Pharmacokinetics Flashcards
Pharmacokinetics
What organism does to drug.
Conc as function of time.
ADME
(fate of drug) Absorption Distribution Metabolism Excretion
Sometimes also: liberation (from medication) and toxic effects
parameters of absorption, distribution, metabolism/excretion
A: bioavailability F
D: volume of distribution Vd
M/E: clearance CL
Therapeutic index
(max non-toxic dose) / (min effective dose)
AUC (drug kinetics)
Area under curve. Total amount of drug absorbed (conc vs time).
Bioavailability
Extent to which drug reaches systemic circulation.
AUC) / (AUCiv
iv= intravenous
Routes of drug administration determined by..
Physiochemical properties of drug
Therapeutic objectives
Stability of drug
Routes of administration
Enteral: oral, sublingual/buccal, rectally
Parenteral: intravenous, intramuscular/subcutaneous
Other: inhalation, topical, transdermal
Oral
Safe, convenient, high compliance, antidotes possible.
But: slow onset, limited bioavailability, first-pass effect.
Sublingual, buccal
Under tongue / between gums and cheek.
Safe, convenient, high compliance, rapid absorption, avoids first-pass metbolism.
Rectal
Partially avoids first-pass. Avoids drug damage in GI. Suitable for vomiting/unconscious patients, babies.
But: low compliance, may cause irritation, difficult to control.
parenteral - suitable for?
Drugs with low enteral bioavailability / that are unstable in GI. For unconscious patients. Rapid onset.
Intravenous
Directly into systemic circulation, immediate effect > emergencies. Highest bioavailability. Suitable for peptides. Easily controlled, predictable.
But: low ocmpliance, local tissue damage/infection, irreversible, not for highly lipophilic drugs.
Intramuscular, subcutaneous
Sustained, slow release (depot). For poorly soluble suspension / larger drug molecules. High bioavailability. Avoids first-pass.
But: low compliance, ltissue damage/ infection, pain,local adverse effects
Inhalation
Rapid delivery, local application, lower systemic side-effects.
But: some systemic absorption.
Topical
Local application > lower side-effects.
Some systemic absorption may occur, low delivery to target tissue
Transdermal
Slow, sustained. Safe, convenient. Lipophilic drugs.
But: only highly lipophilic drug, allergic reaction from patches,.
Mechanisms of drug passage across biological membranes
- Passive diffusion
- Facilitated diffusion (carriers)
- Activated transport (transport proteins, ATP!)
- Endocytosis (large drugs)
Distribution depends on:
- Local blood flow (> perfusion rate)
- Capillary permeability
- Protein binding in plasma and tissue
- Lipophilicity and size of drug, substrate specificity for transporters
Volume of distribution
Vd = Dose of drug / C0
C0 = conc at time point 0
Routes of drug elimination
Excretion through kidneys (hydrophilic drugs)
Hepatic metabolism (lipophilic drugs)
Biliary elimination
Intestinal metaboism
Secretion into gut lumen after absorption
Elimination via faeces/lung/breast milk/sweat/saliva/skin
Drug clearance
Amount of drug eliminated over time.
CL = [ln(2)xVd] / [t1/2]
Enzymatic reactions in the liver to increase hydrophilicity of lipophilic drugs
Phase 1: additional of polar functional groups via oxidation/reduction/hydrolysis
Phase 2: conjugation with hydrophilc molecules eg glutathion/sulfate/aa
Then: excretion via kidneys/bile
CYP enzymes
Phase I enzymes. Cytochrome P450.
Cofactor haem. Liver and GI. Metabolise 50% of all drugs by oxidation.
Important: CYP3A4, CYP2D6
