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ß,ß-Dimethylcysteine chelation with Cu2+ and Pb2+
Dissolution of cystine stones:
Inhibition of collagen polymerization
Antidotes for cyanide poisoning (A). Cyanide ions (CN-) enter the organism in the form of hydrocyanic acid (HCN); the latter can be inhaled, released from cyanide salts in the acidic stomach juice, or enzymatically liberated from bitter almonds in the gastrointestinal tract. The lethal dose of HCN can be as low as 50 mg. CN- binds with high affinity to trivalent iron and thereby arrests utilization of oxygen via mitochondrial cytochrome oxidases of the respiratory chain. An internal asphyxiation (histotoxic hypoxia) ensues while erythrocytes remain charged with O2 (venous blood colored bright red).
In small amounts, cyanide can be converted to the relatively nontoxic thiocyanate (SCN-) by hepatic "rhoda-nese" or sulfur transferase. As a therapeutic measure, thiosulfate can be given i.v. to promote formation of thiocya-nate, which is eliminated in urine. However, this reaction is slow in onset. A more effective emergency treatment is the i.v. administration of the methe-moglobin-forming agent 4-dimethyl-aminophenol, which rapidly generates trivalent from divalent iron in hemoglobin. Competition between methemoglo-bin and cytochrome oxidase for CN- ions favors the formation of cyanmethemo-globin. Hydroxocobalamin is an alternative, very effective antidote because its central cobalt atom binds CN- with high affinity to generate cyanocobalamin.
Tolonium chloride (Toluidin Blue). Brown-colored methemoglobin, containing tri- instead of divalent iron, is incapable of carrying O2. Under normal conditions, methemoglobin is produced continuously, but reduced again with the help of glucose-6-phosphate dehydrogenase. Substances that promote formation of methemoglobin (B) may cause a lethal deficiency of O2. To-lonium chloride is a redox dye that can be given i.v. to reduce methemoglobin.
Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type (p. 102). Phos-phorylation of acetylcholinesterase causes an irreversible inhibition of ace-
tylcholine breakdown and hence flooding of the organism with the transmitter. Possible sequelae are exaggerated parasympathomimetic activity, blockade of ganglionic and neuromuscular transmission, and respiratory paralysis.
Therapeutic measures include: 1. administration of atropine in high dosage to shield muscarinic acetylcholine receptors; and 2. reactivation of acetyl-cholinesterase by obidoxime, which successively binds to the enzyme, captures the phosphate residue by a nu-cleophilic attack, and then dissociates from the active center to release the enzyme from inhibition.
Ferric Ferrocyanide ("Berlin Blue," B) is used to treat poisoning with thallium salts (e.g., in rat poison), the initial symptoms of which are gastrointestinal disturbances, followed by nerve and brain damage, as well as hair loss. Thallium ions present in the organism are secreted into the gut but undergo reabsorption. The insoluble, nonabsorb-able colloidal Berlin Blue binds thallium ions. It is given orally to prevent absorption of acutely ingested thallium or to promote clearance from the organism by intercepting thallium that is secreted into the intestines.
An anginal pain attack signals a transient hypoxia of the myocardium. As a rule, the oxygen deficit results from inadequate myocardial blood flow due to narrowing of larger coronary arteries. The underlying causes are: most commonly, an atherosclerotic change of the vascular wall (coronary sclerosis with exertional angina); very infrequently, a spasmodic constriction of a morphologically healthy coronary artery (coronary spasm with angina at rest; variant angina); or more often, a coronary spasm occurring in an atherosclerotic vascular segment.
The goal of treatment is to prevent myocardial hypoxia either by raising blood flow (oxygen supply) or by lowering myocardial blood demand (oxygen demand) (A).
Factors determining oxygen supply. The force driving myocardial blood flow is the pressure difference between the coronary ostia (aortic pressure) and the opening of the coronary sinus (right atrial pressure). Blood flow is opposed by coronary flow resistance, which includes three components. (1) Due to their large caliber, the proximal coronary segments do not normally contribute significantly to flow resistance. However, in coronary sclerosis or spasm, pathological obstruction of flow occurs here. Whereas the more common coronary sclerosis cannot be overcome pharmacologically, the less common coronary spasm can be relieved by appropriate vasodilators (nitrates, ni-fedipine). (2) The caliber of arteriolar resistance vessels controls blood flow through the coronary bed. Arteriolar caliber is determined by myocardial O2 tension and local concentrations of metabolic products, and is "automatically" adjusted to the required blood flow (B, healthy subject). This metabolic autoregulation explains why anginal attacks in coronary sclerosis occur only during exercise (B, patient). At rest, the pathologically elevated flow resistance is compensated by a corresponding de crease in arteriolar resistance, ensuring adequate myocardial perfusion. During exercise, further dilation of arterioles is impossible. As a result, there is ischemia associated with pain. Pharmacological agents that act to dilate arterioles would thus be inappropriate because at rest they may divert blood from underper-fused into healthy vascular regions on account of redundant arteriolar dilation. The resulting "steal effect" could provoke an anginal attack. (3) The intra-myocardial pressure, i.e., systolic squeeze, compresses the capillary bed. Myocardial blood flow is halted during systole and occurs almost entirely during diastole. Diastolic wall tension ("preload") depends on ventricular volume and filling pressure. The organic nitrates reduce preload by decreasing venous return to the heart.
