Pharmacology

parenteral anticoagulant

1. unfractionated heparin (indirect)

2. LMWheparin (Indirect)

3. fondaparinux (Indirect)

4. bivalirudin (direct)

oral anticoagulant

1. warfarin

2. dabigatran

3. rivaroxaban

unfractionated heparin

• parentral

• high bound to plasma proteins

• low bioavailabiliy

• rapid

• short half life

• no need for dose adjustment in renal failure

• safe during pregnancy and lactation

• antidote: protamine sulfate

mechanism of action:

• bind to antithrombin3

• inhibit factors 2,10,11,12,13

• inhibit free thrombin only

• monitor by aPTT, CT

adverse effects of heparin

1. bleeding

2. re thrombosis

3. HITT

4. osteoprosis

5. cutaneous necrosis

6. hyprekalemia

LMWH

• enoxaparin

• bind more to factor Xa than to thrombin

• can be given outside the hospital

• no need for regular monitoring

• adjusted in renal insufficiency and obesity

• longer duration of action

• less tendency to develop bleeding and HITT

factor Xa inhibitors

• used as subsitiuation for heparin in patients with HITT

• not improved during pregnacy

• no need for regular monitring

• need adjustment in renal impairment

indirect: fondaparinox:

parentral IV or SC, good bioavalibility, long half life

direct: revaroxaban:

oral, once or twice daily, metabolized by CYP3A4, antidote: andexanet

direct thrombin inhibitors

• used instead of heparin in patients with HITT

• not approved during pregnancy

• avoided in severe renal impairment

• no need for regular monitoring

• inhibit free or fibrin bound thrombin

parentral: bivalirudin

cardiac intervention, eliminated by kidney and liver

oral: dabigatran

pro drug, renally excreted, antidote: idarucizumab

warfarin

• high bioavailability

• high bound to plasma proteins

• onset of action 72 hours

• metabolized by cytp450

• teratogenic

• inhibit vit k reductase enzyme

• need bridging time with parentral anticoagulant

• monitored by PT, INR

adverse effect of warfarin

1. bleeding (fresh frozen plasma)

2. teratogenic

3. skin necrosis (rare)

vit k to reverse its effect, it take 6 to 12 hours

drugs cause warfarin toxicity

1. broad spectrum antibiotics

2. cytp450 inhibitors: clarithromycin

3. aspirin (bound to plasma proteins)

drugs decrease efficacy of warfarin

1. vit k

2. cholestyramine decrease absorption

3. cytp450 inducers: carbamazepine

4. estrogen, oral contraceptive increase synthesis of vit k

thromboxane A2 inhibitors

• ASA, aspirin

• iriivrsible cox1 inhibitor

• its inhibition sustained throughout life span of the platelet

• small dose of aspirin will not suppress prostacyclin (325 mg)

• in acute conditions (ACS, stroke) use chewable forms

• DAPT with ADP antagonist for secondary prevention

• long term use cause peptic ulcers, use enteric coated aspirin

• use with ibuprofen result in aspirin resistence

ADP receptors antagonists

• clopidogrel, ticagrelor (clop, tic)

• antagonists to ADP receptors subtype (P2Y12)

• clop: irreversible, prodrug, give loading dose, DAPT

• tic: active, reversible, vasodilating, faster, induse dyspnea

glycoprotein 2b 3a receptors antagonist

• tirofiban

• reversible, competitve inhibitor of GP 2b3a receptors

• inhibit final common step in thrombus formation

• IV infusion, during and after PCI

• must be adjusted in renal insufficiency

protease activated receptor 1 antagonist

• vorapaxar

• oral, selective antagonist

• indicated in myocardiac infarction and during cardiac intervention

• PAR1 is platelet thrombin receptor

fibrinolytic drugs

• cleave plasminogin ino plasmin, hydrolyse fibrin

• recently formed thrombus within 6/12 hours

• fibrin specific agents: alteplase, non antigenic, fibrin bound plasminogen

• non fibrin specific: streptokinase, synthesized by streptocci, act on both circulating and fibrin bound plasminogen

hemostatic drugs

1. vit k:

• factors 1972

• anaphylactic reaction may occur with too rapid IV injection

2. antiplasmin:

