Clinical Pharmacology Lecture 3 PDF

CLINICAL PHARMACOLOGY LECTURE 3 DR KEREANN NELSON OHS 3011  HEMOSTASIS HEMATOLOGI Keeps blood in its fluid state & C& within vessels LYMPHORETI Relies on balance between CULAR PHARMACOL coagulation & clot dissolution OGY...

CLINICAL PHARMACOLOGY LECTURE 3 DR KEREANN NELSON OHS 3011  HEMOSTASIS HEMATOLOGI Keeps blood in its fluid state & C& within vessels LYMPHORETI Relies on balance between CULAR PHARMACOL coagulation & clot dissolution OGY HEMOATOPOIESIS Bone marrow produce blood cells Involves differentiation of pluripotent stem cells  RBCs, platelets, WBCs Differentiation regulated by specific growth factors HEMATOLOGIC & LYMPHORETICULAR PHARMACOLOGY DRUGS THAT AFFECT HEMOSTASIS PLATELET ANTAGONISTS ASPIRIN: Pharmacologic Properties: Inhibit cycloxygenase  prevent synthesis of PG & TXA2 Effect permanent on life of platelet (7-10 days) Prolong bleeding time [BT](single dose  7 days) HEMATOLOGIC DRUGS THAT AFFECT HEMOSTASIS & (cont) LYMPHORETICU PLATELET ANTAGONISTS (cont) LAR ASPIRIN: (cont) PHARMACOLOG Indication: Y MI: prevent recurrence & re- infarction Coronary artery bypass: prevent occlusion TIAs: prevent stoke  DRUGS THAT AFFECT HEMOSTASIS HEMATOLOGI (cont) C& PLATELET ANTAGONISTS (cont) LYMPHORETI ANTICOAGULANTS: CULAR HEPARIN PHARMACOL OGY Pharmacologic Properties: Anionic mucopolysaccharaide (straight chain) Accelerates antithrombin 111 (heparin factor) binding to thrombin Antithrombin 111 inactivates thrombin HEMATOLOGIC & LYMPHORETICULAR PHARMACOLOGY DRUGS THAT AFFECT HEMOSTASIS (cont) PLATELET ANTAGONISTS (cont) ANTICOAGULANTS: HEPARIN Pharmacologic Properties: Administered IV or subcutaneous Metabolized by liver (heperanase) Prolong partial thromboplastic time (PTT), thrombin time Produce anticoagulation in minutes  DRUGS THAT AFFECT HEMOSTASIS (cont) HEMATOLOGI PLATELET ANTAGONISTS (cont) C& LYMPHORETI ANTICOAGULANTS: (cont) CULAR HEPARIN PHARMACOL Indications for Use: OGY Patients with high risk for thrombosis & pulmonary emboli (e.g. prolonged bed rest) Thrombophlebitis (ongoing thrombosis) Acute MI Can be used in pregnancy, does not cross placenta. HEMATOLOGI DRUGS THAT AFFECT HEMOSTASIS C& (cont) LYMPHORETI PLATELET ANTAGONISTS (cont) CULAR ANTICOAGULANTS: (cont) PHARMACOL HEPARIN OGY Side Effect & Toxicity: Bleeding (PTT monitored carefully) Protamine sulfate (positively charged) reverse effect of heparin  DRUGS THAT AFFECT HEMOSTASIS HEMATOLOGI (cont) C& PLATELET ANTAGONISTS (cont) LYMPHORETI ANTICOAGULANTS: (cont) CULAR WARFARIN PHARMACOL OGY Pharmacologic Properties: Interferes with vtamin-K- dependent hepatic post- translation modification of factors 11, V11, 1X & X Prolong prothrombin time (PT) Extensively bound to albumin Metabolized by liver  ANTICOAGULANTS: (cont) HEMATOLOGIC WARFARIN & Pharmacologic Properties: (cont) LYMPHORETIC Administered orally Crosses placenta, not used in ULAR pregnancy PHARMACOLO Use same as heparin, not as rapid GY anticoagulation, require concomitant heparin Rx because fibrinolytic factors (protein C & S) are depleted first  clotting Side effect: bleeding, Rx with vitamin K HEMATOLOGIC & LYMPHORETICULA R PHARMACOLOGY ANTICOAGULANTS: (cont) DICUMARAL (comarin anticoagulant) Mechanism of action same as warfarin THROMBOLYTIC AGENTS Streptokinase Urokinase Tissue Plasminogen activator (t- PA) Activate fibrinolysis  thrombus dissolution Promote conversion of plasminogen  plasmin  fibriolysis HEMATOLOGIC & LYMPHORETICULAR PHARMACOLOGY DRUGS THAT AFFECT HEMATOPOIESIS HEMATOPOIETIC GROWTH