Jamie K. Alan RPh, PharmD, PhD [email protected] TOXICOLOGY
Tricyclic Antidepressants (TCAs) Mechanism of Action- TCAs increase noradrenergic and serotonergic neurotransmission by blocking the NE and the 5HT transporter (NET or SERT) at presynaptic terminals.
Metabolism- The TCAs, or their active metabolites, have plasma half-lives of 8–80 h. TCAs are largely eliminated by hepatic CYPs. About 7% of patients metabolize TCAs slowly due to a variant CYP2D6 isoenzyme, causing a 30-fold difference in plasma concentrations among different patients given the same TCA dose. To avoid toxicity in “slow metabolizers,” plasma levels should be monitored and doses adjusted downward. Concentrations can also be increased in hepatic disease. Drugs that inhibit CYP2D6, such as bupropion and SSRIs, may increase plasma concentrations of TCAs. TCAs can potentiate the actions of sympathomimetic amines and should not be used concurrently with MAOIs. A number of other drugs have similar side-effect profiles as TCAs (phenothiazine antipsychotic agents, type 1C antiarrhythmic agents, and other drugs with antimuscarinic, antihistaminic, and α adrenergic antagonistic effects), and concurrent use can increase the risk of side effects.
Effects on Organs and Toxicity- The TCAs are potent antagonists at histamine H1 receptors, and this antagonism contributes to the sedative effects of this class of drugs. Antagonism of muscarinic ACh receptors contributes to cognitive dulling as well as a range of adverse effects mediated by the parasympathetic nervous system (blurred vision, dry mouth, tachycardia, constipation, difficulty urinating). Antagonism of α1 adrenergic receptors contributes to orthostatic hypotension and sedation. The TCAs have quinidine-like effects on cardiac conduction that can be life threatening with overdose and limit the use of TCAs in patients with heart disease. Like other antidepressant drugs, TCAs also lower the seizure threshold.
Calcium Channel Blockers (CCBs) Mechanism of Action- Calcium channel blockers predominantly block the L-type calcium channel. Dihydropyridines (DHPs, amlodipine, nifedipine, etc.) are relatively selective for the vasculature, and the non-DHPs (verapamil and diltiazem) are more selective for cardiac tissue. Verapamil is the most selective for cardiac tissue, and diltiazem has intermediate effects at the vasculature and cardiac tissue. The primary effect of the DHPs (at therapeutic doses) is to reduce the vascular tone. This can result in reflex tachycardia and edema. The primary effects of the non-DHPs (at therapeutic doses) is to reduce contractility by action on cardiac tissue, and cause decreased automaticity and conduction velocity through slow recovery of calcium channels.
Metabolism- Some calcium channel blockers undergo hepatic metabolism by the CYP3A enzyme system, and therefore their metabolism may be enhanced or inhibited by other drugs.
Effects on Organs and Toxicity- Overdosage with calcium channel blockers typically results in bradycardia and hypotension. Many patients become lethargic and may develop agitation and coma. If the degree of hypotension becomes severe or is prolonged, the secondary effects of seizures, coma, and metabolic acidosis usually develop. Pulmonary edema, nausea and vomiting, and hyperglycemia are frequent complications of calcium channel blocker overdoses. Paralytic ileus, mesenteric ischemia, and colonic infarction have been observed in patients with severe hypotension. Many symptoms become manifest within 1 to 2 hours of ingestion. If a sustained-release formulation is involved, the onset of overt toxicity may be delayed by 6 to 18 hours from the time of ingestion. Severe poisoning can result in refractory shock and cardiac arrest. Death can occur within 3 to 4 hours of ingestion.
Most toxic effects of calcium channel blockers are produced by three basic actions on the cardiovascular system: vasodilation through relaxation of smooth muscles, decreased contractility by action on cardiac tissue, and decreased automaticity and conduction velocity through slow recovery of calcium channels. Calcium channel blockers interfere with calcium entry by inhibiting one or more of the several types of calcium channels and binding at one or more cellular binding sites. Selectivity of these actions varies with the calcium channel blocker and provides some therapeutic distinctions, but these differences are less clear with an overdose. Calcium channel blockers also inhibit insulin secretion, which results in hyperglycemia and changes in fatty acid oxidation in the myocardium that alter myocardial calcium flow and reduce contractility. Current experiences suggest that the signs and symptoms of calcium channel blocker toxicity upon overdose or poisoning are similar among the drugs in this class.
Sources:
Goodman and Gilman: The Pharmacological Basis of Therapeutics 13th edition
Katzung: Basic and Clinical Pharmacology, 14th edition
DiPiro: Pharmacotherapy, A Pathophysiological Approach Chapter e9 https://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146078151#1145218177 emedicine.medscape.com