Topic B1- Drugs influencing blood coagulation I: Antiplatelet agents. Fibrinolytic drugs.

Drugs inhibiting bleeding

Drugs hemostatic mechanism of platelets-

Drugs affecting hemostasis-

category MOA indications- kinetics Side effects:

Platelet aggregation inhibitors

1-Acetylsalicylic acid/ →NSAID, •inhibit COX1 by covalently attaching •platelet aggregation Inhibitor- low dose (75-100g) A: p.o. •Gl mucosal damage, ulcers,
aspirin →irreversible COX-1 to its acetyl group •analgesic, antipyretic, anti-inflammatory- high doses (500g) At low con- 1st pass metabolism to salicylic acid, •bleeding
inhibitor •indirectly inhibits TXA2 which is a reversible inhibitor •Pseudo-allergy
(thromboxane A2). D: Salicylic acid: plasma protein binding.
E: urine - pH affected Contraindications:
Childhood - risk of Reye's syndrome

2-Clopidogrel(po) →irreversible P2Y12-R •P2Y12= ADP-R in platelets •platelet aggregation Inhibitor- slower effect in 4-11 days. A: p.o.high 1st-pass effect •GI disturbances,
inhibitor •bleeding,
→prodrug compound Interactions: •leuko/ thrombocytopenia (especially w/ticlopidine,
CYP2C19 inhibit the conversion of clopidogrel to blood tests in the first 3 months)
active drug in the liver (e.g. omeprazole, fluoxetine,
3-Prasugrel(po) →irreversible P2Y12-R fluconazole) •Clopidogrel and prasugrel cause fewer side effects
inhibitor
→prodrug compound Contraindications:
Pregnancy, lactation
4-Ticagrelor (po) →reversible P2Y12-R •platelet aggregation Inhibitors- rapid onset
inhibitor In combination with Aspirin:
•Ticagrelor - p.o. prophylaxis of arterial thromboembolic events
5-Cangrelor (iv) •Cangrelor - i.v. PCI.

6-Abciximab →irreversible GpIIb/IIIa binds to endothelial cells and •platelet aggregation Inhibitor Pharmacokinetics: •Bleeding
(parenterally) inhibitor vitronectin receptors Primarily PCI: percutaneous coronary intervention A: effective only i.v •Drug induced thrombocytopenia
→ Monoclonal IgG t1/2- 30 min •hypotension
antibodies inhibit GPlIb/Illa Duration of action- 18-24 h •bradycardia
complex. •nausea, vomiting

7-Cilostazol PDE-3 inhibitor • cAMP → Ca2+ •platelet aggregation Inhibitor A: per os, effective after 2-4 weeks •coronary steal
• platelet aggregation, •vasodilation T1/2: 11-13h •Headache, dizziness
• vasodilation •intermittent claudication (enhance circulation in skeletal muscles) D: strong plasma protein binding •diarrhea,
• triglyceride levels M: liver, CYP3A4 •tachycardia,
• HDL levels E: urine, stool •cough, dyspepsia
Contraindications:
Chronic heart failure, active bleeding, ulcer

Fibrinolytics
Agents which the conversion of plasminogen to plasmin, thereby thrombus lysis (thrombolytics).
● 2nd-generation fibrinolytics- Clot specific- selective for the fibrinolysis for specific forming thrombus → systemic fibrinolysis is weaker → risk for systemic bleeding.

1-Alteplase •tPA synthetic analogue •Produced by endothelial cells w/ • PE, DVT, peripheral vessel occlusion iv infusion • Main risk: bleeding
(tissue plasminogen recombinant technology • Acute MI- if percutaneous coronary intervention is not accessible short t1/2!
activator)- •directly activating serine-protease • Ischemic stroke with strict criteria Contraindications:
against fibrin. Active bleeding (except for menstruation)
•No antibody against it • Surgical intervention, biopsy, severe trauma in the
•plasminogen→ plasmin •inactivated by plasminogen activator last 10 days
→ lysis of fibrin mesh. inhibitor-1 (PAI-1) in the circulation Severe hypertension
Aortic dissection, acute pericarditis
2-Reteplase •Recombinant deletion mutant of tPA, iv infusion
•lack certain domains therefore- lack Longer t1/2!
the affinity fibrin-binding domain →
fibrin-specificity.
•Inactivated by PAI-1

Hemostatic agents- systemic coagulation promoters/ fibrinolysis inhibitors.

1-Tranexamic acid •lysine analogue- (Structural similarity to lysine). •Bleeding (due to fibrinolytic therapy/ post-surgical/ postpartum) 5-10X more potent •Thrombosis,
competitive inhibitor on •Additional treatment of haemophilia A: p.o. fast absorption, also i.m. or i.v. slow inj./inf. •hypotension,
plasminogen lysine •2nd prophylaxis of bleeding from intracranial aneurysm M: none, E: fast - needs repeated administration daily •myopathy,
binding site •abdominal discomfort, diarrhea

2-Epsilon-amino- •lysine analogue- bind

caproic acid (EACA) plasmin
•blood clotting stimulant

3-Vitamin K •fat soluble vitamins •activating clotting factors via gamma •warfarin- oral anticoagulants inhibitor. INR: 5-7< A: can be given i.v. (oil injection!!!) or orally (s.c. - notes-
essential for post- carboxylation (their final synthesis •newborns (especially preterm) routinely - until breastfed exclusively uncertain absorption) i.v. dosing should be very slow Vitamin K1 - Found in the diet (vegetables)
translational phase) there is no intestinal flora to produce enough factors. (rapid infusion - risk of dyspnoea and chest pain, may Vitamin K2 - Synthesised by bacteria in the gut flora
modification of blood
•factors II, VII, IX, X, protein C and S •Severe hepatic failure, malabsorption, prolonged parenteral feeding, be fatal in extreme cases) Vitamin K3 - Synthetic form, Fat soluble vitamins, bile
clotting factors
(y-carboxylation). intestinal flora impairment onset time- 6h acids are needed for their absorption
complete effect- 1day

4-Etamsylate • stimulates • tct-adhesion, • Prophylaxis and control of haemorrhages from small blood vessels
thrombopoiesis and • capillary resistance (its action on hyaluronic acid limits capillary bleeding- may in
platelet release from bone •unknown mechanism intraventricular haemorrhage)
marrow • neonatal intraventricular haemorrhage
• activate thromboplastin • capillary bleeding of different etiology
formation on damaged
blood vessels and PGl2
synthesis
•induce platelet agg.,
adhesion and
vasoconstriction.

Hemostatic agents- local

1-Fibrin foam applied topically, release large molecule w/large surface, applied topically
fibrin → stop bleeding. activate the intrinsic pathway of
coagulation cascade

2-Epinephrine catecholamine with

vasoconstriction and
hemostatic effect when
applied topically
Topic B2- Drugs influencing blood coagulation II: Anticoagulant drugs
● Topics to discuss-
○ coagulation cascade- proteolytic steps catalase by serine protease- convert fibrinogen->insoluble fibrin
○ PTT= activated partial thromboplastin time- function of intrinsic/common coagulase complex- heparin activity can be monitored which blocks this pathways.

Indirect factor inhibitors-

MOA- structure- kinetics- indications- side effects-

Heparin Sulphated polysaccharide that UFH/HMWH- inactivate thrombin + FXa A: 1) prevent or treat thrombosis (e.g DVT) • Bleeding- i.v. therapy is asso. W/ bleeding risk.
inactivate factors II and X (1:1) parenteral i .v. or s.c. 2)acute PE (pulmonary embolisation)
by antithrombin-III activity 3)treat MI (=rapture of AS plaque) • HIT: heparin-induced thrombocytopenia (=antibodies against heparin
water soluble, penta-polysaccharide •non linear pharmacokinetics, the effect must be 4) pregnancy anticoagulant therapy- No bound to Factor 4-> activate platelets-> aggregation-> paradoxically
(functional unit) and negative charged monitored! placenta crossing- can be given in pregnancy, hyper-coagulable state-> thromboembolic events)
glucosaminoglycan. Monitoring- aPTT, platelet count breastfeeding • Type I: 5-10% - reversible, transient (within treatment first 4 days)
• Type II: 0.5-3% - extremely dangerous (fatal 20-30%),
•T1/2 -60-90 min
• Rare: Hair loss, allergy, mild elevation of transaminase,

•hyperkalemia- toxic effect in adrenal cells-> aldosterone synthesis->>

hypo-aldosteronism (type 4 Reno-tubular acidosis)-> K+ excretion

•osteoporosis- by bone formation/density

enoxaparin bind to antithrombin-III → its LMWH (low molecular weight) A: parenterally- usually s.c. (high BA (>90%)) Most side effects are less frequent with the use of LMWHs.
activity shorter than 18 monosaccharide units D: binding- more predictable dose-response+E.
→ create complex FXa longer t1/2 of 2-4 hours
nadroparin → irreversible inactivate it.
Monitoring isn’t necessary- reliable kinetics+ no
prolong effect on aPTT (necessary in renal failure-
anti-Xa).

fondaparinux heparinoid penta-saccahride, synthetic pentasaccharide= fractionated A: only parenterally, s.c. 100% BA, Primarily prevent venous thromboembolic •Bleeding (cannot be antagonised by protamine!!)
inactivate factors X heparin which went through depolarization- t/2:15-17h events. •does not cause type II HIT
by antithrombin-III activity. The "smallest LMWH”
•Contraindications-: Kidney failure

protamin heparin antidote- positive charge protamine sulphate Heparin overdoses less effective against fondaparinux
bind to negatively charged heparin positive-charged protein- neutralize
→ reverse it. negatively-charged heparin by complexing
with heparin to form a stable salt.

Direct factor inhibitors-

drug notes kinetics indication- side effects

Thrombin inhibitors

bivalirudin hirudin-like compound A: only i.v. use Thrombosis prevention- mainly in HIT or during planned intervention. Bleeding,
faster onset /shorter duration (compared to E: largely independent of renal function no antidote
hirudin)

dabigatran- novel oral anticoagulant A: orally (1-2x/day), prodrug - activated by Prevention of venous thromboembolic events. Bleeding
etexilate (no need in monitoring) non-specific esterases Antidote: Idarucizumab inj/inf. (antibody - specific anti-dabigatran
antibody)

factor Xa inhibitors-

rivaroxaban novel oral anticoagulant A: orally effective (1-2x/day) prevention of thrombotic events Bleeding, possible antivirals
(no need in monitoring) Antidote- Adexanet-alpha (recombinant analogue of factor Xa)
apixaban Prevention of venous thromboembolic events- even in non-valvular atrial fibrillation
(signal from atria causes ventricle irregular beating-> abnormal blood flow increases clot
development-> stroke).

Factor synthesis inhibitors- coumarins- warfarin

MOA kinetics indication- side effects interactions further properties

•coagulation factors/ proteins synthesis in the liver- lipid soluble- cross the placenta •prevent thromboembolic events (e.g in cardiac •Bleeding (risk if INR >4) Pharmacokinetic interactions •Coumarin resistance
→Ca2+ binds to final carboxylation at y position on M: liver, main step glucuronide arrhythmias, patients w/ artificial valves) •Developmental defects, death of fetus A: Coumarins abs inhibitors: antacids, Rare, due to mutation in
the glutamate side chains of the factors. conjugation •Necrosis of subcutaneous tissues and skin cholestyramine V-KOR
continuation of heparin therapy (Heparin bridge) •rare- „Purple toe" syndrome D: albumin binding - (e.g. NSAIDs) may
→V-KOR (vit K-epoxide reductase) catalyzes the
suppress coumarins • coumarin sensitivity:
oxidation of reduced vit-K (hydroquinone form) to its T1/2- 25-60h (≈40h) •Suspension of effect - M: CYP450 Enzyme inhibitors: warfarin Genetic polymorphism of the
epoxide form.. Vitamin K1 (effect develops slowly), metabolism and its activity (e.g phenylbutazone) gene encoding the enzyme
→y carboxylation is coupled to this oxidation process. •Effect monitoring by- in more severe cases- FFP (fresh-frozen CYP450 Enzyme Inducers: warfarin that breaks down coumarins
•Coumarins block V-KOR →thus, block the INR (international normalized ratio) plasma), factor concentrates. metabolism and its activity (e.g barbiturates) (CYP2C9)
reversion of vitK to its hydroquinone form. INR= (PTpatient/PTreference/Sl)
→PT (prothrombin time)- monitor warfarin Pharmacodynamic interactions Contraindications of
•result- activity- measure the function of the extrinsic
• coumarins effect: heparin, aspirin, liver coumarins-
→production of functionally inactive coagulation pathway.
Extrinsic pathway main component is FVII disease, hyperthyroidism, certain cephalosporins -Teratogenic!!- Pregnancy,
factors II, VII, IX, X and protein-C. • coumarins effect Inhibitors- Vit-K, lactation
(has the shortest t1/2).
→8-12h delay in development of anticoagulant effect. Warfarin prolongs PT time due to FVII hypothyroidism, strong diuretic therapy, -Active bleeding
inhibition. corticosteroids -Underlying disease w/ a
→ISI (international sensitivity index)- for the
thromboplastin reagent.
bleeding risk.

