2 ANTIANGINAL DRUGS ILOs By the end of those 2 lectures
[24 slides for studing] you will be able to: Recognize variables contributing to a balanced myocardial supply vs demand Identify etiopathogenic cascades contributing to ischemic heart disease Justify the different related clinical presentations of ischemic heart disease Expand on the drugs used to alleviate acute anginal attacks vs those meant for prophylaxis & improvement of survival Detail the pharmacology of nitrates, other vasodilators, and other drugs used as antianginal therapy Sum up the varied therapeutic recommendations for treatment of different clinical presentations of ischemic heart disease
3 O2 ATP G FFA O2 G O2 O2 O2 ATP G O2 O2 FFA FFA G O2 ATP
Coronary SUPPLY Pumping Heart DEMAND WORK O2 ATP G FFA O2 G O2 O2 O2 ATP G O2 O2 FFA FFA G O2 ATP Shortening of D Ventricular End-DP DP [D] [S]
4 ISCHEMIC HEART DISEASE
Coronary SUPPLY Pumping Heart DEMAND WORK O2 ATP G FFA O2 G O2 O2 O2 ATP G O2 O2 FFA FFA G O2 ATP ? ? ? ISCHEMIC HEART DISEASE
5 FUNCTIONAL STRUCTURAL SPASM ATHEROSCLEROTIC PLAQUE CORONARY NARROWING
CORONARY HEART DISEASES [CHD] FUNCTIONAL STRUCTURAL SPASM ATHEROSCLEROTIC PLAQUE ISCHEMIC HEART DISEASES [IHD] + THROMBOSIS SPASTIC ANGINA ANGINA Stabilized Vulnerable STABLE ANGINA UNSTABLE ANGINA ACUTE MYOCARDIAL INFARCTION [AMI] ACUTE CORONARY SYNDROME [ACS]
7 Plaque ACUTE OCCLUSION Vulnerable Plaque
RELATION OF PATHOPHYSIOLOGICAL FINDINGS TO ACS Vulnerable Plaque ACUTE OCCLUSION (~Subtotal / Total) ACS Vulnerable Plaque Rupture / erosion / fissuring exposure of thrombogenic surface platelets adhere thrombosis OCCLUSION Internal haemorrhage sudden growth OCCLUSION
8 Inflam. Mediators, ROS TNFa, NFkB, …. Proteolysis, Membrane damage….
Acute ~Subtotal / Total OCCLUSION ACUTE CORONARY SYNDROMES [ACS] Umbrella term that covers a spectrum of acute clinical conditions ranging from Unstable angina (38%) NSTEMI (25%) STEMI (30%) ATP, Ion PumpsCa ~~Action Potention, elect. Activities & functions Inflam. Mediators, ROS TNFa, NFkB, …. Apoptosis Proteolysis, Membrane damage…. Necrosis Cardiac Enzymes (Markers) ECG CHANGES Non ST – Elevation ST – Elevation -ve +ve Unstable Angina AMI AMI NSTEMI STEMI
9 DRUGS USED IN TREATMENT OF ANGINA
Agents that improve symptoms & ischemia Organic nitrates Calcium channel blockers Potassium channel openers -adrenoceptor blockers Metabolically acting agents Others Vasodilators. Agents that improve prognosis Aspirin / Other antiplatelets Statins ACE Inhibitors -AD blockers ANTIANGINAL DRUGS
10 DRUGS USED IN TREATMENT OF ANGINA
Vasodilators.
11 For terminating an acute attack For long-term prophylaxsis
NITRODILATORS Release NO via enzymatic reaction Release NO spontaneously ORGANIC NITRATES Na NITROPRUSSIDE ANTIANGINAL DRUGS ANTIHYPERTENSIVES Short Acting Long Acting Nitroglycerine [GTN] Amyl Nitrite Isosorbide mono & dinitrate Erythrityl tetranitrate Pentaerythritol tetranitrate Unstable angina Heart Failure Rapid Slower For terminating an acute attack For long-term prophylaxsis I.V. or infusion Sublingual Oral sustained release Transdermal patches Preparations; can influence a change in indications
12 ANTIANGINAL DRUGS ? ORGANIC NITRATES Nitrosothiols Nitrates
Nitrite Ion in endothelial cell (EC) Acts as NO donner Mimick action of Endogenous NO Endothelial Cell [EC] O2 H2O Vascular Smooth Muscle [ VSMC] PKG Phosphorylate Diffusion ? Mechanism In VSMC [ In SMC ] Binds soluble GC Formation of cGMP Activation of PKG RELAXATION MLCK P MLC Inactive form Active form Contraction Actin Relaxation N.B. NO is well developed in Arteriolar > Venular System Exogenous NO donners act on Venular > Arteriolar system
13 ORGANIC NITRATES Pharmacodynamic Actions 1. Anti-Anginal Actions
Myocardial Oxygen Supply; Dilatation of large coronary vessels. Redistribution of coronary flow from normal to ischemic region. Dilatation of collaterals. Myocardial Oxygen Demand by cardiac work indirectly ; Venodilatations: of capacitance vessels preload central venous P CO Arteriolar vasodilatation: peripheral resistance & afterload (reflex tachycardia. ) BP at high dose Platelet Aggregation Endothelial protective action leukocyte-endothelial interactions (anti- inflammatory); antiatherogenic potentials 2. Other Pharmacodynamic Actions SMC Relaxation of Bronchi NO activates cGMP in BSMC bronchodilatation Gastrointestinal tract & biliary system Genitourinary tract
