Classification of Antianginal Drugs

I. Classification

A. Traditional (First-Line) Antianginals

B. Agents by Angina Subtype

C. Newer/Adjunct Antianginals

II. Organic Nitrate Pharmacology

Chemistry

• Glyceryl trinitrate (GTN / nitroglycerin) - short-acting, volatile liquid
• Isosorbide dinitrate (ISDN) - intermediate-acting solid
• Isosorbide-5-mononitrate (ISMN) - long-acting, no first-pass metabolism

Mechanism of Action

Hemodynamic Effects and Antianginal Mechanism

1. Preload reduction (dominant effect):
   • Venodilation → ↓ venous return → ↓ end-diastolic volume → ↓ ventricular wall tension (via Law of Laplace: T ∝ P × r)
   • Also improves subendocardial perfusion by increasing the pressure gradient across the ventricular wall
2. Afterload reduction (modest, mainly at higher doses):
   • Dilates large conductance arteries (aorta) and, to a lesser extent, arterioles → ↓ peripheral resistance
3. Coronary vasodilation:
   • Dilates large epicardial coronary arteries and collateral vessels
   • Redistributes flow toward the ischemia-prone subendocardium
   • Especially relevant in variant (Prinzmetal) angina, where vasospasm is the dominant mechanism

Key evidence: When GTN is injected directly into the coronary circulation of patients with CAD, anginal attacks (induced by pacing) are not aborted even when coronary flow increases. But sublingual GTN does relieve pain - proving the major benefit is preload reduction, not coronary dilation in typical stable angina. - Goodman & Gilman's, p. 636

Pharmacokinetics and Preparations

Adverse Effects

Nitrate Tolerance

1. Depletion of sulfhydryl (-SH) groups required for bioactivation
2. Downregulation or inactivation of ALDH2 (mitochondrial aldehyde dehydrogenase) - key mechanism for GTN
3. Neurohormonal counter-regulation: Reflex activation of renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system in response to vasodilation
4. Oxidative stress: Superoxide generated during nitrate metabolism scavenges NO

• Provide a nitrate-free interval of 10-12 hours (usually overnight when demand is lowest)
• GTN patches: apply for 12 h, remove for 12 h
• ISMN once-daily extended-release tablet provides a natural nitrate-free period
• Caution: Patients with variant angina may experience rebound vasospasm during the nitrate-free interval - a significant limitation

Drug Interactions

• PDE5 inhibitors (sildenafil, tadalafil, vardenafil): Absolute contraindication - synergistic hypotension can be fatal
• Antihypertensives/vasodilators: Additive hypotension
• Ergotamine: May antagonize nitrate effect and provoke coronary spasm

Clinical Use Summary

• Goodman & Gilman's Pharmacological Basis of Therapeutics, pp. 625-690 - Chapters on ischemic heart disease pharmacotherapy
• Lippincott Illustrated Reviews: Pharmacology, pp. 412-425 - Chapter 12, antianginal agents
• Katzung's Basic and Clinical Pharmacology, 16e, pp. 315-320 - Chapter 12, newer antianginal drugs

ANTIANGINAL DRUGS

Classification

ANTIANGINAL DRUGS
├── Nitrates
│   ├── Short acting
│   │   ├── Glyceryl trinitrate (GTN)
│   │   └── Isosorbide dinitrate — sublingual
│   └── Long acting
│       ├── Isosorbide dinitrate — oral
│       ├── Isosorbide mononitrate
│       ├── Erythrityl tetranitrate
│       └── Pentaerythritol tetranitrate
│
├── β-blockers
│   ├── Propranolol
│   ├── Metoprolol
│   ├── Atenolol
│   └── (others)
│
├── Calcium channel blockers
│   ├── Verapamil
│   ├── Diltiazem
│   ├── Amlodipine
│   └── (others)
│
├── Potassium channel opener
│   └── Nicorandil
│
└── Other antianginal drugs
    ├── Trimetazidine
    ├── Ranolazine
    ├── Ivabradine
    └── Dipyridamole

Organic Nitrate Pharmacology

Key Points

• All organic nitrates share the same action; they differ only in time course
• The only major action is direct nonspecific smooth muscle relaxation
• Nitroglycerin (GTN) is the prototype drug
• Nitrates have no direct action on the heart

