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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
Relevant Drugs
- 3 categories
1) PHENYLALKYLAMINES (VERAPAMIL)
- primarily acts on the heart
- also has a weak action on blood vessels
- 1 type
-1-
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
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
-2-
Clinical usages
- treatment of hypertension (strong arterial
vasodilation)
Side effects
- reflex tachycardia
- headache (cerebral artery vasodilation)
- flushing (cutaneous artery vasodilation)
- ancle edema (arterial vasodilation)
Clinical usages
- treatment of hypertension (strong arterial
vasodilation)
- treatment of cerebral vasospasms following
subarachnoid hemorrhage (then administered
IV)
Side effects
- same as nifedipine
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
-3-
NITRENDIPINE General information
- same as nifedipine
Clinical usages
- same as nicardipine
Side effects
- same as nifedipine, but less pronounced
reflex tachycardia
C) LONG/SLOWLY-ACTING DHPS
- 40-60 hours
- 1 type
Clinical usages
- same as nicardipine
Side effects
- same as nitrendipine, but even less
pronounced reflex tachycardia
-4-
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
Relevant Drugs
- 5 categories
-5-
2) RENIN INHIBITORS
- renin inhibitors inhibit the enzymatic activity of renin, thus decrease the
conversion of angiotensinogen to angiotensin I
- 1 type
3) ACE INHIBITORS
- ACE inhibitors inhibit the enzymatic activity of ACE, thus decrease the
conversion of angiotensin I to angiotensin II
- 3 types
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)
-6-
- same as enalapril
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)
-7-
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
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)
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
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
CARBONDIOXIDE + WATER
CA (carbonic anhydrase)
CARBONIC ACID
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
- 10 -
hydrogen secretion and increased loss of
bicarbonate due to no hydrogen ion in
the tubular fluid to react with to form
carbondioxide and water)
Medical uses
- coadministered with non-potassium
sparing diuretics to preserve potassium
- treatment of hyperaldosteronism
(“conn’s syndrome”)
Side effects
- hyperkalemia (decreased potassium
secretion)
- metabolic acidosis (decreased
hydrogen secretion and hyperkalemia)
- testicular atrophy
- impotence
- gynecomastia
- amenorrhea
Medical uses
- 11 -
- coadministered with non-potassium
sparing diuretics to preserve potassium
Side effects
- hyperkalemia
- metabolic acidosis (due to
hyperkalemia)
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
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
- 12 -
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)
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
CONSEQUENCE DESCRIPTION
- 13 -
POSITIVE BATHMO- - due to decreased negative
TROPIC EFFECT membrane potential and following
easier excitability of the myocytes
CONSEQUENCE DESCRIPTION
NEGATIVE CHRONO- - due to depression of the SA-node
TROPIC EFFECT and following decreased heart rate
- 2 types
- 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)
2) DIRECT VASODILATORS
- decrease total peripheral resistance
- see 28
- 15 -
4) DIURETICS
- decrease blood volume
- see 25
- 16 -
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
- if angina pectoris remains untreated it can progress to irreversible myocardial ischemia (acute
myocardial infarction, AMI)
Relevant Drugs
- 3 categories
1) ORGANIC NITRATES
- reacts with tissue sulfhydryl (-SH) groups to form nitric oxide (NO), thus
inducing systemic vasodilation
- affects the heart in 2 ways
CAUSE CONSEQUENCE
INCREASED MYOCARDIAL Increased myocardial oxygen supply
BLOOD 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)
- 17 -
WORKLOAD consumption
- decreased preload (venous
vasodilation)
- decreased afterload (arterial
vasodilation)
- 3 types
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)
Medical uses
- prophylaxis of stable angina
- treatment of chronic heart failure
Side effects
- same as glycerol trinitrate
- 18 -
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
- 19 -
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
Relevant Drugs
- 8 categories
1) DIRECT VASODILATORS
- dilate the blood vessels, thus decreasing total peripheral resistance
- 4 types
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)
- 20 -
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)
3) ORGANIC NITRATES
- cause both arterial and venous vasoldilation, thus decrease total peripheral
resistance
- see 27
- 21 -
6) BETA-1 ADRENERGIC RECEPTOR ANTAGONISTS
- decrease sympathetic action on the heart, thus decreasing cardiac output
- see 21
8) DIURETICS
- decrease blood volume, thus decreasing total peripheral resistance
- see 25
- 22 -
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 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)
- 23 -
- there are 4 types of cardiac arrhythmias
TYPE DESCRIPTION
ACTIVE ECTOPIC BEATS General information
(SUPRAVENTRICULAR-, - “extrasystole”, “premature beat”
VENTRICULAR-) - 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.)
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.)
- 24 -
Relevant Drugs
- antiarrhythmic drugs may be divided in 4 classes (vaughan williams’ system)
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)
Medical uses
- treatment of ventricular arrhythmias
Side effects
- ventricular paroxysmal tachycardia
- SLE-like disorder (autoantibodies against
own DNA)
- 25 -
B) CLASS Ib ANTIARRHYTHMIC DRUGS
- cause weak voltage-gated sodium channel block
- selectively block refractory voltage-gated sodium channels
- 2 types
Medical uses
- treatment of arrhythmias associated with
irreversible myocardial ischemia (AMI, due
to selective refractory blockage)
- local anaesthesia
Side effects
- see 22
Medical uses
- treatment of arrhythmias associated with
irreversible myocardial ischemia (AMI, due
to selective refractory blockage)
- treatment of epilepsy
Side effects
- see 43
- 26 -
Side effects
- heart failure (in patients with symptoms,
due to strong general suppression)