FACTORS ERYTHROPOIETIN Physiologic Properties Produced by kidney  RBCs production Recombinant form administer parenterally Use: Rx anemia secondary to renal failure Rx anemia secondary to chemotherapy Rx anemia secondary to zidovdine (AZT) for patients with AIDS HEMATOLOGIC & LYMPHORETICULAR PHARMACOLOGY DRUGS THAT AFFECT HEMATOPOIESIS (cont) HEMATOPOIETIC GROWTH FACTORS (cont) WBC GROWTH FACTORS Glycoproteins that stimulate differentiation of myeloid cell line GLANULOCYTE-MACROPHAGE COLONEY-STIMULATING FACTOR (GM- CSF) Produced by T-lymphocytes (and others) Stimulate proliferation of granulocytes, (eosinophils, basophils), monocytes, macrophages, megakarycytes (platelets)  HEMATOPOIETIC GROWTH HEMATOLOGIC FACTORS (cont) & WBC GROWTH FACTORS (cont) LYMPHORETIC GRANULOCYTE ULAR COLONY_STIMULATING FACTOR G- CSF) PHARMACOLO Produced by monocytes, GY fibroblasts & endothelial cells Stimulate production of neutrophils Re-combinant form = filgrastrim, lenograstrim  DRUGS THAT AFFECT HEMATOPOIESIS (cont) HEMATOLOGI SUPPLEMENTS that Rx ANEMIA C& LYMPHORETI IRON CULAR Iron deficient anemia (most common PHARMACOL nutritional anemia)  hypochromic & OGY microcytic) Oral administration of ferrous sulphate or iron dextran FOLIC ACID Foliate deficiency anemia (due to absorption disorders of small intestine, alcoholism, pregnancy & lactation)Anemia = megaloblastic  DRUGS THAT AFFECT HEMATOLOGI C& HEMATOPOIESIS (cont) LYMPHORETI SUPPLEMENTS that Rx ANEMIA CULAR (cont) PHARMACOL VITAMIN B12 (cynaocobalamin) OGY Deficiency due to inadequate absorption secondary to failure of parietal cells to produce intrinsic factor (pernicious anemia) Anemia = megaloblastic CARDIOVAS ANTIHYPERTENSIVES CULAR Decrease vascular tone: PHARMACOL Modified by agents that OGY alter CNS sympathetic outflow block sympathetic tone at the arterial smooth muscle receptor Decrease intravascular volume  ANTIHYPERTENSIVES (cont) CENTRAL-ACTING SYMPAYHOLYTIC CARDIOVASC AGENTS CLONIDINE & Guanabenz) ULAR Pharmacologic Properties PHARMACOL Stimulates central & peripheral α- adrenergic (norepinephrine) OGY receptors  diminish sympathetic outflow Rx: moderate to severe essential (idiopathic) hypertension Side Effects: xerostomia & sedation (50%) Insomnia nightmares depression  ANTIHYPERTENSIVES (cont) CENTRAL-ACTING SYMPAYHOLYTIC CARDIOVAS AGENTS CULAR METHYDOPA PHARMACOL Pharmacologic Properties OGY Related to catecholeamine neurotransmitter Stimulate CNS α-adrenergic receptors  inhibit sympathetic outflow Rx: moderate essential hypertension Side Effects: xerostomia, sedation, headache, nightmare, depression, postural hypotension, impotence, lactation (both sex), & hepatitis  ANTIHYPERTENSIVES (cont) AGENTS ACTING AT PERIPERAL CARDIOVASC ADRENERGIC RECEPTORS ULAR Beta-ADRENERGIC BLOCKERS PHARMACOL “a beam” of β1-blockers: OGY Acebuterol Betaoxolol Esmolol Atenolol Metoprolol Pharmacologic Properties: Block peripheral sympathetic β receptors  decrease vascular resistance  ANTIHYPERTENSIVES (cont) AGENTS ACTING AT PERIPERAL CARDIOVAS ADRENERGIC RECEPTORS CULAR Beta-ADRENERGIC BLOCKERS (cont) PHARMACOL Rx: OGY Hypertension Control tacharrhythmias Chronic angina pectoris Migraine headache Decrease mortality post MI Glaucoma Hyperthyroidism NOT in cases of asthma, diabetes, CHF CARDIOVASCULAR PHARMACOLOGY ANTIHYPERTENSIVES (cont) AGENTS ACTING AT PERIPERAL ADRENERGIC RECEPTORS Alpha-ADRENERGIC BLOCKERS Prazosin & Terazosin (α-selective) Pharmacologic Properties Block vasoconstrictive α-adrenergic type1 receptors  relax vascular smooth