Drugs may produce toxic effects by a variety of mechanisms.  These may be summarised as

1) Toxic effects that are direct and predictable following an overdose of the drug.  The effect may be due to the drug itself or it may reflect a change in the metabolism of the drug, resulting in a toxic metabolite.

2) Toxic effects may be direct and predictable following repeated dosing of the drug.  The effect may be mediated by metabolites, it may be pharmacologic in nature, or it may be immunologic.

3) Toxic effects may be direct and unpredictable, either following one dose or just a few doses.  These effects often represent the idiosyncratic response to drugs and may be immunologic or pharmacologic in mechanism.  They appear in only a very few patient and have no good predictors for their occurrence.

4) Toxic effects that are the result of some drug interaction.

The following examples are supplied as representative types of drug toxicity which may occur.

1. Hydralazine
The toxic effect of hydralazine is a classic example of a drug whose toxicity is the result of several factors, which combine to result in a toxic response.  The toxicity of hydralazine presents as a lupus erythematosus-like reaction with signs and symptoms similar to arthritis with a dermatological component.  The factors associated with hydralazine toxicity include
1) Dose -- the higher the dose, the greater the risk of toxicity
2) Acetylator phenotype -- recall that certain individuals possess biochemical pathways that cause acetyl conjugation rapidly.  Others acetylate compounds more slowly.  Persons who are slow acetylators are the patients that exhibit this type of hydralazine toxicity.
3) HLA DR4 titre -- Human leukocyte antigens are a series of biomarkers that reflect the relative ability of a person to experience an allergic reaction.  Specifically, those patients who have a high HLA DR4 titre are at much greater risk to develop hydralazine toxicity.
4) Gender -- Females are more susceptible to toxicity.  The reason is not know.
5) Duration of therapy -- typically, patients who do experience hydralazine toxicity are on therapy an average of 18 months before the toxic reaction is manifest.
Mechanistically, it is thought that since the person is a slow acetylator, the hydralazine is metabolised by an alternate pathway that forms a metabolite that is recognised by the body as a foreign compound, thus initiating an immune response (thus the relevance of the HLA titre) which is presented as a lupus-like syndrome.  One study indicated that within the United Kingdom, approximately 10% of the population would meet all of the five factors.  Therefore, if these factors were used as a predictor, then 10% of patients on hydralazine should experience the lupus-like syndrome.  The actual figure was a little over 7% (which means the factors are a relatively good predictor to lupus-like incidence in hydralazine toxicity).
 
2.  A toxic response that is similar to hydralazine in that it is predicated by the deficiency (rather than the slow nature) of an enzyme is that which occurs with PRIMAQUINE.  Patients who are deficient of glucose-6-phosphate dehydrogenase (G6PDH) are more susceptible to toxic effects of certain drugs such as the anti-malarial primaquine.  Normally, G6PDH is required to maintain NADPH levels.  NADPH is required to maintain GSH in its reduced state.  Therefore, if there is no G6PDH, there is no NADPH and without NADPH, GSH cannot be regenerated.  Therefore, drugs that are normally metabolised by GSH conjugation or reduction cannot be metabolised.  Primaquine, which must enter the red blood cell to exert its anti-malarial effect, is normally metabolised by this route.  Since there is no GSH, the primaquine reacts with RBC components causing lysis of the cell, thus causing as a toxic effect, haemolytic anaemia.  This deficiency is an X-linked deficiency occurring predominantly in males, with males of African descent showing a slighter higher incidence than the general population.  The greatest incidence of the deficiency occurs in Sephardic Jewish males.

