Principles of pharmacokinetics Flashcards
What is pharmacodynamics?
The biochemical, physiological and molecular effects of a drug on the body.
What the drug does to the body.
What is pharmacokinetics?
The fate of a chemical substance administered to a living organism.
What the body does to the drug.
What are the processes of pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
Describe absorption
Transfer of a drug molecule from site of administration to systemic circulation (barriers vary with route of administration)
What are examples of route of administration?
IV
IA (intra arterial)
IM
SC
PO
SL
INH
PR
PV
TOP
TD
IT (intrathecal)
Which routes of administration allows 100% of a drug to reach circulation?
IV and IA
How do drugs penetrate membranes?
- Passive diffusion via the hydrophobic membrane. (Lipid soluble molecules).
- Passive diffusion aqueous pores. (Very small water soluble drugs (Lithium). Most drugs are too big.
- Carrier mediated transport. (Proteins which transport sugars; AA, neurotransmitters and trace metals).
What factors affect absorption?
Lipid solubility + drug ionisation
Ionised drugs
Poor lipid solubility -> poorly absorbed.
Most drugs are weak acids or weak bases with ionisable groups.
What does the proportion of ionisation depends on?
pH of the aqueous environment.
Weak acids are best absorbed where?
In the stomach.
Weak bases are best absorbed where?
In the intestine.
What factors affect oral drug absorption in the stomach?
Gastric enzymes - molecules may be digested.
Low pH - molecule may be degraded.
Food - full stomach = slower absorption.
Gastric motility - altered.
Previous surgery - gastrectomy.
What factors affect oral drug absorption in the intestine?
Drug structure - lipid soluble/unionised diffuse down conc. gradient.
Large/hydrophilic - poor absorption.
Medicine formulation - coating controls time between administration and release.
P-glycoprotein - substrates removed from intestinal endothelial cells back into the lumen.
What is first pass metabolism?
Metabolism of drugs preventing them reaching systemic circulation.
What affects first pass metabolism?
- Degradation by enzymes in intestinal wall.
- Absorption via hepatic portal vein -> metabolism via liver enzymes.
- It varies between individuals.
- Avoid giving via routes that avoid sphlanchnic circulation (i.e. rectal)
What is the proportion of a dose which reaches the systemic circulation called?
Bioavailability (F)
Bioavailability depends on
- Extent of drug absorption.
- Extent of first pass metabolism.
Is bioavailability affected by the rate of absorption?
No
Does bioavailability varies with route of administration?
Yes
What other factor causes variation in bioavailability between individuals?
Genetics
Disease state
Bioavailability is expressed as a
Fraction
What are the four compartments in the body for drug distribution?
Plasma (5%)
Fat (20%)
Interstitial fluid (15%)
Intracellular fluid (35%)
How does molecule size affect distribution?
Small molecules high distribution between plasma and ECF.
Large molecules low distribution between plasma and ECF.
How does lipid solubility affect distribution?
Hydrophilic molecules low distribution between plasma and ECF.
Lipophilic molecules high distribution between plasma and ECF.
How does protein binding affect distribution?
Increased protein binding leads to low distribution between plasma and ECF.
Decreased protein binding leads to increased distribution between plasma and ECF.
Volume of distribution (Vd)
Theoretical volume of a drug distributed in the body.
Volume of plasma required to contain the total administered dose.
Well distributed drugs have
High Vd
Poorly distributed drugs have
Low Vd
BBB
Membrane that separates foreign substances in the blood from the CNS.
Continuous layer of endothelial cells with tight junctions
Efflux pumps remove water soluble molecules
BBB maintains a stable environment and protects the brain, but poses a challenge for treating CNS conditions
Ways for drugs to reach the CNS
High lipid solubility. e.g. Ѱ drugs usually very lipid soluble (therefore large Vd)
Intrathecal administration (e.g. baclofen in MS and spinal cord injury, chemotherapy)
Inflammation (causes barrier to become leaky)
Can be advantageous (e.g. naloxegol for opioid induced constipation)
Aciclovir administration in obese patients
Based on ideal body weight.
Drug elimination
Process by which the drug becomes no longer available to exert its effect on the body.
Drug metabolism
Modification of chemical structure to form a new chemical entity (metabolite).
What are the two phases of metabolism?
Phase 1 reactions: oxidation/reduction/hydrolysis to introduce reactive group to chemical structure.
Phase 2 reactions: conjugation of functional groups to produce hydrophilic, inert molecules.
Excretion
Of unchanged drug (hydrophilic, polar molecules).
Phase 1 metabolism
CYP450 (mostly located in the liver, also in small intestine and lung)
Lipophilic, unbound drug will readily cross hepatocyte membrane.
Produces a reactive metabolite (creating/unmasking a reactive functional group).
What causes variation in CYP enzyme function?
Genetic variation
Reduced function in severe liver disease
Interaction enzyme inhibiting/inducing drugs or food can reduce/increase enzyme activity.
How many CYP450 enzymes are there?
57
What are the most significant CYP enzymes?
3A4, 2C9, 2C19, 1A2, 2D6
What are the substrates for CYP1A2?
Caffeine, paracetamol, theophylline, warfarin
What are the substrates for CYP2C9?
Ibuprofen, warfarin
What are the substrates for CYP2C19?
Omeprazole, phenytoin
What are the substrates for CYP2D6?
Codeine, warfarin
What are the substrates for CYP3A4?
Simvastatin, warfarin, DOACs (apixaban), carbamazepine, diltiazem
Pharmacogenomic variation in CYP450
Codeine example.
Pro-drug is activated by CYP2D6
Poor metabolisers: minimal therapeutic benefit
Intermediate metabolisers: reduced benefit
Extensive metabolisers: 10% of dose converted to morphine
Ultra-rapid metabolisers: greater proportion converted to morphine - risk of toxicity.
Phase 2 metabolism
Conjugation of an endogenous functional group (glycine, sulfate, glucuronic acid) to produce a non-reactive polar molecule.
Hydrophilic metabolite can be renally excreted.
Paracetamol toxicity
Reduced paracetamol dose in low body weight and severe hepatic impairment.
What is paracetamol toxicity treated with?
N-acetylcisteine (NAC)
Excretion (ways)
Liquids (small polar molecules): urine, bile, sweat, tears, breast milk
Solids (large molecules): faeces (through biliary excretion)
Gases (volatiles): expired air
What three processes account for renal excretion of drugs?
- Glomerular filtration rate (20% of plasma filtered, free/unbound drug molecules, very large molecules excluded).
- Active tubular secretion (80% of renal blood flow passes on to peritubular capillaries, drug molecules transported by carrier system (organic anion/cation transport), can clear protein bound drug, most effective renal clearance mechanism).
- Passive reabsorption (diffusion down the conc. gradient from tubule into peritubular capillaries, hydrophobic drugs diffuse easily, highly polar ones will be excreted).
Gentamicin in reduced kidney function
Reduced renal excretion -> plasma levels rise -> nephrotoxicity and ototoxicity.