14 ORGANIC NITRATES CV effects of Nitrates on Preload & Afterload
15 ORGANIC NITRATES How Nitrates increases flow to ischemic zone ? With Nitrates In Ischemia
16 ORGANIC NITRATES Pharmacokinetics Nitroglycrine [GTN];
Significant first pass metabolism occurs in the liver (10-20%) bioavailability (so sublingual or via transdermal patch) Oral isosorbide dinitrate & mononitrate Very well absorbed & 100% bioavailability The dinitrate undergoes denitration to two mononitrates both possess antianginal activity (t1/2 1-3 hours) Further denitrated metabolites conjugate to glucuronic acid in liver. Excreted in urine. Indications IN STABLE ANGINA; Acute symptom relief sublingual GTN Prevention; Persistant prophylaxis Isosorbide mono or dinitrate Situational prophylaxis as before exercising, climbing…etc sublingual GTN IN VARIANT ANGINA sublingual GTN IN UNSTABLE ANGINA IV GTN Refractory AHF IV GTN CHF Isosorbide mononitrate + hydralazine [ if contraindication to ACE Is ] AMI IV GTN
17 Sublingual tablets or spray Transdermal patch
Preparations Nitroglycerine Sublingual tablets or spray Transdermal patch Oral or bucal sustained release I.V. Preparations Isosorbide dinitrate & mononitrate Dinitrate Sublingual tablets Dinitrate Oral sustained release Mononitrate Oral sustained release Infusion Preparations
18 Flushing of blush area (face, neck and upper trunk) is unpleasant
ORGANIC NITRATES ADRs Postural hypotension with reflex tachycardia: especially if the patient is standing stationary. Nitrite syncope with fainting & collapse due to dilatation of venous capacitance vessels + severe of venous return CO & BP. Nitrite syncope is treated by putting the patient in a low head position. Flushing of blush area (face, neck and upper trunk) is unpleasant Throbbing headache (>common) & tendency to intra-cranial pressure used cautiously in cerebral bleeding & head trauma Drug rash. Visual disturbance. Carcinogenesis Met-hemoglobinemia (in overdose & accidental poisoning)
19 ORGANIC NITRATES NIRATE TOLERANCE
Loss of vasodilator response of nitrates on use of long-acting preparations (oral, transdermal) or continuous intravenous infusions, for more than a few hours without interruption. Magnitude of tolerance is a function of dosage & frequency of use. Causes After 1st day of continuous nitrates, compensatory neurohormonal counter-regulation occurs (RAAS, NE, Vasopressin ….etc activation) therapeutic efficacy (PSEUDOTOLERANCE). After 3 days, dysfunction of ECs & VSMC occur by many different molecular mechanisms, aside the partial depletion of free-SH groups that permits formation of nitrosothiols from the organic nitrate to give NO (TOLERANCE) Nitrate tolerance can be overcomed by: Smaller doses at increasing intervals (Nitrate free periods twice a day). Giving drugs that maintain tissue SH group e.g. Captopril.
20 Precautions during nitrate therapy ORGANIC NITRATES
10 hours nitrate free period. Never stop nitrate therapy suddenly. Do not take double dose. Do not use after expiry date; GTN is volatile; shelf-life ~6w after opening Must be stored in cool, tightly capped dark container, no cotton wool or others. PDE5 Inhibitors Contraindication Known sensitivity to organic nitrates. Glaucoma; nitrates aqueous formation Head trauma or cerebral haemorrhage Increase intracranial pressure . Uncorrected hypovolemia Concomitant administration of PDE5 Inhibitors that are used for the treatment of erectile dysfunction BP Myocardial Ischemia VSMC Dilatation
21 ORGANIC NITRATES X BP coronary perfusion MYOCARDIAL ISCHEMIA PDE5 Is
cGMP Vasodilatation BP coronary perfusion MYOCARDIAL ISCHEMIA
22 Quiz? Nitroglycerin, either directly or through reflexes, results in which one of the following effects? (A) Decreased heart rate (B) Decreased venous capacitance (C) Increased afterload (D) Increased cardiac force (E) Increased preload
23 Quiz? An active metabolite of another drug and an active
antianginal drug for oral administration in its own right. (A) Isosorbide dinitrate (B) Amylnitrite (C) Isosorbide mononitrate (D) Nitroglycerin (E) Pentaerythritol tetranitrate
24 A side effect least likely to be seen with nitroglycerin:
Quiz? A side effect least likely to be seen with nitroglycerin: A- headache B- dizziness C- palpitations D- cancer of oesophagus E- flushing