Factors determining oxygen demand. The heart muscle cell consumes the most energy to generate contractile force. O2 demand rises with an increase in (1) heart rate, (2) contraction velocity, (3) systolic wall tension ("afterload"). The latter depends on ventricular volume and the systolic pressure needed to empty the ventricle. As peripheral resistance increases, aortic pressure rises, hence the resistance against which ventricular blood is ejected. O2 demand is lowered by p-blockers and Ca-antago-nists, as well as by nitrates (p. 308).
Antianginal agents derive from three drug groups, the pharmacological properties of which have already been presented in more detail, viz., the organic nitrates (p. 120), the Ca2+ antagonists (p. 122), and the p-blockers (pp. 92ff).
Organic nitrates (A) increase blood flow, hence O2 supply, because diastolic wall tension (preload) declines as venous return to the heart is diminished. Thus, the nitrates enable myocardial flow resistance to be reduced even in the presence of coronary sclerosis with angina pectoris. In angina due to coronary spasm, arterial dilation overcomes the vasospasm and restores myocardial perfusion to normal. O2 demand falls because of the ensuing decrease in the two variables that determine systolic wall tension (afterload): ventricular filling volume and aortic blood pressure.
Calcium antagonists (B) decrease O2 demand by lowering aortic pressure, one of the components contributing to afterload. The dihydropyridine nifedi-pine is devoid of a cardiodepressant effect, but may give rise to reflex tachycardia and an associated increase in O2 demand. The catamphiphilic drugs ve-rapamil and diltiazem are cardiode-pressant. Reduced beat frequency and contractility contribute to a reduction in O2 demand; however, AV-block and mechanical insufficiency can dangerously jeopardize heart function. In coronary spasm, calcium antagonists can induce spasmolysis and improve blood flow (p. 122).
P-Blockers (C) protect the heart against the O2-wasting effect of sympathetic drive by inhibiting P-receptor-mediated increases in cardiac rate and speed of contraction.
Uses of antianginal drugs (D). For relief of the acute anginal attack, rapidly absorbed drugs devoid of cardiode-pressant activity are preferred. The drug of choice is nitroglycerin (NTG, 0.8-2.4 mg sublingually; onset of action within 1 to 2 min; duration of effect ~30min). Isosorbide dinitrate (ISDN)
can also be used (5-10 mg sublingually); compared with NTG, its action is somewhat delayed in onset but of longer duration. Finally, nifedipine may be useful in chronic stable, or in variant angina (5-20 mg, capsule to be bitten and the contents swallowed).
For sustained daytime angina prophylaxis, nitrates are of limited value because "nitrate pauses" of about 12 h are appropriate if nitrate tolerance is to be avoided. If attacks occur during the day, ISDN, or its metabolite isosorbide mononitrate, may be given in the morning and at noon (e.g., ISDN 40 mg in extended-release capsules). Because of hepatic presystemic elimination, NTG is not suitable for oral administration. Continuous delivery via a transdermal patch would also not seem advisable because of the potential development of tolerance. With molsidomine, there is less risk of a nitrate tolerance; however, due to its potential carcinogenicity, its clinical use is restricted.
The choice between calcium antagonists must take into account the differential effect of nifedipine versus verap-amil or diltiazem on cardiac performance (see above). When p-blockers are given, the potential consequences of reducing cardiac contractility (withdrawal of sympathetic drive) must be kept in mind. Since vasodilating p2-receptors are blocked, an increased risk of va-sospasm cannot be ruled out. Therefore, monotherapy with p-blockers is recommended only in angina due to coronary sclerosis, but not in variant angina.
Relaxation of resistance vessels
Relaxation of resistance vessels
Relaxation of coronary spasm
B. Effects of Ca-antagonists
C. Effects of ß-blockers
Angina pectoris Coronary sclerosis Coronary spasm
Therapy of attack
D. Clinical uses of antianginal drugs
Myocardial infarction is caused by acute thrombotic occlusion of a coronary artery (A). Therapeutic interventions aim to restore blood flow in the occluded vessel in order to reduce infarct size or to rescue ischemic myocardial tissue. In the area perfused by the affected vessel, inadequate supply of oxygen and glucose impairs the function of heart muscle: contractile force declines. In the great majority of cases, the left ventricle (anterior or posterior wall) is involved. The decreased work capacity of the in-farcted myocardium leads to a reduction in stroke volume (SV) and hence cardiac output (CO). The fall in blood pressure (RR) triggers reflex activation of the sympathetic system. The resultant stimulation of cardiac p-adreno-ceptors elicits an increase in both heart rate and force of systolic contraction, which, in conjunction with an a-adren-oceptor-mediated increase in peripheral resistance, leads to a compensatory rise in blood pressure. In ATP-depleted cells in the infarct border zone, resting membrane potential declines with a concomitant increase in excitability that may be further exacerbated by activation of p-adrenoceptors. Together, both processes promote the risk of fatal ventricular arrhythmias. As a consequence of local ischemia, extracellular concentrations of H+ and K+ rise in the affected region, leading to excitation of nociceptive nerve fibers. The resultant sensation of pain, typically experienced by the patient as annihilating, reinforces sympathetic activation.
The success of infarct therapy critically depends on the length of time between the onset of the attack and the start of treatment. Whereas some therapeutic measures are indicated only after the diagnosis is confirmed, others necessitate prior exclusion of contraindications or can be instituted only in specially equipped facilities. Without exception, however, prompt action is imperative. Thus, a staggered treatment schedule has proven useful.
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