3. Halothane is a drug that produces a classic idiosyncratic-type reaction.  Although it is capable of causing mild, reversible liver damage in almost all patients, halothane will cause a severe, life-threatening liver failure in 0.001-0.01% of patients exposed to the drug.  Although toxicity occurs more frequently in females and obese patients the only reliable factors to this response is prior exposure and a history of allergic reaction, which supports the theory that the idiosyncratic effect is immune mediated.  The mechanism of toxicity is similar to that of hydralazine.  Halothane is taken up by the liver where it is metabolised in susceptible individuals to a metabolite that has the ability to acylate proteins (non-susceptible individuals metabolise halothane by an alternate pathway).  The active metabolite then does acylate the hepatic proteins, causing them to be recognised as an antigen, thus producing an immune response that results in hepatocyte damage by lysis and cell degradation via normal immunologic mechanisms.

4. Debrisoquine is an antihypertensive whose toxicity is an extension of its pharmacologic effect.  However, again the response is mediated through an alternate metabolic pathway.  Debrisoquine is normally metabolised by the cytochrome P₄₅₀ to inactive metabolites.  However, some individuals lack the specific isozyme that is responsible for the metabolism.  These persons then do not metabolise debrisoquine, resulting in higher blood levels of the drug which may produce further vasodilatation and severe hypotension as a toxic response.

5.  Succinylcholine may produce toxicity by a very similar mechanism in persons who lack or are deficient in pseudocholinesterase.  Succinylcholine is normally metabolised very rapidly by circulating cholinesterase.  Those individuals that are deficient will not metabolise succinylcholine as rapidly will demonstrate a longer, more pronounced skeletal muscle relaxation and paralysis than individuals with adequate cholinesterase. (Again, the response is an extension of the drug's action.)

1. Acetaminophen (Paracetamol, APAP)
The toxic effect of acetaminophen is due to the accumulation of the toxic metabolite N-acetyl parabenzoquinone imine.  Normally, APAP is metabolised by glucuronide, sulphate, cysteine, and cytochrome P₄₅₀ systems.  The conjugated metabolites are excreted while the P₄₅₀ metabolite (N-acetyl parabenzonequinone imine) which is highly reactive is conjugated by glutathione (GSH).  In overdose situations, the conjugation pathways are saturated and metabolism shifts to the P₄₅₀ pathway.  Glutathione is then depleted, resulting in an accumulation of the reactive intermediary which will bind to hepatic proteins, causing necrosis.

The fatal dose of APAP may be as low as 140 mg/Kg (9.8 G or 30 of the 325 mg tablets/capsules for a 70 Kg person)  In chronic alcoholics or persons who are taking microsomal inhibitors, the fatal dose may be as low as 100 mg/Kg.  Additionally, actue administration of ethanol and APAP will increase the potential for toxicity.  Note that APAP may enter zero order or dose-dependent kinetics with an acute dose as low as 2 Grams.  Chronic ingestion of as little as 3 G daily for one year may also cause hepatic damage.
APAP toxicity will present in four distinct phases
1) Within the first day of overdose -- anorexia, nausea, vomiting, malaise
2) 1-2 days post-ingestion -- patient feels better, may eat, get up, but liver enzymes are elevated
3) 3-5 days -- hepatic necrosis, liver enzymes may peak
4) 7-8 days -- either hepatic failure and death OR if appropriate measures were taken or the overdose not extensive, improvement and recovery.

Treatment -- N-Acetylcysteine -- This compound may either scavenge the toxic intermediate directly and/or regenerate additional GSH.  It is given IV or PO as a 5% solution within 36 hours of ingestion.  NOTE that it is most effective if given within 10 hours of ingestion.  Either route of administration will require extemporaneous compounding of the drug from the solution for aerosol that is currently available.  If the parenteral route is chosen, the pharmacist must observed aseptic technique in compounding the solution for injection.  Oral solutions are often diluted in cola and should be administered within one (1) hour of preparation.  The loading dose is 140 mg/Kg, then 70 mg/Kg q4h for 17 doses or until the risk of hepatoxicity has passed.  NOTE that this is based upon the blood level of APAP.  The liver is at risk for irreversable damage if the plasma level of APAP is approximately 200 mcg/ml 4 hours post ingestion.  The risk for damage continues linearly over time as a function of the log plasma concentration such that 24 hours post ingestion, the risk is still present when plasma APAP is over 5 mcg/ml.


