Pharmacokinetics Flashcards
What can influence the pharmacodynamics?
Age, gender, disease, genetic predisposition and other chemicals
What can influence the pharmacokinetics?
Age, dietary factors, disease, genetic differences and other chemicals
4 key events in pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
Intra-individual differences?
Changes that take place over a period of time in the same person
How should we think about ADME processes?
rate - speed
extent - amount
What happens to most drugs as the plasma conc increases?
The therapeutic response proportionally increases
Different routes of drug administration?
Intramuscular dose –> body tissues –> general circulation
Intravenous dose –> general circulation
Oral dose –> liver –> general circulation. Gets metabolised and excreted by liver.
Inhaled dose –> lungs –> general circulation
Which organs are good at eliminating drugs?
Liver, Kidneys and Lungs
What is tyramine in?
Cheese
What is 5-HT in?
Bananas
What is benzopyrene in?
Combustion products
What is in coffee?
200 different low Mw components.
Chlorogenic acid & caffeine.
How does a drug pass across a membrane?
Membrane pores - low Mw and small ions
Diffusion - lipid soluble
Carrier mediated - drug must resemble natural ligand/substrate
Factors affecting absorption?
Lipid Solubility Ionisation Formulation GI function First pass metabolism
What is first pass metabolism?
rapid uptake and metabolism of an agent into inactive compounds by the liver, immediately after enteric absorption and before it reaches the systemic circulation
pKa?
How strong an acid or base is/
Low = strong acid, readily donate H+
High = strong base, readily accept H+
When does 50% ionisation occur
When pH = pKa
What happens to acids in high pH?
A weak acid converts to become ionised.
Water soluble so less crosses membranes.
What happens to bases in high pH?
Weak bases become deionised. Lipid soluble so more can cross membranes.
When are acids most ionised?
High pH
What is formulation?
The drug dissolving to create a molecular solution
Which size is best for absorption?
smallest - larger surface area
large particles don’t produce a molecular solution in the gut lumen
What are sustained release dosage forms?
Designed to release a drug at a predetermined rate in order to maintain a constant drug concentration for a specific time period with minimum side effects
What is gastric emptying?
How long it takes food to reach the intestine (major site of absorption - large SA and large blood supply)
What affects gastric emptying?
Meal
Contents of meal
Temperature of meal
What enzymes are present on the gut wall?
Esterases
Proteases
Conjugation occurs
Why is insulin injected?
So that proteases on the gut wall don’t act on the drug
What happens in the liver?
Oxidation
Hydrolysis
Conjugation
How does the drug get to the general circulation via the liver?
Gut Gut wall Hepatic portal vein Liver Hepatic vein
What is BIOAVAILABILITY?
F
Fraction of dose passing from administration site into general circulation.
IV = 1.0
Why might bioavailability be low?
Decomposition in gut lumen First pass metabolism in gut wall First pass metabolism in lilver Not absorbed from gut lumen Tablet hasn't fully dissolved
How can bioavailability be measured?
Compare plasma conc when the same dose is given IV or orally.
F = oral/iv
Compare the area under the curves
Why don’t you get paralysed when eating meat injected with tubocurarine?
Antagonist of nicotinic muscle acetylcholine receptor.
Quaternary ammonium ion stops it being absorbed.
pKa of the drug stops it being deionised.
An example of a drug interaction?
Tyramine levels get higher when given gruyere cheese whilst on an MAOI.
L-DOPA levels get higher when given carbidopa when on DDC.
Sublingual?
Under tongue. Good blood supplies to tongue. Doesn’t go via liver.
Rectal?
Doesn’t have to go via liver. Rapid absorption.
Why is cocaine not effective when taken orally?
It isn’t active due to first pass metabolism.
If you mix with lime, the buccal pH increases and lowers ionisation of the drug molecule –> gets into circulation.
Snorting and Inhalation avoid first pass metabolism
Define distribution?
Rate and extent of movement of the parent drug from the blood into the tissues after administration and its return from the tissues into the blood during elimination.
pH partitioning?
If the membrane separates fluids at different pH values, the drug will concentrate at the pH where it is most ionised.
How can a drug get eliminated from plasma?
Binding to plasma or tissue proteins.
Drug protein binding?
non specific low affinity high capacity saturable at high concs reservoir of drug
What does plasma albumin bind?
acidic drugs
A1 acid glycoprotein binds?
basic drugs
How can protein drug binding affect distribution?
Drugs:
If the drug is highly protein bound, then a second drug can change the volume of distribution of the drug.
Endogenous compounds:
If the compound is highly bound/toxic. e.g. bilirubin in neonates can lead to brain damage
Volume of distribution?
V
total in tissues/total in plasma
tissue binding/plasma binding
Large V?
More extensive distribution in tissues
BBB purpose?
Constant CNS environment, as the brain isn’t exposed to polar components in the plasma. Drugs barrier.
Physiological basis of BBB?
Small membrane pores. Tight Junctions Active transporters IN - essential nutrients OUT - waste, acid , P-glycoprotein
Area postrema?
No BBB
Emetic centre - safeguard against poisoning
Parkinson’s disease description?
Decrease in dopamine from substantia nigra
Decrease in dopaminergic activity in nigrostriatal pathway
Treatment of Parkinson’s?
Dopamine cannot pass BBB.
L-DOPA is dopamine’s precursor, but can pass the BBB as similar to amino acids.
DDC converts it to dopamine in the brain for clinical benefit.
Carbidopa is too polar to pass BBB and inhibits DDC in the plasma.
