M&R S9 - Pharmacokinetics Flashcards
Define pharmacokinetics
What the body does to the drug
What are the different ‘formulations’ of drugs?
Solid or liquid
What are the different sites of administration on a patient?
Make sure to split them into their categories and name the categories
Focal:
- Eye
- Skin
- Inhalation
Systemic:
- Enteral (Sublingual, oral, rectal)
- Parenteral (Subcutaneous, intramuscular, intravenous, transdermal, inhalation)
What is bioavailability?
The proportion of the done given by any route other than intravenously that reaches the systemic circulation in an unchanged form
How is bioavailability expressed?
Can be expressed as an amount or rate
Amount:
- Depends on G.I. absorption and first pass metabolism
- Measured by area under the curve of a blood drug level vs time plot
Rate:
- Depends on pharmaceutical factors and rate of gut absorption
- Measured by peak height and rate of rise of a drug level in blood
Define therapeutic ratio
Define LD50 and ED50
Maximum tolerated dose divided by minimum effective dose
Expressed as LD50/ED50
LD50:
- Lethal dose to 50% of people
ED50:
- Effective dose to 50% of people
Describe the 1st pass effect
Substances absorbed from the lumen of the ileum enter venous blood
This drains into the portal vein and is transported directly to the liver
Liver is the main site of drug metabolism, containing all the necessary enzyme systems
Any drug absorbed from the ileum may therefore be subject to extensive metabolism before reaching the systemic circulation
How can the First pass effect be avoided?
Give an example of a drug extensively metabolised during first pass metabolism
Parenteral, sublingual and rectal routes avoid it
Oral paracetamol, 90% on first pass
Define volume of distribution
How is it calculated?
The theoretical volume into which a drug has distributed assuming that this has occurred instantaneously
Amount given divided by plasma [drug] at time 0
Describe how drugs are affected by protein binding in the blood
Many drugs bind to plasma proteins and protein binding interactions could occur
Only the drug free in plasma exerts effect
They are therefore important if:
- Drug is highly bound to albumin (>90%)
- Drug has a small volume of distribution
- Drug has a low therapeutic index
What are protein binding interactions?
How are they used therapeutically?
The interactions between different drugs binding to plasma proteins, determining the relative proportion of each drug that is bound to plasma proteins
An object drug is used at a dose that is lower than albumin binding sites
A precipitant drug is then used at a dose which is greater than the number of albumin binding sites
Adding the precipitant drug will temporarily lead to higher levels of the object drug free in plasma as the precipitant drug occupies albumin binding sites (there is therefore higher risk of toxicity)
Give examples of object drugs and their respective precipitants
Object = Warfarin Precipitants = Sulphonamides, aspirin, phenytoin
Object = Tolbutamide Precipitants = Sulphonamides, aspirin
Object = Phenytoin Precipitant = Valproate
What is meant by first order kinetics?
When do they apply?
Means metabolism of a drug is proportional to drug concentration
Applies when:
- Drug is being metabolised by an enzyme that obeys Michaelis-Menten kinetics
- The drug is used at a lower concentration than Km
Describe how [drug] appears when plotted against time in a graph
Assume first order kinetics of drug metabolism
Gives a straight line when plotted on a log scale against time
Half life can be found because the rate of metabolism is proportional to [drug]
What is meant by zero order kinetics?
When do they apply?
Rate of decline of plasma [drug] is constant regardless of concentration as enzyme is saturated
Applies when:
- Drug is being metabolised by an enzyme that obeys Michaelis-Menten kinetics
- The [drug] is much greater than Km
Describe how [drug] appears when plotted against time
Assume zero order kinetics of drug metabolism
[Drug] gives a straight line when plotted against time on a linear (not log) scale
What needs to be done when administering a drug with zero order kinetics that need to be effective quickly?
Why does this need to be done?