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
- 28 -
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
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
- 29 -
derived from cell breakdown and transfers it to vLDL
and LDL
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
Medical uses
- reduction of LDL and
VLDL
Side effects
- mild GI disturbances
- mild sleep disturbances
- mild skin rashes
- 30 -
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
- 3 types
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
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
Medical uses
- reduction of LDL
Side effects
- nausea
- vomiting
- bloating
- constipation or diarrhea
- fat-soluble vitamin
deficiency
- 32 -
31. ANTICOAGULANTS. FIBRINOLYTICS.
ANTIFIBRINOLYTICS. ANTIPLATELET DRUGS
Overview
- hemostasis consists of 4 (5) mechanisms
MECHANISM DESCRIPTION
VASOCONSTRICTION - both neurally- and humorally mediated
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
- 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 heparin-
platelet factor 4 complexes (and following
thrombocytopenia) and platelet factor 4-vascular
endothelium complexes)
- osteoporosis
2) ORAL ANTICOAGULANTS
- oral anticoagulants bind to the active site of vitamin K reductase, thus
inhibiting reduction of vitamin K to it’s active form
- reduced vitamin K is a cofactor of alpha-carboxylase, consumed with
modification of coagulation factor X, IX, VII and II (thrombin) after primary
protein translation
- only the modified coagulation factors are able to be activated, thus inhibition
of vitamin K reductase leads to decreased activation of fibrin and following
inhibition of coagulation
- 1 type
- 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
Medical uses
- treatment of thrombosis, DIC and emboli
Side effects
- hemorrhage (fibrinolysis)
- stroke (hemorrhage)
- anaphylaxis (antistreptococcal antibodies)
- 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)
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
Medical uses
- treatment of severe hemorrhages
- treatment of fibrinolytic overdose
Side effects
- thrombosis
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
Medical uses
- treatment of thrombosis, DIC and emboli
Side effects
- hemorrhages
- blood dyscrasias
- diarrhea
- skin rashes
- 37 -
CLOPIDOGREL General information
- same as triclopidine
Medical uses
- treatment of thrombosis, DIC and emboli
Side effects
- hemorrhages
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
- 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
GRANULOCYTES - neutrophils
- eosinophils
- basophils
LYMPHOCYTES - B lymphocytes
- T lymphocytes
TYPE DESCRIPTION
APLASTIC ANEMIA - due bone marrow failure
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
Medical uses
- treatment of microcytic, hypochromic
deficiency anemia
Side effects
- nausea
- diarrhea
- abdominal cramps
- 40 -
FOLATE Gereral information
- administered orally (parenterally in case
of malabsorption syndromes)
Medical uses
- treatment of macrocytic, hyperchromic
deficiency anemia
Medical uses
- treatment of macrocytic, hyperchromic
deficiency anemia
Medical uses
- treatment of leucopenia (mainly
neutropenia)
Side effects
- 41 -
- fever
- skin rashes
- muscle pain
- muscle weakness
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 DESCRIPTION
CNS - histaminergic neurons
General Effects
- 6 types
ORGAN DESCRIPTION
CNS - inhibition of neurotransmitter release
- nausea
- 43 -
RESPIRATORY TRACT - bronchoconstriction
Relevant Drugs
- 2 categories
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)
- 44 -
action
- weak local anaesthetic action
- administered orally
- may cross the blood brain barrier
- same as prometazine
Medical uses
- treatment of emesis (especially motion
sickness)
Side effects
- diarrhea/constipation
- sedation
Medical uses
- treatment of anaphylactic reactions (allergic
rhinitis, urticaria (allergic skin rashes), insect
bites, drug hypersensitivities etc.)
Side effects
- diarrhea/constipation
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
Medical uses
- treatment of peptic ulcer (gastric- and/or
duodenal)
- treatment of reflux esophagitis
Side effects
- hypergastrinemia
- diarrhea
- gynecomastia (androgen receptor
antagonism)
Medical uses
- same as cimetidine
Side effects
- same as cimetidine (but no gynecomastia)
- 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
LOCATION DESCRIPTION
CNS - serotonergic neurons
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
Relevant Drugs
- 3 categories
1) 5-HT 1 AGONISTS
- 3 types
Side effects
- restlessness (alertness)
- headache
- nausea (effect on 5-HT 3 receptors)
- 49 -
Medical uses
- treatment of migraine (vasoconstriction of
meningeal blood vessels)
Side effects
- cardiac ischemia (coronary artery
vasoconstriction)
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
3) 5-HT 4 AGONISTS
- 1 type
- 50 -
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
1) 5-HT 2 ANTAGONISTS
- 2 types
Medical uses
- prophylaxis of migraine (cerebral blood
vessel vasodilation)
Side effects
- nausea
- vomiting
- retroperitoneal/mediastinal fibrosis
Medical uses
- 51 -
- prophylaxis of migraine (cerebral blood
vessel vasodilation)
Side effects
- sedation
- weight gain
2) 5-HT 3 ANTAGONISTS
- 2 types
Medical uses
- treatment of emesis (vomiting)
- treatment of anxiety
- 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 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
- 53 -
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
Effect
- bronchoconstriction
- GI tract smooth muscle contraction
- fever (increase the hypothalamic temperature set point)
- hyperalgesia (sensitization of afferent C nerve fibers, see
49)
Effect
- vasodilation
- bronchodilation
- GI tract smooth muscle relaxation
- intestinal fluid secretion
- 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) Location
RECEPTORS - uterus
Effect
- uterine smooth muscle contraction
Effect
- vasodilation
- inhibition of platelet aggregation
- renin release
- hyperalgesia (sensitization of afferent C nerve fibers)
Effect
- vasoconstriction
- platelet aggregation
Effect
- neutrophil/macrophage chemotaxis
- neutrophil degranulation
- macrophage/lymphocyte cytokine release
- macrophage/lymphocyte proliferation
- 55 -
CYSLT (LTC4, LTD4, Location
LTE4) RECEPTORS - blood vessels
- lungs
Effect
- vasodilation
- increase vascular permeability
- bronchoconstriction
- bronchial mucous secretion
Overview
- …
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
- 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 HORMONE
FACILITATION - PGE2 (EP3 receptors)
- PGF2-alpha
- histamine (H1 receptors)
- serotonin (5-HT 2A receptors)
INHIBITION - PGD2
- adrenalin (beta-2 receptors)
Relevant Drugs
- 2 categories
1) OXYTOCIC DRUGS
