Chapter 8 - Individual Variation In Drug Responses
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CHAPTER 8 INDIVIDUAL VARIATION I.
IN
DRUG RESPONSES
Body Weight and Composition
- the absence of adjustments in dosage, body size can be a significant determinant of drug effects - response to a drug is determined in large part by the concentration of the drug at its sites of action - the higher the concentration, the more intense the response - when adjusting dosage to account for body weight, the clinician may base the adjustment on body surface area rather than on weight per se - surface area determinations account not only for the patient’s weight but also for how fat or lean the patient may be - dosage adjustments based on body surface area provide a more precise means of controlling drug responses than do adjustments based on weight alone II.
Age
- infants and elderly are especially sensitive to drugs - the very young have heightened drug sensitivity as a result of organ immaturity - the elderly have a heightened drug sensitivity due to organ degeneration - the elderly also have an increased severity of illness, the presence of multiple pathologies, and treatment with multiple drugs III.
Gender
- for most drugs, we don’t know much about gender-related differences because, until recently, essentially all drug research was done in men - clinicians must keep in mind that the information currently available may fail to accurately predict responses in female patients IV.
Pathophysiology
- abnormal physiology (someone that is sick) can alter responses to drugs A.
KIDNEY DISEASE - can reduce drug excretion, causing drugs to accumulate in the body, possibly to toxic levels B.
LIVER DISEASE - can cause drugs to accumulate - if the liver ceases to function, rates of metabolism will fall and drug levels will climb
- applies only to those drugs that are eliminated primarily by the liver - liver dysfunction will not affect plasma levels of drugs that are eliminated largely by nonhepatic mechanisms V.
Tolerance
- decreased responsiveness to a drug as a result of repeated drug administration A.
PHARMACODYNAMIC TOLERANCE - refers to the familiar type of tolerance associated with long-term administration of drugs such as morphine and heroin - requires increased drug levels to produce effects that could formerly be elicited at lower drug levels - MEC of a drug is abnormally high - thought to result from adaptive processes that occur in response to chronic receptor occupation B.
METABOLIC TOLERANCE - tolerance resulting from accelerated drug metabolism - brought about by the ability of certain drugs (e.g., barbiturates) to induce synthesis of hepatic drugmetabolizing enzymes, thereby causing rates of drug metabolism to increase - because of increased metabolism, dosage must be increased to maintain therapeutic drug levels C.
TACHYPHYLAXIS - form of tolerance that is a reduction in drug responsiveness brought on by repeated dosing over a short time - occurs quickly - not a common mechanism of drug tolerance - ex. Transdermal nitroglycerin – using a transdermal patch, effects are lost in less than 24 hours VI.
Placebo Effect
- patient’s beliefs affect the response to drugs - preparation that is devoid of intrinsic pharmacologic activity - any response that a patient may have to a placebo is based solely on his/her psychologic reaction to the idea of taking a medication and not any direct physiologic or biochemical action of the placebo itself - primary use of the placebo is as a control preparation during clinical trials - fostering a positive attitude may help promote beneficial effects
- also important, is that members of the team be consistent with one another
VII. VARIABILITY
IN
ABSORPTION
- both the rate and extent of the drug absorption can vary - both the timing and intensity of responses can be changed - differences in manufacturing are a major cause of variability in drug absorption - other causes include the presence or absence of food, diarrhea or constipation, and differences in gastric emptying time A.
BIOAVAILABILITY - ability of a drug to reach the systemic circulation from its site of administration - such factors as tablet disintegration time, enteric coatings, and sustained-release formulations can alter bioavailability, and can thereby make drug responses variable - occur primarily with oral preparations and not with parenteral preparations - differences in bioavailability are of greatest concern for drugs with a narrow therapeutic range - narrow range calls -- a relatively small change in the drug level can produce a significant change in response - a small decline in drug level may cause therapeutic failure, whereas a small increase in drug level may cause toxicity VIII.
