Anti-anginal drugs

Antianginal drugs

Classification 

1.       Nitrates

a.       Short acting : Glyceryl trinitrate (GTN, Nitroglycerine)

b.      Long acting: Isosorbide dintrate (short acting by sublingual nitrate), Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate

2.       β blockers: Propanolol, Metoprolol, Atenolol and others

3.       calcium channel blocker:

a.       phenyl alkylamine: Verapimil

b.      benzothiazepine: Diltiazem

c.       Dihydropyridine: Nifedipine, Felodipine, Amlodipine, Nitrendipine, Nimodipine, Lacidipine, Lecarnidipine, Benidipine

4.       Potassium cannel opener: Nicorandil

5.       Others: Dipyridamole, Trimetazidine, Ranolazine, Ivabradine, Oxyphedrine

Clinical classification

1.       Used to abort or terminate the attack : GTN, Isosorbide dinitrate (sublingually)

2.       Used for chronic prophylaxis: All other drugs   Nitrates (GTN) Pharmacological action: 1. Preload reduction

• Nitrates dilates veins more than arteries – peripheral pooling of blood – decreased venous return ie preload to the heart is reduced – end diastolic size and pressure are reduced – decreased cardiac work
• Nitrates reduce outflow resistance as well as preload in congestive heart failure, and the magnitude of the former response is dependent upon the base line cardiac index and Left ventricular filling pressure (LVFP). ⁽¹⁾

 2. Afterload reduction 

• Nitrates also produce some arteriolar dilation – slight decrease in total peripheral resistance (tpr) or afterload on heart – BP falls systolic more than diastolic.

 3. Redistribution of coronary flow

• Nitrates preferentially relax bigger conducting coronary arteries than arterioles or resistance vessels
• Dilatation of conducting vessels all over by nitrate along with ischemia induced dilatation of autoregulatory resistance vessels only in the ischemic zone increases blood flow to this area, while in the non ischemic zones – resistance vessels maintain their tone – flow does not increase or may decrease to compensate for increased flow to ischemic zone
• By dilatation of the large coronary arteries, nitrates cause redistribution of the coronary blood supply to areas that are ischemic. The non nitrate coronary dilatirs may cause an inappropriate distribution of blood flow, producing an excess in areas where it is not required at the expense of ischemic areas. ⁽²⁾

4. Relief of angina

• Relaxant effect in large coronary vessels
• Exercise tolerance of angina patients is improved because the same amount of exercise causes lesser augmentation of cardiac work

 5. Heart and peripheral blood flow

• Nitrates have no direct stimulant or depressant action on the heart
• They dilate cutaneous and meningeal vessels causing headache
• Splanchnic and renal blood flow decreases to compensate for vasodilatation in other areas
• Nitrates tends to decongest lungs by shifting blood to systemic circulation

 6. Other smooth muscles

• Bronchi, biliary tract and esophagus are mildly relaxed
• Effect on intestine, ureter, uterus is variable and insignificant

Mechanism of action ​Organic nitrates are rapidly denitrated enzymatically in the smooth muscle cell to release the reactive free radical nitric oxide (NO) which activates cytosolic guanylyl cyclase – increased cGMP – causes dephosphorylation of myosin light chain kinase (MLCK) through a cGMP dependent protein kinase.​Reduced availability of phosphorylated (active) MLCK interferes with activation of myosin – it fails to interact with actin to cause contraction. Consequently relaxation occurs. Raised intracellular cGMP may also reduce Ca2+ entry – contributing to relaxation. Pharmacokinetics ​Organic nitrates are lipid soluble; well absorbed from buccal mucosa, intestine and skin. Ingested orally, all except isosorbide mononitrate undergo extensive and variable first pass metabolism in liver. They are rapidly denitrated by a glutathione reductase and a mitochondrial aldehyde dehydrogenase. The partly denitrated metabolites are less active, but they have longer t ½.​GTN and isosorbide dinitrate are both short acting from sublingual but longer acting from oral route.  

