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ANTI-ANGINAL DRUGS - Pharmacology Lecture, Study notes of Pharmacology

University of British ColumbiaPharmacology

Angina Pectoris II. Therapy III. Nitrates and Nitrites IV. Calcium Channel Blockers V. Beta-blockers VI. Combination Therapy of Angina VII. Newer Antianginal Drugs

Typology: Study notes

2022/2023

Available from 08/17/2023

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ANTI-ANGINAL DRUGS
Pharmacology (Lecture)
Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 4
ANGINA PECTORIS
Ø Denotes chest pain
Ø Caused by accumulation of metabolites resulting from
myocardial ischemia
Ø Most common condition involving tissue ischemia à
vasodilators used
Ø ISCHEMIC HEART DISEASE: most common
cardiovascular disease in developed countries
Ø Most common cause: atheromatous obstruction of
the large coronary vessels (CAD)
PATHOPHYSIOLOGY
Ø Primary cause: imbalance between the oxygen
requirement of the heart and the oxygen supply to the
myocardium via the coronary vessels
DETERMINANTS OF MYOCARDIAL OXYGEN DEMAND
Ø Wall stress: intraventricular pressure, ventricular
radius (volume), wall thickness
Ø Heart rate
Ø Contractility
DETERMINANTS OF CORONARY BLOOD FLOW AND
MYOCARDIAL OXYGEN SUPPLY
Ø Coronary Flow and distribution
• Coronary BF: near zero during systole
• Directly related to diastolic pressure and duration
• Inversely proportional to coronary vascular
resistance (determined mainly by intrinsic factors
like metabolic products and autonomic activity)
• Resistance increased by coronary vascular
endothelial damage
Ø Arterial pO2 Hgb Concentration
Ø O2 extraction and coronary microcirculation
DETERMINANTS OF VASCULAR TONE
Ø Plays a role in determining myocardial wall stress
Ø Arteriolar tone à directly controls PVR à ABP
• Systole: intraventricular pressure must exceed
aortic pressure à eject blood
• ABP: determines the LV systolic wall stress
Ø Venous tone
• Determines capacity of venous circulation and
controls amount of blood sequestered in the
venous system vs. blood returning to heart
• Determines RV diastolic wall stress
WAYS BY WHICH DRUGS RELAX VASCULAR SMOOTH
MUSCLE
1) Increasing cGMP
2) Decreasing Intracellular Ca++
3) Stabilizing or preventing depolarization of the vascular
smooth muscle cell membrane
4) Increasing cAMP in the vascular cells
1) Increasing cGMP
2) Decreasing intracellular Ca++
3) Stabilizing or preventing depolarization of the smooth
muscle cell membrane
Ø Increasing K+ permeability: stabilizes membrane
potential of excitable cells near the resting potential
Ø cGMP: increase permeability of Ca++ activated K+
channels à opens
Ø ↑ permeability of ATP-dependent K+
Overview
I. Angina Pectoris
II. Therapy
III. Nitrates and Nitrites
IV. Calcium Channel Blockers
V. Beta-blockers
VI. Combination Therapy of Angina
VII. Newer Antianginal Drugs
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ANTI-ANGINAL DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 4

ANGINA PECTORIS

Ø Denotes chest pain Ø Caused by accumulation of metabolites resulting from myocardial ischemia Ø Most common condition involving tissue ischemia à vasodilators used Ø ISCHEMIC HEART DISEASE : most common cardiovascular disease in developed countries Ø Most common cause : atheromatous obstruction of the large coronary vessels (CAD) PATHOPHYSIOLOGY Ø Primary cause : imbalance between the oxygen requirement of the heart and the oxygen supply to the myocardium via the coronary vessels DETERMINANTS OF MYOCARDIAL OXYGEN DEMAND Ø Wall stress : intraventricular pressure, ventricular radius (volume), wall thickness Ø Heart rate Ø Contractility DETERMINANTS OF CORONARY BLOOD FLOW AND MYOCARDIAL OXYGEN SUPPLY Ø Coronary Flow and distribution

