Nursing Pharmacology Chapter 2:  General Principles:  Pharmacokinetics

 

Basis for individual to individual variation in drug responses

  • Response Variation Secondary to Pharmacokinetic Differences in:

    • Bioavailability

    • Renal function

    • Liver function

    • Cardiac function

    • Patient Age

  • Response Variation Secondary to Pharmacodynamic Differences may be due to:

    • Enzyme activity

    • Genetic differences

  • Response Variation may be due to drug-drug interactions.

Genetic Factors: in Biotransformation of Drugs

  • Genetic influences: Variation in drug metabolism rates or in receptor sensitivity:

  • Metabolism:

    • Patients can be categorized as either rapid or slow acetylators.

      • This classification refers to the patients ability to relatively rapidly or slowly catalyze acetylation reactions. 

      • Biotransformation of some drugs are affected by acetylation rates, examples include hydralazine (Apresoline) and isoniazid (INH).:

  • Pharmacogenetics: One major concern is that on underlying disease state may not be appreciated until an unexpected reaction to an anesthetic agent in fact occurs.  The anesthetic agent essentially exposes on underlying disease state and then appropriate inner operative responses required.  Examples:

    • Atypical cholinesterase enzyme suggested by prolonged succinylcholine (Anectine) or mivacurium (Mivacron)- induced neuromuscular blockade

    • Succinylcholine (Anectine) or volatile anesthetic induced malignant hyperthermia-Malignant hyperthermia is a very serious reaction requiring a definitive treatment approach including dantrolene (Dantrium).

    • If the patient exhibits glucose-6-phosphate dehydrogenase deficiency certain drugs may induce hemolysis

    • Barbiturates may induce intermittent porphyria attacks.  It is extremely important to determine therefore preoperatively if the patient has history of intermittent porphyria.

Influence of Age on Drug Responses

  • Variation in drug responses may be due to several factors such as:

    • Diminished cardiac output:

      • A reduction in cardiac output reduces hepatic perfusion which may decrease delivery of drug to the liver for metabolism.  This type of an effect would prolonged duration of action of, for example, lidocaine (Xylocaine) or fentanyl (Sublimaze).

    •  Increased body fat:

      • An increase in body fat tends to increase Vd .  An increased Vd would tend to prolong clearance time.

      • Increased body fat also promotes accumulation of highly lipid-soluble agents such as diazepam (Valium) and thiopental (Pentothal).

    • Altered protein binding can affect drug responses because only the "free", unbound drug is active and for a highly protein-bound drug small changes in the extent of protein binding can substantially influence the free drug concentration [free drug].

    • Decreased or compromised renal function can prolong drug action  if renal excretion is the primary mechanism for clearance.

Drug-Drug Interactions

  • Definition: Drug interaction occurs when one drug affects the pharmacological response of a second drug given at the same time.

    • Drug interactions may be due to:

      •  Pharmacodynamic effects

      •  Pharmacokinetic effects

    • Consequences of drug interactions:

      •  Increased drug effects or decreased drug effects

      •   Consequences may be adverse or undesired effects

    • Examples of positive, beneficial drug interaction effects include:

      • Propranolol + hydralazine (reflex tachycardia (undesirable) caused by hypotensive hydralazine-mediated response is prevented by propranolol-mediated β-adrenergic receptor blockade

      • Opioid-induced respiratory depression may be counteracted by administration of the opioid receptor antagonist naloxone

    •  Adverse effects or toxic reactions

      •  One drug may interact with another to impede absorption

      •  One drug may compete with another for the same plasma protein-binding sites

      •  One drug may affect metabolism of another by either enzyme induction or enzyme inhibition

      •  One drug may change the renal excretion rate of the other.

References
  • Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000

  • Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.