Pharmacological Actions

1. On Vascular Smooth Muscle (Main Action)

• Decreasing O2 requirement of the myocardium
• Increasing O2 delivery to the myocardium

a) Venodilatation (Predominant Effect)

Peripheral pooling of blood → ↓↓ Venous return to the heart → ↓↓ Preload → ↓↓ Left and right end-diastolic ventricular volume → ↓↓ Cardiac work → ↓↓ O2 requirement of myocardium (↓ O2 demand) → Relief of anginal pain

b) Arteriolar Dilatation

↓↓ PVR (peripheral vascular resistance) → ↓ Afterload → Relief of anginal pain

c) Dilatation of Large Coronary Vessels and Collateral Vessels

Increased blood flow to ischaemic area due to redistribution of coronary blood flow → Increased O2 delivery to ischaemic area → Relief of anginal pain

2. On Other Smooth Muscles

Pharmacokinetics

• Organic nitrates are readily absorbed through the buccal mucous membrane, skin, and GI tract
• When ingested orally, all except isosorbide mononitrate undergo extensive and variable first-pass metabolism in the liver
• They are rapidly denitrated by:
  • Glutathione reductase
  • Mitochondrial aldehyde dehydrogenase (ALDH2)
• The partly denitrated metabolites are less active but have a longer t½
• Metabolites are excreted mainly in urine as glucuronide derivatives

Classification by Duration

• Sublingual route → rapid onset (2-5 minutes) but short duration
• Transdermal route → slow absorption through skin → used for prolonged effect
• Duration of action is governed by the rate of absorption from the site of administration and the rate of metabolism
• GTN and isosorbide dinitrate are both short-acting from sublingual but longer-acting from the oral route

ANTI-ANGINAL DRUGS

(As per GTU BP502TP - Pharmacology II, Sem 5)

ANGINA PECTORIS - Introduction

• Stable (Classical/Effort) angina - Fixed atherosclerotic narrowing; pain on exertion
• Unstable angina - Plaque rupture + partial thrombus; pain at rest; medical emergency
• Variant (Prinzmetal) angina - Coronary vasospasm; pain at rest; ECG shows ST elevation

CLASSIFICATION OF ANTI-ANGINAL DRUGS

ANTIANGINAL DRUGS
│
├── 1. NITRATES
│   ├── Short Acting
│   │   ├── Glyceryl trinitrate (GTN) — sublingual
│   │   └── Isosorbide dinitrate — sublingual
│   └── Long Acting
│       ├── Isosorbide dinitrate — oral
│       ├── Isosorbide mononitrate (ISMN)
│       ├── Erythrityl tetranitrate
│       └── Pentaerythritol tetranitrate (PETN)
│
├── 2. β-BLOCKERS
│   ├── Propranolol
│   ├── Metoprolol
│   ├── Atenolol
│   └── (others)
│
├── 3. CALCIUM CHANNEL BLOCKERS (CCBs)
│   ├── Verapamil
│   ├── Diltiazem
│   ├── Amlodipine
│   └── (others)
│
├── 4. POTASSIUM CHANNEL OPENER
│   └── Nicorandil
│
└── 5. OTHER ANTIANGINAL DRUGS
    ├── Trimetazidine
    ├── Ranolazine
    ├── Ivabradine
    └── Dipyridamole

ORGANIC NITRATES

A. Mechanism of Action

Organic Nitrate → Intracellular conversion (via ALDH2/glutathione reductase) → Nitric Oxide (NO) → Activates Guanylate Cyclase → ↑ cGMP → Dephosphorylation of myosin light chain → Vascular smooth muscle relaxation

B. Pharmacological Actions

1. On Vascular Smooth Muscle (Main Action)

2. On Other Smooth Muscles

C. Pharmacokinetics

• Duration is governed by the rate of absorption from the site + rate of metabolism
• GTN and ISDN are short-acting via sublingual, but longer-acting via oral route

