06.05 Combating Pharmacological and Toxicological Effects

There are a number of ways of combating pharmacological and toxicological effects of drugs. For instance, as discussed in Section 3.5, hemodialysis (cleaning of the blood) can be used to remove drugs with low volume of distribution e.g. heparin. This is because drugs with a low volume of distribution are largely confined to the plasma and can be removed by heamodialysis. Drugs with high volume of distribution e.g. the antidepressant nortriptyline, and the lipid soluble drugs, cannot be removed with haemodialysis.

Another approach is competitive reversible antagonism. For example, naloxone is a competitive reversible antagonist at opioid μ receptors, which are the receptors that morphine stimulates. Morphine stimulates opioid μ receptors to be analgesic. With high doses of morphine, the stimulation of opioid μ receptors can cause excessive respiratory depression. The opioid μ receptor competitive reversible antagonist naloxone can be used to overcome excessive respiratory depression with morphine.

Another example of competitive reversible antagonism is the muscarinic receptor antagonist atropine which is used to overcome excessive stimulation of cholinergic muscarinic receptors be acetylcholine. Excessive neostigmine and other acetylcholinesterase inhibitors (e.g. Organophosphate pesticides) increase the levels of acetylcholine in the synapse, and the acetylcholine stimulates its receptors. The excessive stimulation of cholinergic muscarinic receptors leads effects which mimic activity of the parasympathetic nervous system, and are diarrhea, urination, miosis (constricted pupils), bronchospasm, emesis, lacrimation, salivation, bradycardia and hypotension. The muscarinic receptor competitive reversible antagonist atropine can be used to overcome these effects of excessive acetylcholine at its receptor.

For some poisons, specific antidotes have been developed. Certain calcium channel blockers (e.g. Amlodipine) are used in the treatment of hypertension, and other calcium channel blockers (e.g. Verapamil) are used in treatment of cardiac arrhythmias. Too much amlodipine can lead to hypotension, whereas too much verapamil can lead to bradycardia and/or heart block. The specific antidote to calcium channel blocker poisoning is calcium gluconate. Increasing the concentration of calcium at the channel, with calcium from calcium gluconate, overcomes the effect of blocking the channel with amlodipine or verapamil.

Another example of a specific antidote is for life-threatening digoxin intoxication, anti-digoxin immunotherapy can be used to combine with the digoxin and inactivate it. Digoxin is used in the treatment of heart failure. Digoxin has a low therapeutic index (overlap of therapeutic and toxic levels). Toxicity with digoxin includes life threatening cardiac arrhythmias. In life-threatening digoxin intoxication, anti-digoxin immunotherapy is used. The anti-digoxin immunotherapy combines with digoxin to inactivate it.

Finally, chemical antagonism can be used to combat toxicological effects. The best known example of chemical antagonist is to heparin. Thus, heparin induced life-threatening hemorrhage can be overcome with chemical antagonism. Heparin is strongly acidic. Protamine sulphate is strongly basic. Heparin and protamine combine and the combined product is inactive.