lacking the second binding site

- only accelerate inactivation of factor X

- administered subcutaneously

- same as heparin

2) ORAL ANTICOAGULANTS

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

inhibiting reduction of vitamin K to 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


- 35 -

WARFARIN Gereral information

- also used in rat poison


- may cross the placenta

- only inhibits formation of new coagulation factors,

thus previously synthetized coagulation factors will

still be able to induce coagulation until they are

catabolized (around 48 hours)

Medical uses


Side effects

- hemorrhage (deceased clotting factor production)

- teratogenesis (may cross the placenta)

FIBRINOLYTICS

Overview

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

following removal of blood clots

Relevant Drugs - 3 types


STREPTOKINASE General information

- streptococcal protein

- may only be administered once per year (antistreptococcal

antibodies will be formed within 1 week (!))

Medical uses


Side effects

- hemorrhage (fibrinolysis)

- stroke (hemorrhage)

- anaphylaxis (antistreptococcal antibodies)

ALTEPLASE General information

- recombinant tPA (tissue plasminogen factor, the physiological

- 36 -

protein responsible for plasmin activation)

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

- very short half-life

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

Medical uses


Side effects

- hemorrhage (fibrinolysis)

- stroke (hemorrhage)

RETEPLASE General information

- short half-life

- administered by IV bolus

- same as alteplase

ANTIFIBRINOLYTICS

Overview

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

following increase the integrity of blood clots

Relevant Drugs - 1 type


TRANEXAMIC ACID General information

- 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

- 37 -

- treatment of fibrinolytic overdose

Side effects

- thrombosis

ANTIPLATELET DRUGS

Overview

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

thus inhibiting platelet plug formation


1) COX-1 INHIBITORS

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

PGI2 (prostaglandin I2) synthesis in vascular endothelium

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

inhibits it

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

platelet-fibrinogen adhesion

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

are not, thus platelet plug formation is inhibited

- see 51/52

2) THIENOPYRIDINE DERIVATIVES

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

formation

- 2 types


TRICLOPIDINE General information

- pro-drug


Medical uses


Side effects

- hemorrhages

- blood dyscrasias

- diarrhea

- skin rashes

- 38 -

CLOPIDOGREL General information

- same as triclopidine

3) GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONITS

- antagonizes TXA2 and ADP, thus inhibiting platelet plug formation

- 2 types


ABCIXIMAB General information

- hybride rodent/human monoclonal antibody

- administered IV

- may only be administered once (antibodies against the

rodent part will be formed)

Medical uses


Side effects

- hemorrhages

TIROFIBRAN General information

- administered IV

Medical uses


Side effects

- hemorrhages

4) PGI2 AGONISTS

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

- 1 type


EPOPROSTENOL

- 39 -

32. DRUGS AFFECTING HEMATOPOIESIS

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

- there are 5 types of blood cells

CELL TYPE DESCRIPTION

ERYTHROCYTES - RBCs

PLATELETS - cell fragments of megakaryocytes

MONOCYTES - differentiate to macrophages

GRANULOCYTES - neutrophils

- eosinophils

- basophils

LYMPHOCYTES - B lymphocytes

- T lymphocytes

- anemia is a decrease in circulating RBCs

- there are 4 types of anemia

TYPE DESCRIPTION

APLASTIC ANEMIA - due bone marrow failure

DEFICIENCY ANEMIA - normocytic, normochromic deficiency anemia (due to

erythropoietin and/or GM-CSF deficiency)

- microcytic, hypochromic deficiency anemia (due to

iron deficiency)

- macrocytic, hyperchromic anemia (due to folic acid

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

deficiency)

HEMOLYTIC ANEMIA - due to increased sequestration of RBCs

HEMORRHAGIC ANEMIA - due to hemorrhages


- 40 -

1) IRON

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

hemoglobin synthesis

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

- 5 types


FERROUS SULFATE General information


Medical uses

- treatment of microcytic, hypochromic

deficiency anemia

Side effects

- nausea

- diarrhea

- abdominal cramps

FERROUS SUCCINATE General information

- same as ferrous sulfate

FERROUS GLUCONATE General information


FERROUS FUMARATE General information


IRON-DEXTRAN General information

- administered IV


2) FOLATE (VITAMIN B9)