Dependence: 

• ​On organic nitrates is now well recognized. Sudden withdrawal after prolonged exposure has resulted in spasm of coronary and peripheral blood vessels. MI and sudden deaths have been recorded. Angina threshold is lowered during the nitrate free interval in some patients; episodes of angina may increase. In such patients an antianginal drug of another class should be added. Withdrawal of nitrates should be gradual.
• Frequent administration of isosorbide dinitrate has led to early development of nitrate tolerance. Concomitant use of hydralazine with isosorbide dinitrate has shown to prevent the development of nitrate tolerance and maintain the favourable hemodynamic effect of nitrates. ⁽³⁾

  Interactions:• Sildenafil causes dangerous potentiation of nitrate action: severe hypotension, MI and deaths are recorded• Additive hypotension is also possible when nitrate is given to a patient receiving other vasodilators 

Drug	Dose and route	Duration of action
GTN (Nitroglycerine)	0.5 mg sublingual	10-30 min
	0.4 – 0.8 mg s I spray	10-30 min
	5-15 mg oral	4-8 hrs
	One patch for 14-16 hr per day	Till applied max. 24 hrs
	5-20 µg/ min iv	Till infused
Isosorbite mononitrate	5 – 10 mg sublingual	20-40 min
	10-20 mg oral	2-3 hr
	20-40 mg oral	6-1 hr
Isosorbide 5- mononitrate	20-40 mg oral	6-10 hr
Eryrthrityl- tetranitrate	15-60 mg oral	4-6 hr
Pentaerythritol – tetranitrate	10-40 mg oral	3-5 hr
	80 mg oral	6-12 hr

  Side effects:

• Headache is the most commonly reported side effect. Other side effects are hypotension and dizziness. Severe headaches and/ or symptomatic hypotension may necessitate discontinuation of nitrate therapy. These are mitigated by lying down. Erect posture and alcohol accentuate these symptoms
• Severe life threatening hypotension or even death may occur when nitrates are used in patients with acute inferior myocardial infarction associated with right ventricular dysfunction or infarction, or with concomitant use of phosphodiesterase-5 inhibitors or N-acetylcysteine. ⁽⁴⁾
• Methemoglobinemia: is not significant with clinically used doses. However, in severe anemia, this can further reduce O2 carrying capacity of blood. 
• Its use is associated with gastric cancer, adult methemoglobinemia and acute toxicity, balkan nephropathy and slowing of motor reflexes in children. ⁽⁵⁾
• Rashes are rare, though relatively more common with pentaerythritol tetranitrate.

 Uses: 

1. Angina pectoris:

• Nitrates are effective in classical as well as variant angina
• For aborting or terminating an attack, sublingual GTN tablet or spray, or isosorbide dinitrate is taken on ‘as and when required’ basis
• GTN produces relief within 3 min in 75% patients, the rest may require another dose or take longer (upto 9 min)
• Nitrates increase exercise tolerance and postpone ECG changes of ischemia

2. Acute coronary syndrome

• These are characterized by rapid worsening of angina status of the patient: include unstable angina (UA) and non ST segment elevation myocardial infarction (NSTEMI)
• Initially, GTN is given sublingually, but if pain persists after 3 tablets 5 min apart, iv infusion of GTN is started.

 3. Myocardial infarction

• Administered by carefully titrated iv infusion to avoid hypotension and tachycardia, GTN is frequently used during evolving MI with the aim of relieving chest pain, pulmonary congestion and limiting the area of necrosis by favorably altering O2 balance in the marginal partially ischemic zone.
• GTN should not be administered if:
• Systolic BP is < 90 mm Hg
• Heart rate is < 50 or > 100 beats/ min
• Right ventricular infarction is suspected
• Hypotension caused by nitrate limits the administration of β blockers which have more powerful salutary effects
• Patient has taken sildenafil in the past 24 hours. 4. CHF and acute LVF
• Nitrates afford relief by venous pooling of blood – reduced venous return – decreased end diastolic volume – improvement in left ventricular function and regression of pulmonary congestion.
• Addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality. ⁽⁶⁾
• Long term vasodilator therapy is beneficial in congestive heart failure. ⁽⁷⁾

 5. Biliary colic

• Glyceryl trinitrate produces gall bladder dilatation in the fasting state and reduces post prandial gall bladder emptying. ⁽⁸⁾
• Glyceryl trinitrate (GTN) does not influence the sphincter of Oddi motility but it relaxes very effectively the sphincter of Oddi muscle. GTN can be used in the treatment of biliary colic. ⁽⁹⁾