- facilitate uteral contraction
- 3 groups
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
Medical uses
- treatment of postpartum hemorrhage
Side effects
- hypertension (vasoconstriction)
- angina (vasoconstriction)
- nausea (stimulation of the chemoreceptive
trigger zone)
- vomiting (nausea)
- headache
- blurred vision
C) PROSTAGLANDIN ANALOGUES
- 3 types
- 58 -
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
2) TOCOLYTIC DRUGS
- inhibit uteral contraction
- 2 groups
Medical uses
- prevention of premature labor
Side effects
- hypertension (vasoconstriction)
- nausea
- vomiting
- hyperglycemia
- 59 -
- skin rashes
- 60 -
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
CYTOKINE DESCRIPTION
ACUTE PHASE CYTOKINES - bronchoconstrictory cytokines
- chemotactic cytokines
BRONCHODILATOR DRUGS
Overview
- used to treat the early phase of asthma
Relevant Drugs
- 5 categories
- 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
Medical uses
- treatment of asthma
Side effects
- headache
- constipation/diarrhea
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
Medical uses
- treatment of asthma
Side effects
- irritation of the upper airways
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
- 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 FACTOR
PROTECTIVE FACTORS - mucin
- bicarbonate (HCO3-)
- blood flow
- gastric acid secretion by the parietal cells are regulated by 5 (3+2) substances
REGULATION SUBSTANCE
STIMULATION - acetylcholine
- gastrin
- histamine
INHIBITION - PGE2
- PGI2
Relevant Drugs
- 5 categories
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
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
- 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
Medical uses
- treatment of duodenal ulcers (not
gastric-)
- treatment of dyspepsia
- treatment of reflux esophagitis
Side effects
- diarrhea
Medical uses
- same as magnesium hydroxide
Side effects
- constipation
Medical uses
- same as magnesium hydroxide
- 67 -
Side effects
- belching (deliberates carbondioxide)
- secondary hypergastrinemia
(stimulated by carbondioxide)
- metabolic alkalosis
5) MUCOPROTECTIVE DRUGS
- 3 types
Medical uses
- treatment of gastric ulcer
Side effects
- constipation
- dry mouth
- nausea
Medical uses
- treatment of peptic ulcer
- 1st trimester abortion (then
administered coherently with
mifepristone, see 57)
- 68 -
Side effects
- diarrhea
- abdominal cramps
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
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
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
Medical uses
- treatment of chemotherapy-
induced 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)
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
- 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 RECEPTOR
STIMULATION - 5-HT 4 serotonergic receptors
PROKINETIC DRUGS
Relevant Drugs
- 4 categories
1) LAXATIVES
- increase peristalsis without interfering with the normal neurohormonal
regulation
- 2 groups
- 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
Medical uses
- treatment of constipation
Side effects
- diarrhea
- flatulence
- abdominal cramps
Medical uses
- treatment of constipation
Side effects
- diarrhea
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
Medical uses
- treatment of constipation
Side effects
- diarrhea
3) PERISTALTICS
- fascilitate the parasymphatetic innervation of the intestines, thus increasing
acetylcholine release and following increased peristalsis
- 2 types
B) D2 RECEPTOR ANTAGONISTS
- see 37
4) FECAL SOFTENERS
- decrease the surface tension of the feces, thus easing it’s transition through
the intestines
- 1 type
- 74 -
- 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
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
- 75 -
CHALK
PECTIN
Relevant Drugs
- 3 categories
1) 5-AMINOSALICYLIC ACID
- scavenges free radicals produced by neutrophils, thus decreasing the
inflammatory response
- 3 types
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
- 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
CICLOSPORIN
Relevant Drugs
- 3 categories
2) CHOLINESTERASE INHIBITORS
- inhibit cholinesterase, thus increasing acetylcholine half-life, increase activity
of GI smooth muscle, and following increase peristalsis
- see 14
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
2) BILE SUPPLEMENTS
- 1 type
TRYPSIN
AMYLASE
Relevant Drugs
- 3 categories
1) BILE ACIDS
- form micelles around free cholesterol in the bile, thus preventing further
aggregation
- 2 types
- 78 -
(URSODEOXYCHOLIC ACID) - same as CDCA
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 LOCATION
CENTRAL COMPONENT - locus ceruleus of the CNS
DISORDER DESCRIPTION
GENERALIZED ANXIETY DISORDER - chronic fear response without any
definite stimulus
Relevant Drugs
- anxiety and sleep disorders are pharmacologically interconnected, thus normally (but not
necessary) drugs treating one may also be used in treating the other
- 4 categories
1) BENZODIAZEPINES
- bind to the allosteric seat of presynaptic GABA A receptors, thus facilitate
increased responsiveness to GABA
- GABA is an inhibitory neurotransmitter of the CNS, thus increased
responsiveness to GABA leads to increased inhibition of neuronal
transmission
- effects of benzodiazepines include
EFFECT DESCRIPTION
ANXIOLYTIC/ - inhibit adrenergic neurons of
ANTIAGGRESSIVE locus ceruleus
- 80 -
SEDATIVE - decrease time to fall asleep
- increase duration of sleep
- decrease REM sleep
- decrease slow wave sleep
MECHANISM CAUSE
TOLERANCE - downregulation of GABA A
receptors
A) SHORT-ACTING
- 12-18 hours
- 2 types
Medical uses
- treatment of insomnia (sleeping pills)
- 81 -
- treatment of anxiety
Side effects
- drowsiness
- sedation
- confusion
- amnesia
- impaired coordination
B) INTERMEDIATELY-ACTING
- 18-24 hours
- 2 types
Medical uses
- treatment of anxiety
- treatment of depression (antidepressive
action)
Side effects
- same as lorazepam
B) LONG-ACTING
- 24-48 hours
- 2 types
- 82 -
- has an active metabolite (nordazepam)
- nordazepam has yet another active
metabolite (oxazepam), thus prolonging it’s
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
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 TYPE
POSITIVE REINFORCEMENT - see 47
CONDITIONING - see 47
- 83 -
- 3 groups
A) SHORT-ACTING
- less than 1 hour
- 2 types
Medical uses
- induction of general anaesthesia
Side effects
- euphoria
- drowsiness (sedation)
- respiratory depression
- cardiovascular depression
- death (if overdosed)
B) INTERMEDIATELY-ACTING
- 1-6 hours
- 2 types
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
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
- 85 -
40. ALCOHOLS: PHARMACOLOGY AND TOXICOLOGY
ETHANOL
Overview
- ethanol is a low potency abuse-drug
- it has 3 effects on CNS neuronal transmission
