Cardiovasc.pptx

Clinical Toxicology Lec=5 Toxicity Of Cardiovascular Drugs Cardiovascular Drugs  Digitalis glycoside DGs  Angiotensin converting enzyme inhibitors ACEIs  Beta-adrenergic blocking agents BBs  Calcium channel blocking agents CCBs  Anti-arrthyhemic agents Digitalis glycosides (DGs) D...

Clinical Toxicology Lec=5 Toxicity Of Cardiovascular Drugs Cardiovascular Drugs  Digitalis glycoside DGs  Angiotensin converting enzyme inhibitors ACEIs  Beta-adrenergic blocking agents BBs  Calcium channel blocking agents CCBs  Anti-arrthyhemic agents Digitalis glycosides (DGs) DGs have played a prominent role in the therapy of congestive heart failure and supraventricular rhythm disturbances. Digoxin and digitoxin, which are the most widely used cardiac glycosides. digoxin is the most widely prescribed drug of this class in the U.S., due to the ready availability of techniques for measuring its levels in serum, flexibility in routes of its administration, and its intermediate duration of action. Because the digitalis have an extremely narrow therapeutic index, 20% to 30% of patients taking a digitalis preparation will experience toxicity. Therapeutic plasma concentration of digoxin should not exceed 2 ng/ml. Concentrations exceeding 15 ng/ml are potentially fatal. Usual therapeutic range: 0.5 to 2 ng/ml. Toxicokinetics  Absorption of DGs occurs in GIT, because digoxin is more polar than digitoxin,so GI absorption of digoxin is less rapid and less complete than that of digitoxin.  DGs bind to plasma proteins.  DGs are widely distributed throughout the body, with the highest concentrations in muscular tissues(the concentrations of DGs in the myocardium are about 30 times higher than those in blood).  DGs are mainly metabolized in the liver. In addition, gut flora may also metabolize digoxin to inactive products.   Renal excretion is the major route of elimination. The half-life of digoxin is about 36 h, whereas that of digitoxin is 5 to 7 days. Causes of digoxin toxicity:  Excessive intake is a common cause of poisoning .  Accidental over dosage usually occurs in children who ingest medication belonging to a relative  Concurrent administration of a diuretic that induces potassium loss is repotted to be the most frequent cause of toxicity.  Variability in bioavailability of digoxin tablets was a common cause of toxicity until recently. Digitalis intoxication is influenced by the presence of  DRUGS:  quinidine, and verapamil reduce the elimination of cardiac glycosides or displacement of digoxin from tissue-binding sites.  diuretics (except potassium sparing), because of hypokalaemia  Individuals with the anaerobic microorganism Eubacterium lentum in their colon may require larger doses of digitalis to achieve therapeutic serum concentrations. This microorganism reduces the lactone ring of digitalis.When these patients receive antibiotics, such as tetracycline or erythromycin, which eradicate the organism, digitalis blood concentrations may become toxic  PATHOLOGIC FINDING; S.For example, renal disease increases the likelihood of toxicity. Mechanisms of toxicity • The toxic effects of DGs are at least partially the extension of their pharmacological actions. • Digitalis glycosides inhibit active transport of Na and K ions across cell membranes by binding onto a specific site on the Na-K ATPase. The force of contraction of the heart (positive inotropic effect) is increased due to increase in cytosolic Ca during systole. During relaxation,Ca is pumped back into the sarcoplasmic reticulum by CaATPase and is removed intracellularly by a Na-Ca exchanger, and a sarcolemmal Ca++-ATPase. • In acute overdose, the sodium-potassium pump is poisoned, producing a fall in intracellular potassium and a rise in extracellular potassium, which may be marked. Accumulation of Ca+2 intracellularly produce a positive inotropic action . • The normal membrane resting potential is reduced, and electrical conduction is slowed, with eventual complete loss of myocardial electrical function. Clinical (Toxic) Features  Early manifestations of intoxication that occur in approximately 50% of all cases GIT: anorexia, nausea, vomiting, and abdominal pain are common, but not universal. Nausea and vomiting due to direct drug action on the chemoreceptor trigger zone.  Blurred vision, loss of visual acuity, and green-yellow halos have been described as early appearing symptoms (specific sign of digoxin intoxication).  