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Flashcards in M&R S9 - Pharmacokinetics Deck (31):

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

- Eye
- Skin
- Inhalation

- 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

- Depends on G.I. absorption and first pass metabolism
- Measured by area under the curve of a blood drug level vs time plot

- 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

- Lethal dose to 50% of people

- 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


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


This corresponds to zero order metabolism


What are the two stages of drug elimination?



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

- 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