EFFECT DESCRIPTION
FACILITATION OF GABA-A RECEPTORS - facilitation of GABA-mediated
neuronal inhibition
- the effects of ethanol consumption are classified according to the circulating amount of
ethanol
QUANTITY EFFECT
50 MG/100 ML - decreased intellectual function
- decreased motor coordination
- increased self-confidence
- euphoria
- , 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 CAUSE
POSITIVE REINFORCEMENT - inhibition of voltage-gated calcium
channels, thus inhibiting release of
inhibitory neurotrasmitters that
regulate the mesolimbic-mesocortical
dopaminergic pathway
CONDITIONING - see 47
- epilepsy-like seizures
- hallucinations
- confusion
- agitation
- aggression
- it is used orally and is absorbed by the mucosa of the stomach and the small intestine
- 90% is metabolized in the liver, while the remaining 10% is excreted unchanged by the
kidneys and lungs
- metabolism of ethanol is done in 2 steps
ETHANOL
alcohol dehydrogenase
ACETALDEHYDE
aldehyde dehydrogenase
ACETIC ACID
- both of the enzymes envolved in is dependent on NAD+ as a cofactor for its enzymatic
action, thus the availability of NAD+ is the rate-limiting factor of ethanol metabolism
- 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 EFFECT
CNS - ventricular enlargement
- cerebellar neuronal degeneration
- dementia
- 88 -
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
- 89 -
41. ANTIPSYCHOTIC DRUGS
Overview
- there are 3 main D2 dopaminergic pathways of the CNS
PATHWAY DESCRIPTION
MESOLIMBIC-MESOCORTICAL - between the midbrain, hippocampus and
PATHWAY cerebral cortex
- “reward center”
GROUP DESCRIPTION
POSITIVE SYMPTOMS General information
- mental processes absent in well
individuals, but present in schizophrenia
Symptoms
- delusion
- hallucination
- disturbance of thinking
- aggression
Symptoms
- isolation
- apathy/anhedonia
- memory impairment
- 90 -
- intellectual impairment
- speech impairment
Relevant Drugs
- antipsychotic drugs are D2 receptor antagonists
- they work by decreasing the activity of the mesolimbic-mesocortical pathway, thus
decreasing the positive symptoms of schizophrenia
- however, the negative symptoms remain unaffected
- their antipsychotic effect takes weeks to develop
- they are effective in 70% of the cases, while ineffective in the last 30% (treatment-resistant
schizophrenia, the cause is unknown)
- the effective dose is also highly variable, thus administration must be adjusted on a trial-and-
error basis
- antipsychotic drugs are administered orally or intramuscularly (, then esterified with
heptanoic or decanoic acid to increase lipophilicity)
- they also cause upregulation of D2 receptor expression, thus decreasing their effectiveness
over time
- they are also partial muscarinic-, alpha-adrenergic-, H1-, and 5-HT 2 antagonists to varying
degree
- general side effects of antipsychotic drugs include
- 91 -
TUBEROINFUNDIBULAR SIDE EFFECTS - hyperprolactinemia
- lactation (even in males (!))
- gynecomastia
- amenorrhea
- impotence (males)
- infertility (females)
- 2 categories
A) PHENOTHIAZINES
- 2 types
Side effects
- see above
B) BUTYROPHENONES
- 2 types
- 92 -
DRUG NAME DESCRIPTION
HALOPERIDOL General information
- same as chloropromazine
RISPERIDONE
- 93 -
42. ANTIDEPRESSANTS
Overview
- there are 3 types of monoamine neurotransmitters
TYPE DESCRIPTION
SEROTONIN - see 34
NORADRENALINE - see 18
DOPAMINE - see 41
- not relevant in depression
TYPE DESCRIPTION
UNIPOLAR DEPRESSION
GROUP DESCRIPTION
EMOTIONAL SYMPTOMS - misery
- apathy
- pessimism
- low self esteem
- loss of motivation
- indecisiveness
- 94 -
Relevant Drugs
- 3 categories
Overdose
- excitement
- delirium
- convulsions
- respiratory depression
- coma
Overdose
- ventricular fibrillation (prolongation
of QT interval
- death (ventricular fibrillation)
- 95 -
- 2 groups
A) NON-SELECTIVE TCAS
- 2 types
AMITRIPTYLINE
B) NORADRENALINE-SELECTIVE TCAS
- 2 types
CLOMIPRAMINE
Medical uses
- treatment of depression
- treatment of anxiety
- treatment of obsessive-compulsive
disorders
Side effects
- nausea
- anorexia
- insomnia
- decreased libido
- failure of orgasm
- 96 -
- same as fluoxetine
A) IRREVERSIBLE MAOIS
- 3 types
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))
- 97 -
TRANYLCYPROMINE General information
- same as phenelzine
B) REVERSIBLE MAOIS
- 1 type
- 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 DESCRIPTION
STAGE I “Analgesia”
- conscious
- drowsy
- amnesic
- voluntary movement is still present
- coherent speech is still present
- reduced reaction to stimuli
STAGE II “Excitement”
- loss of consciousness
- delirious
- involuntary movement
- incoherent speech
- loss of reaction to non-painful stimuli
- reflex reactions to painful stimuli
- exaggerated reflexes
- irregular respiration
- irregular heart rate
STAGE IV “Overdose”
- medullary paralysis
- cessation of respiration
- cardiovascular collapse
- cessation of muscle tone
- death
- 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 DESCRIPTION
OIL/GAS PARTITION General information
COEFFICIENT - the oil/gas partition coefficient describes
the solubility of the gas in oil (ie. the
lipophilicity of the inhalation anaesthetic)
- partially or completely determines 2 of
the characteristics of the inhalation
anaesthetics
Potency
- the higher the oil/gas partition
coefficient is, the more efficacious it can
bind to the hydrophobic domains of the
ligand-gated ion channels to produce
general anaesthesia
- , thus the higher the oil/gas partition
coefficient is, the smaller alveolar partial
pressure of the inhalation anaesthetics is
needed to produce general anaesthesia
Recovery
- however, higher oil/gas partial pressure
also results in higher amounts of gas to be
redistributed to adipose tissue by
secondary distribution
- , thus the higher the oil/gas partition
coefficient is, the longer time is needed
for it’s elimination
- 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 it’s elimination
Side effects
- irritation of the respiratory tract
- postoperative nausea and vomiting (long
recovery)
- 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)
Side effects
- hypotension
- ventricular extrasystoles
- malignant hyperthermia
- seizures
- 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)
Side effects
- postoperative nausea and vomiting (long
recovery)
- adrenal cortical suppression
- 103 -
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
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 DESCRIPTION
PARTIAL SEIZURES General information
- localized seizure not exceeding the cerebral
hemisphere from which it originates
- 2 types
Simple Seizure
- the seizure stays in it’s location of origin
- no loss of consciousness
- symptoms depend on where the seizure is located
(motor seizure, sensory seizure, autonomic seizure,
psychomotor seizure etc.)