A steady state of desired [drug] is not reached in the system until 5 half lives of the drug has passed since starting administration or changing the dose
This effect is counteracted by making the initial dose (loading dose) significantly larger than subsequent maintenance doses
Compare the pattern of therapeutic response for drugs with first order and zero order kinetics
Which of the two types are the most common for drugs to have?
First order kinetics give predictable therapeutic response from dose increases (They are also the most common)
Zero order kinetics give therapeutic responses that can suddenly escalate as elimination mechanisms are saturated
Give the full Michalis-Menten equation
Rate of metabolism
=
Vmax x [drug]
Divided by
Km + [drug]
Give the Michaelis-Menten equation
However, in this case assume that [drug] is lower than Km
What order kinetics does this correspond to?
Rate of metabolism =
Vmax x [drug]
divided by
Km
This corresponds to first order kinetics
Give the Michaelis-Menten equation
However, in this case assume that [drug] is much greater than Km
What order kinetics does this correspond to?
Rate of metabolism =
Vmax x [drug]
Divided by
[drug]
This corresponds to zero order metabolism
What are the two stages of drug elimination?
Metabolism
Excretion
Describe phase 1 of liver metabolism
Semester 1 - Metabolism
Most drug molecules are stable and unreactive (prodrug)
Phase 1 exposes or adds a reactive group to the parent molecule
Generates a reactive intermediate
Most common chemical reactions to accomplish this are:
- Oxidation
- Reduction
- Hydrolysis
Requires complex enzyme system (cytochrome P450) and a high energy cofactor (NADPH)
Enzymes are inducible and inhibitable
Some drugs alredy have a reactive group and can bypass phase 1 (E.g. morphine, paracetamol)
Describe phase 2 of liver metabolism
Reactive intermediate from phase 1 is conjugated with a polar molecule to form a water soluble complex (conjugation)
Conjugates include:
- Glucoronic acid (most common)
- Sulphate ions
- glutathione
Phase 2 requires specific enzymes and a high energy cofactor, uridine diphosphate glucoronic acid (UDPGA)
Give some examples of phase 1 drug inhibitors and inducers and the drugs affected
Phenobaritone induces:
- Warfarin
- Phenytoin
Rifampicin induces:
- Oral contraceptives
Cigarettes induce:
- Theophylline
Cimetidine inhibits:
- Warfarin
- Diazepam
Drug interactions with warfarin are important, give some potentiators of warfarin and their mechanism of potentiation
Alcohol:
- Inhibits warfarin metabolism
Aspirin, sulphonamides, phenytoin:
- Displacement from plasma proteins
- Aspirin also reduces plateelt function
Broad spec antibiotics:
- Reduced Vit K synthesis by gut bacteria
Drug interactions with warfarin are important, give some inhibitors of warfarin and their mechanism of inhibition
Barbituates, rifampicin
- Induces liver metabolism enzymes for warfarin
In what 3 circumstances are drug interactions likely to matter clinically?
Drugs with low therapeutic ratio
Drug is being used a minimum concentration
Drug metabolism follows zero order kinetics
What are the 3 major factors affecting renal excretion of drugs?
Only the unbound free in plasma drug molecules are filtered through the glomerular tuft
Drugs can be actively secreted by the tubule (E.g. penicillin by the PCT)
Urine pH can determine how much of the drug is excreted
How does urine pH influence renal drug excretion?
For a weakly acidic drug:
- Making the urine alkaline will make the drug ionised
- There is therefore less tubular absorption as charged drugs stay in the lumen
For a drug that is a weak base:
- Acidic urine will ionise the drug
- Charged drug stays in the lumen
How is the kidney’s response to drugs altered by renal disease?
If drug is excreted by the kidneys it will have a longer half live if renal disease is present, therefore a lower maintenance dose is required
Longer half lives also mean longer time to reach steady state (5 half lives)
Loading dose is unchanged unless volume of distribution changes
Protein binding of drugs is altered
