Nitrates (GTN as prototype)

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

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


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.

 

Pharmacokinetics

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.

 

Interactions

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.


INDIVIDUAL DRUGS

 

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.

 


 

Uses

 

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 2004110, 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.

 

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