Pharm Tutorial 5 - Variability

Question 1

How does clarithromycin affect warfarin?

Answer 1

• Increases bioavailability due to inhibition of the CYP450 enzyme involved in warfarin metabolism, which reduces function of the enzyme and therefore reduces metabolism of warfarin
• Warfarin has a narrow therapeutic window, so this causes excess bleeding

Question 2

List other drugs that increase the action of warfarin

Answer 2

• Macrolide antibiotics (including clarithromycin)
• Quinolones
• Some antifungal drugs
• Proton pump inhibitors
• Anti-HIV drugs

Question 3

What is INR?

Answer 3

• International normalised ration to look at the ability of blood to clot. Low value means increased clotting, while high value results in reduced value
• (Prothrombin time/control)^ISI
• ISI is international sensitivity index, must be provided as different companies use slightly different forms of thrombin which may have different effects
• Below 2.0 increased thrombus risk, above 4.0 seriously increased bleeding risk

Question 4

How does St Johns Wort affect warfarin?

Answer 4

• St Johns Wort increases warfarin metabolism by upregulating CYP450
• Involves the active ingredient hyparcin

Question 5

List other drugs that decrease warfarin function

Answer 5

• St Johns Wort
• Rifampicin (antibiotic)
• Anti-epileptic drugs
• Griseofulin (anti-fungal)

Question 6

What must be measured before altering dose of digoxin in patients with AF?

Answer 6

• Potassium
• Hypokalaemia will result in reduce competition of potassium with digoxin for the sodium/potassium ATPase, which therefore means digoxin will be more active and could cause heart block
• Hyperkalaemia may be a sign of renal failure. In renal failure, less digoxin will be excreted and therefore there is risk of heart block

Question 7

Why does benzodiazepine have stronger effects in older patients?

Answer 7

• Older patients are more sensitive to CNS active drugs
• Decreased metabolism and plasma proteins in older patients means increased bioavailability
• However, temazepam is metabolised by phase II metabolism and unaffected by ageing
• Can cause confusion in high doses

Question 8

How does malnutrition affect drug bioavailability?

Answer 8

• Metabolism of many drugs is reduced by malnutrition
• Similar effect to giving a drug that inhibits the cytochrome pathway
• Also decreases plasma proteins, metabolism and GFR affecting distribution and excretion

Question 9

Why might absolute differences in the dose administered occur?

Answer 9

Deliberate or accidental

• Error in prescription or dispensing
• Patient non-compliance
• Drug formulation

Question 10

List reasons for relative overdose or underdose

Answer 10

• Environmental exposure to chemicals, including other drugs (enzyme induction or enzyme inhibition)
• Food intact (foods delay gastric emptying and alter gastric pH)
• Fluid intake (most rugs better absorbed if taken with water, as they may dissolve better and may stimulate gastric emptying)
• Age (newborn infants have more body water, poorer renal function, immature BBB and lower capacity for drug metabolism; elderly have decrease in everything)
• Disease (general nutritional status, GI disorders, heart failure, kidney failure and liver failure)

Question 11

How does old age affect drug effect?

Answer 11

Absorption

• Decreased absorptive surface of small intestine
• Altered gastric and gut motility
• Increased rate of gastric emptying

Drug distribution:

• Reduced lean body mass and body water, relative increase in fat
• Lipid soluble drugs have increased volume of distribution (stored in fat) and decreased blood levels
• Water soluble drugs have decreased volume of distribution and increased blood levels
• Reduced plasma albumin, so fewer plasma protein binding sites

Metabolism

• Splanchnic and hepatic blood flow decrease by 0.3 – 1.5%/year
• Liver size and hepatocyte number decrease
• Hepatic enzyme activity and induction capacity decrease

Excretion

• Changes in renal function are probably the most important factors affecting drug handling in the elderly. With age there is a steady decline in the following factors…
• Reduced renal mass
• Reduced renal perfusion
• Reduced glomerular filtration rate
• Reduced tubular excretion

The elderly are more sensitive to CNS drugs

Question 12

How does nutritional status affect drug variation?

Answer 12

• Unbalanced diets may lead to deficiency states and enzyme abnormalities
• Starvation causes decreased plasma protein binding and metabolism
• Obesity causes increased lipid fraction

Question 13

How do GI disorders affect drug variation?

Answer 13

• Alter drug absorption
• Eg. achlorhydria (lack of bicarbonate ions), coeliac disease, Chron’s disease (ulcers can increase drug absorption as they have lack of epithelial cells, though also a decreased pH which intereferes with absorption)

Question 14

How does congestive heart failure affect drug variation?

Answer 14

• Reduced splachnic blood flow
• Intestinal mucosal oedema
• Reduced hepatic clearance
• Build up of drug in oedema areas if water soluble

Question 15

How does kidney failure affect drug variation?

Answer 15

• Reduced metabolism
• Reduced first pass metbaolism
• Increased biliary secretion and hence decreased removal
• Decreased albumin synthesis and hence reduced plasma protein binding

Question 16

Why might the dose a patient takes of a drug differ to the dose prescribed?

Answer 16

Mistake in prescription by doctor

• Mistake in dispensing prescription by pharmacist
• Misunderstanding of dosing instructions by patient ( e.g believing that taking 3 pills all at once, the same as taking one pill three times a day)
• Non-compliance by patient (e.g. because of fears of side effects [esp with glucococorticoids], as a result of confused or depressed mental state)
• Also, patient may take correct dose, but it may not be absorbed due to interaction with food in stomach e.g. bisphosphonates (used to stabilise/build bone in patients with osteoporosis) which are chelated by calcium, magnesium and iron, so are not absorbed if taken with food or milky drinks.

Question 17

Why is aspirin taken with food?

Answer 17

• Risk of stomach ulcers

- It is ionised

Question 18

What is volume of distribution?

Answer 18

• Theoretical concept
• The distribution of drugs in lipid stores
• Eg. Increased drug distributed in fat (lipid soluble) results in decreased drug in the blood. This causes increased volume of distribution
• Ratio of dose present in the body and its plasma concentration when at equilibrium