Antianginal Drugs

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Chapter: Essential pharmacology : Antianginal and Other Anti-Ischaemic Drugs

Antianginal drugs are those that prevent, abort or terminate attacks of angina pectoris.



Antianginal drugs are those that prevent, abort or terminate attacks of angina pectoris.


Angina Pectoris


Is a pain syndrome due to induction of an adverse oxygen supply/ demand situation in a portion of the myocardium. Two principal forms are recognized:


Classical angina (common form) Attacks are predictably provoked (stable angina) by exercise, emotion, eating or coitus and subside when the increased energy demand is withdrawn. The underlying pathology is—severe arteriosclerotic affliction of larger coronary arteries (conducting vessels) which run epicardially and send perforating branches to supply the deeper tissue (Fig. 39.1). The coronary obstruction is ‘fixed’; blood flow fails to increase during increased demand despite local factors mediated dilatation of resistance vessels (Fig. 39.2) and ischaemic pain is felt. Due to inadequacy of ischaemic left ventricle, the end diastolic left ventricular pressure rises from 5 to about 25 mm Hg—produces sub-endocardial ‘crunch’ during diastole (blood flow to the subendocardial region occurs only during diastole) and aggravates the ischaemia in this region. Thus, a form of acutely developing and rapidly reversible left ventricular failure results which is relieved by taking rest and reducing the myocardial workload.



Drugs that are useful, primarily reduce cardiac work (directly by acting on heart or indirectly by reducing preload hence end diastolic pressure, and afterload). They may also cause favourable redistribution of blood flow to the ischaemic areas.


Variant/Prinzmetal’s  angina 

(uncommon form)


Attacks occur at rest or during sleep and are unpredictable. They are due to recurrent localized (occasionally diffuse) coronary vasospasm (Fig. 39.2) which may be superimposed on arteriosclerotic coronary artery disease.


Abnormally reactive and hypertrophied segments in the coronary arteries have been demonstrated. Drugs are aimed at preventing and relieving the coronary vasospasm.


Unstable angina with rapid increase in duration and severity of attacks is mostly due to rupture of an atheromatous plaque attracting platelet deposition and progressive occlusion of the coronary artery; occasionally with associated coronary vasospasm.


Chronically reduced blood supply causes atrophy of cardiac muscle with fibrous replacement (reduced myocardial work capacity CHF) and may damage conducting tissue to produce unstable cardiac rhythms. Antianginal drugs relieve cardiac ischaemia but do not alter the course of coronary artery pathology: no permanent benefit is afforded. On the other hand, aspirin, ACE inhibitors and statins (hypocholesterolaemic) can modify coronary artery disease and improve prognosis.


Glyceryl trinitrate, the drug unsurpassed in its ability to abort and terminate anginal attack, was introduced by Murrell in 1879. Other organic nitrates were added later, but a breakthrough was achieved in 1963 when propranolol was used for chronic prophylaxis. The calcium channel blockers have been a major contribution of the 1970s and continue to proliferate. A number of vasodilator and other drugs have been promoted from time to time, but none is as uniformly effective. Some potassium channel openers (nicorandil) and metabolic modulators (trimetazidine, ranolazine) have been introduced lately.




1. Nitrates

Short acting: Glyceryl trinitrate (GTN, Nitroglycerine)

Long acting: Isosorbide dinitrate (short acting by sublingual route), Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate


2. β Blockers Propranolol, Metoprolol, Atenolol and others.


3. Calcium Channel Blockers


Phenyl alkylamine:Verapamil

Benzothiazepine: Diltiazem

Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine, Nimodipine, Lacidipine, Lercanidipine, Benidipine


4. Potassium Channel Opener                                                          



5. Others Dipyridamole, Trimetazidine, Ranolazine, Oxyphedrine


Clinical Classification


A. Used To Abort Or Terminate Attack GTN, Isosorbide dinitrate (sublingually).

B. Used For Chronic Prophylaxis All other drugs.


NITRATES ( (GTN as prototype)


All organic nitrates share the same action; differ only in time course. The only major action is direct nonspecific smooth muscle relaxation.


Preload Reduction The most prominent action is exerted on vascular smooth muscle. Nitrates dilate veins more than arteries peripheral pooling of blood decreased venous return i.e. preload on heart is reduced end diastolic size and pressure are reduced decreased cardiac work according to Laplace relationship—which describes the effectiveness of ventricular wall tension in elevating intraventricular pressure and the extent to which fibre shortening results in systolic ejection.


Wall Tension = intraventricular Pressure × ventricular Radius


Thus, reduction in ventricular radius decreases the tension that must be generated in the ventricular wall—hence decreased O2 consumption. Reduction in cardiac output (c.o.) occurs at rest but is less marked during angina due to better ventricular emptying. The decrease in end diastolic pressure abolishes the subendocardial crunch by restoring the pressure gradient across ventricular wall due to which subendocardial perfusion occurs during diastole. It is through their action on peripheral veins that nitrates exert major beneficial effects in classical angina.


Afterload Reduction Nitrates also produce some arteriolar dilatation slightly decrease total peripheral resistance (t.p.r.) or afterload on heart; BP falls somewhat; systolic more than diastolic (reflex sympathetic activity tends to maintain diastolic BP). This action contributes to the reduction in cardiac work which is directly proportional to aortic impedance.