2. Aspirin -- Aspirin, which produces a classic toxic response with salicylism and the consequent metabolic changes, exerts it toxic effect not through immune responses, active metabolites, or wayward enzyme systems, but simply as a direct result of the various actions of the drug and its active moieties.  Mild ASA toxicity (salicylism) may be observed at acute doses greater than 150 mg/Kg while severe toxicity may not occur until doses greater than 400 mg/Kg are ingested.  Note, however, that as little as 200 mg/Kg has been fatal in adults, which corresponds to 14 Gm or 43 of the 5 grain tablets for a 70 Kg person.

The toxicity profile for ASA is complex.  In its chronic, yet milder form, it often presents with reversible CNS effects and is termed "salicylism".  The first signs of toxicity, other that GI pain described above, are tinnitus, decreased hearing, visual disturbances, and vertigo.  As the toxicity progresses the patient may become hyperglycaemic (NOTE that in children hypoglycaemia often occurs), confused and exhibit thirst, lassitude, drowsiness, petechial haemorrhage, and diaphoresis (secondary to vasodilatation).  Paradoxically, hyperpyrexia may occur with CNS stimulation and cause convulsions.  If the patient survives this episode then a phase of CNS depression occurs and the patient may die of cardiovascular collapse, respiratory depression, or hyperthermia.  Of additional concern during the progression of salicylate toxicity are the acid/base imbalances and effects on respiration.  In mild toxicity, salicylates are direct respiratory stimulants.  Therefore the patient will exhibit tachypnea (increase respiratory rate) which leads to respiratory alkalosis.  Later in toxicity, as noted above, salicylates will depress the respiratory centre and respiratory rates will decrease below normal.  In addition to the early respiratory alkalosis, as the salicylates enter 0 order kinetics and accumulate, the increase in acid will cause metabolic acidosis.

Clinical presentation most often presents initially as hpyerventilation and respiratory alkalosis.  The metabolic acidosis follows and increased anion gap presents as a characteristic of the acidosis.  Hyperthermia, seizures, coma, and cardiovascular collapse lead to death.

Recall that the other toxicity due to other salicylates will present with the same signs, symptoms, and urgency.  Methyl salicylate (oil of wintergree) is the most toxic, with as litte as 4 ml causing fatality in children.
 

ASA toxicity treatment is primarily supportive and preventative, through gastric lavage and activated charcoal to remove un-absorbed ASA and alkalinisation of the urine to hasten its excretion, plus fluids (for dehydration), cool baths (for hyperpyrexia), bicarbonate (to counter metabolic acidosis), and anti-convulsants, if necessary.
 
3.  Amphetamines and other CNS Stimulants
Toxicity from these drugs most often presents as consequences from substance abuse, however overdose with oral decongestants such as pseudoephedrine may also be seen clinically.  More commonly abused drugs having stimulant activity in the U.S.A. include methamphetamine, methylenedioxymethamphetamine (MDMA), cocaine, and the psychedelic phencyclidine (PCP).
Mild toxicity presents as hypertension, tachycardia, restlessness, agitation, and psychotic episodes.  As toxicity progresses, arrhythmias, increased skeletal muscle tone (ultimately causing rhabdomyolysis), hyperthermia, dehydration, and seizures can occur (as dehydration progresses, decreases in total body water volume may lead to hypovolaemia and hypotension, despite the increased vascular tone).  Both vertical and horizontal nystagmus may be observed with PCP toxicity.

Treatment is generally symptomatic and supportive.  Siezures and hyperthermia should be treated aggressively with parenteral benzodiazepines and cool baths and evaporative cooling, respectively.   In cases of extreme hyperthemia (equal to or greater than 105^oF), neuromuscular blockers may be used to diminish muscle hyperactivity.
 

