Session 9 - Pharmacokinetics Flashcards
Define pharmacokinetics
What the body does to a drug
Define pharmacodynamics
What the drug does to the body
Give four questions which should be asked when administering a drug,
Is the drug getting into the patient?(pharmaceutical process)
Is the drug getting to the site of action? (pharmacokinetic process)
Is the drug producing the desired pharmacological effects? (pharacodynamic process)
Is the pharmacologic effect translated into a therapeutic effect? (therapeutic process)
What are the two methods of drug formulation?
What is another factor on the administration of a drug?
Solid, liquid
Compliance - simplified regime
If solid, what extra factors must be considered?
Solubility and acidic stability in stomach must be considered
Give two sites of administration?
Local (eye, skin, inhalation)
Systemic (enteral or parenteral)
Give three examples of enteral systemic administration
Sublingual
Oral
Rectal
Give five examples of parenteral systemic administration
Subcutaneous/intramuscular/intravenous injection, inhalation, transdermal
Define the term oral bioavailability
Oral Bioavailability is the proportion of a dose given orally (Or by any other route other than intravenous) that reaches the systemic circulation in an unchanged form.
What can bioavailability be measured by?
1) Amount (depends on GI absorption and first pass metabolism)
2) Rate of availability (depends on pharmaceutical factors and rate of gut absorption)
What are two factors which effect gut absorption?
Altered by food or disease
How is amount measured on graph?
Area under curve of blood drug level vs. time
How is rate measured on a graph?
peak height and rate of rise of drug level in blood
What is maximum tolerated dose?
Lethal Dose to 50% of people
What is minimum effective dose?
Effective Dose in 50% of people
What is the equation for measuring therapeutic ratio?
Maximum Tolerated Dose/Minimum Effective Dose
LD50/ED50
Advantage of local admin?
Less systemic side effects, more direct action
What is the first pass effect?
Substances absorbed from the lumen of the ileum enter the venous blood, which drains into the hepatic portal vein and is transported directly to the liver. Liver is main site of drug metabolism, so any drug which enters it may be extensively metabolised before it reaches systemic circulation - first pass effect
How can the first pass effect be avoided?
The parenteral, sublingual or rectal routes can avoid it.
Glyceryl trinitrate is a particular example
How much of an oral dose of paracetamol is metabolised via first pass effect?
90%
Define drug distribution
The theoretical volume into which a drug has distributed assuming that mixing occurs instantaneously
What is drug distribution calculated by?
mount Given / Plasma Concentration at Time 0
What happens to many drugs once they reach circulation?
Protein binding interaction - this is significant as it is the free concentration of drug which has an effect, not the total
What does rate of action depend on?
Dissolution
When is protein binding important? (3)
The drug is highly bound to albumin (>90%)
The drug has a small volume of distribution
The drug has a low therapeutic index
Give two examples of drugs where protein binding is important
Warfarin and tolbutamide
What is an object drug? (class 1)
Drug is used at a dose that is much lower than the number of albumin binding sites
What is a precipitant drug? (class 2)
Drug is used at a dose that is greater than the number of available binding sites.
What drug should you take now?
Caffeine, you look a little tired.
I mean, not tired drawn out, just fatigued? Go ahead scamp, it’s going to be a couple of weeks of intense revision - you can afford to go make a coffee (or a tea, if you prefer!).
Name three object drugs and their precipitants
Warfarin - Sulphonamides, aspirin, phenytoin
Tolbutamide - Sulphonamides, aspiin
Phenytoin - Valproate
What happens if class 1 and class 2 drugs are given simultaneously?
When the drugs are administered simultaneously, Object (class1) drugs are displaced by precipitant drugs (Class II), raising the free levels of the object drug and therefore, higher risk of toxicity.
What law do enzymes which metabolise drugs follow?
Why are the effects of drugs transient?
Michaelis Mentin Kinetics
As free drug level rises, so to does rate of elimination
What is the standard equation for rate of metabolism?
V max x (concentration)/Km + (C)
In a situatioon where a drug is used at concentration lowerer than km, what is the equation?