With usual doses, and if the patient does not stand still (which favours pooling of blood in the legs), tachycardia is not prominent. With large doses and if the mean BP falls significantly, reflex sympathetic stimulation occurs tachycardia, increased cardiac contractility increased cardiac work angina may be precipitated. Fainting and cold sweat occur due to cerebral ischaemia. All these can be prevented by lying down and raising the foot end.


Redistribution Of Coronary Flow In the arterial tree, nitrates preferentially relax bigger conducting (angiographically visible) coronary arteries than arterioles or resistance vessels. This pattern of action may cause favourable redistribution of blood flow to ischaemic areas in angina patients. Dilatation of conducting vessels all over by nitrate along with ischaemia-induced dilatation of autoregulatory resistance vessels only in the ischaemic zone increases blood flow to this area, while in the non-ischaemic zones, resistance vessels maintain their tone flow does not increase, or may decrease to compensate for increased flow to ischaemic zone. In fact, nitrates do not appreciably increase total coronary flow in angina patients.


Mechanism Of Relief Of Angina  The dilator effect on larger coronary vessels is the principal action of nitrates benefiting variant angina by counteracting coronary spasm. In classical angina undoubtedly the primary effect is to reduce cardiac work by action on peripheral vasculature, though increased blood supply to ischaemic area may contribute. Exercise tolerance of angina patients is increased because the same amount of exercise causes lesser augmentation of cardiac work.


Heart And Peripheral Blood Flow Nitrates have no direct stimulant or depressant action on the heart. They dilate cutaneous (especially over face and neck flushing) and meningeal vessels headache. Splanchnic and renal blood flow decreases to compensate for vasodilatation in other areas. Nitrates tend to decongest lungs by shifting blood to systemic circulation.


Other Smooth Muscles Bronchi, biliary tract and esophagus are relaxed; effect on intestine, ureter, uterus is variable and insignificant.


Mechanism of action


Organic nitrates are rapidly de-nitrated enzymatically in the smooth muscle cell to release the reactive free radical nitric oxide (NO) which activates cytosolic guanylyl cyclase increased cGMP causes de-phosphorylation of myosin light chain kinase (MLCK) through a cGMP dependent protein kinase (Fig. 39.3). 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.



Veins express greater amount of the enzyme that generates NO from GTN than arteries—may account for the predominant venodilator action. It has been indicated that preferential dilatation of epicardial conducting arteries over autoregulatory arterioles is also due to differential distribution of nitrate metabolizing enzymes in these vessels.


Platelets The NO generated from nitrates activates cGMP production in platelets as well, leading to a mild antiaggregatory effect. This action may be valuable in unstable angina.



Organic nitrates are lipidsoluble: well absorbed from buccal mucosa, intestines and skin. 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 have longer t½. Though nitrates have been traditionally classified into short-acting and long-acting, it is the rate of absorption from the site of administration and the rate of metabolism that govern the duration of action of a particular nitrate. For example, GTN and isosorbide dinitrate are both short-acting from sublingual but longer-acting from oral route.


Adverse Effects

These are mostly due to vasodilatation.


1.    Fullness in head, throbbing headache; some degree of tolerance develops on continued use.


2.    Flushing, weakness, sweating, palpitation, dizziness and fainting; these are mitigated by lying down and accentuated by erect posture and alcohol.


3.    Methemoglobinemia: is not marked with clinically used doses. However, it can reduce O2 carrying capacity of blood in severe anaemia.


4.    Rashes are rare, though relatively more common with pentaerythritol tetranitrate.


Tolerance Attenuation of haemodynamic and anti-ischaemic effect of nitrates occurs if they are continuously present in the body. This tolerance weans off rapidly (within hours) when the body is free of the drug. Clinically, no significant tolerance develops on intermittent use of sublingual GTN for attacks of angina. However, it may become important when GTN is used orally, transdermally or by continuous i.v. infusion round the clock, as well as with the use of long acting agents, especially sustained release formulations. Cross tolerance occurs among all nitrates. Tolerance occurs more readily with higher doses.


The mechanism of nitrate tolerance is not well understood. Reduced ability to generate NO due to depletion of cellular SH radicals has been demonstrated experimentally. However, thiol replinishing agents only partially overcome nitrate tolerance. This form of therapy has not met clinical success. Other changes which interfere with NO production like inactivation of mitochondrial aldehyde dehydrogenase could be involved. Activation of compensatory mechanisms including volume expansion, sympathetic and renin-angiotensin system stimulation or other humoral pathways as well as oxidative stress due to free radicals generated during de-nitration may contribute to nitrate tolerance.


The most practical way to prevent nitrate tolerance is to provide nitrate free intervals everyday.


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 may be lowered during nitrate free interval in some patients: episodes of angina may increase. In such cases a drug of another class should be added. Withdrawal of nitrates should be gradual.



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




Glyceryl trinitrate (GTN, Nitroglycerine)


It is a volatile liquid which is adsorbed on the inert matrix of the tablet and rendered nonexplosive. The tablets must be stored in a tightly closed glass (not plastic) container lest the drug should evaporate away. The sublingual route is used when terminating an attack or aborting an imminent one is the aim. The tablet may be crushed under the teeth and spread over buccal mucosa. It acts within 1–2 min (peak blood level in 3–6 min) because of direct absorption into systemic circulation (bypassing liver where almost 90% is metabolized).


Plasma t½ is 2 min, duration of action depends on the period it remains available for absorption from buccal mucosa. The remaining part of the tablet may be spit or swallowed when no longer needed. A sublingual spray formulation has been recently marketed—acts more rapidly than sublingual tablet. Hepatic metabolizing capacity can be overwhelmed by administering a large dose (5–15 mg) orally. Sustained release oral capsules containing much larger amounts of GTN can be used for chronic prophylaxis.