Chronic nicotine intake may cause hypertension (with resultant MI, stroke, aneurysm), COPD, emphysema, and cancer.  Many of the cardiovascular effects may be due, in part, in carbon monoxide generated by burning the tobacco.  Acute nicotine intoxication with fatal consequences may occur with doses as low as 60 mg.  Rapid signs and symptoms of toxicity include nausea, salivation, GI pain, vomiting, diarrhoea, diaphoresis, headache, vertigo, visual and auditory disturbances, confusion, and weakness.  Profound hypotension (with resulting weak, irregular reflex tachycardia), convulsions, and death due to respiratory failure ensue.
Treatment is primarily supportive (assisted respiration, treatment of shock).
 
4. Anticholinergics -- atropine, antihistaminics, Amanita mushrooms.
Toxicity from drugs possessing anti-muscarinic activity presents with a distinct profile that has been described as "red as a beet" (flushing); "hot as a hare" (hyperthermia); "dry as a bone" (decreased sweating and mucous membranes); "blind as a bat" (blurred vision); and "mad as a hatter" (behavioural effects including delerium, hallucinations, and confusion).  Other signs and symptoms include tachycardia, arrhythmias, hypertension, pupillary dilatation (mydriasis), muscle twitching, and urinary retention (chronic overingestion may also cause severe constipation).  Overdose with antihistaminics may also cause seizures.

Treatment is primarily supportive (evaporative cooling, catheterisation).  In patients with profound behavioural effects, benzodiazepines or antipsychotics such as haloperidol may be given.  The specific antidote is physostigmine (eserine) which inhibits acetylcholinesterase. This drug will increase circulating levels of acetylcholine which may then counteract the effects of the reversible blockade by the anti-cholinergic drug.  However, it should be administered in small (0.5-1 mg, IV) doses only with careful monitoring, since bradycardia and seizure may result if given too rapidly or in too high a dose.
 

5.  Antidepressants (Tricyclics) -- amitryptiline, nortryptiline, imipramine, et c.  This class of drugs represents one of the most commone classes involved in life-threatening overdoses.  Ingestion of as little as 15 mg/Kg (roughly 1 G) may be fatal.
Many of the common toxic effects of the TCAs include anti-muscarinic effects.  However, since they possess other mechanisms, additional toxic actions alter their toxicity profile.  Recall that many of these agents also possess alpha-adrenergic blocking activity and inhibit the re-uptake of catecholamines and serotonin.  Central and cardiac effects are common in overdose and have led to the 3C mnemonic for TCA overdose -- coma, convulsions, and cardiac complications.  Patients may present with agitation (CNS excitation), seizures, and arrhythmias.  The arrhythmias are similar to those produced by quinidine and are characterised by a widened QRS interval leading to supraventicular progressing to ventricular tachycardias.  Hypotension is common.

Treatment consists of supportive care (control of seizures, acidosis, ventilation, and fluids), noradrenaline for the hypotension (NA is more effective than dopamine, since neurones may be depeted of endogenous catecholamines), and sodium bicarbonate (1-2 mEq/Kg or 50-100 mEq, bolus) for the arrhythmias (this is effective by helping to counteract the quinidine-like sodium channel blockade).  NOTE that physostigmine should NOT be used, since it will increase the risk for seizures and may also cause cardiac asystole.


6.  Beta-adrenergic antagonists -- propranolol et al.

Overdose with beta-blockers (even those with beta-1 selectivity, which is lost at higher doses) will prevent adrenergic activity at both beta-1 and beta-2 receptors.  As little as double or treble the normal therapeutic dose of propranolol may cause fatalities.  Common presentation signs and symptoms include bradycardia, hypotension (partial agonists such as pindolol may cause tachycardia and hypertension at higher doses), and reduced cardiac output to the point of causing cardiogenic shock, seizures, and arrhythmias.

Treatment is generally supportive.  The antidote for beta-blocker overdose is glucagon, which acts at cAMP-mediated endogenous receptors in the myocardium.  This will overcome the negative inotropic effects of the beta blocker.  Doses of 5-20 mg IV will counteract the cardiac and vascular effects of beta-blocker overdose.
 

