Pharmacokinetics Flashcards
What is pharmacokinetics?
the study of how an organism affects a drug
Provides a mathematical basis for the description and
prediction of the time course of drugs (and their metabolites) in the body.
What is pharmacodynamics?
the study of how the drug affects the organism
Pharmacokinetics refers to the quantitative study of ADME. What does this stand for?
ABSORPTION
DISTRIBUTION
METABOLISM
ELIMINATION
Define absorption.
All processes from the site of administration (anything non-intravenous) to the site of measurement (typically blood)
Define distribution.
The reversible transfer of drug between the site of measurement and other sites within the body.
Define metabolism.
The irreversible loss of drug from the body by biochemical conversion
Define elimination.
The irreversible loss of drug from the site of measurement within the body.
Define excretion.
The irreversible loss of drug from the body
Define disposition.
Elimination + distribution
What do the following stand for... AUC Cmax Tmax MTC MEC?
area under the curve max concentration time to max concentration minimal toxic concentration minimal effective concentration
Drugs must move across hydrophobic diffusion barriers - how? (2)
Diffusion
Carrier-mediated transport
Where are the majority of drugs absorbed from?
What is key here? (2)
GI tract
solubility (dissolution) and ionisation
What is solubility dependent on?
What is solubility a major determinant of?
The properties of the tablet i.e. surface area, drug concentration, thickness
Drug plasma levels
How do large insoluble molecules (e.g. glucose and proteins) move through the plasma membrane?
Carrier-mediated transport - they require a carrier molecule
Give some examples of carrier molecules. (4)
Ion channels, ABC transporters, water channels, ATP pumps, etc…
What is facilitated diffusion?
How does it differ for water-soluble and lipid soluble agents?
A passive process where solute moves down a concentration or charge gradient
Water-soluble agents use aqueous pores in the membrane, while lipid soluble agents diffuse through the membrane
What is active transport?
the movement of solute against a concentration (or other) gradient
utilises energy directly
Cell membranes are generally only permeable to…?
Why?
uncharged solutes
hydrophobic fatty acids repel charged molecules
What equation determines the proportion of a substance that is ionised at a given pH?
Henderson-Hasselbach equation
pH = pKa + log (A-/Ha)
If pH < pKa, what does this mean?
The non-ionised form of an acid dominates.
In the acidic stomach (pH 1.5 - 3.5), weak acids are present in what form - ionised or non-ionised?
Non-ionised
What can impair absorption of weak acids? (4)
– Gastric pH is elevated by drugs (i.e. PPIs, H2 antagonists, antacids)
– Gastric pH is physiologically higher in neonates as their gastric secretions are relatively achlorhydric (pH 6-8)
– Gastric resections (primarily for cancer) remove acidic
environment
– Modified delivery systems reduce solubility in the stomach and thus increase delivery to intestines (pH >6)
Solubility and diffusion - which favours ionised/non-ionised?
Solubility favours ionised species, diffusion favours nonionised
What factors affect gastrointestinal absorption? (4)
- pH
- Blood flow to stomach/intestine
- Gastrointestinal tract transit time
- Gastric contents
Most drugs are either ____ acids or _____bases (weak/strong).
WEAK
Clopidogrel and omeprazole - what is the interaction?
What is therefore recommended?
omeprazole added to clopidogrel therapy reduces the inhibition of platelet aggregation
Concomitant use of clopidogrel and omeprazole or esomeprazole is to be discouraged unless considered essential. Consider PPIs other than omeprazole or esomeprazole, or other gastrointestinal therapy such as H2 blockers (except cimetidine) or antacids
Why do antacids have multiple interactions?
How many this be avoided?
Can interfere with absorption of other drugs, e.g. by forming insoluble chelate complexes
Typically suggests taking 1-2 hours apart from other medications
What is p-glycoprotein?
Where is it extensively expressed?
ATP-dependent efflux pump with broad substrate
specificity.
Intestinal epithelium, liver, proximal tubule and blood brain barrier.
Which p-gp varient is associated with multi-drug resistance?
ABCB1/MDR1 gene
Define bioavailability.
the fraction of unchanged drug that is absorbed intact and reaches the site of measurement
Bioavailability (F) is defined as a unity (100%) for an
intravenous preparation, and all other routes are
compared to this.
What is doxazosin?
α1-adrenoceptor antagonist licenced for treatment of hypertension
Standard immediate release formulation of doxazosin
describe the pharmacokinetics.
linear PK across dosing range (1-16 mg/day).
Bioavailability 65%
tmax = 2h
t1/2 = 14h
Why does doxazosin require slow dose titration?