Nitroglycerine is readily absorbed from the skin. In the early 1970s, cutaneous application as ointment was found to produce haemodynamic effects for 4–6 hours. A transdermal patch in which the drug is incorporated into a polymer bonded to adhesive plaster (see p. 9) has been developed which provides steady delivery for 24 hours. It starts working within 60 min and has a bioavailability of 70–90%. However, development of tolerance and dependence may jeopardise its value. It is advised that the patch be taken off for 8 hours daily. A transmucosal dosage form which has to be stuck to the gums under the upper lip has also been produced—acts in 5 min and releases the drug for 4–6 hours.


Intravenous infusion of GTN provides rapid, steady, titratable plasma concentration for as long as desired. It has been successfully used for unstable angina, coronary vasospasm, LVF accompanying MI, hypertension during cardiac surgery, etc. Begin with 5 μg/min, adjust according to need. Early institution of infusion may limit the size of infarct in MI.


Isosorbide dinitrate


It is a solid but similar in properties to GTN; can be used sublingually at the time of attack (slightly slower in action than GTN, peak in 5–8 min) as well as orally for chronic prophylaxis. Presystemic metabolism on oral administration is pronounced and variable. The t½ is 40 min, but sustained release formulation may afford protection for 6–10 hours. Last dose should not be taken later than 6 PM to allow nitrate level to fall during sleep at night.


Isosorbide mononitrate


This is an active metabolite of isosorbide dinitrate. When administered orally it undergoes little first pass metabolism: bioavailability is high, interindividual differences are minimal and it is longer acting (t½ 4–6 hr). Last dose is to be taken in the afternoon; SR tablet once a day in the morning.


Erythrityl tetranitrate and pentaerythritol tetranitrate


These are longer-acting nitrates used only for chronic prophylaxis. Sustained release oral preparations are now available for 2–3 times a day dosing. There has been considerable scepticism in the past about the efficacy of orally administered long-acting nitrates. Studies with high doses have shown that first-pass metabolism in liver can be saturated and haemodynamic effects lasting 4–6 hours do occur.





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 ischaemia. Longeracting formulations (oral, transdermal) of GTN or other nitrates are used on regular schedule for chronic prophylaxis. However, development of tolerance and dependence may limit the usefulness of this approach: 6–8 drug free hours daily are advisable.


Acute Coronary Syndromes


These are characterized by rapid worsening of anginal status of the patient : include unstable angina (UA) and non-ST segment elevation myocardial infarction (NSTEMI). It needs aggressive therapy with a combination of drugs intended to prevent further coronary occlusion, increase coronary blood flow and decrease myocardial stress (oxygen demand). Nitrates are useful by decreasing preload (myocardial work) as well as by increasing coronary flow (dilatation and antagonism of coronary spasm, if present). Initially GTN is given sublingually, but if pain persists after 3 tablets 5 min apart, i.v. infusion of GTN is started. The role of nitrates appears to be limited to relief of pain, because no mortality benefit has been demonstrated in large randomized clinical trials such as GISSI3 (1994) and ISIS4 (1995).

Antiplatelet drugs like aspirin, clopidogrel, GPIIb/IIIa antagonists, with or without heparin are the primary measures in UA/NSTEMI. The β blockers are indicated in all patients (if there are no contraindications) to reduce myocardial oxygen demand. A CCB is indicated only when coronary spasm is not effectively counteracted by the nitrate. Revascularization by thrombolytics/coronary angioplasty with stents/coronary bypass surgery is considered in high risk patients.


Myocardial Infarction (MI)


Administered by carefully titrated i.v. 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 favourably altering O2 balance in the marginal partially ischaemic zone (a consequence of preload reduction). However, the evidence that it decreases mortality is not robust; prognostic benefits appear marginal. Proper patient selection is important. 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.


CHF and Acute LVF


The role of vasodilators in CHF is described in Ch. No. 37. Nitrates afford relief by venous pooling of blood (which can be aided by sitting posture while managing acute LVF or severe chronic CHF) reduced venous return (preload) decreased end diastolic volume improvement in left ventricular function by Laplace law and regression of pulmonary congestion. Intravenous GTN is the preparation of choice for emergency use: rate of infusion must be guided by continuous haemodynamic monitoring.


Biliary Colic due to disease or morphine— responds to sublingual GTN or isosorbide dinitrate.


American Heart Association/American College of Cardiology guidelines for the management of patients with acute myocardial infarction. Circulation 2004, 110, 588636.


Esophageal Spasm


Sublingual GTN promptly relieves pain. Nitrates taken before a meal facilitate feeding in esophageal achalasia by reducing esophageal tone.


Cyanide Poisoning


Nitrates generate methaemoglobin which has high affinity for cyanide radical and forms cyano-methaemoglobin. 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.


Cytochrome and other oxidative enzymes are thus protected from cyanide; even that which has complexed CN is reactivated. However, early treatment is critical. The antidotes should be repeated as required.



Sodium nitrite is used for this purpose because it is a very weak vasodilator; large doses (>300 mg) sufficient to generate enough methaemoglobin can be injected i.v. without producing hypotension.