Dysfunction of CNS, including delirium, fatigue, malaise, confusion, dizziness, and abnormal dreams. All portions of the cardiac conduction system are affected. These include bradyarrhythmias, tachyarrhythmias, or a combination of both. Younger persons without significant heart disease usually develop bradyarrhythmias and heart block. Older individuals and those with cardiac pathology generally present with ventricular arrhythmias with or without heart block. Atrioventricular block and severe bradycardia may be mediated by increased vagal activity, whereas sympathetic stimulation may be manifested in digoxin toxicity as tachyarrhythmias. Serious arrhythmias are more likely to appear when the heart is compromised by concurrent disease Treatment 1- Decontamination: Emesis, lavage (may enhance vagal stimulation and exacerbate bradycardia or heart block), activated charcoal , resins such as cholestyramine or colestipol and cathartic . 2-Antidote: Digoxin-specific antibody fragments (Fab) Fab therapy is of proven efficacy (multiple dose activated charcoal may be useful in situations in which Fab fragments are not available). Fab fragments are administered intravenously. They bind intravascular free digoxin and then diffuse into the interstitial space and bind free digoxin there. Digoxin and potassium levels should be followed; continuous ECG monitoring is also indicated. Antidotal therapy indicated in : 1-Ingestion of greater than 10 mg digoxin by an adult (4 mg by a child). 2-Potassium concentration exceeding 5 mEq/L. 3-Serum digoxin level of more than 15 ng/ml. 4-Progressive bradyarrhythmias or severe ventricular arrhythmias.  Dosage can be calculated from the amount of digoxin or digitoxin in the patient’s body After acute ingestion, the estimated total body concentration of digoxin is assumed to be equal to 80% of the total amount ingested ; this corrects for incomplete absorption. For digitoxin, the total body load is equal to 100% of the quantity ingested. When steady-state serum concentrations of digoxin or digitoxin are known, the total body load can be estimated as shown below:  Digoxin: Body load (mg)= (SDC)(5.6)(wt in Kg) 1000  Digitoxin: Body load (mg) = (SDC)(0.56)(wt in Kg) 1000 SDC is the serum digitalis concentration in ng/mL Vd: of digoxin (5.6 L/kg) or digitoxin (0.56 L/kg), times the patient’s weight in kg. The product is then divided by 1000 to obtain the estimated amount of drug in the body in mg. Each vial of antidote contains 38 mg of digoxin-specific antibody fragments. This will bind 0.6 mg digoxin or digitoxin. The total number of vials needed can be obtained by dividing the total body load of drug in mg, by 0.6 mg/vial. Adverse effects to digoxin immune Fab have been minimal. Sensitivity, erythema at the site of injection, and rash and urticarial have been reported 3-Hypokalemia is more common after chronic digitalis toxicity. Massive acute overdoses often cause hyperkalemia (5.5 to 13.5 mEq/L). Hypokalemia treared with IV potassium chloride in 0.9 or 0.45 % sodium chloride). 4-Hyperkalaemia: IV insulin, dextrose, sodium bicarbonate, and oral ion-exchange resins (sodium polystyrene sulfonate).  The patient should be monitored continuouslywith frequent electrocardiogram and electrolyte determinations. 4- Arrhythmias: Specific treatment to reverse digitalis-induced arrhythmias is chosen based on the type of arrhythmia present phenytoin increases AV nodal conduction and directly reverses the toxic action of digitalis at the AV node without interfering with its inotropic action. If digitalis has produced AV block, the vagolytic action of atropine may increase the heart rate and AV conduction. Beta-adrenergic blockers, such as propranolol, are useful to suppress supraventricular and ventricular arrhythmias induced by digitalis toxicity. However, these drugs may further depress SA node and AV node conduction, which can be disadvantageous in a person with an already failing heart. This, therefore, limits their usefulness. 5-Haemodialysis is ineffective in removing cardiac glycosides but may assist in restoring serum potassium to normal levels Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)  ACEIs are among the most widely prescribed antihypertensive drugs.  In general, these drugs are well absorbed from the GI tract, reaching peak serum conc. within 1 to 4 hours. These drugs are primarily eliminated through the kidneys. These agents are specific inhibitors the enzyme which converts angiotensin I to angiotensin II; thus preventing vasoconstriction. They may also inhibit bradykinin degradation resulting in a decrease in blood pressure. ACE inhibitors act by inhibiting the conversion of angiotensin I to angiotensin II in the lung and vascular endothelium. This results in vasodilation, decreased peripheral vascular resistance, decreased blood pressure, increased cardiac output, and a slight increase in renal, cerebral, and coronary blood flow. Clinical (Toxic) Features Hypotension is the most common manifestation in patients with ACEI overdoses. Adverse effects reported at therapeutic doses include firstdose hypotension, headache, cough, hyperkalemia, dermatitis, renal dysfunction, and angioedema.  