Pharmacokinetics in Disease States Modifying Protein-Binding and Body Perfusion

Introduction

Theoretically, all diseases can modify one or more of the pharmacokinetic phases namely; Absorption, Distribution, Metabolism and Elimination [ADME]. However, the major diseases that often draws attention includes, renal disease, hepatic disease, cardiac failure, gastrointestinal disease, endocrine disorders, obesity and burn injury. Of these, cardiac, hepatic and renal are the most frequent in any population and they also have the potential to affect more phases of pharmacokinetics simultaneously.

1. Circulatory Disorders 

Circulatory disorders such as heart failure have been known to cause a wide range of pharmacokinetic variability because reduced vascular perfusion of one or more parts of the body. This reduction in perfusion can affect different pharmacokinetic mechanisms such as;

  1. Absorption: -Perfusion of absorption sites (G.I.T & intramuscular) will influence absorption of administered medication.     
  2. Distribution: Variation of body perfusion may alter the drug distribution to certain organs 
  3. Metabolism and Excretion: Perfusion of the liver and kidneys will affect the metabolism and excretion of drugs respectively. 

Effects of Circulatory Disorders

Examples of the effects of circulatory disorders includes but not limited to;

  1. Decrease in splanchnic blood flow, bowel wall edema, alteration of gastric pH and secretions and gastrointestinal mobility.
  2. Patients with cardiac failure have impaired absorption of Disopyramide, Quinidine, Hydrochlorthiazide and Prazocin
  3. Patients with low cardiac output, blood flow to muscle groups is reduced rendering absorption from intramuscular route more unpredictable

Thus in critically ill patients with variable degrees of acute and chronic cardiac dysfunction, the enteral and intramuscular routes becomes unreliable and may even be hazardous

2. Hepatic Diseases 

  1. Drugs that are largely metabolized in the liver will be greatly affected by liver disease such as cirrhosis.
  2. Biliary excretion may be altered by conditions such as obstructive jaundice
  3. Liver diseases do not only affect metabolism and excretion of drugs but also their absorption (through the First-pass effect) and distribution (through plasma-protein binding)
  4. Patients with impaired liver functions, there is a decrease in the synthesis of plasma proteins which may result in hypoproteinaemia which in-turn will affect the volume of distribution of drugs that are extensively plasma protein bound

In the clinical setting, there is no widely accepted marker to quantify the level of hepatic functions.
2. Renal Diseases

  1. In patients with compromised renal functions, urinary excretion of drugs is reduced. i.e. Clearance of many drugs will also be reduced and this reduction is roughly proportional to the decrease in renal function
  2. Also note that renal diseases may also affect the pharmacokinetics of drugs that are eliminated largely via metabolism. E.g. Uremia decreases liver enzymatic activity and displaces drugs from plasma-proteins. Also insufficient excretion of drugs metabolites can itself induce toxicity.

In the clinical setting, creatinine clearance (CLcr) is considered to be a suitable marker of renal function and is used for dosage adjustment.
 

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