These drugs do not dilate coronaries or other blood vessels; total coronary flow is rather reduced due to blockade of dilator β2 receptors. However, flow to the ischaemic subendocardial area is not reduced because of favourable redistribution and decrease in ventricular wall tension. They act by reducing cardiac work and O2 consumption (decreased heart rate, inotropic state and mean BP). This is marginal at rest. More importantly, blockers limit increase in these modalities that occurs during exercise or anxiety (due to antiadrenergic action on heart).


All β blockers are nearly equally effective in decreasing frequency and severity of attacks and in increasing exercise tolerance in classical angina, but cardioselective agents (atenolol, metoprolol) are preferred over nonselective β1 + β2 blockers (e.g. propranolol), which may worsen variant angina due to unopposed α receptor mediated coronary constriction that may accentuate the coronary spasm. Long term β blocker therapy lowers risk of sudden cardiac death among ischaemic heart disease patients.


In angina pectoris, βblockers are to be taken on a regular schedule; not on ‘as and when required’ basis. The dose has to be individualized. Abrupt discontinuation after chronic use may precipitate severe attacks, even MI.


Unstable Angina (UA)/Non-STelevation MI (NSTEMI): Unless contraindicated, β blockers are routinely used in UA/NSTEMI. However, they should be given only after starting nitrate ± calcium channel blocker to counteract coronary vasospasm, if present (β blockers carry the risk of worsening coronary vasospasm). β blockers reduce myocardial O2 demand and afford additional benefit by reducing risk of impending MI/sudden cardiac death.




Verapamil was developed in Germany in 1962 as a coronary dilator. It had additional cardio-depressant property, but its mechanism of action was not known. Fleckenstein (1967) showed that it interfered with Ca2+ movement into the cell. In the subsequent years, a large number of chemically diverse Ca2+ channel blockers (CCBs) with different pharmacological profiles have been produced.


Three important classes of calcium channel blockers are examplified by:


Verapamil—a phenyl alkylamine, hydrophilic papaverine congener.

Nifedipine—a dihydropyridine (lipophilic).

Diltiazem—a hydrophilic benzothiazepine.


The dihydropyridines (DHPs) are the most potent Ca2+ channel blockers, and this subclass has proliferated exceptionally.


Calcium Channels


Three types of Ca2+ channels have been described in smooth muscles (other excitable cells as well):


(a) Voltage Sensitive Channel Activated when membrane potential drops to around –40 mV or lower.


(b) Receptor Operated Channel Activated by Adr and other agonists—independent of membrane depolarization (NA contracts even depolarized aortic smooth muscle by promoting influx of Ca2+ through this channel and releasing Ca2+ from sarcoplasmic reticulum).


(c) Leak Channel Small amounts of Ca2+ leak into the resting cell and are pumped out by Ca2+ATPase.



Mechanical stretch promotes inward movement of Ca2+, which may be occurring through activation of the leak channel or through separate stretch sensitive channel.


The voltage sensitive Ca2+ channels are heterogeneous: three major types have been identified.


All voltage sensitive Ca2+ channels are membrane spanning funnel shaped glycoproteins that function as ion selective valves. They are composed of a major α1 subunit which encloses the ion channel and other modulatory subunits like α2,β, γ and δ. In L-type Ca2+ channels each subunit exists in multiple isoforms which may be site specific, e.g.

Skeletal muscle L-channels are: α1s . α2/δa . β1 . γ

Cardiac muscle L-channels are: α1ca . α2/δc . β2

Smooth muscle L-channels are: α1cb . α2/δ . β3


Even smooth muscle L-channels differ between vascular and nonvascular. Moreover distribution may be heterogeneous in different parts of the vascular bed.


Only the voltage sensitive L-type channels are blocked by the CCBs. The 3 groups of CCBs viz. phenylalkylamines (verapamil), benzothiazepine (diltiazem) and dihydropyridines (nifedipine) bind to their own specific binding sites on the α1 subunit; all restricting Ca2+ entry, though characteristics of channel blockade differ. Further, different drugs may have differing affinities for various site specific isoforms of the L-channels. This may account for the differences in action exhibited by various CCBs. The vascular smooth muscle has a more depolarized membrane (RMP about –40 mV) than heart. This may contribute to vascular selectivity of certain CCBs.


Pharmacological Actions And Adverse Effects


The common property of all three subclasses of CCBs is to inhibit Ca2+ mediated slow channel component of action potential (AP) in smooth/ cardiac muscle cell. The two most important actions of CCBs are:


·      Smooth muscle (especially vascular) relaxation.

·      Negative chronotropic, inotropic and dromotropic action on heart.


Smooth Muscle


Smooth muscles depolarise primarily by inward Ca2+ movement through voltage sensitive channel. These Ca2+ ions trigger release of more Ca2+ from intracellular stores and together bring about excitation contraction coupling through phosphorylation of myosin light chain as depicted in Fig. 39.3. CCBs cause relaxation by decreasing intracellular availability of Ca2+. They markedly relax arterioles but have mild effect on veins. Extravascular smooth muscle (bronchial, biliary, intestinal, vesical, uterine) is also relaxed.



The dihydropyridines (DHPs) have the most marked smooth muscle relaxant and vasodilator action; verapamil is somewhat weaker followed by diltiazem.


Nitrendipine and other DHPs have been shown to release NO from endothelium and inhibit cAMP-phosphodiesterase resulting in raised smooth muscle cAMP. These additional mechanisms may account for their predominant smooth muscle relaxant action. Released endothelial NO may exert anti-atherosclerotic action.


