Pharm 100 - Lesson C.1
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Drugs for the Treatment of Angina Pectoris - three major classes
There are three major classes of antianginal drugs: (1) the organic nitrates which include theshort-acting nitroglycerin, and the long-acting isosorbide dinitrate; (2) the $-adrenergicantagonists of which propranolol is a prototype drug; and (3) the calcium channel blockers ofwhich nifedipine is a prototype drug. Newer classes of drugs are in clinical trial.
- Angina pectoris was first described by the English physician William Heberden in 1768. Hedescribed the condition as follows:
- “Those who are afflicted with it are seized while they are walking (more especially if it beup hill and soon after eating) with a painful and most disagreeable sensation in the breast,which seems as if it would extinguish life, if it were to increase or continue; but the momentthey stand still, all uneasiness vanishes.”
- He went on to acknowledge that: “With respect to this complaint I have little or nothing toadvance” (from J.C. Krantz Jr., Historical Medical Classics Involving New Drugs, page 24, Williamand Wilkins, 1974).
- Amyl nitrite was the first agent in this class introduced by Lauder Brunton in 1857. It wasadministered by inhalation and anginal pain was relieved in 30 to 60 seconds. The action of the drugwas transitory and lasted for 3 to 5 minutes. Moreover, the dosage was difficult to adjust.
- There was clearly a need for an improved therapy for angina and in 1879, William Murrellintroduced sublingual nitroglycerin (glyceryl trinitrate). The effect of the drug lasted for 20 to 30minutes.
Angina pectoris (a choking pain in the chest) is usually due to lipid deposits in the coronaryarteries hindering blood flow (atherosclerosis). There is a sudden, severe pressing pain in the chest. The pain arises from diminished blood flow and a diminished oxygen supply to an area of the heartmuscle. To reduce the pain, one must decrease the oxygen requirement of the heart and/or increasethe oxygen supply to oxygen deficient areas of the heart muscle.
the four “E’s”
Angina pectoris is precipitated by the four “E’s”, namely Eating, Exercise, Excitement, Exposureto cold. A good candidate for angina pectoris is an aging professor, such as the author, who spends atiring day working in the research laboratory. He returns home, Eats a large dinner, engages in anargument with adult children and becomes Excited. It is a very cold night and he decides he needsExercise and will shovel the driveway to remove the snow. Obviously he has all the precipitatingfactors for angina pectoris
Mechanism of Action of Organic Nitrates
- The mechanism of action of organic nitrates has been studied for many years and a great deal ofargument has been provoked by proponents of different theories. There is now a general consensusthat organic nitrates relax the smooth muscle of blood vessels and exert their therapeutic effect by thefollowing two mechanisms.
- 1. Relaxation of large veins, leading to vasodilation. This effect results in a decrease in venousblood returning to the heart. This results in a decrease in cardiac output, a decrease in heart size,and a decrease in blood pressure. As a result, there is a decrease in energy expenditure and adecrease in the oxygen requirement of the heart.
- 2. Dilates large coronary arteries. As a result, blood is diverted to areas of the heart with low bloodflow. There is, therefore, enhanced oxygen supply to areas of the heart which are deficient inoxygen
- Nitroglycerin, which is used as an antianginal agent, is also the active component in dynamite. At one time, liquid nitroglycerin was used as an explosive. It was very unstable in the liquid form andmany deaths resulted from its use. The huge fortune of Alfred Nobel was made when he learned tostabilize nitroglycerin by adsorbing it on the absorbent, Kieselguhr. The product, known as dynamite,facilitated warfare as well as peaceful uses of nitroglycerin. Nobel, feeling guilty, instituted the NobelPeace Prize and other Nobel prizes.
- Nobel suffered from a heart condition and wrote in 1895: “It sounds like the irony of fate that Ishould be ordered by my doctor to take nitroglycerin internally.”
John C. Krantz, Jr
- John C. Krantz, Jr., an internationally known pharmacologist, wrote in 1974 (HistoricalMedical Classics Involving New Drugs, page 36, Williams and Wilkins, Baltimore, 1974):
- “One who has watched this field of medicine change from empiricism to scientific exactnessis still awed by the fact that nitroglycerin, the active ingredient in dynamite, dilates thecoronary vessels. At present this remains an enigma enveloped in an inscrutable puzzle. Perhaps some day the puzzle will yield to the researches of man.”
- In recent years, this puzzle has in fact yielded to the researches of men and women. We nowunderstand that in the endothelial lining of cells of blood vessels a simple gaseous molecule, nitricoxide (NO), consisting of one atom of nitrogen and one atom of oxygen, is being continually madefrom an amino acid arginine (see figure below). The nitric oxide passes from the endothelial cell intothe smooth muscle cell of the blood vessel to catalyze a series of reactions resulting in relaxation ofthe blood vessel.
- Nitroglycerin enters blood vessels and is converted in blood vessels into nitric oxide. Nitroglycerin therefore owes its effectiveness to its conversion into a normal body constituent, namelynitric oxide.
