Pharmokinetics 2 Flashcards
Define pharmokinetics
What the body does to a drug
What are the possible fomulations of drugs?
Solid (tablet)
Liquid
What does the rate of action of a tablet depend on?
Dissolution
What is important to consider with formulation of drugs?
Patient compliance is important, and a once daily dose is easier
What are the possible sites of administration?
Local
Systemic
Give 3 examples of local sites of administration
Eye
Skin
Inhalation
What are the types of systemic adminisration?
Enteral
Parenteral
Give 3 examples of enteral sites of administration?
Sublingual
Oral
Rectal
Give 5 examples of parenteral sites of administration
Subcutaneous injection Intramuscular injection Intravenous injection Inhalation Transdermal
What is oral bioavailability?
The proportion of a dose given orally (or by any other route other that intravenous) that reaches the systemic circulation in an unchanged form
What can bioavailability be expressed as?
Amount or rate
How is amount of bioavailability measured?
Area under curve of blood level vs time
How is rate of bioavailability measured?
By peak height and rate of rise of drug level in blood
How is bioavailability calculated?
(Area under curve oral / area under curve injected) * 100
What is the therapeutic ratio?
Maximum tolerated dose (LD50) / minimum effective dose (ED50)
What is the maximum tolerated dose?
The lethal dose to 50% of people
What is the minimum effective dose?
The effective dose in 50% of people
What happens to substances absorbed from the lumen of the ileum?
They enter the venous blood
Where happens to venous blood from the ileum drain?
It drains the hepatic portal vein, and is transported directly to the liver
What is the problem with drug absorbed from the ileum?
May give the first pass effect
What is the first pass effect?
The liver in the main site of drug metabolism, as it contains all of the necessary enzyme systems, so any drug absorbed from the ileum may be extensively metabolised during the first pass through the liver
How can the first pass effect be avoided?
Parenteral, sublingual or rectal routes
How much of an oral dose of paracetamol is metabolised by the first pass effect?
90%
What is drug distribution?
The theoretical volume into which a drug has distributed, assuming that this is occurring instantaneously
How is drug distribution calculated?
Amount given / plasma concentration at time 0
What do many drugs bind to?
Plasma protein
What of the drug exerts an effect?
The free level of drug (not the total)
Can protein binding actions occur?
Yes
When is drug binding to plasma proteins important?
If 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 plasma protein binding is important
Warfarin
Tolbutamine
At what dose is an object drug (class I drug) used?
One that is much lower than the number of albumin binding sites
At what dose is a precipitant drug (class II drug) used?
One that is greater than the number of available binding sites
What happens when class I and II drugs are administered simultaneously?
Class I drugs are displaced by class II, raising the free levels of the object drug
What is the result of class II raising the free levels of the object drug?
High risk of toxicity
What are the precipitant drugs for warfarin?
Sulphanoamides
Aspirin
Phenytoin
What are the precipitant drugs for tolbutamide?
Suphonamindes
Aspirin
What is the precipitant drug for phenytoin?
Valproate
What is the rate of metabolism if drugs are metabolised by enzymes that obey Michaelis-Menten kinetics?
(Vmax [C]) / (Km + [C])
What is the rate of metabolism in a situation where a drug is used at a concentration that is lower than Km?
Vmax [C] / Km
What kind of kinetics are being displayed when a drug is used at a concentration that is lower than Km?
First order
What is happening in first order kinetics?
Metabolism is proportional to drug concentration
What does first order kinetics give when a log scale is on the Y-axis versus time?
A straight line
Can half life be defined with first order kinetics?
Yes
Why can half life be defined with first order kinetics?
Because the rate of decline of plasma drug level is proportional to drug level
What is the rate of metabolism in a situation where the drug is used at a concentration much greater than Km?
Vmax [C] / [C]
What kind of kinetics are being displayed when a drug is used at a concentration much greater than Km?
Zero order
Why are zero order kinetics displayed when the drug is used at a concentration much greater than Km?
Because the enzyme is saturated, and so the rate of decline of plasma drug level in constant, regardless of concentration
What does zero order kinetics give when plasma concentration is plotted against time?
A straight line
When will a steady state be reached during drug administration?
Within 5 half-lives of that drug
What is required if an immediate effect of drug is necessary?
A loading dose
What does first order kinetics give from dose increases?
A predictable therapeutic response
What kind of response does zero order kinetic give?
A therapeutic response that can suddenly escalate as elimination mechanisms saturate
How do most drugs behave?
With first order kinetics
Give an example of a drug that displays zero order kinetics?
Alcohol
What is the loading dose often determined by?
The volume of distribution
What is true of most drug molecules?
They are stable and relatively unreactive
What is a drug that is stable and relatively unreactive termed?
A pro-drug
What happens in phase I of drug metabolism of the liver
A reactive group is exposed on the parent molecule, or added to the molecule
What does phase I of drug metabolism generate?
A reactive intermediate that can be conjugated with a water-soluble molecule to form a water-soluble complex
When is the reactive drug intermediate conjugated with a water-soluble molecule?
Phase II
What are the most common chemical reactions in phase I of pro-drug metabolism by the liver?
Oxidation
Reduction
Hydrolysis
What does the phase I process require?
A complex enzyme system called the cytochrome P450 (CYP) system, and a high energy cofactor (NADPH)
What is true of the enzymes in phase I of drug metabolism in the liver?
They are inducible and inhibitable
Give 3 examples of enzyme inducers involved in drug metabolism in the liver?
Phenobarbitone
Rifampicin
Cigarettes
What drugs does phenobarbitone affect?
Warfarin
Phenytoin
What drug does rifampicin affect?
Oral contraceptive
What drug does cigarettes affect?
Theophylline
Give an example of an enzyme inhibitor involved in drug metabolism in the liver?
Cimetidine
What drugs does cimetidine affect?
Warfarin
Diazepam
Why can some drugs bypass phase I?
They already have a reactive group on their molecule
Give an example of a drug that can bypass phase I?
Morphine
What happens in phase II of drug metabolism?
The reactive intermediate from phase I is conjugated with a polar molecule to form a water soluble-complex, in a process known as conjugation
What is the most common phase II conjugate?
Glucoronic acid
Why is glucoronic acid the most common phase II conjugate?
It’s an available byproduct of cell metabolism
Other than glucoronic acid, what can drugs be conjugated with?
Sulphate ions
Glutathione
What does phase II drug metabolism require?
Specific enzymes and a high energy cofactor, uridine diphosphate glucuronic acid (UDPGA)
What is filtered through the glomerular tuft?
Only the free unbound drug
What can actively secrete drugs?
The kidney tubule
Give an example of a drug that can be actively secreted by a the tubule?
Penicillin
What can determine how much of the drug is excreted?
Urine pH
What affect will making the urine alkaline have on weakly acidic drugs?
It will make the drug ionised, so there will be less tubular absorption, because the charged drug stay in the tubular lumen, and so increased excretion
Give an example of a weakly acidic drug?
Aspirin
How can the pH manipulation of urine be clinically useful?
Forced alkaline diuresis in aspirin overdose
What affect will acidic urine have on weakly basic drugs?
It will increase secretion
Why will acidic urine increase secretion of weakly basic drugs?
Because it will ionise a weak base, making the charged drug stay in the tubule lumen
Give an example of a weakly basic drug?
Amphetamine
