Tutorial 7 - Variability in Human Responses to Drugs Flashcards
What are the reasons for differences in response to the same dose of a drug?
Absolute differences in dose administered –deliberate (patient non-compliance) or accidental (errors).
Relative overdose or under-dose.
- Environmental exposure to chemicals, including other drugs –enzyme induction/inhibition
- Food intake –grapefruit juice?
- Fluid intake –stimulate gastric emptying or better absorbed
- Age
- New-born
- More body water than adults
- Poorer renal function with immature tubular secretion
- Immature BBB
- Lower capacity for drug metabolism
- Elderly –may have overall deterioration
- Decreased drug absorption –villous atrophy of SI
- Drug distribution –reduced lean body/water mass with relative increase in fat
- Lipid soluble drugs –increased volume of distribution and decreased blood levels
- Water soluble –decreased Vd and increased blood levels
- Reduced albumin so fewer PPB sites
- Decreased drug metabolism –reduced liver size and blood flow to the organs
- Decreased drug excretion –kidneys deteriorate
- Organ sensitivity –more sensitive to CNS active drugs
- New-born
- Disease
- General nutritional status
- GI disorders –e.g. Crohn’s disease
- Congestive heart failure
- Kidney failure
- Liver failure
- Other acute/chronic disease states
Arthur Jones is a 72-year-old gentleman who has atrial fibrillation which could not be converted back to sinus rhythm. He has suffered a small stroke. It was decided to prescribe warfarin to prevent a recurrence. The dose is stabilised but he later develops a chest infection and is given clarithromycin for one week. This effectively treats the infection but he has a severe nosebleed and notices that he bruises very easily. Why? What other drugs might produce a similar effect?
The metabolism of warfarin, by the cytochrome P450 pathway, is inhibited by erythromycin leading to increased plasma levels of warfarin. Many other drugs may do this:
- other antibiotics of the same class (macrolides) eg clarithromycin
- some antibiotics of other classes such as quinolones like ciprofloxacin
- systemic antifungal drugs eg fluconazole, itraconazole
- proton pump inhibitors used for peptic ulcers eg omeprazole
- some anti-HIV drugs esp protease inhibitors
Several months later it is noticed in the anticoagulant clinic that the INR has fallen sharply and that he therefore needs a much higher dose of warfarin. He tells the doctor in the clinic that he has felt depressed, so he has been taking St John’s wort which he buys from a health food shop. What is INR, how is it measured and what does a fall in INR signify? Why might his self-medication with St John’s wort be relevant to the change in warfarin requirement? What else might do this?
The prothrombin time, or PT, test measures the time it takes for a blood sample to clot, but the results of the prothrombin time test may vary from lab to lab, because of differences between different batches and manufacturers. Therefore the International Normalised Ratio (INR) is used to standardise the results.
Each manufacturer gives an ISI (International Sensitivity Index) for any tissue factor they make. The ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 1.4.
The INR is the ratio of a patient’s prothrombin time to a normal (control) sample, raised to the power of the ISI value for the control sample used.
The normal range for INR is 0.9-1.2. When the INR falls below 2.0 thrombosis risk increases and when the INR rises above 4.0 serious bleeding risk increases. The recommended INR for patients with a history of atrial fibrillation is 2.0 – 3.0.
Sr John’s wort, widely used as a self-administered antidepressant, contains a compound (called hypericin) which is an inducer of the cytochrome system and therefore speeds up the clearance of warfarin. There are fewer enzyme inducers than inhibitors, or at least we think so because there are probably many in plants still to be recognized. Other drugs that have similar effects include:
rifampicin, used in TB therapy – short half life, therefore induction within 24h
carbamazepine and phenytoin, as well as the older and largely obsolete antiepileptic drugs phenobarbitone and primidone – t1/2 3-5days therefore induction after 1 week
the antifungal drug griseofulvin
Hypericin has weak monoamine oxidase activity. Another component of St John’s wort – hyperforin is believed to inhibit serotonin reuptake and therefore convey most of the anti-depressant activity.