Post-dose hypotension and risk of orthostasis
Distribution - what is it dependent on? (4)
– plasma protein binding
– ratio of compartment blood flow to compartment size
– barriers to distribution (i.e. blood brain barrier)
– affinity of drug for tissue (Kp)
Define volume of distribution (Vd).
Hypothetical value that relates the amount of drug in
the body to the amount at the measured site
Vd equals the volume of fluid required to contain the
total amount of a drug in the body at the same concentration as measured in the plasma
Equation for Vd.
Vd = amount in body/conc. in plasma
If drug is highly lipid soluble, what will the Vd be?
high
High Vd can also reflect…?
high tissue binding
What are compartment models?
Mathematically describes the movement of drug around the body
How is metabolism categorised?
phase I and phase II
Describe phase I metabolism - type of reactions, enzymes…
Catabolic reactions e.g. oxidation, reduction and hydrolysis
P450 enzymes important
Reactive handle introduced to facilitate phase II
Describe phase II metabolism - type of reactions
Anabolic reactions; e.g. conjugation
Usually results in inactive compounds
Usually results in polar molecules; this increases renal elimination
Cytochrome P450 - what are they?
proteins of a superfamily containing heme as a co-factor.
Cytochrome P450 - where are they located?
Located in mitochondria and endoplasmic reticulum.
P450 enzymes are prone to induction and inhibition. Give two examples.
Drugs can act as their own P450 inducers/inhibitors
Non-drugs can modify (e.g. grapefruit juice)
Give examples of P450 inducers.
– Carbamazepine – Rifampicin / ritonavir – Alcohol (acute) – Phenytoin / phenobarbitone – Griseofulvin / Fluconazole – St John’s Wart – Isoniazid (CYP2A1)
Give examples of P450 inhibitors.
– Clarithromycin / azithromycin /erythromycin – Amiodarone – Dexamethasone – Valproate – Metronidazole – Cimetidine – Ciprofloxacin – Isoniazid (CYP1A2) – Grapefruit juice – Ketoconazole – Ritonavir – Verapamil / Diltiazem – Alcohol (chronic)
How does codeine exert its analgesic effect?
conversion of codeine to morphine by CYP2D6.
Phenotype - poor metaboliser
Prevalence - ?
Genotype - two non-functional alleles
Phenotype Prevalence Genotype
5-10%
Phenotype - intermediate metaboliser
Prevalence - 2-11%
Genotype - ?
One reduced and one non-functional allele
Phenotype - extensive metaboliser
Prevalence - 77-92%
Genotype - ?
Two functional or reduced function alleles, or one
functional with a non-functional or reduced function allele
Phenotype - ultra-rapid metaboliser
Prevalence - ?
Genotype - more than two functional alleles
1-2% (30% ethiopian)
CYP2C9 inhibitors - examples. (5)
– Amiodarone – Efavirenz – Fluconazole – Fluvastatin – Ketonazole
CYP2C9 inducers - examples. (4)
– Carbemazepine
– Phenobarbitol
– Phenytoin
– Rifampicin
Why enzyme metabolises S-warfarin?
CYP2C9
What is first pass metabolism?
Where does it usually occur?
Metabolism of a drug before it reaches the site of measurement
Gut wall or liver
Why is levodopa given with DOPA decarboxylase inhibitor?
To avoid first pass metabolism
Why are transdermal patches applied above nipples?
To avoid hepatic drainage
Explain how rectal medications avoid hepatic first pass metabolism.
blood supply is systemic rather than portal
Renal excretion - what molecules are filtered through the glomerulus?
Unbound molecules <20k Da
Renal excretion - where does active tubular secretion predominantly take place?
proximal tubule
Explain zero order kinetics and give some examples.
– Constant rate of drug is eliminated/metabolised
– Independent of drug concentration
– Mechanism saturable
– e.g. ethanol, phenytoin, high dose salicylates, theophylline
Explain first order kinetics.
Rate of drug elimination/metabolism is proportion to [drug] concentration
Therefore has a drug half-life
Mechanism non-saturable
e.g. 95% of all drugs
What does half life (t1/2) represent?
The time for the (plasma) drug concentration to decline by half.
How many half-lives to 90% steady state?
3.3
How many half-lives to <5% of initial concentration?
5
What does clearance measure?
Measures of the ability of the body to eliminate a drug
CLTotal = ?
(CLRenal + CLHepatic + CLother)
What is the unit of clearance?
volume per unit time
CL organ = Q organ X E organ
What does this mean?
Clearance is the product of the organ’s blood flow (Q) and the extraction ratio (ER) of the drug
Total clearance can be derived from known values.
CL total = ?
(F x Dose) / AUC
