Drug Metabolism and Kinetics Flashcards
Pharmaceutical Phase
Disintegration of the pill / capsule in gastrointestinal
tract (GI), release of the drug, dissolution of drug
Pharmacokinetic Phase
Absorption from GI tract into bloodstream and
what the body does to the drug
Pharmacodynamic Phase
Mechanism by which the drug interacts with the
molecular target. What the drug does to the body
Pharmacokinetics required by a drug
- Absorbed well by the body
- Reaches target easily
- Not modified, inactivated, or removed from the body
too quickly
Pharmacodynamics required for a drug
- Effective at targeting the
disease process - Not toxic
Potency
- Dose required to achieve the effect.
- Measured as the 50% effective concentration (EC50).
- Units of concentration
Efficacy
- The maximal effect.
- Measured as “response.”
- Usually a percentage
ADME
Absorption
- Process of drug entering the body and therapeutic agent entering the blood
ADME
Distribution
- Drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular
fluids of various compartments in the
body
ADME
Metabolism
chemical conversion of drug
molecules
ADME
Elimination
- Clearance of drugs and
metabolites from the body (urine, bile,
faeces)
Absorbtion adminstration method
Intravenous
- Polar charged and high molecular weight drugs
Absorbtion adminstration method
Intramuscular
- Oily vehicles that are irritating
- Neutral chemicals
Absorbtion adminstration method
Inhaled
- Neutral molecules
- Highly volatile
Absorbtion adminstration method
Topical and subcutaneous
- Neutral molecules
Factors Affecting Drug Absorption
Solubility
- Drugs need to be water-
soluble to pass into the blood for
distribution
Factors Affecting Drug Absorption
Ionisation
Drugs need to be close to
neutral to pass through membranes
Factors Affecting Drug Absorption
Stability
Drugs need to be chemically
stable until they reach their site of
action
Factors Affecting Distribution
Plasma solubility
Including binding to plasma proteins (bind and release)
Factors Affecting Distribution
Lipophilicity
- Balance between water and fat solubility.
- Influences drug levels in blood, muscles, adipose tissue, and organs
Factors Affecting Distribution
Perfusion
- Level of blood flow to a tissue.
- Major organs e.g. well perfused
- Brain is a special case – blood-brain barrier more difficult to reach
Elimination
- Get metabolites and exogenous
molecules out of their system - Drug is removed without metabolism, the process is called excretion
Metabolism
- Metabolic enzymes attack drug molecules forming metabolites
- Metabolites may be inactive, less active or even more active than parent drug molecules
- Side effects and toxicity
Why is the metabolism of drugs required
- Designing new drugs which do not form unacceptable metabolites
- Designing pro-drugs / understanding pre-drug strategy
- Understanding half-lives and tailoring drug action
Minor metabolites
- Accumulation of minor
metabolites can be extremely toxic
Exreation of Polar Drugs
- Kidneys will excreate polar drugs at a faster rate
Excreation of Non-polar Drugs
- Needs to be chemically modified to make them more hydrophilic so they can
be eliminated more easily
Phase I Transformations
- Mostly in liver
- Chemical Modifications
- Oxidation, Reduction, Hydrolysis
CYP- P450 Reactions
- Haemoproteins (contain haem)
- Located in the liver cells
- Split molecular oxygen so one of the oxygen atoms is introduced into the drug, the other ends up in water
1 - lowest order of oxidation
Oxidation of carbon
- Oxidation of exposed alkyl groups & exposed regions of cycloalkyl rings
- Exposed CH3 molecule and alkyl substitution
- Most ecposed hydrogen the one opposing the R group
2 oxidation level
Oxidation of carbon
- CH3 opposing the the R group on the benzene to alcohol to carbocylic acid