The rate of Mr Jones’ atrial fibrillation had been controlled by a combination of digoxin and a beta-blocker (bisoprolol). At a regular check-up it is found that his ventricular rate has speeded up. One solution might be to increase the dosage of digoxin but, thinking carefully about its mechanism of action, what is the most important blood test that should be checked first and why? How else could you try to ensure that the dose of digoxin is correct?
Digoxin binds to the Na/K exchange ATPase on cardiac myocytes. ATPase generates the energy to pump Na+ out of the cell and potassium in. Therefore inhibition of ATPase results an increase in intracellular Na . This reduces the steepness of the sodium concentration gradient across the cell membrane. This in turn sloes down the Na-Ca-exchanger, so less calcium is removed from the cell. The extra Ca is stored in the sarcoplasmic reticulum and is then available for release following an the arrival of an action potential and this results in increased contractility.
Digoxin clearance is almost entirely dependent on renal function especially glomerular filtration rate. It is therefore very important to know if the patient has any renal impairment so that digoxin dose can be adjusted or, if renal function is very poor, the drug can be avoided altogether. It is also essential to know if plasma potassium levels are abnormally low, since hypokalaemia enhances most of the adverse effects of digoxin. Potassium levels should then be corrected (not necessary to discuss here how this should be done). It is possible to measure plasma levels of digoxin directly, since there is a recognised target range for these. It is important to emphasise that toxic effects of the drug, and others, do occur at therapeutic plasma levels.
Digoxin competes with K+ with binding site on ATPase enzyme. If K+ falls, digoxin has a greater effect due to less competition with this binding site. Therapeutic and toxic effects both increased. Commonly prescribed with diuretics which would cause a decrease in plasma K+. Cardiac side effects biggest problem e.g. heart block
Worth noting that the large AFFIRM trial (rate control vs. rhythm control) found that digoxin use was associated with a 42% increase in mortality!
Some months later Mr Jones again complains of anxiety and poor sleep at night. His GP prescribes a benzodiazepine, temazepam. The day after he has taken the first dose his wife rings the surgery to say he has been very confused overnight. She notes that this has never happened with her 45 year old daughter who takes the same pill. What might be the reason for this difference?
Two main reasons. The metabolism by the liver of some drugs, but not all, is reduced in older patients. Some drugs which are very similar can behave very differently: this is often unpredictable. In addition older patients may have increased sensitivity to drugs even in metabolism is normal. The basis of this is very poorly understood, and it is not known whether this is related to receptor number or function, or some other mechanism(s).
Temazepam is metabolized directly by phase II metabolism that seems relatively unaffected by aging. Temazepam less lipophilic than other BZPs, therefore levels in blood likely to be relatively higher (since older people generally have more body fat).
Digoxin has been suggested to have anti-cholinergic effects in older patients, particularly if patient is on multiple medications. Confusion might be one of the CNS outcomes of the anti-cholinergic effects.
The temazepam is withdrawn immediately, but Mr Jones medication is otherwise unchanged. The following year he becomes depressed and his appetite deteriorates. He loses nearly 10 kg in weight but (perhaps unsurprisingly) is reluctant to consider antidepressants. It is noticed that his INR has increased significantly, even though his warfarin treatment is unchanged. Why might this be happening?
Although this is somewhat controversial the general view is that the metabolism of many drugs is affected by malnutrition, such as seen here. The end results as far as warfarin is concerned is similar to giving a drug which inhibits the cytochrome pathway. Some experts believe that effect is negligible except in extreme cases.
Malnutrition – particularly protein maltnutrition has been shown to decrease plasma proteins (warfarin heavily plasma protein bound), decrease oxidative metabolism (warfarin is metabolised by oxidation) and decreased GFR.