•Therapeutic target range:

INR=1.5-3
for prophylactic use (possibly lower- 1.2)
Topic B3- Agents used in anemias
● Hematopoiesis= production of formed elements of the blood- RBC,WBC and platelets in the bone marrow.
● Anemia= condition in which RBC count and its parameters (haematocrit, hemoglobin con) are lower than normal blood range.
○ Macrocytic MCV>95-100 fl
○ Normocytic
○ microcytic <80fl
Drugs used in anemias-

Drug MOA- kinetics- Indications: Side effects:

Iron-hydroxide •per os iron compound •Absorption-in the intestine by an active •iron deficiency anemia. side effects-
polymaltose •complex with iron-hydroxide core, surrounded by polymaltose molecules mechanism due to its high molecular •nausea
weight. •obstipation
•black stools.
•Distribution-
transfer protein: transferrin. Iron poisoning:
Storage protein: ferritin, hemosiderin. Acute poisoning
• Mainly in children, can be fatal
1st phase: necrotizing gastroenteritis with vomiting and bloody stool
2nd phase: shock, metabolic acidosis, dyspnoe, coma.
• Treatment: Intestinal lavage, parenteral deferoxamine.
Chronic poisoning: Hemosiderosis, rare.

folic acid •Vitamin B9, •oral compounds indications- •Should not be used in undiagnosed megaloblastic anaemias because if
•Cannot be produced by the body- must obtain from food. •Mostly combined with vitamin B12 and •prevent/ treat anaemias caused by folate the anaemia is due to Vit B12- defciency the anemia may improve but
•In the THF form- involve in the transport of C1 fragments and in iron supplementation. deficiency the neurological lesions will persist and could get worse-
thymidylate synthesis. •absorbed by active transport into •prevent or treat the development of folate
intestinal mucosa →reduced and than deficiency in susceptible individuals
methylated → than can pass into the (pregnants).
plasma cells.

vitamin B12 •Cobalamin A: Absorbed in distal ileum, when bound •treat pernicious anemia (vitamin B12 •hypersensitivity reactions
•Cannot be produced by the body- must obtain from food. to intrinsic factor. deficiency form- autoimmune produce •hypokalaemia at start of treatment.
antibody against intrinsic factor). •in megaloblastic anemia diagnosis- folic acid cannot reverse the
•Active forms- neurologic symptoms- differential diagnosis!
1.5-deoxyadenosylcobalamin: breakdown of fatty acid with odd number of
carbon atoms.
2.Methyl-cobalamin: folic acid activation in thymidylate synthesis.

● Hematopoietic stem cells are differentiated into lymphoid/ myeloid progenitors, which are further differentiated into the their final form.
● This differentiations are stimulated by growth/stimulated factors.
● The following drugs are analogous to this stimulating/growth factors:

Drug MOA- kinetics- Indications: Side effects:

Epoetin-alfa •recombinant erythropoietin hormone. •Synthesized in the kidneys, in response to • renal failure Contraindications:
• RBC production. tissue hypoxia. • Anemia during HIV therapy Uncontrolled hypertension
• after chemotherapy bleeding

Filgrastim •G-CSF (granulocyte colony-stimulating factor) kinetics- Indications:

•enhance neutrophil maturation + activity i.v. or s.c. administration •Neutropenia (neutrophil deficiency)- due to chemotherapy/ other
•origin (congenital)
•mobilization of stem cells before transplantation
Topic B4- Positive inotropic drugs
Topic to discuss-

MOA kinetics indication- toxications

digoxin Na+/K+ ATPase inhibitor cardiac glycosides- Digitalis=cardiac glycosides •atrial fibrillation in chronic Toxic dose easily reachable! TD50≈ED50= 1-2ng/ml
IC Na+→ Na+/Ca2+ ex→ •T1/2- 36-40h -shorter heart failure. • Hypokalemia: toxicity
Ca2+IC , replenish the *Glycoside= •Elimination by the kidney only one used chronically!! • MOA: K+ antagonists- in hypokalemia- inhibitory effect on Na+/K+-ATPase- (and
thus the toxicity as well)
myocardial cell → steroid core (digoxigenin/ digoxigenin)+
• Hyperkalemia: effect and toxicity
positive inotropic effect sugar chain • MOA: K+ antagonists (and in reverse)
• enhance toxicity- Hypercalcemia (thiazid diuretics, tumors, dialysis) and
digitoxin *active substance= •Chronic congestive Heart hypomagnesemia
digoxin/ digitoxin •T1/2- 5-7 days- longer! failure. • MOA: Na+/K+-ATPase are Mg-dependent (Mg and Ca can be regarded as each
•metabolized in the liver only one used chronically!! other's „antagonists"): Mg (or Ca)->
higher protein binding Na+/K+-ATPase-> toxicity of cardiac glycosides
*defense mechanism produced by plants against
insects

stimulates the vagus nerve →

negative chronotropic effect.

milrinone PDE3 Inhibitor Ca2+ influx by IC cAMP→ positive inotropic effect only usable in acute cases-
•acute heart failure
•cardiogenic shock.

levosimendan •Ca2+ sensitizer bind to troponin-C during systole! In Ca2+ dependent • active metabolite- OR-1896 found
•acts on K+ ATP channels- manner-> stabilize it in a contraction for>7 days in circulation (long effect)
PDE3 inhibitor conformation→positive inotropic effect without Ca2+IC
con.

dobutamine •beta1 Agonist Ca2+ level by enhancing cAMP synthesis →positive •Tolerance- due to sensitivity-> slower onset of drug, need dose
direct sympathomimetic inotropic. •Tachyphylaxis- promote development
Side effects-
ischemia
extrasystole, arrhythmia
hypokalemia
hyperglycemia
Topic B5- Drugs influencing cardiac electrophysiology.

Antiarrhythmic drugs-

VW classification MOA Pharmacokinetics: Indications: Side effects:

class I- Na+ channel blockers

quinidine I/A •Na+ channel blockers A: per os atrial fibrillation/ flutter •QT prolongation triggers “torsade der pointes”-
in atrial & vent. myocytes •K+ channels blocker M: liver, CYP3A4 Ventricular arrhythmias twist of points (QT complex twist around iso-electric
in purkinje cells More T1/2: 6 hours line)- limiting its clinical use.
Quinidine tinnitus (ringing in the ears), vertigo, Gl
symptoms

Contraindications:
digitalis intoxication (CYP3A4)

lidocaine I/B •frequency- dependent Na+ channel blockers •parenteral administration •anti-arrhythmic (ventricular/ post-infarction). •Sedation
in vent. myocytes (=drug’s inhibitory potency increases with the channel •fast dissociation kinetics •local anesthetic
in purkinje cells activity). M: CYP3A4,
t1/2- short ≈2h

propafenone I/C • inhibit Na+ channel even in normal rhythm (strongest •slow dissociation kinetics •anti-arrhythmic (Supraventricular). •pro-arrhythmic potential- due to slow dissociation
in atrial & vent. myocytes potency). •M: liver, two active metabolites, kinetics.
in purkinje cells •also B-blocker activity •T1/2: 5-6 h /15-20h depends on metabolizer

class II- ß-blockers

metoprolol ß1 selective blockers. •cardio-selective b-blocker oral administration •anti-arrhythmic (Supraventricular

• pacemaker activity (phase 4) and AV conduction time. tachy-arrhythmias)
•migraine prophylaxis
•hyperthyroidism

esmolol short acting (10-15 min) •anti-arrhythmic

Parenterally due to short t1/2- Used in acute cases
(paranteraly)

class III- K channel blockers

sotalol •K+ channel blocker • K channel blocker - prolonged AP, inhibition of repol. •anti-arrhythmic •hypotension due to ß-blocker effect
•non selective ß blocker • Il-like effect: non selective B-blocker

amiodarone • K channel blocker • K channel blocker - prolonged AP, inhibition of repol. D: accumulation in lungs, skin, eyes-strong plasma •anti-arrhythmic (almost any type) •Thyroid disorders due to iodine content.
•Ca2+ channel blocker • I/A-like effect: Na channel blocker, fast dissociation kinetics protein binding
•Na+ channel blocker • IV-like effect: Ca2+ channel blocker - slower AV conduction Contraindications:
•beta-R blocker. • Il-like effect: non-comp b-blocker - may be bradycardizing Long acting! t1/2 (60-100 days) IODINE ALLERGY
(in chronic use)

class IV- Ca2+ channel blocker

verapamil •frequency dependent inhibition on both cardiac and SM- has both negative Orally ••anti-arrhythmic (PSVT (paroxysmal Contraindications:
L-type VG-Ca2+ channel inotropic and SM relaxant effect. supraventricular tachycardia)) cannot be administered in combination with
blocker •Supraventricular arrhythmias (AVNRT, AVRT), ß-blockers)
Frequency-dependence: drugs inhibitory potency increases
with the channel activity.

class V- others

adenosine •A1 agonist. •negative dromotropic effect by activates A1 receptors •Short duration (10 sec), Treatment of paroxysmal supraventricular
(GPC-adenosine-R). tachycardia (PSVT; tachycardia with narrow
→ Pharmacodynamic interaction: QRS complex)
weaker effect if combined with teofylline and coffeine
(adenosine-receptor antagonists)

digoxin •Na+/K+ ATPase inhibitor •positive inotropic effect- Na+/K+ ATPase inhibitor •T1/2- 36-40h (short) •Chronic Heart failure.
•stimulates the vagus IC Na+→ Na+/Ca2+ ex→ •Elimination by the kidney •Atrial fibrilation.
nerve Ca2+IC →
•negative chronotropic effect- stimulates the vagus nerve

Mg++ •natural Ca2+ channel •Divalent ion with anti-arrhythmic, SM spasmolytic effects. •i.v. In high doses •1st-line treatment of Torsade-de-Pointes
blocker •antidote for digitalis poisoning
•regulates Na+/K+ ATPase
activity
Topic B6- Drugs acting on the renin-angiotensin-aldosterone-system (RAAS)
1st line antihypertensive-
● 5 drug groups (AABCD):
– ACE-I (angiotensin convertase enzyme inhibitor
– ARB (angiotensin-receptor blocker)
– BBL (beta-blocker)
– CCB (calcium-channel blocker)
– DIU (diuretics)
● used for resistant hypertension:
– ABL (α-blocker)
– MRA (mineralocortikoid receptor antagonists)
– Centrally acting drugs
● Other vasodilators

drug MOA- indications side effects contraindications

Angiotensin-convertase enzyme inhibitors (ACE-I)

captopril active substance fast acting • normalize acute hypertension. •Allergic reactions (agranulocytosis/neutropenia) •Pregnancy
•dry cough (bradykinin/SP/PG effect in lungs)
•hyperkalaemia
•orthostatic hypotension
enalapril prodrug metabolized in •hypertension and heart failure- among 1st line of choice.
the liver into acid
and inhibit ACE- •enalapril + hydrochlorothiazide (additive synergism-
enzyme remember this combo antagonised k+ related side effects).
perindopril irreversibly

ramipril

ARB angiotensin-receptor blockers

irbesartan active substance long t1/2- •hypertension and heart failure in ACE-Inhibitor •do not cause dry cough •teratogenic
not for acute intolerance •Allergic reactions (agranulocytosis/neutropenia)
condition •hyperkalaemia
•initial orthostatic hypotonia

losartan metabolite
(+uricosuric
effect-promote
uric acid
excretion)

valsartan

Angiotensin receptor-neprilysin inhibitor –

valsartan combo of- •Chronic heart failure •Allergic reactions

•valsartan: ARB inhibitor •HFrEF (post-MI HF)- if the patient tolerates RAAS-inhibitors. •hyperkalaemia
+sacubitril •sacubitril: neprilysin inhibitor •orthostatic hypotension
•neprilysin=key enzyme in
the degradation of ANP and
BNP (produced by the
heart).

•By inhibiting neprilysin, sacubitril the

levels of ANP and BNP, enhancing their
natriuretic/ vasodilatory effects.

mineralocorticoid receptor antagonists-

spironolactone MRA active inhibit nuclear •Chronic heart failure •Hyperkalaemia GFR <10 ml/min or in HF GFR<30 ml/min
substance receptors for •Palliative therapy for hypertension •Gynecomastia (has high affinity to estrogen and progesterone
K-sparing diuretics- aldosterone in •Hyperaldosteronism receptors)
non-selective cells of distal and
collecting ducts
eplerenone MRA active •Hyperkalaemia
substance
K-sparing diuretics-
selective
Topic B7- Ca2+ channel blockers and other vasodilators
1st line antihypertensive-
● 5 drug groups (AABCD):
– ACE-I (angiotensin convertase enzyme inhibitor
– ARB (angiotensin-receptor blocker)
– BBL (beta-blocker)
– CCB (calcium-channel blocker)
– DIU (diuretics)
● Other vasodilators

Role of Calcium channel blockers (CCB)

They inhibit the influx of calcium ions into vascular SM cells → leads to vasodilation and TPR (total peripheral resistance) which results in BP.
Structure of Calcium Channels- Subunits
• a subunit: This is the primary subunit through which calcium ions (Ca2+) pass.
• B, v, 6, and a2 subunits: These regulate the channel's function (opening/ closing/ sensitivity).