D. Therapeutic Uses (Clinical Uses)

1. Acute anginal attack - Sublingual GTN (drug of choice); acts within 2 minutes
2. Prophylaxis of stable angina - Long-acting nitrates (ISMN, ISDN oral) combined with β-blockers
3. Variant (Prinzmetal) angina - Nitrates + CCBs (dilate coronary spasm)
4. Unstable angina / ACS - IV nitroglycerin (along with heparin + antiplatelets)
5. Acute LVF / Pulmonary oedema - IV GTN reduces preload rapidly
6. Hypertensive emergencies - IV nitroglycerin
7. Congestive cardiac failure - Nitrates + hydralazine (if ACE inhibitors not tolerated)

E. Adverse Effects

F. Drug Interactions

G. Contraindications

1. Hypotension / hypovolaemia
2. Concurrent use of PDE-5 inhibitors (sildenafil, tadalafil) - absolute contraindication
3. Severe anaemia
4. Raised intracranial pressure
5. Constrictive pericarditis / cardiac tamponade
6. Hypertrophic obstructive cardiomyopathy (HOCM)

H. Nitrate Tolerance

• Tolerance develops rapidly (within 24-48 hours) of continuous use
• Also called tachyphylaxis

1. Depletion of -SH (sulfhydryl) groups required for bioactivation
2. Inactivation of ALDH2 (mitochondrial aldehyde dehydrogenase)
3. Neurohormonal counterregulation - RAAS and sympathetic activation

• Provide a nitrate-free interval of 10-12 hours (usually overnight)
• GTN patches: apply 12 h, remove for 12 h
• ISMN once-daily extended-release gives a natural free interval
• Note: Variant angina patients may get rebound vasospasm during nitrate-free interval

GTU Exam Tip: For 10-mark questions, cover Classification + Mechanism + Pharmacological Actions + PK + Uses + ADRs + Tolerance. For 5-mark questions focused on nitrates only, cover mechanism (NO → cGMP pathway), three vascular effects (veno > arterio > coronary), PK (first-pass, ISMN exception), ADRs (headache, hypotension, tolerance), and contraindication with sildenafil.

ANTI-ANGINAL DRUGS

CLASSIFICATION OF ANTI-ANGINAL DRUGS

ANTIANGINAL DRUGS
│
├── 1. NITRATES
│   ├── Short Acting
│   │   ├── Glyceryl trinitrate (GTN) — sublingual
│   │   └── Isosorbide dinitrate — sublingual
│   └── Long Acting
│       ├── Isosorbide dinitrate — oral
│       ├── Isosorbide mononitrate (ISMN)
│       ├── Erythrityl tetranitrate
│       └── Pentaerythritol tetranitrate (PETN)
│
├── 2. β-BLOCKERS
│   ├── Propranolol
│   ├── Metoprolol
│   └── Atenolol
│
├── 3. CALCIUM CHANNEL BLOCKERS
│   ├── Verapamil
│   ├── Diltiazem
│   └── Amlodipine
│
├── 4. POTASSIUM CHANNEL OPENER
│   └── Nicorandil
│
└── 5. OTHER ANTIANGINAL DRUGS
    ├── Trimetazidine
    ├── Ranolazine
    ├── Ivabradine
    └── Dipyridamole

ORGANIC NITRATES — PHARMACOLOGY

1. Mechanism of Action

• All organic nitrates share the same mechanism of action
• They differ only in their time course
• The only major action is direct nonspecific smooth muscle relaxation
• Nitroglycerin (GTN) is the prototype drug
• Nitrates have NO direct action on the heart

Organic Nitrate
        ↓  (Intracellular bioactivation via ALDH2 / glutathione reductase)
    Nitric Oxide (NO)
        ↓
  Activates Guanylate Cyclase
        ↓
      ↑ cGMP
        ↓
  Dephosphorylation of Myosin Light Chain
        ↓
  Vascular Smooth Muscle Relaxation

2. Pharmacological Actions

A. On Vascular Smooth Muscle (Main Action)

Venodilatation
      ↓
Peripheral pooling of blood
      ↓
↓↓ Venous return to the heart
      ↓
↓↓ Preload
      ↓
↓↓ Left and right end-diastolic ventricular volume
      ↓
↓↓ Cardiac work
      ↓
↓↓ O2 requirement of myocardium (↓ O2 demand)
      ↓
   RELIEF OF ANGINAL PAIN

Arteriolar Dilatation
      ↓
   ↓↓ PVR
      ↓
  ↓ Afterload
      ↓
   RELIEF OF ANGINAL PAIN