Heart In the working atrial and ventricular fibres, Ca2+ moves in during plateau phase of AP releases more Ca2+ from sarcoplasmic reticulum contraction through binding to troponin— allowing interaction of myosin with actin. The CCBs would thus have negative inotropic action.


The 0 phase depolarization in SA and AV nodes is largely Ca2+ mediated. Automaticity and conductivity of these cells appear to be dependent on the rate of recovery of the Ca2+ channel.



The L-type Ca2+ channels activate as well as inactivate at a slow rate. Consequently, Ca2+ depolarized cells (SA and AV nodal) have a considerably less steep 0 phase and longer refractory period. The recovery process which restores the channel to the state from which it can again be activated by membrane depolarization is delayed by verapamil and to a lesser extent by diltiazem (resulting in depression of pacemaker activity and conduction), but not by DHPs (they have no negative chronotropic/dromotropic action). Moreover, channel blockade by verapamil is enhanced at higher rates of stimulation, that by nifedipine is independent of frequency, while diltiazem is intermediate. Thus, verapamil slows sinus rate and AV conduction, but nifedipine does not. Effect of diltiazem on sinus node automaticity and AV conduction is similar to that of verapamil.


The relative potencies to block slow channels in smooth muscle do not parallel those in the heart. The DHPs are more selective for smooth muscle L-channels: at concentrations which cause vasodilatation they have negligible negative inotropic action. Diltiazem causes less depression of contractility than verapamil. Important differences between the three representative CCBs are summarized in Table 39.2. Their cardiac electrophysiological effects are compared in Table 38.1.




It dilates arterioles and has some α adrenergic blocking activity—decreases t.p.r. but BP is only modestly lowered. The pronounced direct cardio-depressant effect is partially offset in vivo by reflex effects of peripheral vasodilatation. The HR generally decreases, AV conduction is slowed, but c.o. is maintained by reflex sympathetic stimulation and reduction in aortic impedance. However, ventricular contractility may be markedly impaired in CHF patients. Coronary flow is increased.


Dose: 40–160 mg TDS oral, 5 mg by slow i.v. injection. CALAPTIN 40, 80 mg tabs, 120, 240 mg SR tabs, 5 mg/ 2 ml inj.


Adverse Effects

Nausea, constipation and bradycardia are more common than other CCBs, while flushing, headache and ankle edema are less common. Hypotension is occasional and tachycardia (common with DHPs) is absent. It can accentuate conduction defects (contraindicated in 2nd and 3rd degree AV block) and precipitate CHF in patients with preexisting disease. Cardiac arrest has occurred on i.v. injection and when it is given to patients with sick sinus.



Verapamil should not be given with β blockers—additive sinus depression, conduction defects or asystole may occur.


It increases plasma digoxin level by decreasing its excretion: toxicity can develop.


It should not be used with other cardiac depressants like quinidine and disopyramide.




It is a less potent vasodilator than nifedipine and verapamil, and has modest direct negative inotropic action, but direct depression of SA node and AV conduction are equivalent to verapamil. Usual clinical doses produce consistent fall in BP with little change or decrease in HR. Large dose or i.v. injection decreases t.p.r. markedly which may elicit reflex cardiac effects. It dilates coronaries.


Dose: 30–60 mg TDS–QID oral; DILZEM, 30, 60 mg tabs, 90 mg SR tab; 25 mg/5 ml inj; ANGIZEM 30, 60, 90, 120, 180 mg tab, DILTIME 30, 60 mg tab; 90, 120 mg SR tab.


Adverse Effects

Incidence of side effects is low, but the profile is similar to verapamil. Like verapamil, it also increases plasma digoxin.


Diltiazem should not be given to patients with preexisting sinus, AV nodal or myocardial disease. Only low doses should be given to patients on β blockers.




It is the prototype DHP with a rapid onset and short duration of action. The overriding action of nifedipine is arteriolar dilatation t.p.r. decreases, BP falls. The direct depressant effect on heart requires much higher dose, but a weak negative inotropic action can be unmasked after β blockade. As discussed above, it does not depress SA node or AV conduction. Reflex sympathetic stimulation of heart predominates tachycardia, increased contractility and c.o. (no decrease in venous return along with lowering of afterload aid increase in c.o.). Coronary flow is increased.


Nifedipine has mild natriuretic action, but significant diuresis does not occur.


Dose: 5–20 mg BD–TDS oral.


CALCIGARD, DEPIN, NIFELAT 5, 10 mg tab, also 10 mg, 20 mg S.R. (RETARD) tab; NICARDIA 5, 10 mg tab; 10, 20, 30 mg SR tab.


Adverse Effects

Frequent side effects are palpitation, flushing, ankle edema, hypotension, headache, drowsiness and nausea. These are related to peaks of drug level in blood: can be minimized by low starting dose, fractionation of dose or use of retard formulation. Nifedipine has paradoxically increased the frequency of angina in some patients. Higher mortality among post MI patients has been confirmed. However, it has been safely administered with β blockers and digoxin.


By its relaxant effect on bladder nifedipine can increase urine voiding difficulty in elderly males. It has also been reported to hamper diabetes control by decreasing insulin release.




All DHPs have pharmacodynamic profile similar to nifedipine; there are minor differences in organ selectivity and major differences in pharmaco kinetic characteristics. The slower and longer acting ones induce less reflex sympathetic stimulation. Tachycardia, propensity to increase cardiac work, flushing, headache, dizziness are subdued. They are currently favoured, particularly since increased mortality among postMI patients has been reported with the regular short-acting nifedipine formulation.