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

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

and RNA synthesis

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

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

- is carried in the circulation as methyl-FH4

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

is needed for its utilization

- 1 type


- 41 -

FOLATE Gereral information

- administered orally (parenterally in case

of malabsorption syndromes)

Medical uses

- treatment of macrocytic, hyperchromic

deficiency anemia

3) COBOLAMIN (VITAMIN B12)

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

and pyrimidine synthesis

- 1 type


HYDROXYCOBOLAMIN Gereral information

- administered intramuscularly

(cobolamin deficiency is almost always

due to malabsorption syndromes)

Medical uses

- treatment of macrocytic, hyperchromic

deficiency anemia

4) CSFS (COLONY-STIMULATING FACTORS)

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

of commited progenitors of blood cells (except lymphocytes)

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

basophils)

- 2 types


GM-CSF Gereral information

- granulocyte-macrophage colony-

stimulating factor

- endogenous substance

- involved in differation of all cells

mentioned above

- administered IV or subcutaneously

Medical uses

- treatment of leucopenia (mainly

neutropenia)

Side effects

- 42 -

- fever

- skin rashes

- muscle pain

- muscle weakness

G-SCF Gereral information

- granulocyte colony-stimulating factor

- endogenous substance

- involved in differation of neutrophils

- administered IV or subcutaneously

Medical uses

- treatment of neutropenia

Side effects

- dysuria

- vasculitis

- 43 -

33. HISTAMINE, H1 AND H2 RECEPTOR ANTAGONISTS

Overview - histamine is a paracrine hormone and an inhibitory neurotransmitter

- histamine is primarily found in 3 locations

LOCATION DESCRIPTION

CNS - histaminergic neurons

SYSTEMIC CIRCULATION - granules of mast cells

- granules of basophils

GI TRACT - neuroendocrine cells in the glands of the GI

- histamine acts on histaminergic receptors

- there are 3 types of histaminergic receptors

RECEPTOR TYPE LOCATION

H1 - smooth muscle

- CNS

H2 - parietal cells of the castric glands

- heart

H3 - presynaptically in CNS neurons

General Effects - 6 types

ORGAN DESCRIPTION

CNS - inhibition of neurotransmitter release

- nausea

HEART - positive chronotropic effect (increased heart rate)

- positive ionotropic effect (increased force of

contraction)

BLOOD VESSELS - vasodilation

- increased vascular permeability

- 44 -

RESPIRATORY TRACT - bronchoconstriction

GI TRACT - increased gastric acid secretion

- GI smooth muscle contraction

GENITO-URINARY TRACT - contraction of uterus


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


PROMETAZINE General information

- marked muscarinic receptor antagonist

action

- weak alpha-1 adrenergic receptor antagonist

action

- weak local anaesthetic action


- may cross the blood-brain barrier

Medical uses

- treatment of emesis (especially motion

sickness)

- treatment of insomnia (sedative)

Side effects

- diarrhea/constipation (GI smooth muscle

contraction)

- same as muscarinic receptor antagonists

(see 15)

DIPHENHYDRAMINE General information

- marked muscarinic receptor antagonist

- 45 -

action

- weak local anaesthetic action


- may cross the blood brain barrier

- same as prometazine

CYCLIZINE General information



Medical uses

- treatment of emesis (especially motion

sickness)

Side effects

- diarrhea/constipation

- sedation

CINNARIZINE General information

- same as cyclizine

MEQUITAZINE General information

- administered orally, topically and/or IV

- does not cross the blood-brain barrier

Medical uses

- treatment of anaphylactic reactions (allergic

rhinitis, urticaria (allergic skin rashes), insect

bites, drug hypersensitivities etc.)

Side effects

- diarrhea/constipation

CENTRIZINE General information

- same as mequitazine

FEXOFENADINE General information

- same as mequitazine

2) H2 RECEPTOR ANTAGONISTS

- H2 receptor antagonists decrease histamine-mediated gastric acid secretion

- H2 receptors antagonists also inhibit the secondary messenger systems of

gastrin- and acetylcholine-mediated gastric acid secretion

- 46 -

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

secretion by over 90%

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

- 4 types


CIMETIDINE Gereral information

- minor androgen receptor antagonism

- also inhibit cytochrome P450

- administered orally, intramuscularly or IV

Medical uses

- treatment of peptic ulcer (gastric- and/or

duodenal)

