Pharmacokinetics

Question 1

What is pharmacodynamics?

Answer 1

What the drug does to the body.

Time course for the drug effect.

PD is important in determining the change in drug effect due to PK changes.

Question 2

What is clinical pharmacokinetics?

Answer 2

Clinical pharmacokinetics is the application of pharmacokinetic and pharmacodynamic principles to the safe and effective therapeutic management of an individual person.

Question 3

What is the one compartmental model?

Answer 3

Assumes drug distributes instantaneously throughout the body & equilibrates instantaneously between tissues.

Question 4

What is the two compartmental model?

Answer 4

Assumes drug does not achieve instantaneous distribution, i.e. equilibrium, between compartments.

Slower drug distribution.

Question 5

What is first order drug elimination?

Answer 5

Amount of drug eliminated in a set amount of time is directly proportional to amount of drug in the body.

Fraction of drug eliminated per unit time is constant.

Change in drug dose – proportional change in the drug concentration-time profile in the body.

More predictable changes in plasma concentration during dosage adjustment.

Question 6

What is zero order drug elimination?

Answer 6

Amount of drug eliminated does not change with amount of drug in the body.

Change in dose – disproportional change in the drug concentration-time profile in the body.

More unpredictable.

Narrow therapeutic window, higher end of dosage range.

Question 7

What is the volume of distribution?

Answer 7

Volume of fluid in which total amount of drug needs to be distributed to give a concentration equal to the measured plasma concentration.

Relates to:

Partitioning of drug between plasma and tissues.
Lipid vs water solubility.
Extent of drug plasma protein binding.

Used to calculate loading dose.

Question 8

What factors affect volume of distribution?

Answer 8

Liver, renal, cardiac impairment.
Reduced blood perfusion to tissues.
Changes in plasma protein binding.
Odema, ascites.
Old age.
Pregnancy.

Question 9

What are the main routes of drug elimination:

Answer 9

Excreted unchanged (kidneys) and metabolism (usually liver).

Question 10

Define clearance:

Answer 10

Clearance is the volume of plasma emptied of drug per unit time Lh-1

Clearance alters:

Drug-drug interactions.
Cardiac output.
Hepatic and renal impairment.
Plasma protein binding.

At steady state: rate in = rate out
Rate administration = rate elimination

Decrease in clearance means slower rate of elimination.

Leading to dosage adjustment.

Thus clearance determines the maintenance
dose.

Question 11

What is the Elimination Rate Constant (K)

Answer 11

K is fraction of drug eliminated from compartment per unit time (h-1).

1st order elimination.

Amount drug eliminated decreases as plasma conc. decreases but the fraction of drug eliminated is constant.

K determines the rate of elimination.

Elimination rate = K x A (A = total amount drug in body).

Units of elimination rate: mgh-1.

Question 12

What is half-life?

Answer 12

Time taken for plasma drug conc to fall by half what it was at beginning of measurement period .

Question 13

When is TDM important?

Answer 13

Drug has a narrow therapeutic window.

Good concentration-response relationship.

No easily measurable physiological parameters.

To monitor compliance.

To confirm toxicity.

Question 14

What are some criteria for TDM?

Answer 14

Narrow therapeutic window.

Pharmacokinetic variability.

Genetic factors, concurrent disease, multiple drug therapy.

Non-compliance, poor bioavailability.

Unusually rapid elimination.

Pharmacodynamic resistance to the drug.

Question 15

Why do you need to optimize drug dosing regimen?

Answer 15

Suitable doses at a frequency which ensures maintenance of steady state plasma conc. within the therapeutic window, for entire duration of therapy.

Question 16

How do you individualise the dosing regime

Answer 16

Inter-subject variability - same dose of drug may produce large differences in pharmacologic response in different individuals.

Pharmacokinetic variability - due to difference in drug concentration at the site of action because of individual differences in drug absorption, distribution, metabolism and excretion (ADME).
Major causes are genetics, disease, age, body weight & drug-drug interactions.

Pharmacodynamic Variability - due to differences in effect produced by a given drug concentration.

Optimizing dosage regime - increased pharmacological efficacy, reduced side effects and toxicity & better compliance.

Question 17

How does drug dosing work in obese patients?

Answer 17

Particularly important with medications with narrow therapeutic index.

Clearance is correlated to lean body weight as adipose tissue has little metabolic activity – CL determines maintenance dose which may need adjusting.

Volume of distribution is important for determining the loading dose.

eg. Gentamicin distributes poorly into adipose tissue (Vd is small). Patients who are obese should receive a relatively lower dose of gentamicin.
eg. prophylactic dose of enoxaparin is increased in morbid obesity, as clearance increases with body size and correlates with lean body weight.

Adjusted body weight - mainly used to calculate doses for aminoglycoside antibiotics. It was developed to account for adipose tissue, which does not affect drug clearance.

Lean body weight contributes to approximately 99% of a drug’s clearance,it is useful for guiding dosing in obesity.

Body surface area - traditionally used to calculate dose of chemotherapy agents. Controversial in patients at extremes of size because it does not account for varying body compositions.

