Pharmacokinetics Flashcards
Pharmacokinetics
How the drug is processed by the body.
LADME
Liberation
Absorption (to the blood stream)
Distribution (from blood stream to site of action)
Metabolism
Excretion
Oral Administration
Safe, patients easily comply, economical.
Delay before uptake into blood stream.
Potential it could be metabolised before absorption.
Intravenous Administration
No Absorption! - straight to the bloodstream
Typically immediate effects
Large volumes possible
Expensive, not suitable for lipophilic substances, potential for adverse effects.
Liberation
pH dependent procedure.
Lipinski’s Rule of 5
Failure to comply with 2 or more means the oral drug has poor bioavailability.
- MW < 500
- log P < 5
- Less than 5-H bond donor groups
- Less than 10 H-bond acceptor groups
Volume of Distribution (Vd)
Relates the amount of drug in the body to the conc. of drug in blood plasma (IV administration)
Vd = total amount of drug in the body/ blood plasma concentration of drug = Db/Cp
High Vd = less soluble in water, will bind to tissue and macromolecules.
Duodenum
Organic bases become neutral and are able to be absorbed by lipids, villi allow large total absorption of species with poor diffusion tendency.
Passive Diffusion
From an area of high drug concentration to an area of low drug concentration.
Lipid soluble = pass through the cell membrane.
Water soluble = pass through aqueous channels or pores
Large molecules = transmembrane carrier proteins.
Active Transport
Moves drugs against a concentration gradient, is an energy-dependent process and is driven by the hydrolysis of ATP.
Partition Coefficient
‘Dual solubility’ of a drug is preferable so we take the ratio of a compounds equilibrium solubility in lipophilic solvents to its solubility in water.
log P = log (c in lipid/ c in water)
Bioavailability
The extent or fraction to which a drug reaches a systemic circulation. It can be impacted by digestion of food, formulation, interactions with other drugs/food, enzyme activity, genetics etc.
Blood Tissue Barriers
Drugs can become bound to serum proteins once they enter the blood stream, they act as a depot for maintaining sufficient concentration at the target site.
Since cell membranes are phospholipids (negative charge) they arrange into bilayers. Lipophilic bases tend to permeate these membranes and acids tend to be repelled.
Blood Brain Barrier
Has tight junctions that are extremely resistant to the passage of drugs. Has a more rigid and resistant to passive permeation cell membrane structure. Requires the presence of metabolising enzymes.
What are the 4 main pathways that endogenous ligands can bind to receptors?
- Ligand-gated ion channels
- G protein-coupled receptors
- Enzyme-linked receptors
- Intracellular receptors
Dose Response Curves 101
Efficacy: is the maximal response or effect that can be achieved.
EC50: Concentration of a drug that produces 50% of the maximal effect.
Potency: a measure of the drug activity relative to the amount required.
Agonist
Mimics the natural ligand to get the protein to action.
Full Agonists: bind to the receptor, maximal response possible
Partial Agonist: can’t reach Emax
Inverse Agonist: binds to same receptor but produces opposite effect, can make inactive
Irreversible Agonist: permanently bound, activates receptor.
Antagonist
Do not cause or oppose a response.
Non-competitive: binds at the allosteric site and reduces agonist efficacy.
Competitive: binds at the receptor and competes with agonist for the site, will keep receptor inactive.
Therapeutic Index
Ratio of the dose of a drug that causes a toxic effect versus the dose that produces the clinically desired effects in patients.
TD50/ED50
Cytotoxic Drugs
Small drugs that will have direct access to DNA, large molecules that can manipulate the equilibrium of coiled and uncoiled DNA to the histone.
What are the 3 main drug interactions with DNA?
- Reversible DNA binders: external electrostatic interactions, groove binding or intercalation.
- DNA alkylators: react as electrophiles to form stable covalent bonds, frequent reactions lead to mutations.
- DNA strand breakers: intercalates with DNA to generate radicals, radicals abstract the H from the DNA bases = DAN strand scission
Henderson - Hasselbalch Equation
pH = pKa + log[A-]/[HA]
Xenobiotic Metabolism
The modification of foreign compounds, including drugs and toxins - the main metabolic strategy is to modify drugs to increase hydrophilicity.
Occurs mainly in the liver through enzymatic transformation
Will render metabolites inactive and allow them to be cleared by the kidneys.
Oxidation
Enzymes: flavin-containing monooxygenases (eg. cytochrome P450)
Co-factor: NAD(P)H + NAD(P) (metal catalysis) FAD/FAD(H2) (non-metal catalysis)
Often occurs at the terminal or penultimate carbon, most exposed region of the molecule and acts to increase solubility.