What is the rate?
time taken between dosing and equilibrium of tissues and plasma
What is the extent?
ratio of drug in tissues compared to plasma at equilibrium
Plasma conc vs time graph?
Two component model.
Distribution, equilibrium, elimination.
What can the slope of the distribution phase tell you?
The rate of drug distribution
What does the rate of distribution depend on?
- diffusion rate of drug across membrane
- perfusion rate of tissues that take up the drug
Thiopentone distribution?
Rapid effect with short duration. Drug redistributes out of the brain into the muscle and adipose. Conc in the brain decreases below an effective level.
Factors affecting drug distribution?
RATE
Rate of partitioning into tissues
Organ blood flow (cardiac output)
EXTENT
Plasma protein binding
Tissue composition of body
Define elimination?
Removal of the drug from the body, may involve metabolism or excretion
Routes of drug excretion?
Volatile - exhale Water soluble - urine Lipid soluble - metabolism Small - urine Large - bile
Phases of drug metabolism?
1 - oxidation, reduction and hydrolysis to introduce a functional side group
2 - conjugation to form a covalent bond between phase 1 metabolite and endogenous substrate
Why is metabolism required for lipid soluble drugs?
They aren’t easily eliminated.
Which phase 1 reaction is most important?
Oxidation - at carbon, nitrogen or sulphur atoms.
Are drug metabolism enzymes saturated?
Not usually so half life isn’t affected by dose. Also not affected by a drug which is metabolised by same enzyme
Where are phase 1 enzymes found - such as cytochrome p450?
membrane bound, in most tissues, especially liver. Part of ER.
Binds drug and oxygen/carbon dioxide
How is phase 1 induced?
By drugs (phenobarbitone) and environment (smoking)
How is phase 1 inhibited?
By cimetidine, quinine and grapefruit juice
Drug extraction from blood into lliver?
Diffuses across the hepatocyte extracellular matrix, across the Space of Disse
Hydrolysis enzyme?
Plasma pseudocholinesterase
Acts on ACh, succinylcholine, procaine and heroin
Difference between procaine and procainamide?
Similar drugs - Na channels.
Procaine is acted upon by esterases so short duration. Local anaesthetic.
Procainamide is acted upon by amidases and long duration of action. Cardiac function.
Types of phase 2 metabolism?
Glucuronidation Sulphation Acetylation Methylation Amino Acid conjugation
Glucuronidation?
C6H9O6 replaces the H to give water soluble inactive products.
Has to convert carbohydrate to UDPGA
Sulphation?
SO3- replaces H to give a very water soluble inactive product.
Sulpho-transferase
Acetylation?
CH3CO- replaces H to inactivate the functional group.
Requires activation of acetate
N-acyl transferase transfers the acetate to drug
Plasma pseudocholinesterase?
1 in 3000 individuals have a genetic polymorphism in this enzyme that makes them a poor metaboliser - muscle relaxants have a much longer effect (important in respiratory muscles)
Aldehyde dehydrogenase?
50% of some Asian populations have a genetic polymorphism that makes them a slow metaboliser of acetaldehyde (production of alcohol breakdown)
Example of enzyme induction?
Phenobarbitone is an inducer of ethoxycoumarin (anticoagulant).
Dicourmarol decreases when phenobarbitone increases.
Inducer interacts with nuclear receptors to increase mRNA transcription of cytochrome P450 enzymes (slow onset). Slow offset too due to protein turnover.
Effects of age on elimination?
Size of liver and blood flow decrease with age.
Reduced phase 1 metabolism
Drug metabolising enzymes are immature in the neonatal liver. First pass metabolism is low
Effects of liver disease on elimination?
Anatomical changes that impair rapid uptake of lipid soluble drugs.
Intracellular enzyme activity is reduced.
Define excretion?
Drug molecule is expelled in the body’s liquid, solid or gaseous waste
Routes of excretion?
Lungs (volatile)
Kidneys (low Mw)
Bile (high Mw)
Types of renal excretion?
Glomerular filtration
pH dependent reasborption
Renal tubular secretion
Glomerular filtration?
Small molecules are filtered through pores 7-8nm diameter
20% of all water soluble, low Mw compounds.
Protein bound drug isn’t filtered.
pH dependent reabsorption?
urine - 6 pH
plasma - 7.4 pH
drug concentrates in the fluid in which it is most ionised.
Weak acids can be reabsorbed into the plasma.
Weak bases are excreted in the urine.
Biliary excretion?
Entero-hepatic circulation
drug gets released in bile
drug may be reabsorbed from the intestine and carried back to the liver via the hepatic portal vein.
How can you see extent on a graph?
Less of the drug remains in the plasma for an extensive drug
What does the AUC show?
total amount of drug that has entered the general circulation
what does curve show for IV?
distribution
what does curve show for oral?
absorption
How to calculate F if iv and oral dose differ?
F = AUC(oral)/AUC(iv) x dose(iv)/dose(oral)
Biphasic two compartment model/
initial slope - distribution
second slope - elimination
Monophasic one compartment model?
if already fully distributed….
only elimination
Define clearance?
ability of the organs of elimination to extract the drug from the general circulation and remove it from the body
volume of plasma cleared of drug per minute
Define apparent volume of distribution?
extent to which the drug reversibly leaves the general circulation and enters the tissues of the body
What will plasma clearance of a drug be close to?
The blood flow for the organ via which it is eliminated
liver - 1500 ml/min
renal - 650 ml/min
glomerular 120 ml/min
Rate of elimination?
Terminal rate of decrease in plasma concentrations.
Half life?
Time it takes for the concentration to half
How long does it take to get to Css?
5 x t 1/2