• aminocapric acid, tranexamic acid

• inhibit plasminogen activator

3. V2 agonist:

• desmopressin

• increase von willebrand factor and factor 8

• used in patients with hemophilia A or von willebrand disease

4. V1 agonist

• terlipressin

• potent vasoconstriction

• used in acute variceal hemorrhage

resistant hypertension

failure to reach goal BP in patients adhering 3 or more drugs including a diuretic

causes: poor compliance, alcohol, high salt intake, diabetes, obisity, concomitant drugs such as sympathomimetics, NSAIDs, corticosteroid

treatment of hypertension

1. nonpharmacological treatment: exercise, dietry, decreased salt intake, increased k intake

2. pharmacological treatment: first line: thiazide diuretics, calcium channel blocker,angiotensin blocker

thiazide diuretics

• moderate natriuretic effect

• most frequently used diuretic in treating hypertension

• effective in low doses

• first response: reduction in plasma volume and cardiac output

• continued use: vasodilatation, decrease PVR (reduce NA content in arterial smooth muscle

• don’t work in renal diseases

loop diuretic

• more natriuresis than thiazide

• less effective in treating hypertension

• preferred in patients with renal insufficiency

• more potential to cause hyponatremia

RAAS

• ACE enzyme convert angiotensin1 to angiotensin2

• induce vasoconstriction, aldosterone secretion, breakdown of bradykinin

1. ACEIs: captopril, lisinopril, prodrug enalapril

2. ARBs: candesartan, losartan

• the drugs of choice in diabetic hypertensive patients, because they reduce proteinuria without adverse metabolic effect

• ACEIs used for diabetic patients regardless of hypertension

pharmacological effect of RAAS

1. vasodilatation of arteries and veins

2. decrease NA reabsorption

3. decrease intraglomerular pressure, dilate efferent more than afferent

4. decrease left ventricular hypertrophy

5. decrease adrenergic activity > suppress reflex tachycardia

adverse effect of RAAS and drug interaction

1. hypotension

2. hyperkalemia

3. teratogenic

4. reversible decline in renal function

5. persistent dry cough and angioedema

drug interaction:

1. potassium sparing diuretics

2. NASIDs (may cause acute renal damage

CCBs

• bind to L type calcium channel

• reduce cytosolic ca

1. dihydropyridines: short: nifedipine, long: amlodipine

2. non dihydropyridine: verapamil, diltiazem

dihydropyridines

• block ca channels in arterial smooth muscle

• arterial vasodilation

• coronary vasodilation

• no effect on veins

• cardiac effect: reflex tachycardia

• therapeutic uses: 1. hypertension, 2. IHD

• adverse effect: 1. hypotension, 2. tachycardia, 3. flushing, headache, 4. ankle edema

• contraindication: 1. hypotension, 2. tachyarrhythmia

• can be combined with beta blocker

non dihydropyridines

• block mainly ca channels in cardiac muscle

• less arterial vasodilation, coronary vasodilation

• cardiac effects: decrease (HR, conduction, contractility)

• therapeutic uses: 1. hypertension, 2. IHD, 3. atrial tachy arrythmia

• adverse effects: 1. hypotension, 2. bradycardia, 3. heart block, 4. constipation

• contraindications: 1. hypotension, 2. bradycardia, 3, HF

• can’t be combined with beta blocker

beta adrenoceptors blocking drugs

• not used as first line

• used in compulsory indications: hypertension with cardiac or non-cardiac conditions angina, HF, glaucoma, pregnancy

• all generations decrease HR, contractility

• suppress release of renin

• inhibit sympathetic outflow from CNS

• 3rd generation has vasodilator effect

alpha 1 adrenergic receptor blockers

• doxazosin, prazosin

• vasodilation

• may be used in resistant hypertension

• adverse effect: postural hypotension

vasodilators

• hydralazine, sodium nitroprusside

1. hydralazine:

induce arteriolar vasodilation, release NO, used in resistant hypertensin, IV in urgency or emergency,

adverse effect: reflex tachycardia, salt water retension, reversible lupus erythematosus

sodium nitroprusside:

potent venodilator, rapid, short duration, used as IV infusion in emergency

adverse effect: hypotension, reflex tachycardia, cyanide toxicity in prolonged infusion

alpha2 adrynegic receptor agonist

• clonidine, methyldopa, moxonidine

• reduce sympathetic outflow from CNS, reduce BP

• clonidine: only in resistant hypertension

• methyledopa: safe during pregnancy

• moxonidine: more specific in imidazoline1 receptors than a2, used in management of hypertension when other treatments are not sufficient

adverse effect: sedation, postural hypotension