- treatment of reflux esophagitis

Side effects

- hypergastrinemia

- diarrhea

- gynecomastia (androgen receptor

antagonism)

RANTIDINE General information


Medical uses

- same as cimetidine

Side effects

- same as cimetidine (but no gynecomastia)

FAMOTIDINE General information

- same as rantidine

NIZATIDINE General information


- same as rantidine

- 47 -

34. SEROTONIN, SEROTONIN RECEPTOR AGONISTS AND

ANTAGONISTS

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

inhibitory neurotransmitter

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

see 17)

TRYPTOPHAN

tryptophan hydroxylase

5-HYDROXYTRYPTOPHAN

DOPA decarboxylase

5-HYDROXYTRYPTAMINE (5-HT, SEROTONIN)

MAO + aldehyde dehydrogenase

5 HYDROXYINDOLEACETIC ACID (5-HIAA)

- serotonin is primarily found in 3 locations

LOCATION DESCRIPTION

CNS - serotonergic neurons

SYSTEMIC CIRCULATION - platelets

GI TRACT - neuroendocrine cells in the glands of the GI

- myenteric plexus

- serotonin acts on serotonergic receptors

- there are 8 types of serotonergic receptors

RECEPTOR TYPE DESCRIPTION

5-HT 1A Location

- CNS

Effect

- CNS depression

- anxiolysis

- alertness

- 48 -

5-HT 1B Location

- CNS

- pulmonary vasculature

Effect

- CNS depression

- pulmonary vasoconstriction

5-HT 1D Location

- CNS

- cerebral vasculature

Effect

- CNS depression

- cerebral vasoconstriction

5-HT 2A Location

- CNS

- smooth muscle

- platelets

Effect

- CNS excitation

- hallucination

- arterial- and venous vasoconstriction

- arteriolar vasodilation

- bronchoconstriction

- contraction of the uterus

- platelet plug formation (platelet aggregation)

5-HT 2B Location

- stomach

Effect

- gastric smooth muscle contraction

5-HT 2C Location

- choroid plexus of the CNS

Effect

- secretion of cerebrospinal fluid

5-HT 3 Location

- 49 -

- CNS

- chemoreceptive trigger zone of area postrema in the

CNS

- spinal cord analgesic system

Effect

- CNS excitation

- nausea

- vomiting

- analgesia

5-HT 4 Location

- smooth muscle of the GI tract

Effect

- increased peristalsis

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

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

SEROTONIN RECEPTOR AGONISTS


1) 5-HT 1 AGONISTS

- 3 types


BUSPIRONE Medical uses

- treatment of anxiety (CNS depression)

Side effects

- restlessness (alertness)

- headache

- nausea (effect on 5-HT 3 receptors)

SUMATRIPTAN General information

- 5-HT 1D selective agonist

- do not cross the blood-brain barrier


- administered orally or subcutaneously

- 50 -

Medical uses

- treatment of migraine (vasoconstriction of

meningeal blood vessels)

Side effects

- cardiac ischemia (coronary artery

vasoconstriction)

ERGOTAMINE General information

- found in the ergot fungus

- 5-HT 1 partial agonist on blood vessels

- 5-HT 1 antagonist in all other locations

- 5-HT 2 agonist

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

- related to ergometrine (see 35)


- administered IV, rectally or by inhalation

Medical uses

- treatment of migraine (vasoconstriction of

meningeal blood vessels and inhibition of

nocioceptive transmission)

- treatment of postpartum hemorrhage

Side effects

- hypertension (vasoconstriction)

- coronary ischemia (vasoconstriction)

- nausea

- vomiting

2) 5-HT 2 AGONISTS

- 1 type


LSD General information

- see 48

3) 5-HT 4 AGONISTS

- 1 type


- 51 -

CISAPRIDE General information


Medical uses

- treatment of reflux esoophagitis (increased tone of

lower esophageal sphincter)

- disorders of gastric emptying (increased tone of

gastric smooth muscle)

- treatment of paralytic ileus (increased peristalsis)

Side effects

- diarrhea

- abdominal cramps

SEROTONIN RECEPTOR ANTAGONISTS


1) 5-HT 2 ANTAGONISTS

- 2 types


METHYLGLYCERGIDE General information

- also partial 5-HT 2 agonist


Medical uses

- prophylaxis of migraine (cerebral blood

vessel vasodilation)

