Clinical Toxicology 5th Stage - Uruk University (2024-2025) PDF

Uruk University 5th Stage College of Pharmacy First Course Clinical Toxicology Dr. Reem Ghanim Hussein Lecturer at College of Pharmacy...

Uruk University 5th Stage College of Pharmacy First Course Clinical Toxicology Dr. Reem Ghanim Hussein Lecturer at College of Pharmacy Uruk University 2024 - 2025 Cardiovascular drugs 1. Digitalis toxicity Digitalis glycosides are life-saving drugs when they are used in therapeutic doses in the treatment of congestive heart failure, and for management of certain supraventricular rhythm disturbances. Pharmacokinetics The half-life of digoxin is about 1.5 days. Renal excretion is the major route of elimination. Digoxin has a large volume of distribution, which limits the usefulness of dialysis.  Pharmacological mechanism of action Mechanism of toxicity A toxic dose of digitalis interferes with transport of sodium and calcium ions. The glycosides bind with high affinity to an inhibitory site on the protein on the Na K-ATPase. Consequently, sodium, and potassium ion transport are blocked as long as the drug molecule remains in place. Since potassium ion transport back into cells is blocked its concentration in the extracellular fluid increases.  K+ will increase extracellular Na+ will increase intracellular The changes in sodium ion fluxes across cardiac cell membrane result in disturbed impulse conduction. Accumulation of calcium intracellularly produces a positive inotropic action. An overdose of digitalis causes a reduction in resting membrane potentials, and cardiac pace maker cells cannot function properly. The outcome is asystole with complete loss of all cardiac function. Arrhythmias may be produced by direct ionic membrane changes, as well as autonomic neuronal effects.  Characteristics of poisoning Digitalis toxicity may appear after acute or chronic administration of therapeutic doses or massive intentional or accidental overdose. Early manifestation 1. GI tract complication:- such as anorexia, nausea, vomiting, and abdominal pain are common. 2. Blurred vision :- loss of visual acuity, and green-yellow halos have been described as early appearing symptoms. 3. CNS effects :- include a variety of neuropsychiatric disturbances. 4. Dysarrhythmias :- include bradyarrhythmias, tachyarrhythmias, or a combination of both. Management of poisoning 1. Removal of ingested drug. After massive overdoses the stomach should be lavaged to remove unabsorbed drug, although vomiting may already have accomplished this. Cardiac glycosides bind to activated charcoal, cholystramine, and cholyestipol. 2. Maintenance of a normal potassium concentration. Hypokalemia is more common after chronic digitalis toxicity. Hyperkalemia is more common after acute digitalis toxicity. Hyperkalemia with insulin, dextrose, bicarbonate, and sodium polystyrene sulfonate. Hypokalemia ? 3. Reversal of arrhythmias. When hypokalemia is encountered with tachy- or bradyarrhythmias, continuous potassium replacement alone may be sufficient. Even in the absence of hypokalemia potassium administration may correct arrhythmias by restoring intracellular concentrations. Potassium administration in a person with digitalis-induced hyperkalemia can result in heart block terminating in sinus arrest. For atrial and ventricular arrhythmias that do not respond to potassium therapy the treatment of choice includes lidocaine. The patient should be monitored continuously with frequent electrocardiogram and electrolyte determinations. Beta-blockers, such as propranolol, are useful to suppress supraventricular and ventricular arrhythmia induced by digitalis toxicity. 4. Use Antidote. More recently it may include the use of specific antidote, digoxin immune Fab.  Beta-adrenergic blockers These drugs have significant pharmacologic and pharmacokinetic differences. The three major pharmacologic considerations include difference in cardioselectivity, intrinsic sympathomimetic activity and membrane stabilizing activity. The pharmacokinetic properties of importance include lipid solubility, route of metabolic elimination, plasma half-life, degree of protein binding and volume of distribution. ‫لالطالع‬ Cardioselective beta-blockers :- drugs are selective block only β1 receptors and affect mostly the heart and cause reduced cardiac output. Ex- metaprolol Beta blockers with intrinsic sympathomimetic activity :- drugs that possess intrinsic sympathomimetic activity (ISA), which means they mimic the effects of epinephrine and norepinephrine and can cause an increase in blood pressure and heart rate. ISA's have smaller effects in reducing resting cardiac output and resting heart rate, in comparison to drugs that do not possess ISA. ex.-pindolol Membrane stabilizing activity:- drugs possess a quinidine-like effect or anesthetic-like membrane action, which affects cardiac action potential. Ex- propranolol  Mechanism of toxicity 1. Toxic effects of acute overdose with beta adrenergic blockers are :- Result from the drug binding to and inhibiting beta adrenergic receptors throughout the body. Clinical manifestations include bradycardia and hypotension. 2. In overdose the membrane stabilizing or quinidine-like action :- Clinical manifestation include severe myocardial depressant actions leading to heart block and possibly CNS effects such as sedation and seizures. 3. High doses of beta-adrenergic blockers with intrinsic sympathomimetic activity (ISA) can cause:- Tachycardia and hypertension as a result of their partial agonist effect.  Characteristics of poisoning 1. Bronchospasm and pulmonary edema and may be more prominent in patients with chronic obstructive pulmonary disease. 2. Diminution of myocardial contractility, producing bradycardia and severe hypotension leading to cardiogenic shock. 3. Cardiac changes are not reported uniformly in all beta adrenergic blocker poisonings they do occur most frequently with drugs that have membrane stabilizing action. 4. Electrocardiographic changes are more prominent at serum drug concentrations that 50 to 100 times greater than needed for beta receptor blockade Management of poisoning 1. Gastric decontamination after a large ingestion may be indicated. Gastric lavage is usually preferred over emesis because of the possibility of beta-blocker seizures. Activated charcoal can be given repeatedly during the first 24 hours to minimize enterohepatic cycling. 2. Other Giving glucose for hypoglycemia, Diazepam for convulsions monitoring potassium levels. 3. If the patient is compromised hemodynamically, atropine may be given. The treatment of choice in the hemodynamically compromised person appear to be glucagon. 4. If vagal blockade is unsuccessful, isoproternol, or a specific beta-1 agonist, can be given cautiously. 5.The hypotensive patient may respond to fluid in the absence of pulmonary edema. Presser agents, such as dopamine, or norepinephrine, may be useful. 6. Hemoperfusion or hemodialysis may be considered in cases involving nadolol, or atenolol, especially if there are signs of renal failure. Thank you