Complex seizure
- the seizure spreads from it’s location of origin to other
areas of the CNS, including the reticular formation
- loss of consciousness (hyperactivity of the reticular
formation)
- symptoms depend on where the seizure originates
from and where it spreads
- 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
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
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
Medical uses
- treatment of petit mal seizure
Side effects
- 107 -
- vertigo
- nausea
- apathy
- anorexia
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
- 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 DESCRIPTION
ENHANCEMENT OF CEREBRAL - increasing cerebral blood flow (vasodilation)
MICROCIRCULATION - increasing RBC plasticity
- inhibiting platelet aggregation
- reducing blood viscosity
Relevant Drugs
- 3 types
- 109 -
Medical uses
- treatment of stroke
- treatment of dementia (including alzheimer’s disease, see 46)
Side effects
- hyperactivity
- insomnia
Medical uses
- treatment of stroke
- treatment of perfusion disorders of the eye and the inner ear
(including tinnitus)
Side effects
- hypotension
- tachycardia
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
Overview
- there are 3 main types of neurodegenerative disorders
TYPE
ALZHEIMER’S DISEASE
PARKINSON’S DISEASE
HUNTINGTON’S DISEASE
ALZHEIMER’S DISEASE
Overview
- alzheimer’s disease is a progressive dementia of idiopathic origin
- it occurs primarily due to loss of neurons in 2 locations of the CNS
Relevant Drugs
- 2 categories
1) CHOLINESTERASE INHIBITORS
- cholinesterase inhibitors inhibit cholinesterase in the cholinergic synapses,
thus inhibiting acetylcholine breakdown and following increased acetylcholine
concentration in those synapses (see 14)
- however, different cholinesterase inhibitors are used centrally to treat
alzheimer’s disease than those used peripherally to treat peripheral disorders
- 4 types
- 111 -
TACRINE Side effects
- cholinergic side effects (see 14)
- hepatotoxicity
Side effects
- cholinergic side-effects
2) NOOTROPIC DRUGS
- enhances the intellectual capacity, thus counteracting the dementia
- see 45
PARKINSON’S DISEASE
Overview
- parkinson’s disease is a progressive motility disorder
- it occurs primarily due to loss of dopaminergic neurons running from substantia nigra to
corpus striatum (“nigrostriatal tract”, see 41)
- these dopaminergic neurons are inhibitory neurons that act on D2 receptors of cholinergic
neurons in the corpus striatum, thus loss of inhibition causes hyperactivity of these
cholinergic neurons
- parkinson’s disease is characterized by 3 (4) symptoms
SYMPTOM DESCRIPTION
HYPOKINESIA - voluntary movement is hard to initiate and -to stop
- due to loss of dopaminergic neurons
TREMOR - at rest
- due to hyperactivity of cholinergic neurons
- 112 -
(DEMENTIA) - decreased mental capacity
- due to loss of other types of neurons elsewhere in the CNS
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
Side effects
- dyskinesia (involuntary movements of face and
limbs)
- on-off effect (rapid fluctuations of symptoms)
- schizophrenia-like syndrome (see 41)
- nausea
- 113 -
- anorexia
2) D2 RECEPTOR AGONISTS
- 3 types
LISURIDE
PERGOLIDE
HUNTINGTON’S DISEASE
Overview
- huntington’s disease is, like parkinson’s disease, a progressive motility disorder
- 114 -
- however, huntington’s disease is due to loss of GABA neurons running in opposite direction
to that of the dopaminergic neurons affected in parkinson’s disease (from corpus striatum to
substantia nigra)
- these GABA neurons are inhibitory neurons of the dopaminergic neurons in the substantia
nigra, thus loss of inhibition causes hyperactivity of these dopaminergic neurons
- , thus huntington’s disease exhibit opposite symptoms to that of parkinson’s disease
Relevant Drugs
- 2 categories
1) GABA AGONISTS
- 1 type
2) D2 RECEPTOR ANTAGONISTS
- “antipsychotic drugs”
- block D2 receptors, thus inhibiting the effect of the hyperactive dopaminergic
neurons
- see 41
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 TYPE
PSYCHOLOGICAL DEPENDENCE Positive reinforcement
- occurs when the abuse-drug is used
- stimulation of the mesolimbic-
mesocortical dopaminergic pathway of the
CNS (reward center, see 41) and following
feeling of reward
Conditioning