It differs from nifedipine in having greater vascular selectivity, larger tissue distribution and longer t½. The extended release preparation is suitable for once daily administration.


Dose: 5–10 mg OD, max. 10 mg BD.


FELOGARD, PLENDIL, RENDIL 2.5, 5, 10 mg ER tab.




Pharmacokinetically it is the most distinct DHP. It has complete but slow oral absorption: peak after 6 to 9 hr—the early vasodilator side effects (palpitation, flushing, headache, postural dizziness) are largely avoided. Because of less extensive and less variable first pass metabolism, its oral bioavailability is higher and more consistent. Volume of distribution and t½ are exceptionally long: diurnal fluctuation in blood level is small and action extends over the next morning.


Dose: 5–10 mg OD; AMLOPRES, AMCARD, AMLOPIN, MYODURA 2.5, 5, 10 mg tabs.


S(–)Amlodipine The single enantiomer preparation is effective at half the dose and is claimed to cause less ankle edema.


Dose: 2.5–5 mg OD;






A DHP with oral bioavailability of 10–30% and elimination t½ of 4–12 hours. It has been shown to release NO from the endothelium and inhibit cAMP phosphodiesterase; which may be the additional mechanisms of vasodilator action. The endothelial NO is claimed to retard atherosclerosis. Ventricular contractility and AV conduction are not depressed. Nitrendipine is indicated in hypertension and angina pectoris.


Dose: 5–20 mg OD; NITREPIN, CARDIF 10, 20 mg tabs.




A highly vasoselective newer DHP suitable for once daily administration. It is claimed to attain higher concentration in vascular smooth muscle membrane; approved only for use as antihypertensive.


Dose: 4 mg OD, increase to 6 mg OD if required.


LACIVAS, SINOPIL 2, 4 mg tabs.




It is a short-acting DHP which penetrates bloodbrain barrier very efficiently due to high lipid solubility. It selectively relaxes cerebral vasculature; approved for prevention and treatment of neurological deficit due to cerebral vasospasm following subarachnoid haemorrhage or ruptured congenital intracranial aneurysms. Side effects are headache, flushing, dizziness, palpitation and nausea.


Dose: 30–60 mg 4–6 hourly for 3 weeks following subarachnoid haemorrhage; VASOTOP, NIMODIP, NIMOTIDE 30 mg tab; 10 mg/50 ml inj.




Another DHP similar to nifedipine, but with longer duration of action. Peak plasma concentrations occur at 1.5–3 hrs; t½ is 5–10 hours. It is indicated in hypertension at a dose of 10–20 mg OD.


LEREZ, LERKA 10, 20 mg tabs.




A long-acting DHP that owes its long duration of action to slow dissociation from the DHP receptor on the smooth muscle cell. It is indicated in hypertension and angina pectoris. It is marketed only in India and Japan.

Dose: 4–8 mg OD; CARITEC 4, 8 mg tab.




The pharmacokinetic parameters of Ca2+ channel blockers are tabulated in Table 39.3. All are 90–100% absorbed orally, peak occurring at 1–3 hr (except amlodipine 6–9 hr). The oral bioavailability of Ca2+ channel blockers is incomplete with marked inter and intra individual variations. This is due to high first pass metabolism (modest and less variable for amlodipine). All are highly plasma protein bound (min.: diltiazem 80%, max.: felodipine 99%).


The Ca2+ channel blockers are high clearance drugs with extensive tissue distribution. All are 90% metabolized in liver and excreted in urine. Some metabolites are active. The elimination t½ are in the range of 2–6 hr, but that of amlodipine is exceptionally long; followed by lacidipine, nitrendipine and felodipine.


On chronic use verapamil decreases its own metabolism—bioavailability is nearly doubled and t½ is prolonged.




Calcium channel blockers can be safely given to patients with obstructive lung disease and peripheral vascular disease in whom β blockers are contraindicated. The problem of rebound worsening of angina on withdrawal after chronic use is less with CCBs than with β blockers.


Angina Pectoris


All CCBs are effective in reducing frequency and severity of classical as well as variant angina. Benefit in classical angina appears to be primarily due to reduction in cardiac work: mainly as a result of reduced afterload. Though, they can increase coronary flow in normal individuals, this is unlikely to be significant in patients with fixed arterial obstruction. Exercise tolerance is increased.


Many controlled studies and meta-analysis have concluded that myocardial ischaemia may be aggravated by short-acting DHPs. This may be due to decreased coronary flow secondary to fall in mean arterial pressure, reflex tachycardia and coronary steal. The direct cardiac effect of verapamil and diltiazem to reduce O2 requirement and less marked sympathetic stimulation makes them less likely to aggravate ischaemia.


Trials using high dose regular short-acting nifedipine formulation have reported increased mortality among MI patients. The sudden rush of sympathetic activity evoked by each dose of these preparations has been held responsible for the deleterious effect. The slow and long-acting DHPs do not share this disadvantage. There is some evidence that verapamil and diltiazem reduce reinfarction and mortality in MI patients (equal to that achieved by β blockers) with uncompromised ventricular function.


Myocardial infarction: The concensus opinion is against use of CCBs in MI, but verapamil/ diltiazem may be employed for secondary prophylaxis when β blockers are contraindicated.


The capacity of CCBs to prevent arterial spasm is undoubtedly responsible for the beneficial effect in variant angina. Reduction of cardiac O2 demand would also work in the same direction. No significant difference in efficacy among different CCBs has been noted in angina pectoris.


