week 6 Flashcards
(18 cards)
drug distribution
Once a drug has been absorbed into the systemic circulation, it can be distributed to different body compartments
In PK, distribution refers to how a drug is distributed between the various body compartments.
Factors affecting drug distribution
plasma protein binding
organ blood flow
lipid solubility of the drug
molecular size
pH partition
plasma protein binding
Almost all drugs are reversibly bound to plasma proteins upon entry into the systemic circulation. The binding forms a drug-protein complex.
Th extent of binding depends on
1. The affinity of a particular drug for protein binding sites
2. The concentrations of the free drug
3. The concentration of the protein
Protein binding is a reversible and dynamic process. As the free (unbound) drug diffuses into interstitial fluid + cells, drug molecules disassociate from the protein-drug complex to maintain the equilibrium between the free drug and the bound drug.
The bound drug is not active as the drug protein complex is too big to diffuse through membranes. ONLY THE FREE OR UNBOUND DRUG CAN EXERT A PHARMACOLOGICAL EFFECT.
organ blood flow
The rate at which a drug is distributed to various organs after the drug is administered depends on the proportion of cardiac output received by the organs.
Drugs are rapidly distributed to highly perfused tissues (brain, heart, liver, kidney). This enables a rapid onset of action of drugs affecting these tissues.
Drugs are distributed slower to less perfused tissues, e.g. skeletal muscle, and even lower to those w/ the lowest blood flow (skin, bone, fat)
lipid solubility of the drug
Lipid soluble drugs can readily cross capillary membranes to enter most tissues and flid compartments. Lipid INSOLUBLE drugs do NOT diffuse readily across membranes.
pH partition
pH of the surrounding environment of a drug affects its distribution + absorption.
biological barriers to drug distribution
blood brain barrier
placenta
testicular barrier
blood brain barrier
o Capillaries of cerebral circulation are different from normal capillaries
o Endothelial cells create a barrier between capillaries and the brain tissue
o Only lipophilic substances or actively transported cells can pass into the CNS
o Becomes leaky in inflammatory conditions (like meningitis), allowing access of drugs that would not normally be able to penetrate the brain.
placenta
o Separates maternal blood vessels from fetus
o Provide protective barrier for some compounds
o Lipophilic drugs can diffuse across the placenta
o Not efficient because most drugs cross into fetus, which may cause malformations.
testicular barrier
o Protects spermatogenesis from blood chemicals
o Not much known about adverse effects.
volume of distribution
Vd = Q/Cp
where Vd = apparent volume of distribution (L)
Q = amount of drugs absorbed (mg)
Cp = plasma drug concentration (mg/L)
main body fluid compartments
- Water constitutes 50-70% of body weight (0.55L/kg)
- 4 fluid compartments
1. Intracellular fluid – sum of the fluid contents in cells
2. Extracellular fluid (0.2L/kg) - Plasma (0.05L/kg)
- Interstitial fluid
3. Transcellular fluid
drug metabolism / biotransformation
the process of chemically modifying a drug into other compounds (metabolites), primarily carried out by enzymes
- Occurs in the liver – but lungs, kidney, gut mucosa + skin also contribute.
- When drugs are metabolised, the change generally involves converting a nonpolar, lipid soluble compound to a more polar form that is more water soluble and can be more readily excreted in the urine.
types of metabolites
- Inactive metabolites: conversion of a pharmacologically active drug to an inactive substance – applies to most drugs
- Active metabolites:
a. Conversion of one pharmacologically active drug to another active substance – prolonging drug action
b. Conversion of pharmacologically inactive to an active substance - Toxic metabolites: conversion of a drug to a toxic substance.
Drug metabolism reactions
consists of phase 1 and phase 2
phase 1
Reactions include oxidation, reduction, hydrolysis -> transform drug into more polar moieties.
Introduce or expose a hydroxyl group, thereby making a more water-soluble metabolite.
Catabolic reaction
Enzymes involved:
Cytochrome P450, alcohol dehydrogenase. The drug must cross the plasma membrane to reach these enzymes.
Principle group of reactions is oxidation – cytochrome P450 oxidases.
phase 2
Involve conjugation, during which the drug molecule is couple to an endogenous substituent group. (e.g. Acetyl CoA)
- Conjugation reaction
- Anabolic (synthetic) reactions.
- Conjugation involves high energy intermediates and specific transfer enzymes (transferases) located in microsomes or cytosol, to catalyse reactions.
- Primarily occurs in the liver.
factors affecting metabolism
- Genetics – variations in expression of metabolising enzymes
- Environmental factors – for example, co-administered drugs, diet, alcohol, smoking
- Age and gender – CYP enzyme expression can vary with age, and gender
- Disease states – for example, hepatic, cardiovascular
- Hormonal changes, e.g. pregnancy