CCB (calcium-channel blocker)

Drug- Classification MOA kinetics indications- side effects

nifedipine DHPs blood pressure by short acting •retarded formulations are used- in hypertension and stable angina, •oedema in the ankles,
(Dihidropiridines) dilating blood vessels T1/2- 2h •rapid-release tablets or sublingual sprays are used in hypertensive crisis, angina attacks, •flushing,
type Ca2+ channel •dizziness,
blocker •constipation.

nimodipine affinity for •prevention and treatment of ischaemic nerve damage induced by cerebral vasospasm following
cerebral blood subarachnoid haemorrhage.
vessels

felodipine medium duration •In hypertension and angina it is the first-line drug of choice.

amlodipine long acting

verapamil non- DHPs +class IV Inhibits CYP3A4 •hypertension, edema,

Ca2+ channel blocker, antiarrhythmic agent. enzyme, which may •angina, dizziness,
cause interactions •supraventricular arrhythmias constipation,
with other agents. •cluster headache prophylaxis. bradycardia.

diltiazem •hypertension,
•angina

Other vasodilation agents-

Drug MOA kinetics indications side effects

sildenafil PDE5 inhibitors- CYP3A4 inhibitor -erectile dysfunction – low blood pressure,
• Higher cGMP levels→ pulmonary May cause severe -pulmonary hypertension -flushing,
vasodilation hypotension when used in -dizziness,
combination with nitrates -headache,
-colour vision disturbances

tadalafil PDE5 inhibitors- -erectile dysfunction- -low blood pressure,

long acting BPH. -flushing,
-dizziness,
-headache,
-Backache

bozentan Endothelin antagonists- - CYP2C9/19 and CYP3A4 pulmonary hypertension -low blood pressure,
competitive ET1-R inhibitors → inducers → decrease the -flushing,
pulmonary vasodilation efficacy of oral -dizziness,
contraceptives -headache,
- increased risk of
hepatotoxicity in combination
with glyburide

dihydralazine Effective antihypertensive that relaxes per os or IV. hypertensive crisis, reflex tachycardia
the smooth muscle of the arteries, eclampsia,
increases cGMP (the exact mechanism
of this is not yet clear).
Topic B8-Drugs influencing the oxygen demand and oxygen supply of the heart. Drugs improving microcirculation.

Part 1-Drugs influencing the oxygen demand and oxygen supply of the heart.
Drugs which heart O2 supply, O2 demand.

Drug MOA kinetics indications side effects

nitroglycerin nitrate and NO donor- Short duration • short duration formula- prevent/ resolve angina attack Long-term use leads to nitrate tolerance.
Venodilator and cardioprotective effects through enzymatic "Monday disease" (=vasodilator-induced headache, dizziness,
NO release, increasing cGMP. tachycardia)

isosorbid- long acting

Serious, dose-dependent side effects:
mononitrate • circulatory dysregulation
• (orthostatic) hypotension → reflex tachycardia → nitrate
syncope (cerebral ischaemia)

nifedipine DHPs (Dihidropiridinas) short acting •retarded formulations are used- in hypertension and stable •oedema in the ankles,
type Ca2+ channel blocker T1/2- 2h angina, •flushing,
•rapid-release tablets or sublingual sprays are used in •dizziness,
blood pressure by dilating blood vessels hypertensive crisis, angina attacks, •constipation.

nimodipine affinity for cerebral blood vessels •prevention and treatment of ischaemic nerve damage induced by
cerebral vasospasm following subarachnoid haemorrhage.

felodipine medium duration •In hypertension and angina it is the first-line drug of choice.

amlodipine long acting

verapamil non- DHPs Inhibits CYP3A4 enzyme, which may cause •hypertension, edema,
Ca2+ channel blocker, interactions with other agents. •angina, dizziness,
•supraventricular arrhythmias- (+class IV antiarrhythmic agent.) constipation,
•cluster headache prophylaxis. bradycardia.

diltiazem •hypertension,
•angina

carvedilol non-selective β-blocking also has α1-receptor antagonist and antioxidant •treatment of hypertension and heart failure
activity.

propranolol •cardiac arrhythmia,

•essential tremor,
•migraine prophylaxis hyperthyroidism.

metoprolol β1-receptor selective inverse agonists. •cardiac arrhythmias,

•angina,
•infarct prevention,
•heart failure
•in combination with other antihypertensives, treatment of
hypertension.

ivabradine →reduces the pulse by inhibiting the funny current. • metabolized with CYP3A4 (drug interactions!) • angina • Visual disturbances (crossreaction with Ih current of retinal
•heart failure. – „phosphenes” (seeing lights without actually seeing lights)

trimetazidine inhibiting the enzyme 3-ketoacyl thiolase, •adjunctive treatment in ischaemia and angina. •Trimetazidine should be avoided in Parkinson-
→ reduces β-oxidation of fatty acids in the heart, disease and need careful evaluation in elderly patients!
→thus glucose oxidation is favoured,
→ requires less oxygen but produces more ATP.

Part 2- Drugs improving microcirculation-

Local circulation boosters-

Drug MOA kinetics indications side effects

cilostazol Enhancement of circulation in skeletal muscle metabolized by Symptomatic treatment of intermittent claudication,
PDE-3 inhibitor- CYP3A4
platelet aggregation inhibitor,
arterial vasodilator
triglyceride levels and HDL levels

nicergoline Ergot alkaloid nootropic agent cerebral circulatory disorders,

α-receptor-blocker vasodilator, platelet aggregation inhibitor, enhance cerebral dopamine dementia
metabolism. stroke rehabilitation

pentoxifylline Improves RBC flexibility, peripheral circulatory disorders

reduces blood viscosity,
inhibits platelet aggregation by stimulating PGI2 biosynthesis.

vinpocetine Nootropic agent of plant origin cerebral circulatory

inhibits memory disorders,
1. Na+ channels hearing loss,
2. Ca2+ channels tinnitus
3. NMDA-R
4. AMPA-R.

cinnarizine Ca2+ channel blocking and histamine antagonistic effects. Méniére disease,
inhibiting excitation of the vestibular system. migraine prophyaxis,
dizziness
kinetoses (travel sickness)

Ca-dobesilate Reduces vascular wall permeability, microangiopathies,

inhibits the action of vasoactive substances on the endothelium and prevents endothelial cell capillary damage, retinopathies caused by diabetes mellitus.
detachment.
Topic B9- Drugs affecting lipid metabolism.

Drug MOA indications Kinetics- side effects-

simvastatin •statins- +other pleiotropic effects that have a beneficial •The CYP3A4 enzyme plays a • mild GI symptoms
HMG-CoA reductase inhibitors effect on cardiovascular risk. central role in statin metabolism • muscle pain
inhibition of the HMG-CoA → Cholesterol synthesis decreases - LDL-receptor rhabdomyolysis (rare, 1000:1), myopathy- muscle pain (common,
upregulation-increasing LDL clearance from the blood. 10:1)
atorvastatin - mostly when other CYP3A4 substrates are given together with the
statins e.g. fibrats, macrolides, grapefruit – „statin intolerance”
• in case of statin intolerance: dose reduction, change to an other
rosuvastatin statin, or discontinuation of statin therapy

Contraindication: pregnancy, severe liver failure

ezetimibe •NPC1L1 sterol transporter inhibitor monotherapy or in combination with statins. • glucuronidation is needed for its •concomitant statin use increases liver enzyme levels
→ inhibits the absorption of cholesterol from the intestine activation
•synergistic combo w/simvastatin- decrease intestinal cholesterol
absorption.
Combo side effects-
•increased liver enzymes
•Contraindicated in liver diseases and pregnancy.

fenofibrate PPARα transcription factor activator. •Interactions- •GI complaints,

→It is able to reduce VLDL and triglyceride levels. beneficial effects for diabetic and gout patients statin + gemfibrozil not •muscle pain
through its pleiotropic effects. recommended, careful •in combination with statins in high doses, rhabdomyolysis.
combination with other fibrates

colesevelam A bile acid binding resin •isolated LDL-C increase, even during pregnancy •GI complaints
→ enhances the conversion of cholesterol to bile acids by preventing their •children may also take
reabsorption. •should be used separately from other medicines-inhibit the
→reduces diarrhoea caused by excess bile acids in the bile by binding them (e.g. in absorption of other drugs
IBD)

alirocumab PCSK9 inhibitor - monoclonal antibody against circulating PCSK9 protein sc injection
→ increase LDL receptor recirculation and thus LDL uptake from the blood to the liver
→ circulating LDL-c decreases.

inclisiran Short interfering RNA (siRNA) that inhibits translation of PCSK9 and reduces
plasma LDL cholesterol levels.
→ more LDL is taken up → circulating LDL-c decreases.
Topic B10-Potassium excreting (wasting) diuretics
● Diuretics= increase their rate of urine flow, increase Na excretion
● Types-
○ extrarenal- act outside the nephron
○ renal diuretics- influence nephron function
● Groups
1. Primarily salt excreting diuretics:
• Carbonic anhydrase inhibitors – proximal tubules
• Loop diuretics – ascending limb of Henle-loop
• Thiazides – distal tubules
• K+-sparing diuretics – upper part of the collecting tubules
2. Primarily water excreting diuretics
• ADH-antagonists – lower part of the collecting tubules
3. Osmotic diuretics
• Proximal tubules and the total lenghth of the nephron

Drug MOA indications side effects-

Carbonic anhydrase inhibitors – proximal tubules

acetazolamide H+ + HCO3- → H2CO3 → H20 + CO2. 1. Glaucoma (→aqueous humor production depends on HCO3)
inhibition consequence- 2. Acute odemas (→ causes H2O excretion)
→ increase Na+ and HCO3- excretion. 3. mountain disease (→ lower pH →increase respiratory rate)

Thiazides diuretic- in the distal tubule

hydrochlorothiazide • Inhibit Na+/Cl- cotransporter Hypertension (water loss → plasma volume → CO, BP) • Hypokalemia
• Stimulate the PTH-dependent Ca2+ reabsorption • hyperuricemia
(due to the [Na+]IC → the activity of the basolateral Na+/Ca2+ exchanger → Ca2+ reabsorption) • glucose intolerance
• elevated LDL/TG levels
→ increase Na+ excretion

indapamide fewer diabetogenic or dyslipidemic side effects.

Loop diuretics-ascending limb- loop of Henle

furosemide • inhibit the Na+/K+/2Cl- symporter in the ascending limb of Henle-loop • odema • Severe Hypokalemia !!!
consequence- • heart failure (water loss → plasma volume → CO, BP) • electrolyte disturbance
(sulfonamide) 1. Na+, K+, Ca2+, Mg2+ ions stay inside the loop • deafness
2. water excretion • hyperuricemia
3. osmotic gradient
etacrynic acid 4. the originally positive lumen potential (luminar membrane is more hyperpolarized than the basolateral =
transepithelial potential) becomes negative – Ca++ and Mg++ excretion
5. PG synthesis (PGs have diuretic+vasodilate effect)
6. RBF and renin secretion
7. K+ loss
Topic B11-Potassium sparing diuretics, ADH antagonists, osmotic diuretics
Groups of diuretics and their targets
1. Primarily salt excreting diuretics:
• Carbonic anhydrase inhibitors - proximal tubules
• Loop diuretics - ascending limb of Henle-loop
• Thiazides - distal tubules
• K+-sparing diuretics - upper part of the collecting tubules
2. Primarily water excreting diuretics
• ADH-antagonists - lower part of the collecting tubules
3. Osmotic diuretics- Proximal tubules and the total lenghth of the nephron

Drug MOA indications side effects

k+ springs diuretics, ADH antagonist

spironolactone • MRA antagonist (aldosterone-R antagonist) • hypertension (palliative therapy) • Hyperkalaemia

aldosterone-dependent Na+/K+-ATPase inhibitor • chronic HF • Gynecomastia
ENAC inhibitor (luminar) • hyperaldosteronism
result- (Conn’s syndrome)
Na+ excretion (& H2O excretion (follows Na+))
eplerenone K+ excretion. • Hyperkalaemia

amiloride • ENAC Inhibitor (Na+ channel) in the collecting duct •hypertension

→ result- •HF- most commonly combined with thiazides
Na+ excretion (& H2O excretion (follows Na+))
K+ excretion.

tolvaptan •ADH-antagonist • policystic kidney disease

selective V2-R inhibitor- in lower collecting tubules • hypervolemic hyponatremia.
→ result- aquaporin channels can’t reabsorbs water.
→water excretion

osmotic diuretics

mannitol •inhibit Na+ reabsorption in the proximal tubule. •acute renal failure
•Reduce IC fluid volume, → increase EC volume, •cerebral edema (Life-threatening).
• blood viscosity
• inhibit renin release → K+ excretion.
glycerol
• parenterally
Topic B12- Glucocorticoids for oral and parenteral use

Cortisol- Naturally occurring glucocorticoids-

synthesized from cholesterol
in absence of stress- 10-20mg secreted daily-> follows a circadian rhythm governed by ACTH pulses that picked in the early morning.
In plasma- cortisol bound to circulating proteins (CBG- corticoid-binding globulin, α2 globulin synthesized by the liver). The rest (5%)- free/ loosely bound to albumin and effect target cells.
T1/2 of cortisol= 60-90min
hydrocortisone (pharmaceutical preparation of cortisol)- admin under stress, hypothyroidism/ liver diseases.
Excretion- 1% of cortisol- excreted uncharged in the urine as free cortisol.
20% of cortisol is converted to inactive cortisone by 11βHSD2 with mineralocorticoids receptors in the kidney before reaching the liver.
in the liver- many cortisol metabolites are conjugated with glucoronic acid or sulfate and than excreted in the urine.

