17.3: Drug Toxicity: Dose-Dependent Reactions

Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.

Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from anxiety relief to coma as doses increase. Other drugs, like nifedipine, may cause hypotension in a dose-related fashion. Certain adverse effects, such as tardive dyskinesia linked to antipsychotics, develop over time, reflecting the duration of exposure rather than dosage alone. Furthermore, the expected dosage of some medications can lead to toxicity in specific contexts, like phototoxic reactions to sunlight in patients treated with tetracyclines and other drugs.

Pathological toxicity results from an overdose of drugs, which produces an excess of harmful byproducts within the body. At therapeutic levels, Acetaminophen produces low levels of a highly reactive metabolite, NAPQI (N-acetyl-p-benzoquinone imine). However, an overdose can lead to the accumulation of NAPQI, which depletes glutathione reserves and, without sufficient detoxification, causes liver necrosis by interacting with other cellular molecules.

Genotoxic effects involve DNA damage, resulting in mutations or cancerous changes. These effects are often associated with environmental factors, such as ionizing radiation and certain chemotherapy drugs, highlighting the importance of understanding both chemical substances' therapeutic and adverse effects.

The occurrence and severity of drug toxicity proportionately correlate to the body’s drug concentration and exposure duration.

Pharmacological toxicity has a dose-dependent relationship. Increasing the dosage of drugs like barbiturates leads to CNS effects progressing from anxiolysis, sedation, and drowsiness to medullary depression and coma.

Another drug, nifedipine, manages hypertension and angina pectoris but may cause severe hypotension at higher doses.

However, some medications may lead to toxicity even when taken at the prescribed dose. For instance, patients treated with tetracyclines or sulfonamides may suffer from sunlight-induced phototoxicity.

In pathological toxicity, drug overdose converts non-toxic drugs into toxic forms. For example, acetaminophen overdose produces its metabolite in excess. The excess metabolite depletes glutathione and interacts with cellular macromolecules, causing hepatic necrosis.

Lastly, genotoxic effects caused by various chemotherapeutic agents damage DNA via single- or double-stranded breaks, crosslinking, alkylation, or oxidation.