  • Coronary BF : near zero during systole
  • Directly related to diastolic pressure and duration
  • Inversely proportional to coronary vascular resistance (determined mainly by intrinsic factors like metabolic products and autonomic activity)
  • Resistance increased by coronary vascular endothelial damage Ø Arterial pO2 Hgb Concentration Ø O 2 extraction and coronary microcirculation DETERMINANTS OF VASCULAR TONE Ø Plays a role in determining myocardial wall stress Ø Arteriolar tone à directly controls PVR à ABP
  • Systole : intraventricular pressure must exceed aortic pressure à eject blood
  • ABP : determines the LV systolic wall stress Ø Venous tone
  • Determines capacity of venous circulation and controls amount of blood sequestered in the venous system vs. blood returning to heart
  • Determines RV diastolic wall stress WAYS BY WHICH DRUGS RELAX VASCULAR SMOOTH MUSCLE 1) Increasing cGMP 2) Decreasing Intracellular Ca++ 3) Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane 4) Increasing cAMP in the vascular cells 1) Increasing cGMP 2 ) Decreasing intracellular Ca++ 3 ) Stabilizing or preventing depolarization of the smooth muscle cell membrane Ø Increasing K+^ permeability : stabilizes membrane potential of excitable cells near the resting potential Ø cGMP : increase permeability of Ca++^ activated K+ channels à opens Ø ↑ permeability of ATP-dependent K+ Overview I. Angina Pectoris II. Therapy III. Nitrates and Nitrites IV. Calcium Channel Blockers V. Beta-blockers VI. Combination Therapy of Angina VII. Newer Antianginal Drugs

ANTI-ANGINAL DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 4

channels : Minoxidil SO 4 , Nicorandil 4 ) Increasing cAMP in the vascular cells TYPES 1) Classic or stable angina (“angina-of-effort”) 2) Unstable angina or “angina at rest” 3) Variant or vasospastic or “Prinzmetal angina” CLASSIC OR STABLE ANGINA

Ø Myocardial O 2 requirement increases but

coronary BF does not increase proportionately

à ISCHEMIA with accumulation of acidic

metabolites à PAIN

Ø Inadequate blood flow in the presence of CAD

Ø Coronary flow reserve frequently impaired due to

endothelial dysfunction à impaired vasodilation

à Ischemia occur at lower level of myocardial

oxygen demand

Ø Due to a fixed narrowing of the coronary arteries

by atherosclerosis.

  • Exertion (exercise, sexual

activity)