MOA-
glucocorticoids effect is mediated by glucocorticoids receptors (nuclear receptors)- this receptors interact with promoters and regulate the transcription of target genes.
→free hormones from plasma/ interstitial fluid enter the cell and bind the receptors
→ligand bound receptor transported to the nucleus and interact with GREs (glucocorticoids receptor elements) and bind to other complexes which influence other transcription factors as NF-kB, AP1.
→result- this complexes mediate them anti-growth, anti-inflammatory and immunosuppressive effect of glucocorticoids,

→alternative splicing of human glucocorticoid receptor pre-mRNA generate 2 isoforms-

1. Human GR-α (hGR-α)-classic liganed-activated glucocorticoid receptor which modulate expression on gluccocorticoid genes.
2. Human GR-β (hGR-β)- endogenous inhibitor of glucocorticoid actions by inhibit the active form (hormone activated form of hGR-alpha).

Synthetic corticosteroids

Drug MOA indications relative antiinflammatory sodium retaining duration of action-

affinity for potency potency after oral dose
receptor (glucocorticoid mineralocorticoid
potency) potency)

hydrocortisone synthetic equivalent- Medical name for cortisol •at low dose- hormone replacement therapy 1 1 1 short (8-12h)
produced by adrenal cortex. •high dose- anti-inflammatory at higher doses

prednisolone Can induce apoptosis in immune cells- systemic •adjuvant therapy in various haematological or immune cell-derived 2.2 4 0.8 intermediate (12-36h)
anti-inflammatory and immunosuppressive effects tumours
•reduce chemotherapy-induced nausea.

methylprednisolone used systemically and topically. Has a weaker Used as an anti-inflammatory, immunosuppressive agent. 11.9 5 minimal
mineralocorticoid effect.

triamcinolone relatively more toxic 1.9 5 non

both systemically and topically applied,
without mineralocorticoid action.

dexamethasone used especially where water retention is undesirable Used as an anti-inflammatory, immunosuppressive agent 7.1 27 negligible long (36-72h)
(e.g. cerebral oedema); drug of choice for suppression of adrenocorticotrophic hormone
production

vamorolone acts through T glucocorticoid receptor Duchenne Muscular dystrophy, 1x/day, PO

Topic B13- Mineralocorticoids. Topically applied glucocorticoids. Adrenocortical antagonists, inhibitors of corticosteroid synthesis.

Drug MOA indications side effects-

fludrocortisone- Synthetic corticosteroid with marked mineralocorticoid activity- Substitution therapy

salt-retaining hormone.

hydrocortisone synthetic equivalent- Medical name for cortisol produced by adrenal •at low dose- hormone replacement therapy
cortex. •high dose- anti-inflammatory at higher doses

Topically applied glucocorticoids.

mometasone Strong, non-halogenated corticosteroid dermal anti-inflammatory and as an anti-allergic nasal spray.

budesonide Strong, non-halogenated corticosteroid inflammatory bowel diseases and as an anti-asthmatic agent. Due to its first pass metabolism, has little systemic effect

fluticasone Potent halogenated corticosteroid dermal anti-inflammatory, an anti-allergic nasal spray and as an anti-asthmatic. Due to its high first pass metabolism, has little systemic effect

fluocinolone Potent halogenated corticosteroid dermal anti-inflammatory

adrenocortical antagonist-

metyrapone 11-β hydroxylase inhibitor diagnosis of hypothalamic-pituitary-adrenal axis disorders can be administers to pregnant women with Cushing syndrome.
reduces glucocorticoid synthesis but increases ACTH secretion in Diagnosis-
healthy humans, - adrenal function (measure blood level and urinary excretion of 11 deoxy-cortisol before and after
metyrapone admin.
- pituitary function- measure ACTH/ 11DC level in blood/ excretion of 17-Hydroxycorticosteroids in
the urine.
Topic B14- Androgens, anabolic steroids, antiandrogens. Agents affecting the sexual activity

● Male sex hormone or androgenic hormone/agent:

○ Testosterone=The physiological androgen hormone, which is produced by the testicles.
○ biochemistry-
■ Testosterone is partly converted by 5-α-reductase to dihydrotestosterone
■ precurdor-DHEA
■ active metabolite= 5-α-dihydrotestosterone; estradiol
■ Inactive metabolite predominant formed in the liver (androsterone,eticholanolone)
● Androgenic effect- mediated by intracellular receptor, and changes in gene expression.
○ Androgenic effect-
■ embryonically - the development of the male reproductive organs
■ In young male: development of secondary male characteristics
■ in the adult male: maintenance of libido,spermatogenesis, male pattern baldness, prostate hyperplasia
■ in adult women: virilization: hirsutism, increased hair growth, deepening of voice, clitoral enlargement, baldness, etc.
○ anabolic effect-
■ nitrogen excretion
■ protein synthesis
■ proteolysis
■ inactivation of osteoclast- protect against osteoporosis.

Therapeutically used androgens/anabolics-

Drug MOA kinetics indications side effects-

Androgens/ anabolic agents-

testosterone- testosterone ester- PO- artially absorbed •testosterone substitution therapy • masculinisation and virilisation in females
Prodrug, which has a prolonged effect due to the ester-bonded fatty acid in its through lymphatics- • hyperlipidemia
undecanoate structure bypass in the liver. • testicular atrophy
• contraindications: pregnancy, young children

nandrolone Anabolic steroids- (17-a-alkylated androgens) •convalescence

doping agent •refractory anaemia

AntiandrogenDs-

bicalutamide 1st generation androgen receptor antagonist prostate cancer therapy as part of a complete androgen
blockade (supplemented with a GnRH analogue).

apalutamide 2nd generation androgen receptor antagonists.

darolutamide

finasteride 5-a-reductase inhibitors- • BPH (it reduces the size of the prostate, thereby improving • Side effects: impotence, reduced libido.
symptoms.)

dutasteride

abiraterone Steroid synthesis inhibitors- • Per os prodrug •prostate cancer • hyperaldosteronism

•17a-hydroxylase/17,20-lyase inhibitor→decreased steroid synthesis, prodrug. (steroid) • QT-prolongation,
• heart failure,
• angina

GnRH related agents-

● GnRH decapeptide, produced in the hypothalamus
● controls the release of gonadotropins (FSH and LH)- physiologically released periodically (pulses: every 90-120 minutes).
This pulsatility stimulates LH, FSH production

goserelin GnRH analogue. •In a pulsatile dosing regimen- for ovulation induction,
•continuous dosing- it inhibits sex steroid synthesis, so it is
Stimulate FSH, LH release, used to treat sex hormone-sensitive tumours, leiomyomas,
leuprorelin in continuous dosing- it inhibits the secretion of LH and FSH. endometriosis, PCOS, precocious puberty.

degarelix GnRH antagonist, treat hormone-dependent tumours (prostate, breast cancer).

inhibits the secretion of LH and FSH.

Drugs affecting sexual activity-

● Erectile dysfunction
● Treatment- phosphodiester enzymes

sildenafil PDE5 inhibitors- CYP3A4 inhibitor -erectile dysfunction – May cause severe hypotension when used in combination with nitrates
• Higher cGMP levels→ vasodilation -pulmonary hypertension -flushing,
-dizziness,
-headache,
-colour vision disturbances

tadalafil long acting -erectile dysfunction- -low blood pressure,

BPH. -flushing,
-dizziness,
-headache,
-Backache
Topic B15- Estrogens and antiestrogens
Estrogen-

drug MOA indication side effect

estradiol Estrogen receptor agonist. • estrogens induce proliferation (endometrium, breast) •hormone replacement
•act together with progesterone •contraception in combination with gestagens.

ethinylestradiol Synthetic estrogen inhibits FSH release from the anterior pituitary. thromboembolism.
→suppresses the development of the ovarian follicle

clomifen SERM- selective estrogen estrogen antagonist in the pituitary gland, • induction of ovulation Menopausal-like hot flashes
receptor modulators thus eliminating the negative feedback effect. ovarian enlargement.
→ gonadotropin release. Sometimes visual symptoms (after images).
GIT disturbances may occur.

tamoxifen endogenous oestrogen comp antagonist in the mammary tissue. • breast cancer
→Inhibit cell activation and proliferation

raloxifene estrogen agonist effect on bone & CV system • osteoporosis

→ inhibit cytokines that recruit osteoclast.

anastrozole Antiestrogens aromatase inhibitor tamoxifen-resistant hormone-dependent breast cancer •osteoporosis

•vasomotor symptoms

goserelin GnRH analogue. initially Stimulate FSH, LH release, •in pulsatile dosing regimen- ovulation induction,
in continuous dosing- it inhibits the secretion of LH and FSH. •continuous dosing- inhibits sex steroid synthesis,
so it is used to treat sex hormone-sensitive tumours,
leuprorelin leiomyomas, endometriosis, PCOS, precocious puberty.

degarelix GnRH antagonist inhibits the secretion of LH and FSH. treat hormone-dependent tumours (prostate, breast cancer). erectile dysfunction,
decreased glucose tolerance,
Topic B16- Progestins and antiprogestins. Contraceptives
Gestagens-
natural gestagen- progesterone
•first pass metabolism – i.m. (orally only micronized formula)
• physiological effects (intracellular receptors – transcription changes)
•main effects: inhibit proliferation, promote differentiation (except in breast - also involved in proliferation) -effects coordinated with estrogens

Types- MOA Clinical use- Side effects-

medroxyprogesterone-acetate Pregnane-type progestogen • depo form is used as a contraceptive.

• similar structure/ effect to progesterone Oral contraceptives- gestagens in monotherapy

drospirenone Pregnane-type progestogen

• similar structure/ effect to progesterone
•antiandrogenic
•aldosterone antagonist actoivty

cyproterone-acetate Pregnane-type progestogen

• similar structure/ effect to progesterone
•antiandrogenic

norethisterone Estrane-type progestogen

•gonadotropin inhibitory and anabolic effects,
•cannot maintain pregnancy (have no pregnancy-sustaining effect, cause non-physiological
changes in the endometrium, inhibit implantation (close structural relatives to androgens))

levonorgestrel Gonane-type progestogen Local contraceptives- androgenic side effects

contraceptive or as a morning-after pill (within 72 hours).

desogestrel oral contraceptive

mifepristone-(RU-486) • Progesterone and glucocorticoid antagonist •chemical abortion • side effects of the combination: vomiting, diarrhea, abdominal pain,
•supportive therapy of inoperable endocrine tumours. vaginal bleeding
• antiglucocorticoid effect

ulipristal acetate- • Selective progesterone receptor modulator Postcoital contraceptives- • headache, nausea, fatigue, period problems, (liver damage)
treat fibroids and as a morning-after pill (within 120
hours).

ethinylestradiol + levonorgestrel- typical estrogen-progestogen combination of contraceptives. Oral contraceptives- estrogen-gestagen combination
Topic B17- Thyroid and antithyroid drugs. Pituitary hormones. Hypothalamic hormones, hormone analogs / antagonists.

Drugs MOA indications kinetics Side effects

Thyroid and anti thyroid drugs

131
iodine I- halogen ion. •in small doses for supplementation, admin orally as solution as sodium-131I. hypothyroidism - levothyroxine administration necessary
Necessary for thyroid function •high doses in hyperthyroidism, thyrotoxic crisis.

levothyroxine Recombinant T4 widely used as a thyroid hormone replacement drug • morning, empty stomach ( t1/2) •subclinical hyperthyroidism Sy- osteoporosis, heat tolerance,
• in order to predict the abs better- must tachycardia
be titrated according to TSH levels. •possible cardiac side effects (since β receptor expression ).

thiamazole •TPO (peroxide) inhibitor • drug of choice during pregnancy bone marrow & liver damage
•Treatment of hyperthyroidism in Basedow–Graves disease
propylthiouracil →thus- inhibit T4→T3 synthesis.
(PTU) (→ thyroxine synthesis by inhibit iodine attachment of tyrosine
molecules).

Pituitary & hypothalamic hormones, hormone analogous and antagonists

somatropin recombinant human GH analogue (rh-GH) •GH deficiency sc. injection •may increase insulin resistance- diabetogenic
•Stimulating the synthesis of IGF-I and II (insulin-like growth •growth disorders- Prader willi syndrome, Turner syn. • ICP, gynecomastia
factors, somatomedins) •hypothyroidism

octreotide somatostatin octapeptide analogue. •Acromegaly •steatorrhea

→Binds to sstr2/5 (Gi mediated responses →inhibit GH, TSH, •Hormonal GI- tumors •Gallstones
•acute GI bleeding- esophageal varices •Hyperglycemia
glucagon, insulin and gastrin release.
and more •prolonged QT
•Bradycardia

bromocriptine Dopamine-R agonists • hyperprolactinemia • Metabolism in liver (CYP3A4) – drug

activates D2-R on striatum neurons → impairs dopaminergic • prolactin-producing microadenoma interaction
transmission → inhibit prolactin secretion on the pituitary level. • inhibit milk secretion
action on D1-R will improve the non-Parkinsonism symptoms.

desmopressin ADH analogue • central diabetes insipidus inj., nasal spray, pill
→vasoconstriction (V2- ADH-R agonist) • night enuresis
→ salt retention effect- • Hemophilia A
• Von Willebrand disease
→ factor VIII and vWF in extra renal cells.

oxytocin Endogenous hormone produced in the pituitary posterior • Induction of rhythmic contraction during labour/ delivery. inj. Can cause water retention due to an antidiuretic hormone-like effect.
lobe • Induce lactation (release of milk)
→oxytocin-R in uterine SM- stimulate uterine contractions. • Emotional regulation
→stimulate lactation
→vasopressin-R activation- emotional regulation

atosiban oxytocin-R antagonist tocolysis- delay labor (Inhibits oxytocin-induced contractions in

preterm labor)
Topic B18- Pancreatic hormones and parenterally applied antidiabetic drugs.