Side effects

- nausea

- vomiting

- retroperitoneal/mediastinal fibrosis

CYPROHEPTADINE General information

- also histaminergic receptor antagonist

(see 33)


Medical uses

- 52 -

- prophylaxis of migraine (cerebral blood

vessel vasodilation)

Side effects

- sedation

- weight gain

2) 5-HT 3 ANTAGONISTS

- 2 types


ONDASETRON General information


Medical uses

- treatment of emesis (vomiting)

- treatment of anxiety

TROPISETRON General information

- same as ondasetron

- 53 -

35. PHARMACOLOGY OF EICOSANOIDS. DRUGS ACTING

ON THE SMOOTH MUSCLE: SMOOTH MUSCLE

RELAXANTS; PHARMACOLOGY OF THE UTERINE

SMOOTH MUSCLE

PHARMACOLOGY OF EICOSANOIDS

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

physiological- and pathological processes

- there are 3 groups of eicosanoids

GROUP TYPE

PROSTAGLANDINS - PGD2

- PGE2

- PGF2-alpha

- PGI2

TROMBOXANES - TXA2

LEUKOTRIENES - LTB4

- LTC4

- LTD4

- LTE4

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

as arachidonic acid esters in phospholipids

PHOSPHOLIPIDS

phospholipase A2

ARACHIDONIC ACID

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

PROSTAGLANDINS/ LEUKOTRIENES

TROMBOXANES

- there are 9 types of eicosanoid receptors

RECEPTOR TYPE DESCRIPTION

- 54 -

DP (PGD2) RECEPTORS Location

- blood vessels

- uterus

- GI tract

- platelets

- pituitary gland

Effect

- vasodilation

- uterine smooth muscle relaxation

- GI tract smooth muscle relaxation

- inhibition of platelet aggregation

- regulation of pituitary hormone release

EP1 (PGE2) RECEPTORS Location

- lungs

- GI tract

- CNS

- C nerve fibers

Effect


- GI tract smooth muscle contraction

- fever (increase the hypothalamic temperature set point)

- hyperalgesia (sensitization of afferent C nerve fibers, see

49)


- blood vessels

- lungs

- GI tract

Effect

- vasodilation

- bronchodilation

- GI tract smooth muscle relaxation

- intestinal fluid secretion


- uterus

- GI tract

- autonomic nervous system

- adipose tissue

- 55 -

Effect

- pregnant uterine smooth muscle contraction

- GI tract smooth muscle contraction

- inhibition of gastric acid secretion

- gastric mucous secretion

- inhibition of autonomic neurotransmitter release

- inhibition of lipolysis

FP (PGF2-alpha)

RECEPTORS

Location

- uterus

Effect

- uterine smooth muscle contraction

IP (PGI2) RECEPTORS Ligand

- PG12

Effect

- vasodilation

- inhibition of platelet aggregation

- renin release

- hyperalgesia (sensitization of afferent C nerve fibers)

TP (TXA2) RECEPTORS Location

- blood vessels

- platelets

Effect

- vasoconstriction

- platelet aggregation

BLT (LTB4) RECEPTORS Location

- neutrophils

- macrophages

- lymphocytes

Effect

- neutrophil/macrophage chemotaxis

- neutrophil degranulation

- macrophage/lymphocyte cytokine release

- macrophage/lymphocyte proliferation

- 56 -

CYSLT (LTC4, LTD4,

LTE4) RECEPTORS

Location

- blood vessels

- lungs

Effect

- vasodilation

- increase vascular permeability


- bronchial mucous secretion

SMOOTH MUSCLE RELAXANTS

Overview -

PHARMACOLOGY OF THE UTERINE SMOOTH MUSCLE

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

ability of spontaneous rhythmic contractions

- the rhythmic contractions are under hormonal control

ACTION HORMONE

FACILITATION - progesterone

- oxytocin

INHIBITION - estrogen

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

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

EVENT DESCRIPTION

MENSTURAL CYCLE Pre-ovulatory phase

- weak rhythmic contractions (estrogen)

Post-ovulatory phase

- strong rhythmic contractions (progesterone)

PREGNANCY Pregnancy

- very weak (or absent) rhythmic contractions

- 57 -

Delivery

- very strong rhythmic contractions (oxytocin)