  • Emotion (stress, anger, fright, frustration)
  • Relieved by rest or nitrates UNSTABLE ANGINA Ø An acute coronary syndrome Ø Occurs at rest with increase in severity, frequency and duration in previous stable angina Ø Mechanisms for reduction of flow :
  • Episodes of increased epicardial coronary artery resistance
  • Small platelet clots in the vicinity of an atherosclerotic plaque
  • Formation of labile partially occlusive thrombi at site of fissured or ulcerated plaque VARIANT OR VASOSPASTIC ANGINA Ø Chest discomfort occurs at rest or awakens patient from sleep Ø Accompanied by palpitations, shortness of breath Ø May be explosive in onset, severe, frightening Ø Transient focal spasm of proximal epicardial coronary arteries Ø Associated with underlying atheromas Ø Relieved by nitrates or Ca++^ channel blockers Ø M anagement
  • Decrease oxygen demand ü Stable : decrease cardiac workà shift myocardial metabolism to substrate that require less O 2 per unit of ATP produced ü Unstable : medical or surgical intervention ü Variant : spasm reversed by nitrates or CCB
  • Increase oxygen delivery : by increasing coronary flow THERAPY AIM OF THERAPY Ø To improve the balance between myocardial oxygen demand and supply Ø Supply = Demand Ø How to achieve the aim? a) Coronary vasodilators : increase blood flow to the myocardium by dilating the coronary arteries b) Drugs that decrease work load of the heart : decrease oxygen demand by reducing cardiac work Ø Types of therapy
  • Prevention
  • Medical therapy using Anti-anginal drugs
  • Revascularization ü PTCA : Percutaneous Transluminal Coronary Angioplasty ü CABG : Coronary Artery Bypass Graft Surgery PREVENTION Ø Quit smoking Ø Lose weight Ø Reduce cholesterol levels Ø Exercise Ø Better control of diabetes Ø Better control of hypertension ANTI-ANGINAL DRUGS (CAN BE USED ALONE OR IN COMBINATION) I.* Nitrates II. Calcium channel blockers III. Beta-adrenoceptor blocking drugs 1) Organic nitrates, CCB, and beta-blockers Ø Decrease myocardial O 2 requirement : decreasing 1 or more major determinants of O 2 demand (HR, heart size, BP, contractility) 2 ) Nitrates and CCB Ø redistribution of coronary BF and increase O 2 delivery to ischemic tissue Ø Reverse coronary artery spasm in variant angina à increase myocardial O 2 delivery NITRATES AND NITRITES Ø Simple organic nitric and nitrous acid esters of polyalcohol Ø Nitroglycerine : prototype Ø Release nitric oxide in vascular smooth muscle

ANTI-ANGINAL DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 4

  • Regenerates active cytochrome à cyanomethemoglobin à detoxify further with Na thiosulfate à thiocyanate ion Ø Excess methemoglobinemia : methylene blue Ø Antidote for cyanide poisoning : hydroxocobalamin (B 12 ) CLINICAL USE OF NITRATES Ø NTG, SL
  • Most frequently used Ø NTG, IV
  • Severe, recurrent rest angina
  • Hemodynamic effects quickly reversed by discontinuation Ø NTG : buccal, oral, transdermal
  • Prolonged blood concentration à develop tolerance OTHER NITRO-VASODILATORS Ø NICORANDIL
  • Nicotinamide nitrate ester
  • ↑ permeability of ATP-dependent K+ channels Ø MOLSIDOMINE
  • Prodrug converted to nitric oxide-releasing metabolite
  • Comparable efficacy to nitrites
  • No tolerance
  • May reduce cerebral vasospasm in stroke CALCIUM CHANNEL BLOCKERS Ø Calcium channels
  • Smooth and cardiac muscle
  • Voltage-activated calcium channels Ø L-type Ca++ channel
  • Voltage-gated
  • Dominantly type in cardiac and smooth muscles
  • Contain several drug receptors
  • Consist of: alpha-1 (larger, pore-forming subunit), alpha-2, beta, gamma, delta subunits Ø T-type Ca++ channel
  • Cardiac muscle : SA and AV node Ø Pharmacokinetics
  • Orally active
  • Verapamil and Diltiazem: IV
  • High first pass effect
  • High plasma protein binding
  • Extensive metabolism
  • Effects evident within 30 to 60 minutes of an oral dose Ø Mechanism of action
  • Acts from inner side of membrane à more effectively to open channels and inactivated channels
  • Blocks Ca2+^ influx via L-type channels in cardiac and vascular smooth muscle à decreased contractility, vasodilation
  • Binding reduces frequency of opening due to depolarization à marked ↓ in transmembrane Ca++^ current ü Smooth muscle : prolonged relaxation ü Cardiac muscle : reduction in contractility and ↓ SA pacemaker rate and ↓ AV conduction velocity Ø Verapamil : synthetic analog of papaverine; vasodilator found in opium poppy Ø Nifedipine : prototype dihydropyridine Ø Midefradil : selective T-type channel blocker

ANTI-ANGINAL DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 4

ORGAN SYSTEM EFFECTS

SMOOTH MUSCLE

Ø Vascular smooth muscles : more sensitive to block than bronchiolar, GI and uterine smooth muscles