Failure to Take Medicine as Prescribed
- medications are not always administered as prescribed: dosage size and timing may be altered doses may be omitted or extra doses may be taken - common explanation for variability in the response to a prescribed dose is failure to take medications as prescribed Factors affecting this failure: - patient compliance (adherence) – cooperative and accurate participation in one’s own therapy - manual dexterity, visual acuity, intellectual capacity, psychological state, attitude toward drugs, ability to pay for medication, and appropriate diet all apply
IN
DRUG RESPONSES
Body Weight and Composition
- the absence of adjustments in dosage, body size can be a significant determinant of drug effects - response to a drug is determined in large part by the concentration of the drug at its sites of action - the higher the concentration, the more intense the response - when adjusting dosage to account for body weight, the clinician may base the adjustment on body surface area rather than on weight per se - surface area determinations account not only for the patient’s weight but also for how fat or lean the patient may be - dosage adjustments based on body surface area provide a more precise means of controlling drug responses than do adjustments based on weight alone II.
Age
- infants and elderly are especially sensitive to drugs - the very young have heightened drug sensitivity as a result of organ immaturity - the elderly have a heightened drug sensitivity due to organ degeneration - the elderly also have an increased severity of illness, the presence of multiple pathologies, and treatment with multiple drugs III.
Gender
- for most drugs, we don’t know much about gender-related differences because, until recently, essentially all drug research was done in men - clinicians must keep in mind that the information currently available may fail to accurately predict responses in female patients IV.
Pathophysiology
- abnormal physiology (someone that is sick) can alter responses to drugs A.
KIDNEY DISEASE - can reduce drug excretion, causing drugs to accumulate in the body, possibly to toxic levels B.
LIVER DISEASE - can cause drugs to accumulate - if the liver ceases to function, rates of metabolism will fall and drug levels will climb
- applies only to those drugs that are eliminated primarily by the liver - liver dysfunction will not affect plasma levels of drugs that are eliminated largely by nonhepatic mechanisms V.
Tolerance
- decreased responsiveness to a drug as a result of repeated drug administration A.
PHARMACODYNAMIC TOLERANCE - refers to the familiar type of tolerance associated with long-term administration of drugs such as morphine and heroin - requires increased drug levels to produce effects that could formerly be elicited at lower drug levels - MEC of a drug is abnormally high - thought to result from adaptive processes that occur in response to chronic receptor occupation B.
METABOLIC TOLERANCE - tolerance resulting from accelerated drug metabolism - brought about by the ability of certain drugs (e.g., barbiturates) to induce synthesis of hepatic drugmetabolizing enzymes, thereby causing rates of drug metabolism to increase - because of increased metabolism, dosage must be increased to maintain therapeutic drug levels C.
TACHYPHYLAXIS - form of tolerance that is a reduction in drug responsiveness brought on by repeated dosing over a short time - occurs quickly - not a common mechanism of drug tolerance - ex. Transdermal nitroglycerin – using a transdermal patch, effects are lost in less than 24 hours VI.
Placebo Effect
- patient’s beliefs affect the response to drugs - preparation that is devoid of intrinsic pharmacologic activity - any response that a patient may have to a placebo is based solely on his/her psychologic reaction to the idea of taking a medication and not any direct physiologic or biochemical action of the placebo itself - primary use of the placebo is as a control preparation during clinical trials - fostering a positive attitude may help promote beneficial effects
- also important, is that members of the team be consistent with one another
VII. VARIABILITY
IN
ABSORPTION
- both the rate and extent of the drug absorption can vary - both the timing and intensity of responses can be changed - differences in manufacturing are a major cause of variability in drug absorption - other causes include the presence or absence of food, diarrhea or constipation, and differences in gastric emptying time A.
BIOAVAILABILITY - ability of a drug to reach the systemic circulation from its site of administration - such factors as tablet disintegration time, enteric coatings, and sustained-release formulations can alter bioavailability, and can thereby make drug responses variable - occur primarily with oral preparations and not with parenteral preparations - differences in bioavailability are of greatest concern for drugs with a narrow therapeutic range - narrow range calls -- a relatively small change in the drug level can produce a significant change in response - a small decline in drug level may cause therapeutic failure, whereas a small increase in drug level may cause toxicity VIII.
Failure to Take Medicine as Prescribed
- medications are not always administered as prescribed: dosage size and timing may be altered doses may be omitted or extra doses may be taken - common explanation for variability in the response to a prescribed dose is failure to take medications as prescribed Factors affecting this failure: - patient compliance (adherence) – cooperative and accurate participation in one’s own therapy - manual dexterity, visual acuity, intellectual capacity, psychological state, attitude toward drugs, ability to pay for medication, and appropriate diet all apply
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