● Insulin
○ Forms-
■ In circulation- monomer form
■ In pancreas- Hexamer form (s.c admin)
○ dissociation-
■ clear Solution → precipitation→ dissociation→ Hexamer (pancreas)→ dimmer→ monomer(circulation)

Drug MOA kinetics indications side effects

Pancreatic hormones

regular insulin Human recombinant insulin. short acting IV- diabetic ketoacidosis
insulin active structure- hexamer (in pancreas) onset: ~30min-1h
B28- proline position- modification target. duration: ~5-6h

lispro insulin lysine based- modification Rapid-acting insulin

B28- replaced by Lysine. onset: 10-20 min
duration- 3-4 h
aspart insulin aspartic acid based- modification
B28- replaced by aspartic acid.

isophan neutral protamine Hagedorn Medium acting

(NPH)-insulin (protamine- basic protein allows its absorption) onset: ~4-5 h,
duration: ~12-14h

glargine Base insulin long acting

insulin high arginine content onset: ~1-3h,
duration: ~24h
s.c

degludec Base insulin long acting

insulin thapsic acid bound to specific amino acid. onset: ~1-3h,
duration: up to 40h

Parenterally applied anti-diabetic agents

liraglutide GLP-1 analogue with fatty acid side chain Administration - 1x/daily SC T2DM GI-related SE
obesity
semaglutid Administration- 1x/daily PO

tirzepatid GLP-1/GIP agonist (“twincretin”) Administration- 1x/ week - Similar to GLP-1 analogues,
- Functional selectivity (biased agonism) GI side
effects and lack of appetite
Topic B19- Oral antidiabetics.

Drug MOA indications- side effects-

PO anti-diabetic agents

metformin Biguanide type → reduces body-weight • T2DM – first choice! • Diarrhea (most common)
→ Increase insulin sensitivity via the AMPK • Can be considered in: • vitamin B12 deficiency (disturbed
pathway (AMP-activated protein kinase) • Polycystic ovary syndrome absorption)
• Diseases associated with • Lactic acidosis
hyperinsulinemia/insulin-resistance (metformin-induced/associated lactic
acidosis, MILA,MALA)

dapagliflozin SGLT-2 inhibitor - Beneficial cardiovascular effects (can be used in heart •Dehydration
→60-70g/day glucose can be excreted in the failure without T2DM) •Euglycemic ketoacidosis
empagliflozin urine. •Fracture
•uroGenital infections
(Beneficial because SGLT-2 expression is increased
in T2DM)

vildagliptin → DPP-4 inhibitor (increatin degrading enzyme) →weight- neutral/no effect •risk for-
→ Nasopharyngitis - reduced immune
sitagliptin function
→ restore physiological incretin levels → Pancreatitis- risk increased w/use.

Acarbose a-glucosidase inhibitor. - But! does not inhibit lactose degradation in •Bloating and cramps
lactase-persistent patients
→ inhibit carbohydrates digestion & absorption

pioglitazone insulin resistance →increased body fat (weight gain) •oedema

→ act through PPARγ activation •bone fracture (osteoporosis)

contraindication in CV patients

Glimepiride sulfanyl-urea type K+-ATPase Channel inhibitor •Hypoglycaemia

pancreas selective
Gliclazid
→ causes depolarization
→ result in insulin release

- Potent active substances

repaglinide NON-sulfanyl-urea type8. mainly in conjugation with meals

K+-ATPase Channel inhibitor
Short acting

→ causes depolarization
→ result in insulin release
Topic B20- Agents affecting bone mineral homeostasis (calcium, vitamin D, parathyroid hormone, calcitonin, etc.).
● Reminder: calcitriol, in combination with PTH and cytokines, stimulates osteoblast RANKL expression → osteoclast precursors maturation, differentiation → bone remodeling
● PTH made up of 84 AA-
○ reduces Ca and increases P excretion
○ stimulates both osteoclast and osteoblast function
○ increases calcitriol formation in the kidney- (calcitriol inhibits PTH production)
○ body Ca level regulates its production: activation of Ca2+ sensitive proteases, receptors reduces PTH secretion
○ effects:
MOA kinetics/properties Indications- side effects-

cholecalciferol (vitamin D3) •used to produce active vitamin D (calcitriol) by fat soluble, accumulates, slow acting (4 weeks) • vitamin D deficiency • rare (hypercalcaemia, hypercalciuria)
hydroxylation in the liver and kidneys. • osteoporosis
interactions- Contraindicated in patients with severe renal
•increases the absorption of Ca2+ and phosphate in • Drugs with enzyme-inducing properties (e.g. impairment.
the intestine, their reabsorption in the kidney and the anticonvulsants, rifampin) may lead to Prefer water-soluble preparations in such cases.
activity of osteoclasts. vitamin D deficiency Important-
• Thiazide diuretics urinary excretion of calcium -> Overdose- may lead to hypercalcemia if extremely
increased risk of hypercalcaemia. doses are taken over a prolonged period-
• Systemic corticosteroids may metabolism and Daily doses > 4000 IU over long-term use (> 6 months)
elimination of vitamin D -> may require an in vitamin D without interruption may be unnecessary or harmful.
dose. • Absorption is improved when taken with dietary fats
• Vitamin D admin may the risk of digitalis toxicity • efficacy in impaired renal function, as activation of
(cardiac arrhythmia). vitamin D is compromised
• Rifampicin may the hepatic metabolism of vitamin D
and result in serum calcifediol concentrations and
osteomalacia.

calcitriol (active form of vitamin • Formation stimulated by PTH, inhibited by FGF23. At low levels- increases bone mineralization. 1.Osteodystrophy Serum calcium and phosphate levels must be monitored
D3-(1,25[OH]2D3)) • the most active metabolite At high levels- increases bone resorption. 2.osteoporosis regularly
3. rickets (Vitamin D dependent- also known as pseudo Overdose may lead to hypercalcemia and
Increases Ca2+ and phosphate release into vitamin D deficient), nephrocalcinosis
bloodstream by stimulating osteoblasts to activate Hypophosphatemic vitamin D resistant rickets.
osteoclasts.

teriparatide (PTH 1-34) Fragment of the parathyroid hormone, • injection (s.c injection 1x daily) • used as a daily subcutaneous injection in severe • most commonly reported side effects: nausea, limb pain,
contain the first 34 AA of PTH=> •enhances the maturation and activity of osteoblasts. osteoporosis headache and dizziness
have its total biological activity. • Ca2+/phosphate absorption at gut,
• activity of 1a hydroxylase in kidney (converts • Expected (side)effects of overdose:
risk of late hypercalcaemia and orthostatic hypotension
calcidiol→calcitriol)

Raloxifene Selective estrogen receptor modulators (SERM) used to treat osteoporosis due to its beneficial effects • Risk of DVT is equivalent to HRT but the risk of stroke is
• Agonists: in bone, (lipid metabolism) on bone metabolism. lower
• Antagonists: in breast and endometrium

clodronat (po) Non-nitrogenous bisphosphonate; It is used PO May cause GI symptoms, oesophagitis and
cytotoxic effect on osteoclasts. ulceration, atypical fractures.
It binds persistently to the bone surface and exerts
its antiresorptive effect.

Zoledronate (iv) Amino bisphosphonates Used intravenously. • Treatment of osteoporosis (postmenopausal) May cause gastrointestinal symptoms, oesophagitis
cytostatic effect on osteoclasts. and ulceration, atypical fractures.
→ They bind persistently to the bone surface and exert
Alendronate (po) anti-resorptive action. long term treatment-
often combined w/VitD Bisphosphonates inhibit osteoclasts, thereby reducing
bone resorption.
This is paralleled by a in osteoblast activity (bone
formation) → as these two processes are physiologically
coupled. Prolonged inhibition leads to suppressed bone
remodeling → bone enters a “stagnant” phase.
As a result, the bone becomes biologically aged

Denosumab Monoclonal antibody against RANK ligand. Used once every six months subcutaneously •Reduces bone turnover quicker than per os
it reduces osteoclast differentiation and activity. bisphosphonate treatment.
• Used in cases of high fracture risk.
Topic B21-Selective β2-stimulants and other bronchodilators.
● Antiasthmatics drugs-
○ Bronchodilators-
■ β2-AR agonists-

■ Xanthines

■ anti-muscarinic drugs

Drugs MOA duration kinetics indication adverse effect

selective β2-AR agonists-

salbutamol β2-AR agonist/ SABA Short acting inhaled, po resolution of asthma attacks. •CV disturbances (palpitation, tachycardia, angina)
- direct cardiac effects (β1,β2)
- vasodilation (β2)
inhaled, po, sc bronchodilation in asthma - presynaptic norepinephrine release (β2)
terbutaline •tremor (declines by chronic treatment)
SM relaxation in obstetrics
•hypokalemia
•metabolic effects (hyperglycemia, hyperlipidemia)
fenoterol inhaled relief of asthma attacks • arterial PaO 2
•mild loss of appetite, disturbed sleep – agitation (children - hyperactivity)
•development of tolerance
salmeterol β2-AR agonist/ LABA long acting

formoterol

other bronchodilators

theophylline Xanthine derivative long acting • E- follows zero-order kinetics at high • in dose-bronchodilation • CNS ↑ → anxiety, insomnia, tremor, seizures
PDE4 inhibitor- cAMP doses. • in dose-vomiting/ anxiety/ headache/ arrhythmia/ • cardiovascular effects
• narrow therapeutic index seizures. - at low doses mild elevation of BP ↑ (A rec. ↓)
• SM relaxation → - at higher doses „inodilator” effect (CAMP ↑)
bronchodilation •PO/IV • diuretic effect (GFR ↑, tubular sodium reabsorption ↓)
•in inflammatory cells- • GI secretions ↑ (gastric acid, digestive enzymes)
mediators release.
Plasma level is ↓by- rifampicin, phenytoin, carbamazepine
plasma level ↑by- erythromycin, diltiazem, fluconazole and caffeine.

ipratropium non-selective muscarinic Short acting inhaled anti-secretory activity in COPD dry mouth, cough
receptor antagonist (quaternary structure → less systemic effects)

tiotropium selective for M3 receptors long acting

(slower dissociation)
Topic B22-Antiinflammatory agents inhibiting bronchial inflammatory processes. Antitussive agents and expectorants

Anti inflammatory agents-

1. Glucocorticoids-

Drugs MOA indication adverse effect

systemic admin. glucocorticoids

prednisolone •alter gene expression- • systemic steroid treatment - in case of severe acute attacks or severe persistent • infections - oropharyngeal candidiasis
interact with intracellular receptors to inhibit the transcription of specific genes asthma (prednisolone p.os or methylprednisolone i.v.) - more side effects • hyperglycemia, diabetes
that code for various cytokines esp. IL-2. • peptic ulcer (PG ↓, defense against H. pylori ↓)
•Inhibits clonal proliferation of T & B cells and macrophage activation. Relative contraind.: • Cushing’s syndrome
methylprednisolone •Other actions : reduction in chronic infammation, autoimmune and • cardiovasc. diseases • osteoporosis, avascular necrosis of the femoral head
hypersensitivity reactions; various metabolic effects; negative feedback action on • peptic ulcer • reduced growth
ant. pituitary and hypothalamus. • glaucoma • muscle weakness, decreased muscle mass
• diabetes • CNS (seizures, depression, intracranial pressure↑)
• osteoporosis • GH, LH, TSH secretion ↓
• psychosis • glaucoma, hypokalemia, delayed wound healing, thinning of the skin
• infections (HSV, TBC) • acute adrenal insufficiency (if chronic treatment is stopped suddenly)

inhaled corticosteroids (ICSs)

fluticasone • anti-inflammatory / immunosuppressive effect • prevention of attacks in patients with mild-severe asthma or COPD • at low doses mild
•vasodilation ↓, extravasation and edema ↓ - oropharyngeal candidiasis
•neutrophil migration ↓, activity of leukocytes and macrophages ↓ Problems - hoarseness (vocal cord changes)
•annexin-1 ↑ → COX-2 expression ↓, PLA2 ↓ (PG, LT ↓) Ø bronchodilation, slow onset (> 4 h) → used only to prevent asthmatic attacks • at medium / high doses risk of systemic adverse effects
budesonide •pro-inflammatory cytokines ↓ (IL-1 - IL-6, IL-8, TNF-α, GM-CSF) relatively flat dose-response curve
•iNOS expression ↓ „non-responder” patients (steroid resistance)
•histamine release ↓
•IgG production ↓
•complement cascade ↓
• bronchial hyperreactivity ↓
• β2 adrenoceptor expression ↑

2. Leukotriene antagonists

Drug MOA Therapeutic effects Disadvantages

montelukast CysLT1 receptor antagonists • inflammation ↓ (LTC4, LTD 4, LTE4↓ → vasc. permeability ↓, edema ↓) • 2,5 h T1/2→ 4x daily administration (oral)
+ chemotaxis ↓ (LTB4) • risk of liver damage (4-5 %)
+ CysLT2 receptor-mediated effects ↓ • metabolism via CYP1A2 (possible interaction with theophylline)
• bronchodilation (mild → only prophylactic use)