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

smooth muscle

- the normal contractions are under prostaglandin- and hormonal control

ACTION HORMONE

FACILITATION - PGE2 (EP3 receptors)

- PGF2-alpha

- histamine (H1 receptors)

- serotonin (5-HT 2A receptors)

INHIBITION - PGD2

- adrenalin (beta-2 receptors)


1) OXYTOCIC DRUGS

- facilitate uteral contraction

- 3 groups

A) OXYTOCIN RECEPTOR AGONISTS

- 1 type


OXYTOCIN General information

- endogenous hormone

- causes strong facilitation of the rhythmic

contractions of the uterus (labor)

- causes contraction of the mammary gland

(lactation)

- also causes vasodilation

- also has a weak antidiuretic effect

- administered IV or intramuscularly

Medical uses

- induction of labor (uteral contraction)

- augmentation of labor (uteral contraction)

- treatment of postpartum hemorrhage (uteral

- 58 -

contraction)

- treatment of milk congestion (mammary

gland contraction)

Side effects

- hypotension (vasodilation)

- reflex tachycardia (hypotension)

- water retention (antidiuretic effect)

B) ERGOT ALKALOIDS

- 2 types


ERGOMETRINE General information

- found in the ergot fungus

- 5-HT 2 receptor agonist

- beta-2 adrenergic receptor antagonist

- also a D2 receptor agonist

- causes strong contraction of the uterine

smooth muscle

- also causes vasoconstriction


Medical uses

- treatment of postpartum hemorrhage

Side effects


- angina (vasoconstriction)

- nausea (stimulation of the chemoreceptive

trigger zone)

- vomiting (nausea)

- headache

- blurred vision

ERGOTAMINE General information

- see 34

C) PROSTAGLANDIN ANALOGUES

- 3 types


- 59 -

DINOPROST General information

- synthetic PGE2 analogue

- causes simultaneous contraction of the

uterus and relaxation of the cervix

- administered orally or intravaginally

Medical uses

- induction of labor

- 2nd trimester abortion

Side effects

- uterine pain

- nausea

- vomiting

CARBOPROST General information

- synthetic PGF2-alpha analogue

- administered intramuscularly

- same as dinoprostone

MISOPROSTOL General information

- see 37

2) TOCOLYTIC DRUGS

- inhibit uteral contraction

- 2 groups

A) OXYTOCIN RECEPTOR ANTAGONISTS

- 1 type


ATOSIBAN General information

- oxytocin receptor antagonist

- administered IV

Medical uses

- prevention of premature labor

Side effects


- nausea

- vomiting

- hyperglycemia

- 60 -

- skin rashes

B) SELECTIVE BETA-2 ADRENERGIC RECEPTOR AGONISTS

- inhibit uteral contraction, thus preventing premature labor

- see 19

- 61 -

36. PHARMACOLOGY OF THE RESPIRATORY TRACT

Overview - asthma is a reversible obstructive disorder of the lungs

- asthma consists of 2 phases

PHASE DESCRIPTION

ACUTE PHASE - activation of mast cells mediated by IgE and

following secretion of cytokines

LATE PHASE - chemotaxis and activation of inflammatory cells

(especially eosinophils) and following secretion of

cytokines

- secreted cytokines include

CYTOKINE DESCRIPTION

ACUTE PHASE CYTOKINES - bronchoconstrictory cytokines

- chemotactic cytokines

LATE PHASE CYTOKINES - chemotactic cytokines

- inflammatory cytokines

- vasodilatory cytokines

- growth factors

- toxic proteins

BRONCHODILATOR DRUGS

Overview - used to treat the early phase of asthma


1) BETA-2 ADRENERGIC RECEPTOR AGONISTS

- stimulates beta-2 adrenergic receptors, thus causing bronchodilation

- also inhibits release of bronchoconstrictors from activated mast cells

- administered by aerosol, orally or IV

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

- see 19

- 62 -

2) MUSCARINIC RECEPTOR ANTAGONISTS

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

bronchodilation and inhibition of bronchial hypersecretion

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

agonists

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

effects

- see 15

3) HISTAMINERGIC H1 RECEPTOR ANTAGONISTS

- blocks histaminergic H1 receptors, thus causing bronchodilation and vasoconstriction (decreased capillary permeability and following decreased