How Nitroglycerin Achieves its Relaxation of Blood Vessels
- In endothelial cells lining blood vessels, the enzyme nitric oxide synthase catalyses theconversion of arginine into citrulline and nitric oxide. Nitric oxide passes from endothelial cells intosmooth muscle cells where it activates the enzyme guanylyl cyclase and leads through a series of stepsto relaxation of the blood vessel. Nitroglycerin enters smooth muscle cells where it is converted tonitric oxide.
Nitroglycerin (Glyceryl Trinitrate, GTN) Sublingual
- Although introduced into therapeutics by William Murrel over a century ago, GTN remains a keydrug in the treatment of angina pectoris. The effects of GTN are much more intense when given bythe sublingual route (under the tongue) than when given orally
- The following diagram shows the plasma level of GTN at different time intervals after sublingualadministration. When placed under the tongue, the GTN dissolves in the fluids under the tongue andis absorbed into blood vessels under the tongue very rapidly. Thus, the onset of effect of GTN occursrapidly as a peak level of GTN is achieved in plasma within 5 minutes. The plasma level of GTNdrops after 5 minutes so that it is not surprising that the action of the drug is terminated within 20 to 30minutes.
Nitroglycerin (GTN) Ointment (2%)
- When 2% GTN ointment is rubbed onto an area of skin, it is absorbed into blood vessels underthe skin as shown in the diagram below. Maximum plasma levels are reached after approximately 1hour and the plasma level remains elevated for at least 3 hours. Thus, this preparation has a slowonset of action but a long duration of action.
Transdermal GTN Systems (GTN Patch)
Because the GTN ointment was prone to soil the patients’ garments, the drug industry designed amore convenient method to administer GTN transdermally. A reservoir of GTN is impregnated into apolymer. The polymer is bonded to a membrane to control the rate of GTN movement across the skinand the membrane is attached to an adhesive bandage which is placed on the skin. This provides aconvenient method to obtain a long lasting effect from GTN (approximately 24 hours) although astolerance develops to the drug use is usually limited to 12 to 16 hours (daytime)
- When GTN is taken sublingually several times a day, reproducible pharmacological effects areobserved; that is, there is no development of tolerance to this agent.
- Tolerance has, however, been observed to GTN in the explosives industry. When workers beginworking in this industry, they experience headache, flushing and dizziness which are the usual adverseeffects of GTN. After several weeks of work in the industry, most workers develop tolerance to theGTN effects and are no longer bothered by these effects. However, upon returning to work after aholiday break, workers can re-experience these adverse effects.
- The therapeutic equivalent of this experience in the explosives industry is the development oftolerance to transdermal GTN after several hours. For this reason, a transdermal GTN patch is appliedto the skin for 12 hours and then removed for a 12-hour period to allow a patient time to recoversensitivity to GTN
Therapeutic Uses of GTN
- (a) For termination of an individual attack: GTN, given sublingually, is the most frequently useddrug. The GTN would be ineffective if swallowed as it would be inactivated in its passagethrough the intestine and liver before reaching the general circulation. GTN, taken sublingually,acts in approximately 2 minutes to relieve pain. The termination of pain is usually sudden and iscomplete.
- (b) Prevention of individual attack: GTN, taken sublingually, increases the exertion tolerated by apatient before the amount of oxygen in the heart muscle drops to the level that pain isexperienced. The therapeutic equivalent of this effect is that a patient can take sublingual GTNprior to undertaking additional exercise that would normally precipitate angina, and therebyprevent the angina from developing. The protective effect would last for approximately 30minutes.
- (c) Chronic prophylaxis: If a patient has numerous anginal attacks daily and has to consume manyGTN tablets sublingually, the physician may prescribe a long-acting organic nitrate preparationwith the aim of cutting down the number of anginal attacks. Such a preparation is isosorbidedinitrate which, when given orally two to three times daily, will cut down on the number ofanginal attacks and the need to take GTN sublingually
B-Adrenergic Blocking Agents
- An alternative drug used for chronic prophylaxis of angina pectoris is a B-adrenergic blockingagent. In order to understand the mechanism of action of $-adrenergic blocking drugs, such aspropranolol, in angina it is necessary to understand that angina is precipitated by factors that increasesympathetic nervous system (SNS) activity, e.g. stress and exercise.
- Increased SNS activity results in an increase in heart rate and an increase in myocardial (heartmuscle) contractility. This in turn leads to an increase in cardiac output and an increase in myocardialoxygen requirement resulting in the pain of angina.
- A $-adrenergic blocking drug such as propranolol will block $ receptors in the heart, therebydecreasing heart rate and myocardial contractility. As a result, cardiac output and myocardial oxygenrequirements will decrease and therefore the pain of angina will be alleviated.
Summary of Clinical Trials with Propranolol
Upon chronic administration of propranolol, there was a decreased frequency of anginal attacksin the majority of patients
Summary of Therapy for Angina Pectoris
- GTN remains the drug of choice.
- Propranolol or isosorbide dinitrate is provided to patients who suffer from frequent anginalattacks in order to cut down on the frequency of anginal attacks. The patient will also have GTN pillsavailable in order to abort individual attacks of angina.