3. Monoclonal antibodies

Drug MOA kinetics indications Adverse effects:

omalizumab • humanized anti-IgE mAB •T1/2- 26 days, •admin-every • used to prevent attacks in severe persistent allergic asthma • allergy (local erythema → anaphylactic reactions)
• prevents IgE-binding to and activation of mast cells, 2-4 weeks (s.c.) (if ICSs combined with LABA fail to control disease symptoms)
monocytes, granulocytes • also used to treat chronic spontaneous urticaria

Cough suppressant-

group groups activity indication drugs- MOA side effect-

Centrally inhibit the activity of the to relieve a non-productive (dihydro-)codein • opioid compounds, the strongest cough suppressants • codeine (contraindicated in children)
cough centre in the medulla (unproductive) dry cough (not • mechanism of action: not fully understood (effect not correlated with affinity for mu opioid • respiratory depression, risk of dependence
acting agents- oblongata recommended for productive receptor)
coughs with increased
secretion) dextrometorphan •synthetic morphinan, •well tolerated (Ø respiratory depression, dependence),
•mu opioid receptor activation negligible → Ø analgesia, •rarely rash, fatigue, nausea,
• mechanism of action: unclear (NMDA inhibition ?) •psychotomimetic effects at high doses
• Also SERT inhibitor- may cause serotonin syndrome in combination with MAO inhibitor

butamirate non-opioid compound, mechanism of action is unclear •well tolerated (rarely nausea, rash)

Peripherally excitability/activity of prenoxdiazine • mechanism of action not clear • mild central effect (but does not cause respiratory depression)
sensory receptors in the • well tolerated (rarely dry mouth, allergies)
acting agents- airways ,
excitability/activity of the
afferent neurons

Mucoactive agents (expectorants)

Mucolytics-

drugs- clinical effect clinical use kinetics side effect-

bromhexine, ambroxol loosening mucous • active metabolite of bromhexine. •Administration: rare (rash, nausea, allergy)
sputum/phlegm (also • increased activity of hydrolytic enzymes in salivary secretory cells cleaving of the mucopolysaccharides of per os (tablets, syrup), but also available as
loosens mucus in the saliva sucking tablets and nasal spray (in
• both secretolytic and mucokinetic (secretomotor) effects combination with oxymetazoline)
stomach, so
contraindicated in peptic
ulcers and
acetylcysteine recommended to •free SH groups - breaks down disulfide bridges in salivary glycoproteins (?) •administration: rare (allergy, headache, diarrhoea)
administer after meals) •both secretolytic and secretomotor effects per os (effervescent tablets, also sucking tablets),
but also i.v. form (also as an
•other uses: as a liver protectant expectorant)
(e.g. paracetamol, fly amanita (Amanita muscaria) - high dose required): can scavenge free radicals +
promotes synthesis of glutathione (GSH) •Interactions:
in vitro observations suggest that when given with
antibiotics, they may reduce each
other's effects (2 hours between ACC and
antibiotics administration recommended)
Topic B23-Drugs influencing gastric acid secretion, protective drugs of gastric mucosa
Ulcer-
● Integrity of gastric mucosa-
○ aggressive factors- HCI, pepsin, H.pylori, NSAIDs
○ protective factors- Mucus-bicarbonate layer, Surface active phospholipid, Tight junction protein, Mucosal microcirculation PG, NO.
● ulcer types-
○ Type I- distal/antral/duodenal ulcers- hyper-secretion → aggressive factor dominancy.
○ Type II-upper gastric- normal/decreased acid secretion → decreased protective factors.
Notes- GERD= gastroenteritis-esophageal reflux disease.

Ulcer therapy-
1. Inhibition of aggressive factors-

Drugs MOA effect- kinetics- indications side effects-

a. anti secretory agents-

famotidine Histamine H2 1. INHIBITION OF GASTRIC SECRETION • Absorption: good absorption from the stomach • GERD: twice/day in not severe, copmplicated cases • Safe drugs
•Inhibit both basal and stimulated (muscarin agonist, (Food, antacids reduce its absorbtion) (less than 3 heartburn/ week) • Headache, dizziness, nausea, diarrhea,
receptor gastrin) gastric acid secretion • First pass metabolism: significant (in erosive esophagitis: PPI!!) constipation,myalgia, skin rashes,pruritus,
antagonists •Especially effective in nocturnal (H2 receptor mediated) • Distribution: wide, cross the placenta, secreted into • Peptic ulcer disease: Duodenal/ gastric- largely Rarely in critically ill patients nosocomial pneumonia
and fasting acid secretion. milk. replaced by PPI
•Less effective against meal stimulated acid secretion • Elimination: most of them are not metabolized, suppression of nocturnal acid secretion, stimulates • CNS disturbance (in elderly people)
(gastrin-, Ach-,H 2-receptor mediated) eliminated by kidney (glomerular filtration, tubular healing of ulcer: bedtime administration results in • Rare effects:
excretion), in renal insufficiency dose reduction is 80-90% healing in 6-8 weeks thrombo-leukocytopenia
2. OTHER necessary. hepato-renal toxicity
•Enhanced immune response (?) • Duration of the effect: 10h; (administration twice daily) Indications (cont.)- i.v. inj.: bradycardia (H2 receptor)
•Antagonism of certain effects of histamine on heart and • NSAID: for prophylaxis of gastric lesion
vessels (H2 receptors) (in case of active ulcer: PPI!) common problems-
• Stress ulcer: though acid secretion is normal or • Hypochlorohydria
reduced, H2 antagonists or PPIs decrease the a) favors the survival of bacteria; respiratory infections,
incidence of bleeding (orally or iv. Infusion) nosocomial pneumonia
• Non-ulcer, intermittent dispepsia (??) b) atrophic gastritis
• Perianaesthetic medication in emergency
• Histologic verification of peptic ulcer is necessary,
since diagnosis of gastric cancer can be retarded in the
presence of H blockers, PPIs,

(es) Proton pump inhibits H+-K+-ATP-ase which is the final step in gastric •should be taken 1h before meal- • GERD • Hypergastrinaemia
acid secretion; since the acid secretion in secretory canaliculi is •Non-erosive reflux: H2 blocking drugs (hyperplasia of ECL-cells, carcinoid tumor in rats)
omeprazole inhibitors stimulated by meals, and acidic environment favors the intermittant with PPI • Potential risk: bacterial overgrowth
(PPIs) → Pro-drugs, lipophillic, weak bases, acid sensitive production of active form of PPI. •Erosive esophagitis: PPI, Rarely: gastrointestinal disturbance
→ Formulated as acid resistant enteric coated capsules, •Extra-oeophageal reflux • CNS: headache, dizziness skin rash, leukopenia,
pantoprazole delayed release omeprazole: also as powder (with •Not all proton pumps are inactivated after the first • Peptic ulcer disease acute interstitial nephritis
bicarbonate), immediate release) dose, 3-4 days are needed for the max effect. gastric ulcer after 6-8 w/s, duodenal ulcer
→ absorbs In alkalic intestines after 4 w/s. Side effects in long term treatment-
rabeprazole → After absorption enter the parietal cells, the secretory • Binds to plasma proteins and metabolized by CYP450 • NSAID/ASA- induced ulcer • Problems related to decrease acid secretion (Bacteria
canaliculi, enzymes (CYP2C19, CYP3A4). •Treatment: NSAID with active ulcer: stop colonisation
→ there, they are concentrated, protonated and form •In extensive metabolizers (EM) and poor taking it + PPI once or twice/day in the stomach, chronic inflammation, atrophic gastritis,
active compound- the reactive thiophillic sulfenamid cation, metabolizers the effectiveness of PPI can •Prevention of ulcer formation, or intestinal metaplasia. In humans no evidence on it)
→ reactive compound forms a disulfide covalent bond with diminish or increase, resp. complications: once daily NSAID-induced • Community aquired and nosocomial pneumonia
the cystein of H+/K+ ATP-ase. intestinal lesionsis: not affected • Diarrhoe induced by clostridium difficile and additional
• Effects: Inhibits both basal and meal-stimulated acid Interactions- bacteria (Salmonella, Shigella, E coli, Campylobacter) !
secretion for 24h. • Omeprazol- clopidogrel Indications (cont.)- • Nutrition problem with impaired absorption of vitamin
→ Omeprazol inhibits the formation of active • Stress ulcer: PPI by nasogastric tube or i.v. B12, iron, calcium !
metabolite of clopidogrel. :omeprazol – immediately release • Osteoporosis, increased risk of hip, spin, wrist fracture
→ Consequently, the anti-aggregation result in • H. pylori associated acute ulcer !
reinfarction. (combined with antibiotics)
Mechanism: CYP2C19 is responsible for the formation • Zollinger Ellison syndrome: first choice
of clopidogrel’s active metabolite, and the metabolism
of omeprazol.
Pantporazol, rabeprazol: minimal interaction.
• Inhibition of the absorbtion of vitamin B12,
ampicillin,ketokonazol and iron-salts

b. neutralizing agents-

MgOH Anti acids Mg(OH)2+2HCl=MgCl+2H poor solubility, cathartic effect- stimulation of intestinal motility →
→ Reacts with hydrochloric acid (HCl) in the stomach. prolonged neutralizing effect leading to bowel movement/ diarrhea.
magnesium → Produces magnesium chloride and water, thereby
hydroxide raising gastric pH.

Al2(OH)3 Al (OH)3+ 3HCl=AlCl3 +H2O AlCl 3: insoluble, slow action, constipation

→ Reacts with gastric acid to form aluminum chloride encephalopathy, Alzheimer? (kidney diseases →
aluminium- and water. Interactions- tetracyclines, phosphate. improper aluminium excretion → Aluminium
hydroxide → Neutralizes acid more slowly than Mg(OH). → AICI3 binds → form insoluble complexes, which accumulation → neurotoxicity).
→ Forms a protective coating on the ulcer base. complex cannot be absorbed from the GI tract
result- antibiotic efficacy.

2. Increase of mucosal resistance-

Drugs General MOA Indication- side effect-

sucralfate Basic aluminium salt of sucrose the (-) sucrose octasulphate binds to (+) protein molecules: gel • critically ill patients by nasogastric tube to the •obstipation,
octasulphate • the back-diffusion of H+ incidence of bleeding 3% can be absorbed, in renal impairment
• stimulation of PG synthesis • prevention of stress-related bleeding (instead of aluminium can accumulate
antisecretory drugs (risk of nosocomial pneumonia)

• Interaction: antacids, H2 antagonist should not be taken

simultaneously (sucralfate is effective only in acidic
environment)

bismuth subsalicylate bismuth salts a. chelating with protein, forms coating, • diarrhea, travellers diarrhea • darkening of oral cavity
protective layer against acid • in combo to eradicate H.pylori (PPI, tetracycline, • encephalopathy,
b. antipeptic activity metronidazole) • osteodistrophy: only, if renal damage
c. stimulates prostagladin, mucus, bicarbonate secretion
d. antimicrobial effect against H. Pylori!!
( e. bismuth subsalicylate reduces stool frequency; salicylate inhibits prostaglandin
formation and chloride secretion)
Topic B24- Antiemetic drugs. Prokinetic agents.

Drugs MOA indication side effects

dimenhydrinate H1 receptor antagonist • Prophylactic, • sedation,

M antagonist • for vomiting of vestibular origin. + effects resulting from M/D/and other receptor blockades
• We use those that have other receptor effects, so they are more
effective.

droperidol D2 receptor antagonists- • Injection preparation available for perioperative antiemetic, strong Consequences of dopamine receptor blockade -
in the chemosenzitive trigger zone (low effect on nausea of vestibular origin) sedative • Extrapyramidal symptoms
• Neuroleptic malignant syndrome
• Hyperprolactinemia

metoclopramide D2 and 5HT3- antagonism: antiemetic effect • Gastroparesis • Extrapyramidal symptoms

D2-antagonism and 5HT4-agonizmus: prokinetic effect (mainly at the level of the Only for short term use due to central side effects (SPC: 5 days, • Hyperprolactinemia
stomach, increases the tone of the lower oesophageal sphincter) FDA: <12 weeks)

ondansetron 5-HT3-receptor antagonists • most effective antiemetics during chemotherapy, but are also • Mild: headache, constipation, hiccups, mild QT prolongation
Both centrally and in the GI tract effective after radiotherapy and surgery.

palonosetron • ondansetron: 1x daily p.o./i.v. (granisetron aspatch as well)

• palonosetron: stronger selectivity for 5HT3 (also called 2.
generation agent) long half-life (40 h), p.o. / i.v.