7.  Calcium channel antagonists
These agents will produce severely compromised cardiac output, bradycardia and hypotension as a toxic response.  Cardiogenic shock may ensue.

Treatment is generally supportive.  Administration of calcium will act antidotally for the negative inotropic effects but has little action on the SA/AV block or hypotensive effects.
 

8.  Digitalis glycosides
Overdose with digoxin or other cardiac glycosides causes severe vomiting, visual disturbances, fatigue, confusion, hyperkalaemia, and numerous arrhythmias including AV block and ventricular arrhythmias.  (Refer to the Pharmacology II notes for a compleat discussion of digoxin toxicity).

Treatment depends upon the clinical situation.  Uncomplicated arrhythmias (normal digoxin and potassium levels) may be treated with lidocaine (the drug of choice) or phenytoin.  Hypokalaemia-induced digoxin toxicity may be treated with parenteral potassium.  The antidote Digibind^R (digoxin immune fab fragments -- antibodies to the digoxin molecule) should only be used in cases of supra-therapeutic plasma concentrations of digoxin.  Note that if the drug is digitoxin, ouabain, or strophantine, Digibind may not be as effective (incompleat cross reactivity) and higher doses may need to be administered.
 

9.  Ethanol
Acute overdose with ethanol presents primarily as CNS depression.   Patients may be comatose with a greatly depressed respiratory centre.  Hypotension and hypothermia are common.  Nystagmus may be observed.  Chronic ethanol intoxication is both hepatotoxic and cardiotoxic, causing potential cirrhosis (this may be greatly complicated by poor diet) and cardiomypathy progressing to failure, respectively.

Treatment is primarily supportive (fluids, dopamine for blood pressure, and assisted ventilation).  Detoxification for chronic ethanol intake often employs chlordiazepoxide, to prevent delerium tremens and other signs of  ethanol withdrawal.
 

10.  Opiates and Opioids. -- heroin, morphine, codeine, meperidine, et al.
Acute overdose of these drugs presents primarily as CNS depression, especially of the respiratory centre.  Signs and symptoms (in order of progression) include drowsiness, lethargy, miosis (pinpoint pupils), flaccid muscle tone, cool skin, hypotension, bradycardia, hypoventilation, apnea and coma.

Treatment is antidotal with the opioid antagonist naloxone or naltrexone.  Naloxone is preferred for its purely antagonistic effect, however given its short half-life, numerous administrations must be made in many instances.  Other treatments are supportive in nature (airway support).
 

11.  Sedative hypnotics (barbiturates and benzodiazepines)
Initial overdose may manifest as signs of disinhibition (excitable, rowdy) but quickly progresses to lethargy, stupor, coma, hypotension, and pinpoint pupils.  Nystagmus may be seen.  Respiratory depression is the primary concern with these CNS depressants.

Treatment is primarily supportive (maintain blood pressure, support ventilation).  There are no antidotes for barbiturate toxicity, although haemoperfusion may hasten the elimination of phenobarbitone.  Flumazenil, a specific benzodiazepine antagonist, may be used cautiously in cases of benzodiazepine toxicity.  It should not be used empirically, since seizures may be precipitated in patients addicted to a benzodiazepine or who have ingested a TCA.


12.    Theophylline -- Overdose may result from mistaken administration or with drugs that inhibit theophylline metabolism, such as cimetidine, ketoconazole, or erythromycin.

Signs and symptoms of theophylline overdose include vomiting, tachycardia, arrhythmias, tremor, hypotension, hypokalaemia, and hyperglycaemia.  Seizures may develop in severe intoxication.

Treatment is generally supportive.  Anticonvulsant therapy is often ineffective, however phenobarbitone is preferred.  Cardiac effects may be treated with a beta blocker (esmolol is preferred since it may be given parenterally and has a relatively short half-life).