- occurs when the abuse-drug is withdrawed
- the association of items, locations or
people with the abuse-drug induced feeling
of reward
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
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 EFFECT
DOPAMINE Abuse dose
- euphoria
- pleasure
- excitement
- increased confidence
- increased sex drive
- increased mental performance
- increased physical performance
- insomnia
Overdose
- hallucinations
- paranoia
- aggression
SEROTONIN - anorexia
- 118 -
- like any other abuse-drug they have 4 mechanisms by which they cause
dependence (see 47)
MECHANISM CAUSE
POSITIVE REINFORCEMENT - release of dopamine, and following
stimulation of the mesolimbic-
mesocortical dopaminergic pathway
CONDITIONING - see 47
ORGAN EFFECT
HEART - tachycardia
- cardiac arrhythmias
- 119 -
- they are used orally or nasally and absorbed from the nasal- and/or small
intestinal mucosa
- 6 types
Medical uses
- treatment of narcolepsy
- treatment of obesity
2) COCAINE ANALOGUES
- cocaine is an abuse-drug found in coca leaves
- it inhibits presynaptic reuptake of monoamines uptake 1, thus increasing
monoamine concentration (dopamine and noradrenaline) in the synaptic cleft
- it also blocks sodium channels, thus is clinically used as a local surface
anaesthetic (see 22)
- the effects of cocaine are classified according to the monoamines increased in
the synaptic cleft
MONOAMINE EFFECT
DOPAMINE - euphoria
- pleasure
- 120 -
- garrulity
- tachycardia
- vasoconstriction
- hypertension
Overdose
- tremor
- convulsions
- respiratory depression
- vasomotor depression
MECHANISM CAUSE
POSITIVE REINFORCEMENT - inhibition of presynaptic dopamine
reuptake, and following stimulation
of the mesolimbic-mesocortical
dopaminergic pathway
CONDITIONING - see 47
ORGAN EFFECT
HEART - tachycardia
- cardiac arrhythmias
- 121 -
- myocardial damage
- 2 types
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
TYPE DESCRIPTION
NICOTINE
- 122 -
POLYCYCLIC
AROMATIC
HYDROCARBONS
(TAR)
TYPE DESCRIPTION
CARBON MONOXIDE
NITROGEN DIOXIDE
HYDROGEN CYANIDE
AMMONIA
FORMALDEHYDE
NITROSAMIDES
TYPE EFFECT
CNS TYPE - satiety
- analgesia
- sedation
- alertness
- increased mental performance
- increased physical performance
- decreased skeletal muscle tone
- 123 -
acids
- decreased glomerular filtration
- decreased peristalsis
- sweating
MECHANISM CAUSE
POSITIVE REINFORCEMENT - stimulation of the mesolimbic-
mesocortical dopaminergic pathway
CONDITIONING - see 47
TYPE CONSEQUENCE
CARDIOVASCULAR - hypertension
DISORDERS - 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
TYPE CONSEQUENCE
PULMONARY - chronic obstructive pulmonary
DISORDERS disorders (COPD)
4) CANNABIS
- cannabis is an abuse drug found in cannabis sativa (“hemp”)
- the pharmacologically active components of cannabis are cannabinoids
- there are 3 main types of cannabinoids
TYPE DESCRIPTION
THC - “delta-9 tetrahydrocannabinol”
- the only pharmacologically active
cannabinoid
- 125 -
CB2 RECEPTOR - lymphoid system
ORGAN EFFECT
CNS - 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
HEART - tachycardia
BRONCHI - bronchoconstriction
- 126 -
- it is used by inhalation, orally or IV
- it is lipophilic, thus will accumulate in adipose tissue over time
- 2 types
TYPE DESCRIPTION
MARIJUANA General information
- dried leaves and flowers of
cannabis sativa
5) METHYLXANTHINES
- methylxanthines inhibit adenylyl cyclase, thus leading to decreased formation
of cAMP
- effects of xanthines include
ORGAN EFFECT
CNS - CNS excitation
- insomnia
- increased mental performance
- nervousness
- increased motor activity
- tremor
- increased respiration
BRONCHI - bronchodilation
- 127 -
THEOPHYLLINE General information
- found in tea (and coffee)
- administered orally
Medical uses
- treatment of asthma
Side effects
- any other effect of xanthines (see
above)
Overview
- psychedelics are abuse-drugs that exhibit only psychological effects in the subject of interest
Relevant Drugs
- 3 categories
1) LSD ANALOGUES
- LSD is an extremely potent abuse-drug
- it is a 5-HT 2 receptor agonist in the CNS and –antagonist in the periphery
- the CNS effects of LSD are classified according to dose
DOSE EFFECT
ABUSE DOSE - hallucinations (visual-, auditory-,
olfactory-, tactile-, and cross-
connections (eg. auditory stimuli
are perceived as visual stimuli (!)))