(fos) aprepitant NK1-receptor antagonists Used during chemotherapy, in combination with steroids • Dizziness, diarrhoea
Neurokinin 1 receptor antagonism: central blockade in area postrema (blocks (dexamethason) and 5HT3-antagonists. • CYP3A4 inhibiton
substance P receptors in the vomiting centre). → Can influence the metabolism of several chemotherapeutics
→ Can increase INR in patients taking warfarin
• aprepitant: p.o.
• fosaprepitant: i.v.

dexamethason Glucocorticoids Used during chemotherapy

In combination with 5HT3-antagonists or D2-antagonists.
as they possibly augment their effect.
Topic B25- Drugs used in constipation (laxatives) and diarrhea. Drugs promoting digestion. Pharmacology of liver and biliary tract

Drugs MOA indication side effects

Drugs used in constipation- Laxative agents-

plant fibers Agents increasing GI content volume- •fibres are not absorbed, they reach the colon, absorb water Very rarely-
as hydrophilic colloids, swell and stimulate motility by •obstruction (need to drink a lot of fluids)
stretching the intestinal wall. •bloating (bacterial breakdown of fibres).
•Effect takes 1-3 days.

magnesium-sulfate (MgSO4) Osmotic laxatives- salts

They are not (or barely) absorbed from the
intestine and retain water in the gut through
lactulose their osmotic action. carbohydrates- prophylaxis for hepatic encephalopathy in liver failure.
Their effect usually takes 3-10 hours to take → converted to lactic and acetic acid in the intestine, Can also be given in pregnancy!
effect (higher doses are used for → inhibits NH3 reabsorption by pH.
surgical/diagnostic preparation).

paraffin oil Stool softener (Paraffinum liquidum) FoNo Can be given to pregnant women and children! may rarely the absorption of fat-soluble vitamins.
It takes 6-12 hours to take effect.

bisacodyl Bowel wall stimulants- diphenylmethanes- synthetic compounds. takes longer to take effect (8-12 hours),
They increase the secretion of electrolytes (Na, and the active metabolite (deacetylbisacodyl) is formed in the liver.
K, Cl) and inhibit Na and water reabsorption.
sennoside- antraquinones- natural compounds found in many plants •dark stools + urine (about 5% absorbed).
•Although they are natural compounds, prolonged use
can also lead to habituation.

Drugs used in diarrhea- obstipants-

active charcoal,kaoline Adsorbents, adstringents •Adsorption: adhesion to surface. •Adsorbents can bind
toxins on their molecular surface
•Activated charcoal, kaolinite (mineral powder, magistral raw
material, component of ‚Bolus adstringens’), diosmectit.
diosmectit •Activated charcoal is also used in certain acute poisonings
when there is hope for surface binding of the poison in the
intestinal lumen.

diphenoxylate •Anti-motility agents-opioids •They inhibit motility and activity of secretomotor neurons of Anticholinergic agents- pl. atropine + diphenoxylate
•peripherally acting µ-opioid receptor agonists the enteric nervous system.

loperamide

racekadotril Inhibitors of intestinal epithelial secretion Prodrug, its active metabolite (thiorphan) inhibits Symptomatic treatment of acute diarrhea Constipation, headache.
enkephalinase.
Elevated enkephalin levels have an antisecretory effect, with
no significant effect on motility.

Appetite stimulants (orexigenics), digestive aids-

simeticon Anti-bloating agents •The surface tension of the gas bubbles is reduced •As there is no absorption, there are no side effects.
(physical),
•the bubble wall collapses,
•the escaping gases are absorbed through the intestinal wall
or are expelled as a result of intestinal motility.

Hepatic and biliary agents-

ursodeoxycholic acid Secondary bile acids- formed in the gut by •more hydrophilic and less toxic than other endogenous bile •Resolving small cholesterol gallstones (when cholecystectomy UDCA generally well tolerated, other bile acids may
bacteria acids! cannot be performed), cause diarrhoea, liver damage.
Bile acids are reabsorbed in the ileum and are • the amount of bile acid circulating, •Primary biliary cirrhosis: mildly reduces cholestasis and alleviates
• the proportion of UDCA in the circulating bile acids, which symptoms (presumably complex effect, e.g. anti-inflammation, Contraindications:
involved in enterohepatic circulation.
is less hepatotoxic, replacement of more toxic endogenous bile acids, but moderate Acute hepatitis, biliary obstruction.
Their role: emulsification of the fat content of can the amount of bile produced: choleretic effect. efficacy)
food and the cholesterol content of bile

colesevelam Bile acid sequestrants Disease of the ileum (e.g. IBD) or surgical removal of the • Bile acid diarrhoea •As bile acids are less able to be excreted into the gut,
ileum reduces enterohepatic • Symptomatic treatment of cholestatis: cholestasis = biliary their levels in the blood and other tissues,
reabsorption of bile acids, causing diarrhoea in the colon, obstruction, e.g. due to biliary causing→itching (pruritus).
which is reduced by bile acid binding resins stricture. •Despite the constriction, the binding and evacuation
• Hypercholesterolaemia: bile acids are replaced by the liver by of bile acids in the intestine can reduce the body's
converting cholesterol taken total bile acid levels to some extent and reduce
from the blood into bile acids, thus cholesterol levels. itching.

acetylcysteine Hepatoprotective agents •(ACC) in high doses (available i.v., as antidote) • Acute liver damage (poisoning with paracetamol, killer gallstones,
•Antioxidant (-SH group reacts with free radicals), and can halogenated
form glutathione, which is important for cell functions. hydrocarbons)
• used as an expectorant in low doses

silymarin extract of the marigold plant, capsule, TK → is responsible •Adjuvant treatment of acute toxic liver injury (e.g. CCl4, poisonous
for the beneficial effects Its active component: silibinin (i.v., gallstones)
TK) •chronic inflammatory liver disease and cirrhosis.
• free radical levels,
• inhibiting lipid peroxidation,
• enhancing protein synthesis.
Topic B26- Histamine and antihistamines

● The autacoids are locally produced hormones which have local effects in the body such as histamine (it is also a NT), bradykinine, prostaglandines
● The antihistamines are indicated in allergic diseases such as hay fever, insect bites, urticaria, itching or conjunctivitis
● The 1st generation antihistamines are lipophilic compounds, so they can enter to the CNS and cause sedation as a side effect,
● The 2nd generation drugs don’t cause sedation, their side effect profile is much better than the first generation

Drug- Type MOA indication side effect- kinetics

betahistine histamine analogue H1-R partial agonist Symptomatic treatment of vertigo associated with Meniere's •Gastro-intestinal disturbances,
H3-R antagonist syndrome. •headache and skin rashes

Contraindications:
•Patients with active peptic ulcer.
•Patients with phaeochromocytoma.

dimenhydrinate 1st generation Inverse agonist of H1-R. •treatment of vomiting. Side effects are due to inhibition of M,α and brain H1-R.
antihistamines- M-R blockers •Diseases associated with allergic reactions fewer anticholinergic side effects.
•lipophilic, cross BBB a1 adrenergic antagonist •Nausea relief (e.g. in case of kinetosis)
•sedative in patients insomnia

dimetinden •Diseases associated with allergic reactions

•Urticaria

chloropyramine •Diseases associated with allergic reactions

•sedative in patients insomnia

(levo) cetirizine 2nd generation H1-receptor antagonist •Urticaria,

antihistamines- •Mainly used systemically in allergic disease
•more selective for peripheral H1-R
(des)loratadine •less lipophilic → don’t cause •Hypersensitivity metabolised by
•dizziness, CYP-enzymes
sedation
•tachycardia, liver and the kidneys
•nausea, eliminate
•rashes

fexofenadin •Hypersensitivity

bilastine •hay fever

•urticaria
Topic B27- Drugs acting on smooth muscles. Drugs influencing uterus contractions.

Mechanism of Smooth Muscle Contraction and Relaxation:

❖ Contraction:
• Ca²⁺ enters the cytoplasm → calmodulin activates myosin light chain kinase (MLCK)
• MLCK phosphorylates the myosin light chain (MLC-P) → actin-myosin interaction → MUSCLE CONTRACTION

❖ Relaxation:
• β₂-receptor activates adenylate cyclase enzyme → cAMP levels increase
• cAMP activates a kinase enzyme that inhibits MLCK → myosin
dephosphorylation → MUSCLE RELAXATION

Drug- MOA indication kinetics side effect-

papaverine SM relaxation Multi-target smooth muscle antispasmodics For the treatment of smooth muscle cramps: GI cramps, biliary, GI absorption is uncertain
Ca2+-channel inhibition, PDE inhibition kidney and ureteral colica

drotaverine

butylscopolamine Anticholinergic agents GI cramps dry mouth, constipation and blurred vision

Contraindications:
Anticholinergic agents Overactive bladder (incontinence and/or frequent urination • Partial or complete GI occlusion
solifenacin Paralytic ileus
(M3-R antagonis):)
Urinary retention
Closed-angle glaucoma
oxybutinine Anticholinergic agents incontinency Gastric retention
Obstructive uropathy

tamsulosin α-receptor antagonists

latanoprost SM constrictor- Lipid autacoids →EICOSANOIDs Open-ended glaucoma and ocular hypertension
Prostanoids [e.g. Prostaglandins, Thromboxanes]

oxytocin uterine constrictor- • Induction and intensification of uterine contractions Short acting (T ½ a few minutes)
Sensitivity only in the period around childbirth Formulas: inj. (i.v., i.m.)
•induction of labor, pain intensification, postpartum atonic
bleeding,
•promotion of milk shedding

ergotamine uterine constrictor- •Postpartum/abortion uterine bleeding (atonia post partum) •Increased blood pressure,
Ergot alkaloids •Prevention and treatment of puerperal subinvolution •Migraine •reflex bradycardia,
attack Gynecological hemorrhages •nausea,
•vomiting
(stimulates the vagus and CTZ)

misoprostol uterine constrictor- Gemoprost (PGE1 analogs) •Initiation and preparation for labor (cervix "maturation") Lower abdominal cramps,
•Helping to give birth to a dead fetus hyperemia,
•Atonic bleeding (abortion/childbirth) bronchial cramps
PGE2 analog •Preparation for abortion (2nd trimester),
sulproston •Chemical abortion (in combintation with
Mifepristone)

terbutaline uterine relaxants β2-receptor agonists

(TOCOLYTICS)

atosiban Oxytocin antagonist iv., 24-33 weeks of gestation

Mg++ orally, infusion

ethanol infusion and p.o.

Topic B28- Immunopharmacology I. (cytotoxic agents).

Drug- MOA indication side effect-

cyclophosphamide Alkylating agents nitrogen mustard gas derivative. •immunosuppressant and antitumor agent. •haemorrhagic cystitis (antidote is
Prodrug, •SLE mesna).
the active metabolite is a bifunctional alkylating agent that •teratogenic
damages DNA- •suppress bone marrow
→ alkylates DNA (on N7) of guanosine, where it forms
cross-links inside/btw the DNA chain
→ inhibits both T and B cells

methotrexate Inhibitors of purine or folic acid antagonist- •Effective in solid and haematological tumours. •may be counteracted by leucovorin.
pyrimidine synthesis → inhibit DHF-reductase →depletion of folic acid → blockade •teratogenic
(Antimetabolites) of DNA synthesis. •suppress bone marrow
→Without activated folic acid, there is no thymidylate
synthesis, so it is cytotoxic (at high doses, administered
intravenously).

antimetabolite

leflunomide → inhibits de novo pyrimidine synthesis by inhibiting DHODH •RA •Hepatic and bone marrow toxic.
(dihydroorotate-dehydrogenase) •teratogenic
→This has a cytostatic effect on lymphocytes, as they are still
able to synthesize pyrimidine bases via the rescue pathway.
→ teriflunomid is the active metabolite of leflunomide.
they block T-cell proliferation and AB production of B-cells

azathioprine immunosuppressive agent, its action- •Mainly used in post-transplant immunosuppressive protocols. •teratogenic
→ converts to 6-MP, •liver and bone marrow toxic.
→Further converts to this-IMP
→Block AMP/GMP synthesis (⇏ purine synthesis).

mycophenolate- It's active metabolite is mycophenolic acid, •transplantation •Damages bone marrow.
→ inhibit purine synthesis by inhibiting the enzyme IMP •teratogenic
mofetil dehydrogenase.
→ The purine rescue pathway does not function in
lymphocytes, so it has a cytotoxic effect on them.

Topic B29-Immunopharmacology II. (Inhibitors of cytokine gene expression, 5-ASA derivatives)

Drug- MOA indication side effect-

cyclosporin A- Inhibitors of inhibits calcineurin via forming complex w/cyclophyllins, after transplantation and in inflammatory diseases. Toxic to kidney and liver,
cytokine (e.g. IL-2) → inhibit IC signaling of TCR and IL-2 synthesis and clonal may cause gingival hyperplasia.
production or action proliferation of Th1 cells.

tacrolimus - They bind to FKBP-12, the complex inhibits calcineurin (more after transplantation and in inflammatory diseases. Toxic to kidney and liver.
potently than cyclosporine A)
thus preventing IL-2 synthesis and clonal proliferation of Th1 cells.

sirolimus antibodies against IL-6R. Effective in RA. bone marrow suppression

→mTOR inhibitor Hepatotoxic
binds to FKBP12, but the complex inhibits mTOR
- mTOR has a central role in the IL-2 activation pathway in
lymphocytes.

tofacitinib JAK1,2 kinase inhibitor, which inhibits the JAK-STAT signalling RA, psoriasis and other inflammatory diseases. bone marrow suppression
pathway → blocks IL-2 (4,6,7,9,15,21) pathway in T cells. Metabolised by CYP
thus exerting an anti-inflammatory effect.

sulfasalazine Inhibitors of In the colon, it is cleaved to 5-ASA (5-aminosalicylic acid) and RA bone marrow suppression
cytokine gene sulfapyridine IBD.
expression → 5-ASA induces PPARγ expression → ⇏ inflammatory response.
(Inflammatory response=
inhibiting the activation of NF-κB and TLRs.
blocks the function of IL-1, TNFα, IL-2, IL-8, COX and LOX.).
Topic B30- Immunopharmacology III. (Antibodies and fusion proteins)

Drug- MOA indication side effect-

ATG Immunosuppressive antibodies- polyclonal antibody from serum of animals (rabbits) immunised with Mainly used against acute rejection.
human thymocytes.
(antithymocyte-globulin) blocking T cell surface
molecules involved in signaling
of immunoglobulins

rituximab Immunosuppressive antibodies- anti-CD20 antibody often used in the therapy of various lymphomas and leukaemias
against B cells

infliximab Immunosuppressive antibodies- chimeric antibody against TNF-α. used in RA, psoriasis or IBD. Preferably combined with Contraindicated in heart failure.
methotrexate.
antibodies against adhesion
molecules or cytokines

adalimumab human antibody against TNF-α. may be used in RA, psoriasis or IBD. Preferably combined with Contraindicated in heart failure.
methotrexate.

ustekinumab antibody against the common p40 subunit of IL-12 and Il-23. Mainly used in psoriasis, IBD

tocilizumab antibodies against IL-6R. Effective in RA.

natalizumab anti-a4-intergrin antibody used in the therapy of MS. It prevents the lymphocytes from
migrating into the central nervous system.

dupilumab monoclonal antibody against IL-4 receptor. It is given as a subcutaneous injection in severe asthma.
Its effect is to reduce inflammatory signalling associated with Th2 cell
activation.

abatacept fusion protein consisting of a fragment of human IgG Fc and the Used in RA therapy.
CTLA-4 domain. It prevents costimulation so that T cells are not
activated.