 6. Esophageal spasm

• Sublingual GTN promptly relieves pain
• Nitrates taken before a meal facilitate feeding in esophageal achalasia by reducing esophageal tone
• If esophageal spam is associated with reflux, the use of nitirtes is less effective in controlling spasm than it is in those who do not show this association. Diffuse esophageal spasm can be effectively managed with long acting nitrites on a long term basis in the absence of reflux. ⁽¹⁰⁾

 7. Cyanide poisoning

• Nitrates generate methemoglobin which has high affinity for cyanide radical and forms cyanomethemoglobin
• However, this may again dissociate to release cyanide.
• Therefore, sodium thiosulfate is given to form Sod. Thiocyanate which is poorly dissociable and is excreted in urine

Subclass	Mechanism of action	Clinical applications	pharmacokinetics	Toxicities, Interactions
Short- acting nitrates Nitroglycerin (SL) Isosorbide dinitrate (SL)	Releases nitric oxide (NO), increases cGMP (cyclic guanosine monophosphate), and relaxes vascular smooth muscle	Acute angina pectoris, acute coronary syndrome	Rapid onset (1min) short duration (15 min) Slightly longer acting (20-30 min)	Tachycardia, orthostatic hypotension, headache
Intermediate -acting nitrate Nitroglycerin (oral) Isosorbide dinitrate and mononitrate (oral)	Same  as GTN (SL) active metabolite dinitroglycerin	Prophylaxis of angina	Slow onset Duration: 2-4 h	Same as GTN (SL)
Long- acting nitrate Transdermal GTN	Same as GTN oral	Prophylaxis of angina	Slow onset long duration of absorption: 24 h Duration of effect: 10 h tachyphylaxis	Same as GTN (SL) Loss of response is common after 10-12 h exposure to drug
Ultra short- acting nitrite Amyl nitrite	Same  as GTN (SL)	Obsolete for angina Some recreational use	Vapors are inhaled Onset in seconds Duration: 1-5 min	Same  as GTN (SL)

References:

1. Joseph A Franciosa, Roy C Blank, Jay N Cohn. Nitrate effects on cardiac output abd left ventricular outflow resistance in chronic congestive heart failure. The American Journal of Medicine. Feb 1978;64(2):207-213. 
2. Martin M Winbury, Burton B Howe, Mildred A Hefner. Effect of nitrates and other coronary dilators on large and small coronary vessels: an hypothesis for the mechanism of action of nitrates. Journal of Pharmacology and experimental therapeutics. July 1969;168(1):70-95. 
3. Uri Elkayam, Fahed Bitar. Effects of nitrates and hydralazine in heart failure: Clinical evidence before the african american heart failure trial. Am J Cardiol 2005;96[suppl]:37i-43i. 
4. Udo Thadani, Toni L Ripley. Side effects of using nitrates to treat heart failure and the acute coronary syndromes, unstable angina and acute myocardial infarction. Expert Opinion on drug safety. July 2007;6(4):385-396. 
5. Bruning-Fann CS, Kaneene JB. The effects of nitrate, nitrite and N-nitroso compounds on human health: a review. Vet Hum Toxicol 1993 Dec;35(6):521-38. 
6. Jay N Cohn, Donald G Archibald, Susan Ziesche, Joseph A Franciosa, W Eugene Harston, Felix E Tristani, W Bruce Dunkman, William Jacobs, Gary S Francis, Kathleen H Flohr, Steven Goldman, Frederick R Cobb, Pravin M Shah, Robert Saunders, Ross D Fletcher, Henry S Loeb, Vincent C Hughes, Bonnie Baker. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Eng J Med 1986;314:1547-1552. 
7. Joseph A Franciosa, Leonard A Nordstrom, Jay N Cohn. Nitrate therapy for congestive heart failure. JAMA 1978;240(5):443-446. 
8. R Greaves, J Miller, L O’Donnell, A McLean, MJG Farthing. Effect of the nitric oxide donor, glyceryl trinitrate on gall bladder motility. Gut 1998;42:410-413. 
9. M Staritz, T Poralla, K Ewe, K-H Meyer Zum Buschenfelde. Effect of glyceryl trinitrate on the sphincter of Oddi motility and baseline pressure. Gut 1985;26:194-197. 
10. Swamy N. Esophageal spasm: clinical and manometric response to nitroglycerine and long acting nitrites. Gastroenterology. 1977 Jan;72(1):23-7.