Question 18

How does drug dosing work in children?

Answer 18

Age, weight, body surface area (BSA) need to be accurate to ensure appropriate dosing.

Absorption:

Increased percutaneous absorption in new born and young infants compared to adults – extreme care needed.
pH and volume of gastric acid determines absorption & bioavailability of many drugs.
Only by age 3yr is gastric acid pH the same as adults (2-3)

Distribution:

Affected by vascular perfusion, body composition, tissue binding characteristics and extent of plasma protein binding.
Greater proportion of body water & extracelluar fluid in the neonate compared to older children and adults.

Metabolism:

Hepatic blood flow is reduced in the neonate and liver enzyme systems mature at different rates in the pediatric population – variable half-life of some drugs eg thiopentone.

Excretion:

Renal efficiency in neonates is considerably reduced compared to the adult. Prolonged half life e.g. aminoglycoside or cephalosporin antibiotics.

Question 19

How does drug dosing work in the elderly?

Answer 19

Ageing results in physiological changes in the ADME of drugs.

Lean body mass and total body water decreases and body fat increases in elderly.

Vd of water soluble drugs (eg cimetidine, digoxin) may decrease and that of lipid soluble drugs like diazepam increases with age.

Plasma albumin decreases with age – free fraction of acidic drugs such as cimetidine, furosemide & warfarin will increase.

Renal function generally declines but marked variability – doses of renally excreted drugs should be individualised.

Drugs with a low therapeutic index, should be reduced eg digoxin, and aminoglycosides.

Impaired clearance of hepatically eliminated drugs has been demonstrated in the elderly

Question 20

How does drug dosing work in people with liver disease?

Answer 20

Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination.

Liver disease can result in reduced extraction of drugs normally highly cleared during 1st pass through liver resulting in increased systemic availability & increased side-effects, eg metoprolol, propranolol, morphine (dosage adjustment).

Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis.

Chronic liver disease can result in prolonged half-life & reduced clearance, eg diazepam, tolbutamide – dosage adjustment.

Question 21

How does drug dosing work in people with renal disease?

Answer 21

Drugs most affected are those that are wholly or largely renally excreted or have active or toxic metabolites which are renally excreted.

Clearance of the drug is decreased and the plasma half-life prolonged.

Dose or dose frequency will need to be adjusted.

Loading doses generally don’t need adjustment as accumulation unlikely to occur after single dose.

Nephrotoxic drugs should be avoided if possible.

Use TDM to adjust drug dosage wherever possible - monitor the patient for efficacy & toxicity of drugs (narrow therapeutic window drugs).

Question 22

How do you work out creatinine clearance?

Answer 22

Estimated Creatinine Clearance in mL/min

= (140 – Age) x Weight x Constant / Serum creatinine

Question 23

Give examples of drugs which require individualisation and optimisation of dosage regime by using TDM:

Answer 23

Gentamicin

Phenytoin

Digoxin

Question 24

Give information about Gentamicin:

Answer 24

Narrow therapeutic index.
Half-life is 2-3hrs
Elimination is by renal excretion.
Eliminated more slowly in renal impairment and requires reduced dosage.

Infants less than 7 days of age and elderly patients also require lower dosages.

Ototoxicity and nephrotoxicity are dose-related side-effects.

Serum-gentamicin concentration must be monitored in all patients and renal function monitored.

In patients with renal impairment, dosing interval may need to be increased according to the level
of renal impairment and the gentamicin level.

In obese patients, gentamicin dose should be calculated according to the corrected body weight.

For all other patients, actual body weight (ABW) should be used to calculate the dose.

Question 25

Give information about Phenytoin:

Answer 25

Phenytoin is poorly absorbed, highly plasma protein bound, and subject to zero-order elimination (capacity-limited metabolism).

Narrow therapeutic window (10-20 µg/mL).

Concentration-related CNS toxicity of phenytoin is generally observed at serum concentrations above 20 µg/ml.

As serum levels rise, so do the frequency and severity of side effects.

Children metabolize phenytoin more rapidly than do adults and may require larger mg/kg doses than adults in order to achieve therapeutic plasma concentrations.

The dosage of phenytoin may need to be increased during pregnancy because of the increased clearance of the drug during this period.

Question 26

Give information about Digoxin:

Answer 26

2-compartmental model, 1st order elimination.
Narrow therapeutic window: 0.8 – 2.0 ng/ml
Half-life in normal renal function: 36-48h. Vd = 7.3 L/kg in healthy young adults
Clearance mainly renal route (60-80%) with some hepatic clearance (20-40%).

Aging leads to changes in body composition which, combined with decreased renal function andreduced volume of distribution, increases half-life and the bioavailability of digoxin.

Renal impairment reduces digoxin clearance
Congestive heart failure reduces digoxin clearance
In all these situations digoxin clearance should ideally be estimated individually.

Question 27

When can monitoring Digoxin levels be helpful?

Answer 27

Poor compliance is suspected.

Response to treatment is poor.

Renal function is fluctuating.

Drugs that interact with digoxin are co-prescribed.

Confirmation of clinical toxicity is required.