Rate of metabolism = Vmax (C)/Km
What are first order kinetics?
metabolism is proportional to drug concentration
Constant fraction of drug broken down in unit time. Half life can be defined.
What do first order kinetics look like on a gaph?
straight line when a log scale is on the Y-axis versus time
Define first order kinetics
When the rate of decline of plasma drug level is proportional to drug level. Half life can be defined.
When are 0 order kinetics obeyed?
When drug is used at a concentration much greater than Km
What is the equation for 0 order kinetics?
Rate of metabolism = Vmax (c)/(C)
Rate of metabolism effectively = vmax and the enzyme is saturated
Define 0 order kinetics
When the rate of decline of plasma drug level is constant, regardless of concentration. Give a straight line when normal (not log) plasma conc plotted against time
How long until steady state of drug is reached after repeated doses? Irrespective of dose or frequencyof administration
Five half lives
What happens if an immediate effect of drug is needed?
A loading dose is given, which is determined by the volume of distribution
What is the advantage of 1st order kinetics?
Gives predictable therapeutic response from dose increases (most drugs behave this way)
What is the major effect of 0 order kinetics?
Gives a therapeutic response which can suddenly escalate as elimination mechanisms saturate (alcohol, yay!)
What are the two stages of drug elimination?
Metabolism (by liver)
Excretion (by kidney)
What is phase 1 of drug metabolism?
Most drug molecules are stable and relatively unreactive (a pro-drug) so in Phase I a reactive group is exposed on the parent molecule or added to the molecule.
Why are reactive groups added or exposed on parent molecule in phase 1 of drug metabolism?
Generates a reactive intermediate that can be conjugated (in Phase II) with a water-soluble molecule to form a water-soluble complex.
What are the three methods via which reactive groups added or exposed on parent molecule in phase 1 of drug metabolism?
Oxidation
Reduction
Hydrolysis
What enzymes are needed for phase one of drug metabolism?
Cytochrome P450 and high energy cofactor (NADPH). Enzymes are inducible and inhibitable.
Low substrate specificity
Affinity for lipid soluble molecules
When do drug interactions matter?
Low therapeutic ratio
Drug at minimum effective concentration
Name three enzyme inducers and the drugs the effect
Phenobarbitone - Warfarin, Phenytoin
Rifampicin - Oral contraceptive
Cigarette smoke - Theophylline
Name an enzyme inhibitor found in phase 1 and the drugs it effects
Cimetidine (stomach ulcer treatment) - Warfarin, Diazepam
Name a drug which can bypass phase 1 of drug metabolism
Morphine
What occurs in phase 2 of drug metabolism?
The reactive intermediate from Phase I is conjugated with a polar molecule to form a water-soluble complex. The process is also known as conjugation.
Name three conjugates involved in phase 2
Glucoronic acid
sulphate ions and glutathione
What high energy cofactor is required in phase 2 drug metabolism?
uridine diphosphate glucuronic acid (UDPGA)
Name three potentiators of warfarin, and how they have effect
Alcohol - inhibits metabolism
Aspririn, suplhonamides, phenytoin - displacement from plasma proteins
Broad spectrum antibiotics - reduced Vit K synthesis
Give two inhibitors of warfarin and their one effect
Barbiturates, rifampicin - Induces liver metabolizing enzymes
What state must a drug be to be excreted by the kidney? Give one method of excretion from tubule
Only the free unbound drug is filtered through glomerular tuft.
Drugs can be actively secreted by the tubule
What determines how much of a drug is excreted?
Urine pH
Pk of drug is pH at which half of it is ionised
What occurs for weak acids in terms of urine excretion?
For weak acids, e.g. aspirin, making the urine alkaline will make the drug ionised, so there will be less tubular absorption because the charged drugs stay in the tubule lumen.
Forced alkaline diuresis used in aspirin overdose
What occurs for weak bases in terms of urine excretion?
For weak bases, e.g. amphetamine, the opposite is true and acidic urine will increase excretion. Acid urine will ionise a weak base, making the charged drug stay in the tubule lumen.
Forced acidic diuresis to increase excretion.