Angioneurotic is an inflammatory reaction in which there is increased capillary blood flow and permeability, resulting in an increase in interstitial fluid. and commonly involves periorbital, perioral, and oropharyngeal tissues. In severe cases dyspnoea, chest pain, and airway compromise may develop  . Elevation of bradykinin levels that appear to be the primary cause of both ACEI-induced angioedema and cough.  Renal failure may develop after therapeutic use in patients in whom renal perfusion is dependant on angiotensin II. This includes patients with renal artery stenosis, volume depletion, and severe CHF. Treatment 1. Monitor BUN and serum creatinine if there is evidence of significant hypotension or pre-existing renal disease. Monitor vital signs, particularly blood pressure. 2. Administration of activated charcoal in the usual manner. 3. Correction of hypotension with IV fluids If hypotension persists, administer dopamine or noradrenaline. Angioedma : Treatment varies depending on the severity and rapidity of the swelling. Because its involve the tongue, face, and oropharynx, the airway must remain the primary focus of management.  Early endotracheal intubation should be considered in patients with ACE inhibitor induced angioedema. Orotracheal intubation may be technically difficult in patients with severe tongue swelling; be prepared to obtain a surgical airway.  All patients with mild or quickly resolving angioedema should be observed for several hours to ensure that the swelling does not progress or return.  Outpatient therapy with a short course of oral antihistamines and corticosteroids is appropriate. Such patients should be instructed to discontinue ACEI therapy permanently and to consult their primary care antihypertensive options. 5. Haemodialysis may be beneficial physicians about other Beta Adrenergic Antagonists (Beta Blockers) Toxic effects of acute overdose with beta blockers are predictable and result from the drug binding to and inhibiting beta-receptors throughout the body ((i.e., diminishing cAMP production), leading to decreased metabolic, chronotropic, and inotropic effects of physiological catecholamines).  -blockers have been suggested to cause cardiotoxicity through disruption of ion transport and homeostasis in cardiac muscle. The mechanism underlying b-blocker-induced CNS toxicity is unclear, but may be associated with cellular hypoxia resulting from suppressed cardiac output or direct neuronal toxicity Clinical (Toxic) Features  Most poisonings involve propranolol while atenolol is safest in overdose and rarely cause death (Lipid soluble beta blockers are capable of producing serious toxicity) • The principle manifestations of poisoning include bradycardia and hypotension. • In overdose, the membrane stabilizing or quinidine-like action of some beta-adrenergic blockers (acebutalolo, pindolol) severe myocardial depressant actions leading to heart block, and possibly CNS effects, such as sedation and seizures.  High doses of beta- blockers with ISA (e.g., acebutolol, carteolol ,oxprenolol, and pindolol) can cause tachycardia and hypertension as a result of their  partial agonist effect. CNS depression is common in patients with significant cardiovascular toxicity. Seizure activity results from hypoglycemia, cerebral hypoxia, or from a membrane-stabilizing effect  Bronchospasm and pulmonary edema, for example may be more prominent in patients with chronic obstructive pulmonary disease.  Hypoglycemia more common in children  .  Ophthalmic preparations containing beta-blockers may cause systemic manifestations. Increased airway resistance(usually in asthmatics), hypoglycaemia, fatigue, behavioural abnormalities, and diplopia may be noted  Abrupt stoppage of beta blockers after chronic use may result in rebound hypertension, tachycardia, palpitations tremor, headache, and sweating. Patients with angina may develop myocardial infarction. Treatment  Most patients respond to simple measures, and aggressive therapy is rarely required. The airway and ventilation should be maintained with endotracheal intubation if necessary  Gastric lavage is usually preferred over emesis because of deterioration of mental status and vital signs in these patients and because vomiting increases vagal stimulation and may worsen bradycardia. Activated charcoal can be given repeatedly during the first 24 hours to minimize enterohepatic cycling.  