- Calcium channel blocking drugs (e.g. nifedipine): If GTN and propranolol fails to produce asatisfactory response, then a calcium channel blocking drug may be added to the therapeutic regimen.
- Newer drugs or drugs in development, modify cardiac work load by either slowing the heart byaltering electrical conduction or alter the metabolism of the heart to require less oxygen
How do calcium channel blocking drugs produce a therapeutic effect in angina pectoris?
- (a) In the relaxed state, the concentration of calcium inside the vascular smooth muscle cell isseveral orders of magnitude lower than the calcium concentration outside the vascular smoothmuscle cell.
- (b) Calcium enters the vascular smooth muscle cell through a voltage-dependent or receptoroperated channel.
- (c) When calcium enters the cell through the channel, the concentration of calcium rises from 10-7 Mto 10-6 in the fluids (cytoplasm) of the cell. The calcium then binds to a calcium-binding protein,namely calmodulin, to form a calcium-calmodulin complex.
- (d) The calcium-calmodulin complex activates the enzyme, myosin kinase. This in turnphosphorylates a light chain of myosin.
- (e) This permits myosin to interact with actin and causes contraction and constriction of arterioles.
- (f) Nifedipine plugs the calcium channel, thus preventing the sequence of events leading toconstriction of arterioles. The vascular smooth muscle will therefore be in the relaxed state anddilated.
- (g) Arterioles are more sensitive than veins to nifedipine. Coronary arteries are particularly sensitiveto the action of nifedipine.
Therapeutic Uses of Digitalis
- (a) Congestive heart failure: This condition results from an inability of the heart to pump sufficientblood to satisfy the body’s needs. Digitalis acts directly on the heart muscle and increases theforce of contraction of the heart, thereby increasing the adequacy of the circulation of the blood.
- (b) Treatment of disordered electrical rhythms of the heart – a condition referred to as an arrhythmia: Digitalis causes changes in the electrical properties of the heart. An important therapeutic actionof digitalis is its ability to decrease the number of electrical impulses passing from the atria to theventricles and to slow the rate of beating of the ventricles in disordered rhythms arising in theatria
Source of Cardiac Glycosides Used in Medicine
Cardiac glycosides are derived from several plant sources. Digitoxin and other cardiacglycosides are extracted from the leaves of Digitalis purpurea, while digoxin, digitoxin and othercardiac glycosides are extracted from the leaves of Digitalis lanata. The cardiac glycoside, ouabain,is extracted from the seed of Strophanthus. Thus, while cardiac glycosides are derived from plantsources in addition to the digitalis plants, the term “digitalis” is used to designate the entire group ofcardiac glycosides, not just those from digitalis plants alone. The major cardiac glycoside used inCanada is Digoxin.
Digitalis is one of the most frequently prescribed drugs. All digitalis preparations havecomparably low margins of safety and all preparations can cause similarly severe reactions. Approximately 25% of hospitalized patients taking digitalis show some signs of toxicity. Becausedigitalis intoxication can be fatal and because it occurs frequently, physicians must exercise everyprecaution in prescribing this drug.
- (a) Nausea and vomiting: These effects are the result of digitalis causing excitation of thechemoreceptor trigger zone located in the medulla.
- (b) Disordered rhythms in the heart (arrhythmia): While digitalis preparations are used to treat somedisordered rhythms of the heart, these preparations can cause fatal rhythm disturbances. Adisordered rhythm of the ventricle (ventricular fibrillation) is the most common cause of death indigitalis poisoning
- (c) Disturbances of vision – often blurred: White halos appear on dark objects; colour vision isdisturbed, objects often appear yellow or green. When I was visiting the Van Gogh art gallery inAmsterdam several years ago, I found an explanatory pamphlet in which I learned that VanGogh’s extraordinary use of colour in his paintings was due, in part, to disturbances of colourvision due to consumption of digitalis.
- (d) Neurological effects: Headache, fatigue, muscle weakness, confusion
Measurement of Plasma Concentration of Digoxin
- Because of the low safety margin of digitalis preparations, measurement of plasma digoxin levelscan be useful to a physician in making appropriate decisions regarding dosage.
- The therapeutic plasma concentration range for digoxin is 0.8-1.6 ng/ml and the toxic range is >2.4 ng/ml.
- Measurement of plasma digoxin levels is useful in several situations; for example:
- (a) In determining whether a patient has received digoxin medication recently.
- (b) When the physician fails to see a therapeutic response, he/she can determine whether the patientis complying with therapeutic instructions.
- (c) To determine whether the patient’s symptoms are due to too little or too much digoxin.
- (d) To determine whether other drugs taken concurrently may be causing a drug interaction andraising digoxin plasma levels
Other drugs in heart failure:
Diuretics are used to reduce fluid volume, angiotensin convertingenzyme inhibitors reduce blood pressure, (discussed under antihypertensives) reduce the work load onthe heart. Extensive research has shown that drugs aimed at none cardiac tissues (ACE inhibitors, aldosterone blockers, and other antihypertensive agents) are more effective in prolonging life than thecardiac glycosides (digitalis). See the chapter on antihypertensives.
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