Interactions Affecting Absorption, Distribution, Metabolism, Excretion of Drugs

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Chapter: Biopharmaceutics and Pharmacokinetics : Pharmacokinetic Drug Interactions

Interactions Affecting Absorption of Drugs, Interactions Affecting Distribution of Drugs, Interactions Affecting Metabolism of Drugs, Interactions Affecting Excretion of Drugs

Interactions Affecting Absorption of Drugs

Altered absorption after oral administration is very common. The interaction may result in a change in the rate of absorption (an increase or a decrease), a change in the amount of drug absorbed (an increase or a decrease) or both. Several mechanisms may be involved in the alteration of drug absorption from the GIT. In general, drugs that are not absorbed completely/rapidly are more susceptible to changes in GI absorption. A decrease in the rate of absorption is clinically significant in acute conditions such as pain where the drug is administered in a single dose but is of little importance for drugs used in chronic therapy.

An alteration in parenteral drug absorption is rare but can occur when an adrenergic agent such as adrenaline or a cholinergic drug such as methacholine is extravascularly injected concomitantly with another drug. These agents alter the systemic absorption of the latter due to vasoconstriction or vasodilation.

Interactions Affecting Distribution of Drugs

Though several factors govern the distribution of drugs to various tissues, clinically significant interactions result due to competition between drugs for binding to proteins/tissues and displacement of one drug by the other. Competitive displacement, which results when two drugs are capable of binding to the same site on the protein, causes the most significant interactions. Greater risk of interactions exists when the displaced drug is highly protein bound (more than 95%), has a small volume of distribution and has a narrow therapeutic index (e.g. tolbutamide, warfarin and phenytoin), and when the displacer drug has a higher degree of affinity than the drug to be displaced. In such situations, displacement of even a small percent of drug results in a tremendous increase in the free form of the drug, which precipitates increased therapeutic or toxic effects.

Drugs may also be displaced from binding sites in tissues. An interesting example of this is oral hypoglycaemics such as the sulphonyl ureas (tolbutamide, glibenclamide, etc.). These agents exert their therapeutic effects by displacing insulin from protein binding sites in pancreas, plasma and other regions resulting in its elevated levels.

Interactions Affecting Metabolism of Drugs

The most important and the most common cause of pharmacokinetic interactions is alteration in the rate of biotransformation of drugs. Major problems arise when one drug either induces or inhibits the metabolism of another drug. Even the environmental chemicals can bring about such an effect. The influence of enzyme inducers and inhibitors become more pronounced when drugs susceptible to first-pass hepatic metabolism are given concurrently. The metabolic pathway usually affected is phase I oxidation. Enzyme inducers reduce the blood level and clinical efficacy of co-administered drugs but may also enhance the toxicity of drugs having active metabolites. In contrast to enzyme induction, which is usually not hazardous, enzyme inhibition leads to accumulation of drug to toxic levels and serious adverse effects may be precipitated.

Interactions Affecting Excretion of Drugs

Clinically significant renal excretion interactions occur when an appreciable amount of drug or its active metabolite(s) are eliminated in the urine. Excretion pattern can be affected by alteration in GFR, renal blood flow, passive tubular reabsorption, active tubular secretion and urine pH. An interesting pharmacokinetic interaction that results due to the pharmacodynamic drug effect is between thiazide diuretics and lithium. Owing to the influence of former on the renal tubular transport of sodium, the lithium ions are retained in the body resulting in its toxicity.

Biliary excretion, the other major mechanism of drug excretion, is altered by agents that inhibit biliary transport or modify bile flow rate.


List of Some of the Important Pharmacokinetic (ADME) Interactions

Reducing the Risk of Drug Interactions – Principles of Drug Interactions Management The consequences of drug interactions may be –

·           Major – life threatening

·           Moderate – deterioration of patient’s status

·           Minor – bothersome or little effect.

The risk of drug interactions is a challenge that embraces a number of considerations.

The following are guidelines to reduce and manage drug interactions.

1.   Identify patient risk factors such as age, the nature of the patient's medical problem (e.g., impaired renal function), dietary habits, smoking, and problems such as alcoholism influence the effect of certain drugs.

2.   Take thorough drug history and maintain complete patient medication records.

3.   Keep knowledge about actions (both primary and secondary pharmacological actions) of drugs being utilized.

4.   Consider therapeutic alternatives.

5.   Avoid complex therapeutic regimens where possible.

6.   Educate the patient to comply with instructions for administering medications. They should be encouraged to ask questions about their therapy and to report any excessive or unexpected responses.

7.   Monitor therapy: Any change in patient behavior should be suspected as drug-related until that possibility is excluded.

8.   Individualize therapy: priority should be assigned to the needs and clinical response of the individual patient, rather than to the usual dosage recommendations, standard treatment, and monitoring guidelines.

9.   Involve the patient as a partner in health care. If the optimal benefits of therapy are to be achieved with minimal risk, each participant must be knowledgeable about and diligent in fulfilling his responsibilities.

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