CCBs are not a first line treatment of unstable angina; may be used as add on therapy to nitrates when coronary vasospasm is prominent and is not counteracted by nitrate alone. Use of nifedipine/DHPs in non β blocked patients is to be avoided.




DHPs, diltiazem and verapamil are among the first line drugs for hypertension (see Ch. No. 40).


Cardiac Arrhythmias


Verapamil and diltiazem are highly effective in PSVT and for control of ventricular rate in supraventricular arrhythmias (see Ch. No. 38).


Hypertrophic Cardiomyopathy


The negative inotropic action of verapamil can be salutary in this condition.


Other Uses


Nifedipine is an alternative drug for premature labour; Verapamil has been used to suppress migraine and nocturnal leg cramps. The DHPs reduce severity of Raynaud’s episodes.


Along with any of the drugs used for chronic prophylaxis of angina, sublingual short-acting nitrate is allowed on ‘as and when’ required basis to abort and terminate anginal attacks when they occur.


Of the three major classes of antianginal drugs described above, generally one agent is used initially; choice depends on the stage of disease, associated cardaic/other medical conditions and individual acceptability of side effects, because long-term prognostic benefit and tolerability of long-acting nitrates (including transdermal GTN), β blockers and long-acting CCBs is similar. However, some direct comparative studies have found β blockers to achieve greater reduction in the number of anginal attacks than CCBs, but objective measurements and outcome were not different. When monotherapy is unable to provide adequate relief in tolerated doses, concurrent use of 2 or 3 drugs may be tried.


I. β blocker + long-acting nitrate combination is rational in classical angina because:


(a) Tachycardia due to nitrate is blocked by β blocker.

(b) The tendency of β blocker to cause ventricular dilatation is counteracted by nitrate.

(c) The tendency of β blocker to reduce total coronary flow is opposed by nitrate.


II. The above advantages may also be obtained by combining a slow acting DHP (in place of nitrate) with β blocker. However, verapamil or diltiazem should not be used with β blocker since their depressant effects on SA and AV node may add up.


III. Nitrates primarily decrease preload, while CCBs have a greater effect on afterload. Their concurrent use may decrease cardiac work to an extent not possible with either drug alone. This combination may be especially valuable in severe vasospastic angina.


IV. In the most severe and resistant cases of classical angina, combined use of all the three classes is indicated. Since their primary mechanism of benefit is different, supra-additive results may be obtained.


·      Nitrates primarily decrease preload.

·      CCBs mainly reduce afterload + increase coronary flow.

·      β blockers decrease cardiac work primarily by direct action on heart.


Verapamil/diltiazem should be avoided in such combinations.

In randomized comparative studies, combinations have been found superior to monotherapy only in more severe cases, but not in mild angina. Recent evidence suggests a greater role of vasospasm of arteriosclerotic segments of coronary arteries in precipitating attacks of angina. As such, coronary dilator action of DHPs/nitrates may be more relevant.





Minoxidil and diazoxide are K+ channel openers which were used earlier in severe hypertension and hypertensive emergencies. Novel K+ channel openers like nicorandil, pinacidil, cromakalim and others have been developed in the 1990s.


Since intracellular concentration of K+ is much higher (150 mM) compared to extracellular (4–5 mM), K+ channel opening results in outflow of K+ ions and hyperpolarization. There are multiple types of K+ channels, e.g. voltage dependent, Ca2+ activated, receptor operated, ATP sensitive, Na+ activated and cell volume sensitive which serve diverse functions and exhibit different sensitivities to drugs. As such, K+ channel openers exhibit considerable diversity in action.


The most prominent action of K+ channel openers is smooth muscle relaxation—vascular as well as visceral: their potential clinical applications (see box) are primarily based on this property. Diazoxide and some other K+ channel openers reduce insulin secretion, while sulfonylureas (glibenclamide) cause hypoglycaemia by blocking K+ channels in pancreatic β cells and promoting insulin release.


Potential Clinical Applications Of K+ Channel Openers


·              Angina pectoris

·              Hypertension

·              Congestive heart failure

·              Myocardial salvage in MI

·              Antihypoglycaemic (Insulinoma)

·              Alopecia

·              Bronchial asthma

·              Urinary urge incontinence

·              Peripheral vascular disease (Raynaud’s, cerebrovascular)

·              Erectile dysfunction

·              Premature labour




This novel antianginal drug activates ATP sensitive K+ channels— hyperpolarizing vascular smooth muscle. The vasodilator action is partly antagonized by K+ channel blocker glibenclamide. Like nitrates it also acts as a NO donor—relaxes blood vessels by increasing cGMP. Thus, arterial dilatation is coupled with venodilatation. Coronary flow is increased; dilatation of both epicardial conducting vessels and deeper resistance vessels has been demonstrated. No significant cardiac effects on contractility and conduction have been noted.


Beneficial effects on angina frequency and exercise tolerance comparable to nitrates, β blockers and CCBs have been obtained in stable as well as vasospastic angina. Mitochondrial K+ATP channel opening by nicorandil is believed to exert myocardial protection by a process of ischaemic preconditioning which appears to reduce myocardial stunning, arrhythmias and infarct size when a coronary artery is suddenly blocked. Myocardial recovery from ischaemic damage after MI as measured by left ventricular wall motion is improved by nicorandil.


The cardioprotective property of nicorandil, has been supported by the large ‘Impact of nicorandil in angina’ (IONA, 2002) randomized trial which found nicorandil to reduce acute coronary events in high risk stable angina patients.