Dilatation of large coronary vessels + collaterals
      ↓
Increased blood flow to ischaemic area
(due to redistribution of coronary blood flow)
      ↓
Increased O2 delivery to ischaemic area
      ↓
   RELIEF OF ANGINAL PAIN

B. On Other Smooth Muscles

3. Pharmacokinetics

• Duration is governed by the rate of absorption from the site of administration and rate of metabolism
• GTN and ISDN are both short-acting from sublingual but longer-acting from oral route
• Sublingual route → rapid onset (2-5 min) but short duration
• Transdermal route → slow absorption through skin → used for prolonged effect

4. Therapeutic Uses

5. Adverse Effects

6. Drug Interactions

7. Contraindications

1. Hypotension / hypovolaemia
2. PDE-5 inhibitors (sildenafil, tadalafil) — absolute contraindication
3. Severe anaemia
4. Raised intracranial pressure
5. Hypertrophic obstructive cardiomyopathy (HOCM)
6. Cardiac tamponade / constrictive pericarditis

8. Nitrate Tolerance

• Tolerance develops rapidly (within 24-48 hours) of continuous exposure
• Also called tachyphylaxis

1. Depletion of -SH (sulfhydryl) groups needed for bioactivation
2. Inactivation of mitochondrial ALDH2
3. Neurohormonal counter-regulation (↑ RAAS, ↑ sympathetic tone)
4. Oxidative stress — superoxide scavenges NO

• Provide a nitrate-free interval of 10-12 hours (usually overnight)
• GTN patches: apply for 12 hours, remove for 12 hours
• ISMN once-daily extended-release provides a natural free period
• Caution: Variant angina patients may get rebound vasospasm during the nitrate-free interval

GTU Exam Strategy:

• 10-mark Q: Classification + Mechanism (NO→cGMP pathway) + 3 vascular effects with flowchart + PK table + Uses + ADRs + Tolerance
• 5-mark Q on nitrates: Mechanism + venodilatation flowchart + PK (first-pass, ISMN exception) + 3 ADRs + sildenafil contraindication
• Always draw the mechanism flowchart - it fetches easy marks in GTU theory papers

DIURETICS

(As per GTU BP502TP - Pharmacology II, Sem 5)

CLASSIFICATION OF DIURETICS

(Based on Site of Action in Nephron)

DIURETICS
│
├── 1. CARBONIC ANHYDRASE INHIBITORS
│   Site: Proximal Convoluted Tubule (PCT)
│   Example: Acetazolamide
│
├── 2. LOOP DIURETICS
│   Site: Thick Ascending Limb of Loop of Henle
│   Examples: Furosemide, Bumetanide,
│             Torsemide, Ethacrynic acid
│
├── 3. THIAZIDE & THIAZIDE-LIKE DIURETICS
│   Site: Distal Convoluted Tubule (DCT)
│   ├── Thiazides: Hydrochlorothiazide,
│   │             Chlorothiazide, Bendroflumethiazide,
│   │             Methyclothiazide
│   └── Thiazide-like: Chlorthalidone,
│                      Indapamide, Metolazone
│
└── 4. POTASSIUM-SPARING DIURETICS
    Site: Collecting Duct
    ├── Aldosterone Antagonists:
    │   Spironolactone, Eplerenone
    └── ENaC Inhibitors:
        Amiloride, Triamterene

THIAZIDE DIURETICS — DETAILED PHARMACOLOGY

1. Introduction

• Thiazide diuretics increase the excretion of sodium (Na+), chloride (Cl-) and water by inhibiting sodium reabsorption in the Distal Convoluted Tubule (DCT)
• They are widely used as first-line drugs for hypertension
• Also effective in treating oedema

2. Mechanism of Action

Step-by-step Mechanism:

Thiazide diuretic enters the tubular lumen
            ↓
Acts on DCT cell — Inhibits Na+/Cl- Cotransporter (NCC)
            ↓
↓ Reabsorption of Na+ and Cl- from lumen into cell
            ↓
More Na+ reaches the Collecting Duct
            ↓
↑ Na+/K+ exchange in collecting duct
            ↓
↑ K+ and H+ secretion into urine
            ↓
↓ K+ in blood → HYPOKALEMIA
↑ H+ excretion → METABOLIC ALKALOSIS