  • Arterioles more sensitive than veins
  • Reduction in PVR à angina of effort
  • Reduction coronary artery spasm à variant angina
  • Dihydropyridines has greater ratio of vascular smooth muscle effects than non-dihydropyridines (K+^ channel blockade) CARDIAC MUSCLE Ø Blocks SA impulse generation and AV conduction Ø Reduced cardiac mechanical function à reduce O 2 requirement Ø Different effects on heart rate and cardiac contractility
  • NON-DIHYDROPYRIDINES (Verapamil, diltiazem): direct negative inotropic, chronotropic and dromotropic effects
  • DIHYDROPYRIDINES (Nifedipine, Amlodipine, etc): negligible direct effects on HR or contractility à reflex increase à may aggravate angina

CEREBRAL NASOSPASM AND INFARCT FOLLOWING

SUBARACHNOID HEMORRHAGE

Ø Nimodipine

  • High affinity for cerebral blood vessels
  • Reduce cerebral vasospasm 2o^ to extravasation of blood into the tissues Ø Nicardipine
  • Similar effects
  • Intravenous and intracerebral arterial infusion Ø Verapamil
  • Non-selective; Intra-arterial route
  • CCB’ s: also reduce cerebral damage after thromboembolic event OTHER ORGAN SYSTEM EFFECTS Ø Verapamil
  • Inhibit insulin release in high doses
  • interfere with platelet aggregation
  • Block P170 glycoprotein ü Responsible for transport of foreign drugs out of cancer cells ü Reverse the resistance of cancer cells to many chemotherapeutic drugs DESIRED THERAPEUTIC EFFECTS OF CCB IN TREATING ANGINA Ø Reduced myocardial oxygen consumption by
  • Reducing afterload
  • Reducing heart rate and contractility (except for dihydropyridines) Ø Improve oxygen delivery to ischemic myocardium by vasodilating coronary arteries **TOXICITY
  1. Excessive inhibition of Ca++**^ influx : serious cardiac depression à cardiac arrest, bradycardia, AV block, CHF 2) ↑ risk of MI in patients with HTN : intermediate- acting; increase mortality 3) Torsades de Pointes arrhythmia
  • Bepridil: prolongs action potential à contraindicated in patients with serious arrhythmia (prolonged QT syndrome)
  • Dihydropyridines: hypotension, headache, flushing, reflex tachycardia
  • Verapamil and Diltiazem : depression of contractility, bradycardia, AV block
  • Minor : dizziness, nausea and constipation, peripheral edema MECHANISM OF CLINICAL EFFECTS Ø ↓ myocardial contractile force à ↓ myocardial O requirement Ø ↓ arterial tone and SVR à ↓ arterial and intraventricular pressure Ø Verapamil
  • Anti-adrenergic effect à peripheral vasodilation
  • ↓ LV wall stress à ↓ O 2 requirement
  • ↓ HR à further ↓ in O 2 demand Ø Most effective treatment for variant angina : relieve and prevent à focal coronary spasm

ANTI-ANGINAL DRUGS

Dr. Ma. Janeth B. Serrano| March 25, 2021 | Topic 4

CLINICAL PHARMACOLOGY OF ANGINA

Ø Angina of Effort : Nitrates, CCBs, β-blockers Ø Vasospastic Angina : CCBs and Nitrates Ø Unstable Angina and Acute Coronary Syndromes

  • Nitroglycerin, β-blockers
  • CCBs in refractory cases for relief of myocardial ischemia
  • Antiplatelet Tp à aspirin, clopidogrel
  • IV heparin or LMW heparin
  • Glycoprotein IIb/IIIa (abciximab)
  • Lipid lowering drugs and ACEI
  • Percutaneous coronary intervention R E F E R E N C E S
  1. Anti-Anginal drugs. Dr. Serrano, 2021. (Annotated Lecture)
  2. Basic and Clinical Pharmacology. (14th^ ed). Katzung.