muscle Rx: mild to moderate essential hypertension (with diuretic & β blocker) CHF BPH (reduce symptoms) CARDIOVASCULAR PHARMACOLOGY ANTIHYPERTENSIVES (cont) ADRENERGIC NEURON BLOCKERS RESERPINE Pharmacologic Properties: Block uptake of neurotransmitter  epletion of catecholamine  decrease cardiac output & peripheral vascular resistance Rx: mild to moderate hypertension (rarely used due its side effects)  ANTIHYPERTENSIVES (cont) CARDIOVAS ADRENERGIC NEURON BLOCKERS CULAR (cont) PHARMACOL OGY GUANETHIDINE Pharmacologic Properties: Inhibit release of norepinephrine from stimulated peripheral sympathetic nerves Rx: severe hypertension (rarely used due to side effects) CARDIOVASCULAR PHARMACOLOGY ANTIHYPERTENSIVES (cont) AGENTS ACTING ON VASCULAR SMOOTH MUSCLE HYDRALAZINE Pharmacologic Properties: Direct relaxation of vascular smooth muscle, more so on arterioles Rx: moderate to severe hypertension Used with β blocker (prevent reflex tachycardia) Used with diuretic (prevent salt/water retention) RX: CHF (along with nitrates) CARDIOVASCULAR PHARMACOLOGY ANTIHYPERTENSIVES (cont) AGENTS ACTING ON VASCULAR SMOOTH MUSCLE (cont) Minoxidil: Pharmacologic Properties: Similar to hydralazine (metabolism & action Rx: severe hypertension, refractory to conventional regimens Used with β blocker & diuretic Side Effect: hirsutism  Rx male baldness Salt/HOH retention, reflex tachycardia CARDIOVASCULA R PHARMACOLOGY ANTIHYPERTENSIVES (cont) AGENTS ACTING ON VASCULAR SMOOTH MUSCLE (cont) DIAZOXIDE Pharmacologic Properties Structural similar to thiazide diuretics Cause Na & HOH retention (no diuresis [increased urine]) CARDIOVASCULA R PHARMACOLOGY ANTIHYPERTENSIVES (cont) AGENTS ACTING ON VASCULAR SMOOTH MUSCLE (cont) SODIUM NITROPRUSSIDE Pharmacologic Properties: Relax smooth muscle (both artery & vein) Short half-life, administered as continuous intravenous infusion (intensive care unit) Rx: Hypertensive emergencies CHF Severe mitral regurgitation with pulmonary congestion  CARDIOVASCUL AR PHARMACOLOG Y ANTIHYPERTENSIVES (cont) CALCIUM CHANNEL BLOCKERS Verapamil Nifedipine Pharmacologic Properties: Block Ca2+ entry into cells Cause exit of Ca2+ out of cell  inhibit excitation-contraction coupling of vascular smooth muscle  decrease peripheral vascular resistance Verapamil also slow conduction thru AV node CARDIOVASCULAR PHARMACOLOGY ANTIHYPERTENSIVES (cont) CALCIUM CHANNEL BLOCKERS (cont) Rx: Mild to moderate hypertension (especially if angina & tachycardia exists) Migraine prophylaxsis Esophageal spasm Raynaud’s phenomenon (intermittent bilateral attacks of ischemia of fingers, toes, ears & nose, with pallor, paresthesia & pain, caused by cold, due to vascular disorder)  ANTIHYPERTENSIVES (cont) ANTAGONIST of the ANGIOTENSIN- CARDIOVAS RENIN SYSTEM CULAR CAPTOPRIL PHARMACOL Pharmacologic Properties: OGY Inhibit angiotensin-converting enzyme(ACE) which coverts angiotensin 1angiotensin 11, a strong vasoconstrictor Rx: Congested Heart Failure (CHF) mild to moderate essential hypertension (in conjunction with thiazide diuretic) CARDIOVASCULAR PHARMACOLOGY ANTIARRHYTHMICS Affect action potential & its conduction  alteration of pulse rate & blood pressure Class 1A Agents: Na+ channel blocker  decrease cell membrane responsiveness Quinidine: Rx atrial arrhythmia, flutter, fibrilation Ventricular arrhythmia Patient must be treated with digitalis ( β blocker), or a Ca channel blocker to avoid increase in ventricular response to atrial dysrhythmias  ANTIARRHYTHMICS (cont) Class 1: (cont) CARDIOVASC