- illogical mental performance
- 128 -
OVERDOSE - “bad trip”
- horrific halucinations
- paranoia
- suicide
- homicide
2) PHENCYCLIDINE
- phencyclidine is an abuse-drug with 2 effects in the CNS
EFFECT CONSEQUENCE
FACILITATION OF SIGMA NON-
OPIOID RECEPTORS
INHIBITION OF NMDA - inhibition of glutamate-mediated
RECEPTORS neuronal excitation
MONOAMINE EFFECT
ABUSE DOSE - analgesia
- same as LSD
- 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 DESCRIPTION
ACUTE PAIN - excited by mechanical- and/or thermal stimuli
- conveys surface pain
- transmitted by A-delta nerve fibers from the
dorsal horns of the spinal cord through the
neospinothalamic tract to the basal ganglia and the
somatosensory cortex
- the main neurotransmitter is glutamate
- the endogenous analgesic system is a CNS reflex arch that inhibit the excitation of A-delta-
and C nerve fibers
- it originates in the periaqueductal grey area in response to chronic pain afferens and transmit
efferent excitatory signals down to nucleus raphe magnus and nucleus reticularis
paragigantocellularis of the brain stem
- these nuclei transmit the efferent signal through the dorsolateral column to the dorsal horn of
the spinal tract where they secrete serotonin (see 34) and enkephalins, respectively
- both serotonin and enkephalins inhibit excitation of A-delta- and C nerve fibers by action on
5-HT 3- and opioid receptors respectively, thus inhibiting spinal pain transmission
- there are 5 types of endogenous opioids classified according to their location of action
LOCATION TYPE
SPINAL CORD - met-enkephalin
- leu-enkephalin
CNS - beta-endorphin
- dynorphin A
- nociceptin
- 130 -
- opioids act on opioid receptors
- there are 3 types of opioid receptors
- euphoria
- pleasure
- sedation
- emesis
- vomiting
- respiratory depression
- vasomotor depression
- increased tone of GI smooth muscle (spincters
especially)
- myosis
- dysphoria
- sedation
- 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 CAUSE
POSITIVE REINFORCEMENT - see 47
CONDITIONING - see 47
- diarrhea
- sweating
- fever
- midriasis (pupillary dilatation)
- piloerection (“cold turkey”)
Relevant Drugs
- 3 categories
1) MORPHINE ANALOGUES
- include morphine and semisynthetic morphine derivatives
- 3 types
Medical uses
- treatment of acute- and chronic
- 132 -
pain
- treatment of diarrhea
Side effects
- see above
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
A) PHENYLPIPERIDINE ANALOGUES
- 2 types
- 133 -
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
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
- 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)
Medical uses
- treatment of mild pain
Side effects
- convulsions (norpropoxyphene)
- same as morphine
C) BENZOMORPHAN DERIVATIVES
- 1 type
- 135 -
Medical uses
- treatment of acute pain
Side effects
- see above
D) THEBAINE DERIVATIVES
- 1 type
Medical uses
- treatment of acute- and chronic
pain
Side effects
- same as morphine
E) OTHERS
- 1 type
Medical uses
- treatment of diarrhea
Side effects
- constipation
- abdominal cramps
- 136 -
3) OPIOID ANTAGONISTS
- 2 types
Medical uses
- treatment of opioid receptor
agonist induced respiratory
depression
- 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 DESCRIPTION
COX-1 Location
- most tissues
Effect
- normal tissue homeostasis
COX-2 Location
- inflammatory cells
Effect
- edema (vasodilation and potentiation of the
effect of the inflammatory mediators that
cause increased capillary permeability)
- pain (potentiation of the effect of the
inflammatory mediators that cause irritation of
afferent C nerve fibers)
- fever (increase in the hypothalamic
temperature set point in response to bacterial
endotoxins)
COX-3 Location
- CNS
Effect
- pain (cerebral vasodilation)
- induction of fever (see above)
- COX inhibitors are primarily administered to obliterate the effects of COX-2 and COX-3
- 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
Relevant Drugs
- 6 categories
- 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 alzheimer’s disease
Side effects
- see above
- hemorrhages (inhibition of platelet
aggregation)
- salicylism (deafness, tinnitus and vertigo, due
to repeated administration of large doses of
aspirin)
- salicylate poisoning (respiratory acidosis (due
to respiratory center depression), metabolic
acidosis (due to uncoupling of oxidative
phosphorylation), hyperpyrexia (due to
uncoupling of oxidative phosphorylation and
following increased metabolic rate) and finally
coma, due to aspirin overdose)
- reye’s syndrome (hepatic insufficiency and
encephalopathy in children, due to aspirin
administration during a viral infection)
- 140 -
Medical uses
- see above
- treatment of gout (inhibition of urate crystal
phagocytosis)
Medical uses
- see above
- treatment of rheumatoid arthritis
(accumulates in synovial fluid)
KETOPROFEN
- 141 -
5) COXIBS
- “COX-2 inhibitors”
- coxibs are selective reversible COX-2 inhibitors
- 3 types
6) ANILINE DERIVATIVES
- “COX-3 inhibitors”
- aniline derivatives are selective reversible COX-3 inhibitors
- 1 type
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 it’s metabolism and
following metabolism by the cytochrome P450
enzyme system leading to the formation of a
toxic metabolite (n-acetyl-p-benzoquinone
imine))
- 143 -
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
Side effects
- blood dyscrasias
- proteinuria