Topic B31-Drugs used in cancer treatment I (antimetabolites)

Drug- MOA indication kinetics- admin side effect-

Pyrimidine analogues

5-fluorouracil •antimetabolite with fluoropyrimidine structure, •colorectal carcinoma. •cardiotoxic (coronary vasospasms)
•cytotoxic agent. •hand-foot syndrome,
Upon activation in the cell →inhibits thymidylate synthase enzyme, •mucositis,
→ thus having S phase specific activity. •bone marrow damage.
•It can be increased with leucovorin.

capecitabine prodrug of 5-FU •mainly for the treatment of colorectal carcinoma. •used per os

Gemcitabine Fluorinated deoxycytidine analogue - solid tumors Thrombotic thrombocytopenic purpura

upon entry into the cell, deoxycytidine is phosphorylated by the (TTP)
enzyme DCK to dFdCMP and then converted to dFdCTP → which
is incorporated into and damages DNA

cytarabine cytidine analogue bound to arabinose •shows considerable sensitivity to bone marrow-derived cells • intrathecally.
→ damages DNA in deoxy form. •mainly used in haematological tumours.

Purine analogues

6-mercaptopurine purine analogue antimetabolites Mainly used in haematological tumours.

inhibit de novo purine synthesis.

fludarabine Purine analogues hematological tumors (leukemia, lymphoma)

Inhibition of Ribonucleotide-reductase (RNR) and DNA-polymerase
- Effective in dividing and resting cells as well

Ribonucleotide reductase inhibitor

hydroxyurea Ribonucleotide reductase inhibitor- •antitumour agent in haematopoietic or head and neck Bone marrow suppression
depletes deoxyribonucleotides → inhibits DNA synthesis tumours.
(hydroxycarbamide) Hematologic and solid tumors

antifolates

methotrexate folic acid antagonist antimetabolite. •immunosuppressive and cytotoxic treatments •in dose- •liver, lung and bone marrow toxic
→anti-inflammatory effect by the inhibition of AICAR- •Effective in solid and haematological tumours. administered
transformylase (by MTX-polyglutamates) weekly •Its side effects may be counteracted by
•at doses, leucovorin.
→DHF-reductase inhibitor →depletion of folic acid → DNA administered
synthesis blockage. intravenously

pemetrexed folic acid antagonist antimetabolite. Effective in solid tumours (NSCLC, mesothelioma) •Its side effects may be counteracted
Without activated folic acid, there is no thymidylate synthesis and by leucovorin.
thus no cytotoxic effect.
Topic B32-Drugs used in cancer treatment II (cytotoxic agents targeting DNA)

Drug- MOA indication side effect-

alkylating agents

cyclophosphamide Nitrogen mustard derivative The active metabolite is a bifunctional alkylating agent that immunosuppressant •Hemorrhagic cystitis (antidote is mesna).
prodrug damages DNA. antitumor agent. •Solid tumors
•cardiotoxicity- hemorrhagic myocarditis
→alkyl group covalently bonds and form cross links with
purines/pyrimidines → DNA-replication & transcription are inhibited.

melphalan local agent for solid tumors lung fibrosis

busulfan Conditioning for autologous or allogeneic bone marrow

Cross-links between DNAstrands →↓ DNA replication transplantation

non-classical alkylating agents

dacarbazine Besides alkylating it is possible that inhibits the binding of the methionine to tRNA melanoma and Hodgkin's lymphoma. Hepatotoxicity

temozolomide it methylates bases after hydrolytic activation. good brain penetration and can be used in glioblastoma.

platinum-based agents

cisplatin it creates cross-links in DNA, which leads to apoptosis after mismatch repair is activated. can be used in multiple indications. Strongly emetic
nephrotoxic

oxaliplatin it creates cross-links in DNA, which in itself leads to apoptosis. mainly in colorectal carcinoma. Neurotoxic

intercalating agents

dactinomycin G2/M specific! cytotoxic and intercalating antibiotic with G2/M phase specificity, mainly for solid tumours vesicant agent (cause blistering)
-pediatric tumors
-Wilma tumor
-Ewing sarcoma
-Rhabdomyosarcoma

bleomycin cytotoxic and intercalating antibiotic with G2/M phase specificity that Mainly used in testicular cancer cause long-term damage to the lungs.
acts through free radical formation Hodgkin lymphoma
Topic B33-Drugs used in cancer treatment III (Topisomerase inhibitors. Inhibitors of mitotic spindle)

Cell cycle phases-

1. Interphase
a. G1-grow
b. S- DNA replication
c. G2- grow
2. Mitosis (M phase)
a. Prophase
b. metaphase
c. anaphase
d. telophase
3. Cytokinesis

Drug- MOA indication side effect-

Topoisomerase inhibitors-
cell cycle specific, during late S, early G2 phases

irinotecan topoisomerase I inhibitor, cytotoxic agent (causing DNA damage during colorectal carcinoma. neutropenia
replication → cell death) severe diarrhoea.
→prodrug, must be activated in the liver

etoposide topoisomerase II inhibitor, a cytotoxic agent •tumours of bone marrow origin and in myeloblastic bone marrow suppression.
and testicular cancer.
•Small-cell lung cancer

doxorubicin anthracycline type chemotherapeutic agent (cytotoxic antibiotics) leukaemia, •Strongly cardiotoxic agent (for prevention:
→ inhibit topoisomerase II, solid tumours. dexrazoxane).
→ free radical formation.
→ intercalation

epirubicin •more lipophilic

•less toxic than Doxorubicin

Mitotic spindle inhibitors-

cell cycle specific, during M phase

vincristine → vinca alkaloids leukaemias, •Neurotoxicity is a significant side effect (interfere with
→ inhibit polymerization of β-tubulin (responsible for formation of lymphomas, neuronal axons’s microtubule polymerization)
microtubules/centrioles/centrosome/spindle fibers) some solid tumours.
→ cell cant perform mitotic spindle → will stop at metaphase
→cell cycle M-phase specific.

docetaxel → taxane-type cytotoxic agents, therapy of breast cancer. •May be allergenic (steroid premedication/specific
→ inhibit depolymerisation of microtubules (prevent them from breaking down formulation may be required).
during anaphase) •Neurotoxicity
cabazitaxel → M-phase specific agents-cell cycle specific
Topic B34-Drugs used in cancer treatment IV. (Hormonal agents)

Drug- MOA indication side effect-

tamoxifen SERM- selective estrogen receptor modulator It is used to treat breast cancer.
acts as an antagonist in mammary tissue.

anastrozole aromatase inhibitor indicated for tamoxifen-resistant breast cancer. May cause osteoporosis
vasomotor symptoms as a side effect.

goserelin GnRH analogue. •In a pulsatile dosing regimen- for ovulation induction,
•in continuous dosing- inhibits sex steroid synthesis →
used to treat-
leuprorelin sex hormone-sensitive tumours, leiomyomas, endometriosis, PCOS, precocious
puberty.

degarelix GnRH antagonist, It can be used to treat hormone-dependent tumours (prostate cancer, breast
→ inhibits the secretion of LH and FSH. cancer).

bicalutamide anti-androgen agent •used in prostate cancer therapy as part of a complete androgen blockade
(supplemented with a GnRH analogue).

prednisolone induce apoptosis in immune cells, •adjuvant therapy in various haematological or immune cell-derived tumours
•reduce chemotherapy-induced nausea.

octreotide somatostatin octapeptide analogue variable indications (e.g. acromegaly, hormonal-gastrointestinal tumours, •steatorrhea,
oesophageal haemorrhage). •gallstones,
•bradycardia,
•prolonged QT,
•hyperglycemia

apalutamide 2nd generation androgen receptor antagonists prostate cancer as part of complete androgen blockade

darolutamide
Topic B35-Drugs used in cancer treatment V. (Small molecule signal transduction inhibitors. Retinoids)

Drug- MOA indication Kinetics side effect-

tyrosine-kinase inhibitors

Imatinib an ATP analog CML and GIST.

inhibits BCR-ABL (Philadelphia chromosome-associated protein), c-kit, PDGF-R
tyrosine kinases.

Ibrutinib irreversible BTK inhibitor, so it inhibits B cells. CLL, MCL (mantle cell lymphoma)

Crizotinib ALK, HGFR (hepatocyte GF-R) and C-met tyrosine kinase inhibitor. NSCLC in ALK, ROS1 positivity.

Lapatinib EGFR1,2 (epidermal) and HER2 kinase inhibitor. breast cancer. cardiotoxic
Cross BBB

Erlotinib reversible EGFR (epidermal) kinase inhibitor. NSCLC CYP3A4 metabolism Causes skin rashes
diarrhoea.

Gefitinib reversible EGFR (epidermal) and PDGFR (platelet derived growth factor-R) kinase cause skin rashes.
inhibitor.

multi-tyrosine kinase inhibitors

Sunitinib multi tyrosine kinase inhibitor- renal cancer and GIST.

VEGFR (vascular endothelial GF)
PDGFR (platelet derived growth factor-R)
c-kit kinases.

Serine/Threonine kinase inhibitors

Palbociclib Inhibits Cyclin dependent kinase 4/6 Treats breast cancer Causes myelosuppression
→ induces arrest at G1-S phase

Dabrafenib exert antiproliferative effects by inhibiting BRAF(Dabrafenib)+ MEK(trametinib) Used in melanoma.

kinases.
trametinib

Everolimus inhibits cell cycle and angiogenesis by inhibiting mTOR. renal, pancreatic and breast tumours.

other signaling inhibitors

Adagrasib G12C inhibitor -mutated KRAS GTPase NSCLC

po

Idelalisib Phosphoinositide 3-kinase inhibitor, For blood cancers

→ blocks P110δ, delta isoform.

Vismodegib SMO inhibitor metastatic basal cell carcinoma

Target the Hedgehog signaling pathway.

Venetoclax Inhibition of Bcl2, an antiapoptotic protein, For CLL, AML. Causes tumor lysis syndrome.
inducing apoptosis in leukocytes.

Olaparib Inhibits PARP For Breast, ovarian, pancreatic, prostate cancers. Causes cytopenias, CI in pregnancy
→decreasing DNA repair causing accumulated damage and apoptosis.

Bortezomib reversible proteasome inhibitor, multiple myeloma.

→ inhibiting the degradation of proteins in the cell.

Tretinoin all-trans retinol leukaemias dryness, depression, photosensitivity

has antiproliferative effect through activation of the RXR receptor.
Topic B36-Drugs used in cancer treatment VI. (Large molecule signal transduction inhibitors. Immunostimulant anticancer drugs.)

Drug- MOA indication side effect-

antibody drugs

trastuzumab monoclonal antibody drug against HER2 receptor, breast cancer

gastric carcinoma.

trastuzumab- conjugated antibody drug against HER2 receptor, inhibits cardiotoxic side effects,
microtubule assembly and activates immune response (cell cycle arrest especially in combination therapy with anthracyclines.
emtansine- and apoptosis)

pertuzumab antibody that inhibits HER2 dimerisation, inhibits signalling and Adjuvant for HER2 positive breast cancer.
opsonises tumour cells.

panitumumab anti-EGFR antibodies colorectal and lung carcinoma if the patient May cause skin rashes.
does not have a KRAS mutation.

rituximab antibody against CD20, B-cell lymphomas lymphocytopenia

which activates the immune response against the cell by binding to it. leukaemias. allergic reactions

bevacizumab is an anti-VEGF antibody, inhibits angiogenesis. adjunctive therapy in cervical, colorectal During its use, wound healing is slower, coagulation disorders
carcinoma, may occur.
off-label macular degeneration.

immune check-points inhibitor

ipilimumab anti-CTLA4 antibody; Mainly used in melanoma.

inhibits T-cell apoptosis,
enhancing the anti-tumour immune response.

pembrolizumab anti-PD1 antibodies;

inhibit T-cell apoptosis,
enhancing the anti-tumour immune response.

recombinant molecules

alfa-interferon recombinant endogenous molecule. tumour therapy proliferation inhibitory effects.

immune response enhancing,

aldesleukin recombinant form of IL-2, difficult-to-treat tumours.

triggering an immune response