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

4) CYSTEINYL-LEUKOTRIENE RECEPTOR ANTAGONISTS

- the bronchoconstrictory leukotrienes secreted by the activated mast cells act on cysteinyl-leukotriene receptors

- cysteinyl-leukotriene receptor antagonists block the cysteinyl-leukotriene receptors, thus causing bronchodilation

- administered in conjunction with beta-2 adrenergic receptor agonists - 2 types


MONTELUKAST General information


Medical uses

- treatment of asthma

Side effects

- headache

- constipation/diarrhea

ZAFIRLUKAST General information

- same as montelukast

5) METHYLXANTHINES

- methylxanthines inhibit adenylyl cyclase, thus leading to decreased formation of cAMP and following broncodilation

- 63 -

- see 48

ANTI-INFLAMMATORY DRUGS

Overview - used to treat the late phase of asthma


1) GLUCOCORTICOIDS

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

inflammatory cell chemotaxis, inflammation, edema (vasodilation/increased

capillary), hypertrophy/hyperplasia and bronchial epithelial damage

- see 55

2) CROMOGLICATE

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

bronchodilation, decreased bronchosecretion and decreased cough

- also inhibits secretion of chemotactic cytokines by the inflammatory cells

- 2 types


CROMOGLICATE General information

- administered by aerosol in conjunction

with glucocorticoids

Medical uses

- 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

- 64 -

Relevant Drugs - 3 types


CODEINE General information

- see 49

DEXTROMETHORPHAN General information

- analgesic opioid analogue

- same as codeine

PHOLCODINE General information

- non-analgesic opioid analogue

- 65 -

37. PHARMACOLOGY OF THE GASTROINTESTINAL TRACT:

DRUGS IN THE TREATMENT OF PEPTIC ULCER;

EMETICS, ANTI-EMETICS

DRUGS IN THE TREATMENT OF PEPTIC ULCER

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

potentially damaging substances

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

protective- and the aggressive factors

- these factors include

TYPE FACTOR

PROTECTIVE FACTORS - mucin

- bicarbonate (HCO3-)

- blood flow

AGGRESSIVE FACTORS - hydrochloric acid (HCl)

- pepsin (gastric protease)

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

REGULATION SUBSTANCE

STIMULATION - acetylcholine

- gastrin

- histamine

INHIBITION - PGE2

- PGI2



- H2 receptor antagonists decrease histamine-mediated gastric acid secretion

- H2 receptors antagonists also inhibit the secondary messenger systems of

gastrin- and acetylcholine-mediated gastric acid secretion

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

secretion by over 90%

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

- see 33

- 66 -


- muscarinic receptor antagonists decrease acetylcholine-mediated gastric acid

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

- see 15

3) HYDROGEN ION/POTASSIUM ANTIPORTER INHIBITORS

- hydrogen ion/potassium antiporter inhibitors irreversibly inhibit the hydrogen

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

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

secretion

- 3 types


OMEPRAZOLE General information


- is degraded rapidly by the gastric

acid, thus must be administered in

enteric-coated granules for absorption

into the systemic circulation in the

small intestine

- weak base, thus, once reaching the

parietal cells through the systemic

circulation, it will be trapped in the

acidic environment of the parietal cell

canaliculi

Medical uses

- treatment of peptic ulcer


- treatment of hypergastrinemia

Side effects

- severe diarrhea

- severe headache

- mild gynecomastia

- mild impotence

- mild joint/muscle pain

LANSOPRAZOLE General information

- same as omeprazole

PANTOPRAZOLE General information

- same as omeprazole

- 67 -

4) ANTACIDS

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

inactivates pepsin - 4 types


MAGNESIUM HYDROXIDE General information


Medical uses

- treatment of duodenal ulcers (not

gastric-)

- treatment of dyspepsia


Side effects

- diarrhea

MAGNESIUM TRISILICATE General information

- also adsobs pepsin

- same as magnesium hydroxide

ALUMINIUM HYDROXIDE General information


- also adsorbs pepsin

Medical uses


Side effects

- constipation

SODIUM BICARBONATE General information

- very strong neutralizer (increase

gastric ph to 7,4 (!))