- skin rashes
- stomatitis
- hepatitis
- encephalopathy
- peripheral neuropathy
Side effects
- 144 -
- blood dyscrasias
- proteinuria
- skin rashes
- stomatitis
- anorexia
- nausea
- vomiting
- taste disturbance (celation of zinc)
Medical uses
- treatment of malaria
- treatment of SLE
- treatment of rheumatoid arthritis
Side effects
- visual disturbance (accumulates in
the retina)
Medical uses
- treatment of rheumatoid arthritis
Side effects
- pulmonary fibrosis
3) IMMUNOSUPPRESSANTS
- powerfully suppress the immune defense system, thus decreasing the
inflammatory response
- see 36
- 145 -
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
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
- 146 -
- 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
Medical uses
- prophylaxis of gout
Side effects
- uolithiasis
3) ANTI-INFLAMMATORY DRUGS
- 1 type
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
- 148 -
A1. DRUGS, 2ND SEMESTER
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
2) RENIN INHIBITORS
- Enalkiren
3) ACE INHIBITORS
- Enalapril
- Lisinopril
- Ramipril
1) LOOP DIURETICS
- Furosemide
- Etacrynic Acid
- 149 -
2) THIAZIDE DIURETICS
- Berndroflumethazide
- Hydrochlorthiazide
- Cyclopenthiazide
4) POTASSIUM-SPARING DIURETICS
- Spironolactone
- Triamterene
- Amiloride
5) OSMOTIC DIURETICS
- Mannitol
2) DIRECT VASOLDILATORS
4) DIURETICS
1) ORGANIC NITRATES
- Glycerol Trinitrate (“Nitroglycerin”)
- Amyl Nitrate
- Isosorbide Mononitrate
1) DIRECT VASODILATORS
- Minoxidil
- Hydralazine
- Nitroprusside
- Diazoxide
3) ORGANIC NITRATES
- 150 -
4) ALPHA-2 ADRENERGIC RECEPTOR AGONISTS
8) DIURETICS
1) STATINS
- Mevastatin
- Lovastatin
- Simvastatin
- Pravastatin
2) FIBRATES
- Fenofibrate
- Ciprofibrate
- Benzafibrate
3) RESINS
- 151 -
- Colestyramine
- Colestipil
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
D) PGI2 AGINISTS
- Epoprostenol
1) IRON
- Ferrous Sulfate
- Ferrous Succinate
- Ferrous Gluconate
- Ferrous Fumarate
- Iron-Dextran
- 152 -
- Hydroxycobolamin
2) H2 RECEPTOR ANTAGONISTS
- Cimetidine
- Rantidine
- Famotidine
- Nizatidine
A) 5-HT 1 AGONISTS
- Buspirone
- Sumatriptan
- Ergotamine
B) 5-HT 2 AGONISTS
- LSD
C) 5-HT 4 AGONISTS
- Cisapride
A) 5-HT 2 ANTAGONISTS
- Methylglyceride
- Cyproheptadine
B) 5-HT 3 ANTAGONISTS
- Ondasetron
- Tropisetron
- 153 -
MUSCLE
1) PHARMACOLOGY OF EICOSANOIDS
A) PROSTAGLANDINS
- PGD2
- PGE2
- PGF2-alpha
- PGI2
B) TROMBOXANES
- TXA2
C) LEUKOTRIENES
- LTB4
- LTC4
- LTD4
- LTE4
A) OXYTOCIC DRUGS
B) TOCOLYTIC DRUGS
1) BRONCHODILATOR DRUGS
- 154 -
C) HISTAMINERGIC H1 RECEPTOR ANTAGONISTS
2) ANTI-INFLAMMATORY DRUGS
A) GLUCOCORTICOIDS
B) CROMOGLICATE
- Cromoglicate
- Neddocromil Sodium
3) ANTITUSSIVES
- Codeine
- Dextromethorphan
- Pholcodine
A) H2 RECEPTOR ANTAGONISTS
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
- 155 -
B) MUSCARINIC RECEPTOR ANTAGONISTS
D) D2 RECEPTOR ANTAGONISTS
I) PHENOTHIAZINES
II) BUTYRPHENONES
III) OTHERS
- Domperidone
- Metoclopramide
1) PROKINETIC DRUGS
A) LAXATIVES
I) BULK LAXATIVES
- Methylcellulose
- Bran
- Agar
B) STIMULANT PURGATIVES
- Bisacodyl
- Sodium Picosulfate
- Senna
C) PERISTALTICS
D) FECAL SOFTENERS
- Docusate Sodium
2) ANTIDIARRHOEAL AGENTS
- 156 -
A) ORAL REHYDRATION
B) ANTIMOTILITY AGENTS
I) OPIOIDS
C) ADSORBENTS
- Charcoal
- Chalk
- Pectin
- Magnesium Aluminium Silicate
A) 5-AMINOSALICYLIC ACID
- Sulfosalazine
- Mesalazine
- Olasalazine
B) GLUCOCORTICOIDS
C) IMMUNOSUPPRESSANTS
- Azathioprine
- Ciclosporin
B) CHOLINESTERASE INHIBITORS
5) DIGESTIVES
B) BILE SUPPLEMENTS
- Dihydrocholic Acid
- 157 -
A) BILE ACIDS
- CDCA (“Chenodeoxycholic Acid”)
- UDCA (“Ursodeoxycholic Acid”)
C) OPIOIDS
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
1) ETHANOL
2) METHANOL
- 158 -
A) PHENOTHIAZINES
- Chloropromazine
- Thioridazine
B) BUTYROPHENONES
- Haloperidol
- Droperidol
42. ANTIDEPRESSANTS
A) NON-SELECTIVE TCAS
- Imipramine
- Amitriptyline
B) NORADRENALINE-SELECTIVE TCAS
- Desipramine
- Clomipramine
2) SEROTONIN-SELECTIVE INHIBITORS
- Fluoxetine
- Fluvoxamine
- Paroxetine
- Sertaline
A) IRREVERSIBLE MAOIS
- Phenelzine
- Iproniazid
- Tranylcypromine
B) REVERSIBLE MAOIS
- Moclobemide
1) INHALATION ANAESTHETIC
- Ether
- Halothane
- Enflurane
- Isoflurane
- Sevoflurane
- 159 -
- Nitrous Oxide
2) INTRAVENOUS ANAESTHETICS
- Metohexital
- Thiopental
- Etomidate
- Fentadyl
- Ketamine
A) VALPROATE
B) LONG-ACTING BENZODIAZEPINES
2) NOOTROPIC AGENTS
- Piracetam
- Vinpocetine
- Pentoxyfilline
A) ALZHEIMER’S DISEASE
I) CHOLINESTERASE INHIBITORS
- Tacrine
- Donepezil
- Rivastigmine
- Galanthamine
B) PARKINSON’S DISEASE
- 160 -
I) DOPAMINE REPLENISHERS
- L-DOPA
- Selegiline
- Entacapone
- Amantidine
C) HUNTINGTON’S DISEASE
I) GABA AGONISTS
- Baclofen
1) OPIOIDS
3) INHALANTS
-…
4) ETHANOL
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
A) LSD ANALOGUES
- LSD
- Psilocybin
B) PHENCYCLIDINE
C) CANNABIS
- Marijuana
- Hashish
1) MORPHINE ANALOGUES
- Morphine
- Diamorphine (“Heroin”)
- 3- Methoxymorphine
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
- 162 -
51./52. CYCLOOXYGENASE INHIBITORS: ASPIRIN. PARACETAMOL.
CYCLOOXYGENASE INHIBITORS: PYRAZOLONS, PROPIONIC ACID
DERIVATIVES, INDOLE DERIVATIVES AND OTHERS. “COX-2 INHIBITORS”
C) IMMUNOSUPPRESSANTS
D) GLUCOCORTICOIDS
E) 5-AMINOSALICYLIC ACID
- 163 -
B) URICOSURIC DRUGS
- Probenecid
- Sulfinpyrazole
C) ANTI-INFLAMMATORY DRUGS
- Colchicine
- 164 -