Procainamide ULAR Use similar to quinidine, PHARMACOL better for ventricular dysrhythmia OGY Can produce lupus-like syndrome Disopyramide Major role in Rx & prevention of ventricular tachycardia CARDIOVASCULAR PHARMACOLOGY ANTIARRHYTHMICS (cont) Class 1B: Lidocaine: Pharmacologic Properties: Amide local anesthetic administered IV/IM Decrease automaticity in Purkinje fibers & ventricular tissue Rx: fist therapy for ventricular arrhythemia Local anesthetic (oral & elsewhere) CARDIOVASCULAR PHARMACOLOGY ANTIARRHYTHMICS (cont) Class 1B: (cont) Lidocaine: (cont) Side Effects: (mainly CNS related) Drowsiness Disorientation Seizures Psychosis (elderly & Hx CHF) Hypotension Cimetidine ( Rx stomach ulcers) & propranolol (Rx HBP) increase lidocaine toxicity CARDIOVASCULAR PHARMACOLOGY ANTIARRHYTHMICS (cont) Class 1B: (cont) Phenytoin (Dilantin) Rx: ventricular arrhythmia Seizures Class 1C Agents: (flecainde, propafenone) Slow impulse in all cardiac tissues Rx: life threating ventricular arrhythmias CARDIOVASCULAR PHARMACOLOGY ANTIARRHYTHMICS (cont) Class 11 Agents: (β-adrenergic blockers) Inhibit AV node conduction E.g. propranolol, acebutolol, sotalol, esmolol Rx: supraventricular tachycardia, tachycardia Atrial flutter, fribrillation Acute & post MI CARDIOVASCULAR PHARMACOLOGY ANTIARRHYTHMICS (cont) Class 111 Agents Prolong action potential, block K channels E.g. Bretylium, amiodarone, sotalol Class 1V Agents: (Ca channel blockers) E.g. Verapamil,, bepridil, dilitiazem Increase conduction time thru AV node Rx: supraventricular tachycardia Atrial flutter & fibrillation CARDIOVASCULAR PHARMACOLOGY CARDIAC GLYCOSIDES Steroids & their glycosides Digitalis leaf = source of cardiac glycosides digoxin & digitoxin Pharmacologic Properties: Inhibit Na-K ATPase in cell membrane Leads to decrease Na gradient  decrease Na - Ca exchange  increase intracellular Ca build up  more Ca available to the Ca-dependent contractile protein of cardiac muscle  increased contractile force CARDIOVASCULAR PHARMACOLOGY CARDIAC GLYCOSIDES (cont) Rx: CHF (due to increased contraction) Atrial fibrillation & flutter AV node depression to control ventricular response to supraventricular tachycardia NOTE: Glycosides produce their antiarrhyhthmic action via increased vagal activity. Produces as many arrhythmia as it treats Increased contraction due to increased intracellular Ca CARDIOVASCULAR PHARMACOLOGY ANTI-ANGINAL AGENTS Signs of angia pectoris: Crushing chest pain  radiate to left arm & neck & jaw Shortness of breath, nausea, vomiting, diaphoresis (increased perspiration) Anti-angina agents: Dilate coronary arteries Decrease heart rate & contractility Decrease vessel wall tension & resistance CARDIOVASCULAR PHARMACOLOGY ANTI-ANGINAL AGENTS (cont) ORGANIC NITRATES E.g nitroglycerin, amyl nitrate Pharmacologic Properties: Pharmacokinetics: Better to give by sublingual route Mechanism of Action: Coronary venous & arterial dilalatation  reduce after load Systemic venous pooling  reduce pre- load CARDIOVASCULAR PHARMACOLOGY ANTI-ANGINAL AGENTS (cont) ORGANIC NITRATES (nitroglycerin) [cont] Rx: Angina pectoris CHF(afterload reduction) Hypertension (short term management) Other Anti-anginal Agents: Calcium Channel Blockers Beta-adrenergic Blockers  SUMMARY USE OF β BLOCKER IN CARDIAC CARDIOVASC PATIENT ULAR Hypertension: decrease cardiac PHARMACOL output & renin secretion OGY Arrythrmia: especially supra ventricular tachycardia) Angina pectoris: reduce heart rate & contractity Post MI: reduce risk of re- infarction & death