- deliberates carbondioxide


Medical uses


- 68 -

Side effects

- belching (deliberates carbondioxide)

- secondary hypergastrinemia

(stimulated by carbondioxide)

- metabolic alkalosis

5) MUCOPROTECTIVE DRUGS - 3 types


SUCRALFATE General information

- binds to positively charged proteins

(including glycoproteins of the gastric

mucous)

- forms a complex gel with the gastric

mucous


Medical uses

- treatment of gastric ulcer

Side effects

- constipation

- dry mouth

- nausea

MISOPROSTOL General information

- synthetic PGE1 analogue

- inhibits both basal- and pranial

gastric acid secretion

- increases secretion of bicarbonate

and mucous

- increases mucosal blood flow

- also causes simultaneous contraction

of the uterus and relaxation of the

cervix

- administered orally or intravaginally

(if used for 1st trimester abortion)

Medical uses

- treatment of peptic ulcer

- 1st trimester abortion (then

administered coherently with

mifepristone, see 57)

- 69 -

Side effects

- diarrhea

- abdominal cramps

CARBENOXOLONE General information

- found in liquorice root

- increases production of mucous

Medical uses

- treatment of gastric ulcer

EMETICS

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

Relevant Drugs - 1 type


IPECACUANHA General information


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

peripherally to induce vomiting

ANTI-EMETICS

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



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

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

sickness)

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

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

ingestion of toxic substances

- see 33

- 70 -


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

- see 15

3) 5-HT 3 RECEPTOR ANTAGONISTS

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

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

(including chemotherapy-induced emesis)

- see 34

4) D2 RECEPTOR ANTAGONISTS

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

41)

- D2 receptor antagonists also inhibit D2 receptors on the chemoreceptive

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

- 3 groups

A) PHENOTHIAZINES

- see 41

B) BUTYROPHENONES

- see 41

C) OTHERS

- 2 types


DOMPERIDONE General information

- also increases tone of GI

smooth muscle

Medical uses

- treatment of chemotherapy-

induced emesis


(increased tone of lower

esophageal sphincter)

- treatment of disorders of

gastric emptying (increased

tone of the stomach smooth

muscle)

Side effects

- see 41

- 71 -

METOCLOPRAMIDE General information

- also increases tone if the GI

smooth muscle

- also stimulates prolactin

release

- may not cross the blood-brain

barrier, central side effects are

absent

Medical uses

- same as domperidone

Side effects

- hyperprolactinemia (increased

prolactin secretion)

5) CANABINOID RECEPTOR AGONISTS

- inhibit emesis due to substances directly stimulating the chemoreceptive

trigger zone (including chemotherapy-induced emesis)

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

peristalsis

- 2 types


NABILONE General information

- synthetic THC derivative (see

48)


Medical uses

- conjunctive to 5-HT 3- and/or

D2 receptor antagonists in

treatment of chemotherapy-

induced emesis

- treatment of diarrhea

(decreased peristalsis)

Side effects

- see 48

DRONABINOL General information

- same as nabilone

- 72 -

38. PHARMACOLOGY OF THE GASTROINTESTINAL TRACT:

PROKINETIC DRUGS, LAXATIVES, ANTIDIARRHOEAL

AGENTS, DRUG TREATMENT OF INFLAMMATORY

BOWEL DISEASE AND PARALYTIC ILEUS, DIGESTIVES,

DRUGS USED IN CHOLELITHIASIS

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

receptors, see 14)

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

REGULATION RECEPTOR

STIMULATION - 5-HT 4 serotonergic receptors

INHIBITION - alpha-2 adrenergic receptors

- D2 dopaminergic receptors

- cannabinoid receptors

PROKINETIC DRUGS


1) LAXATIVES

- increase peristalsis without interfering with the normal neurohormonal

regulation

- 2 groups

A) BULK LAXATIVES (FIBER)

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

the GI tract

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

amount of feces left in the intestines

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

activation of the cholinergic axons of the myenteric plexus, and

following increased peristalsis

- 3 types


METHYLCELLULOSE

- 73 -

BRAN

AGAR

B) OSMOTIC LAXATIVES

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

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

increasing the amount of water and following increased amount of

feces left in the intestines

- 3 types


LACTULOSE General information

- disaccaride of fructose and

galactose

- hydrolyzed and fermented by

bacteria to lactic- and acetic acid

which is not absorbed by the

enter

Documents

BRY's Pharmacology 2nd Semester