Side Effects are flushing, palpitation, weakness, headache, dizziness, nausea and vomiting. Large painful aphthous ulcers in the mouth, which heal on stopping nicorandil have been reported.


Dose: 5–20 mg BD; NIKORAN, 5, 10 mg tabs, 2 mg/vial, 48 mg/vial inj; KORANDIL 5, 10 mg tabs.






It is a powerful coronary dilator; increases total coronary flow by preventing uptake and degradation of adenosine which is a local mediator involved in autoregulation of coronary flow in response to ischaemia. It dilates resistance vessels and abolishes autoregulation, but has no effect on larger conducting coronary vessels. Cardiac work is not decreased because venous return is not reduced. BP is minimally altered. It does not afford symptomatic benefit or avert ECG changes of angina.


The pharmacological success but therapeutic failure of dipyridamole has been explained on the basis of ‘coronary steal’ phenomenon (Fig. 39.4). By dilating resistance vessels in non-ischaemic zone as well, it diverts the already reduced blood flow away from the ischaemic zone.



Dipyridamole inhibits platelet aggregation. By potentiating PGI2 and increasing cAMP in platelets, it enhances antiaggregatory influences. Though not useful as an antianginal drug, it is being employed for prophylaxis of coronary and cerebral thrombosis in postMI and poststroke patients, as well as to prevent thrombosis in patients with prosthetic heart valves (see Ch. No. 44).


Dose: 25–100 mg TDS; PERSANTIN, CARDIWELL 25, 75, 100 mg tab.




This novel antianginal drug acts by non-haemodynamic mechanisms. There is no effect on determinants of myocardial O2 consumption, such as HR and BP, both at rest as well as during exercise, but angina frequency is reduced and exercise capacity is increased. In patients not adequately controlled by long-acting nitrate/β blocker/CCB, addition of trimetazidine further reduced anginal attacks and increased exercise duration. The mechanism of action of trimetazidine is not known, but it may improve cellular tolerance to ischaemia by:


Inhibiting mitochondrial long chain 3ketoacylCoAthiolase (LC3KAT) a key enzyme in fatty acid oxidation—thereby reducing fatty acid metabolism and increasing glucose metabolism in myocardium. Ischaemic myocardium shifts to utilizing fatty acid as substrate, increasing requirement of O2 for the same amount of ATP generated. Since oxidation of fatty acid requires more O2, shift back of substrate to glucose would reduce O2 demand. It has been labelled as pFOX (fatty acid oxidation pathway) inhibitor.


Limiting intracellular acidosis and Na+, Ca2+ accumulation during ischaemia.


Protecting against O• free radical induced membrane damage.

Trimetazidine is absorbed orally, partly metabolized and largely excreted unchanged in urine; t½ is 6 hr. It is generally well tolerated; side effects are—gastric burning, dizziness, fatigue and muscle cramps. Reversible parkinsonism has been reported in the elderly.


Trimetazidine has also been advocated for visual disturbances, tinnitus, Méniére’s disease, dizziness, etc., but conclusive evidence of efficacy in these conditions is lacking. For ischaemic heart disease, it has been widely used in France, Spain, some other European countries and India, but not in the UK or USA. It is mostly an add on medication to conventional therapy in angina and postMI patients.


Dose: 20 mg TDS.


FLAVEDON 20 mg tabs, 35 mg modified release tab; CARVIDON, TRIVEDON 20 mg tab.




This recently developed trimetazidine congener LC3KAT inhibitor is a metabolic modifier approved by USFDA in 2006 for treatment of chronic angina pectoris in patients who fail to respond to standard antianginal therapy. Ranolazine spares fatty acid oxidation and shifts ATP production to more O2 efficient carbohydrate oxidation. It also inhibits late INa current in the myocardium which indirectly facilitates Ca2+ entry. Reduction in Ca2+ overload in the myocardium during ischaemia may play an important role in the cardioprotective action of ranolazine.


The efficacy of ranolazine in decreasing frequency of anginal attacks and in prolonging exercise duration has been demonstrated both as monotherapy as well as when added to conventional drugs (atenolol, amlodipine, diltiazem) in multicentric randomized trials: MARISA (monotherapy assessment of ranolazine in stable angina, 2004), CARISA (Combination assessment of ranolazine in stable angina, 2004), ERICA (Efficacy of ranolazine in chronic angina, 2005). Efficacy in acute coronary syndromes is being assessed in a large (>6000 patients) study MERLINTIMI 36 (Metabolic efficiency with ranolazine for less ischaemia in non ST elevation acute coronary syndromes).


Oral absorption of ranolazine is slow taking 4–6 hours with a bioavailability of 30–50%. It is metabolized in liver and excreted by the kidney with an average t½ of 7 hours. Side effects reported are dizziness, weakness, constipation, postural hypotension, headache and dyspepsia. Prolongation of QTc interval has been noted; torsades de pointes is a risk, but not yet encountered.


Dose:  0.5–1.0  g  BD;  (marketed  in  USA  as  ER  tablet RANEXA)


Ranolazine is at present recommended in angina pectoris only in combination with conventional therapy.




This drug is claimed to improve myocardial metabolism so that heart can sustain hypoxia better. Though used in angina and MI, its efficacy and status in coronary artery disease is not defined. It can diminish or alter taste sensation.


Dose: 8–24 mg TDS oral, 4–8 mg i.v. ODBD; ILDAMEN 8, 24 mg tab., 4 mg/2 ml inj.


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