Other areas of general management include giving glucose for hypoglycemia, diazepam for convulsions, and monitoring potassium levels.  Glucagon has become the first-line therapy for  -blocker intoxication. Act by increasing intracellular cAMP through action on a distinct glucagon receptor on cardiac muscle cells.Thus, glucagon bypasses the blocked  -receptors to restore suppressed cardiac function.  Hypotension usually responds to intravenous glucagon, atropine, isoproterenol. Atropine reduces vagal stimulation and subsequently increases heart rate. Isoproterenol is a beta agonist which competitively antagonises the effect of the beta-blocker  Salbutamol for bronchospasm .  Hemoperfusion or hemodialysis may be considered in cases involving nadolol or atenolol, especially if there are signs of renal failure. Due to their extensive protein binding and large volume of distribution, most other beta adrenergic blockers poor candidates for dialysis. Calcium Channel Blockers All calcium channel blockers (CCBs) act by antagonising L-type voltage-sensitive slow calcium channels. L-channel blockade impairs calcium influx into cardiac and smooth muscle cells, resulting in decreased force of myocardial contraction, negative inotropc, inhibition of SA and AV nodes, and peripheral arteriolar vasodilatation. In general, they have a negative inotropic (contractility) effect on the myocardium not usually manifested with therapeutic doses due to compensation of the sympathetic nervous system. Verapamil has the most powerful myocardial depressant effect, while diltiazem has much less effect, and nifedipine is a weak myocardial depressant but exerts very significant effects on peripheral vascular smooth muscle. Toxicokinetics All CCBs are absorbed well orally and are highly protein-bound. Verapamil, diltiazem, and nifedipine undergo extensive hepatic metabolism. Volumes of distribution are large. Amlodipine differs from the other members of its class (dihydropyridines) in that it has a very long plasma half-life (35 to 45 hours), and prolonged duration of action. Clinical (Toxic) Features  The most common toxic effects caused by the Ca2+ channel antagonists , particularly the dihydropyridines, are due to excessive vasodilation, manifest as dizziness, hypotension, headache, flushing, and nausea. constipation, peripheral edema, coughing, wheezing, and pulmonary edema.  At therapeutic and moderate toxic doses, dihydropyridines are well recognized to produce reflex increases in heart rate with an increase in left ventricular stroke volume,leading to an increase in cardiac output.  With severe overdoses that result in dramatic Ca2+ channel blockage, all Ca2+ channel antagonists exert a negative inotropic effect with depressed cardiac contraction, conduction blockage, hypotension, and shock.  metabolic acidosis with hyperglycemia. The mechanism of hyperglycemia is likely related to the suppressive effect by Ca2+ channel antagonists on pancreatic b cell insulin release coupled with whole-body insulin resistance Treatment 1. Intravenous access; continuous ECG monitoring. Monitor haemodynamic status closely including heart rate, blood pressure, continuous cardiac monitoring and serial ECG, and urinary output. 2-GI decontamination: stomach wash and activated charcoal. For overdoses involving sustained-release preparations, whole bowel irrigation with polyethylene glycol is beneficial. 3-Augmenting myocardial function with cardio-tonic agents.  Bradycardia usually responds to atropine, calcium therapy is beneficial in CCB overdose, serum Calcium should be monitored to prevent hypercalcaemia. Hypotension secondary to reduced systemic resistance and lowered cardiac output may require both fluid replacement, and vasoconstriction with noradrenaline or high dose dopamine.  Glucagon may improve perfusion pressure by stimulating cardiac output.. 4-Seizures should be treated with diazepam initially, progressing to phenobarbitone for nonresponsive cases. 5-Correction of underlying metabolic acidosis, hypoxia, hypergylcemia. 6- In general, the large volumes of distribution and high protein binding of all calcium channel blocking agents would suggest haemodialysis or haemoperfusion would have limited usefulness in removal of significant quantities of these drugs.