Effect on Calcium (Important / Unique Feature):

Thiazide inhibits NCC in DCT
            ↓
↑ Intracellular Na+ depletion in DCT cell
            ↓
Activates basolateral Na+/Ca2+ exchanger
            ↓
↑ Ca2+ reabsorption back into blood
            ↓
↓ Urinary calcium excretion
→ CALCIUM-SPARING EFFECT
→ Useful in nephrolithiasis (calcium kidney stones)

Summary of Ion Effects:

3. Pharmacological Actions

A. Diuretic Effect

• Moderate diuresis - increases urine output
• ↓ NaCl and water excretion → reduces extracellular fluid volume
• ↓ Blood volume (initially) → ↓ Cardiac output

B. Antihypertensive Effect

• Initially: ↓ Blood volume → ↓ Cardiac output → ↓ BP
• Long term: ↓ Peripheral vascular resistance → ↓ BP
• Most effective at normal or mildly reduced renal function (GFR > 30 mL/min)
• Except Metolazone — remains effective even at very low GFR

C. Calcium-Sparing Effect

• ↓ Urinary calcium excretion
• Useful in preventing recurrent calcium kidney stones (nephrolithiasis)
• Also used in osteoporosis as adjunct (decreases urinary calcium loss)

4. Therapeutic Uses

5. Adverse Effects

6. Contraindications

1. Severe renal failure (ineffective at very low GFR — except Metolazone)
2. Sulfonamide allergy — use with caution
3. Severe electrolyte imbalance — absolute contraindication
4. Anuria
5. Severe hepatic disease (risk of electrolyte disturbance precipitating encephalopathy)

7. Drug Interactions

8. Quick Summary Table (GTU Favourite)

MNEMONIC — THIAZIDE

GTU Exam Strategy:

• 10-mark Q: Classification (with sites) + Thiazide mechanism (NCC blockade step-by-step + Ca2+ sparing) + ion effects table + therapeutic uses + ADRs
• 5-mark Q on thiazides: Mechanism (NCC blockade + Ca2+ sparing) + 4 uses + hypokalaemia + hyperuricaemia as key ADRs
• Always mention Metolazone — it works at low GFR unlike other thiazides; this is a common exam distinction

DIURETICS

Classification (Site of Action)

DIURETICS
│
├── 1. CARBONIC ANHYDRASE INHIBITORS
│   Site: Proximal Convoluted Tubule (PCT)
│   Example: Acetazolamide
│
├── 2. LOOP DIURETICS
│   Site: Thick Ascending Limb of Loop of Henle
│   Examples: Furosemide, Bumetanide,
│             Torsemide, Ethacrynic acid
│
├── 3. THIAZIDE & THIAZIDE-LIKE DIURETICS
│   Site: Distal Convoluted Tubule (DCT)
│   ├── Thiazides: Hydrochlorothiazide, Chlorothiazide,
│   │             Bendroflumethiazide, Methyclothiazide
│   └── Thiazide-like: Chlorthalidone,
│                      Indapamide, Metolazone
│
└── 4. POTASSIUM-SPARING DIURETICS
    Site: Collecting Duct
    ├── Aldosterone Antagonists:
    │   Spironolactone, Eplerenone
    └── ENaC Inhibitors:
        Amiloride, Triamterene

THIAZIDE DIURETICS

Mechanism of Action

Thiazide acts on DCT
        ↓
Inhibits Na+/Cl- Cotransporter (NCC)
        ↓
↓ Reabsorption of Na+ and Cl- into tubular cell
        ↓
More Na+ delivered to Collecting Duct
        ↓
↑ Na+/K+ exchange in Collecting Duct
        ↓
↑ K+ and H+ secretion into urine
        ↓
↓ K+ in blood → Hypokalaemia
↑ H+ excretion → Metabolic alkalosis

NCC inhibition → ↑ intracellular Na+ depletion in DCT cell
        ↓
Activates basolateral Na+/Ca2+ exchanger
        ↓
↑ Ca2+ reabsorption back into blood
        ↓
↓ Urinary Ca2+ excretion → Calcium-sparing effect

Therapeutic Uses