VARIABILITY IN DRUG RESPONSE
pharmacodynamic reasons
Variation in the response to equivalent drug concentrations arises because of various factors, such as differences in receptor number and structure, receptor-coupling mechanisms and physiological changes in target organs resulting from differences in genetics, age and health. For example, the beneficial natriuresis produced by the loop diuretic furosemide is often significantly reduced at a given dose in patients with renal impairment while confusion caused by opioid analgesics is more likely in the elderly.
pharmacogenetic reasons
Tolerance to the effect of opioids or other drugs simply means that the drug loses its effectiveness over time and an increased dose is required to produce the same physiological response. When a drug rapidly loses it responsiveness it is termed tachyphylaxis (”fast guarding”). Dependence refers to a complex and poorly understood set of changes in the homeostasis of an organism that causes a disturbance of the homeostatic set point of the organism if the drug is stopped. This disturbance often is revealed when administration of an opioid is stopped abruptly, resulting in withdrawal. Withdrawal is the pathological repsonse to the removal of a drug. An example is the agonist clonidine used to lower blood pressure by potentiating alpha-2 adrenoceptors. Administration of this medication leads to down regulation of these receptors and acute withdrawal may lead to a hypertensive crisis. Addiction is a behavioral pattern characterized by compulsive use of a drug and overwhelming involvement with its procurement and use. Tolerance and dependence are physiological responses seen in all patients and are not predictors of addiction. Four general mechanisms contribute to variability in responsiveness to drugs.
pharmacokinetic reasons :
Variation in the drug concentrations achieved by equivalent doses is a much more important cause of the inter-individual variation in drug response encountered in clinical practice. There are many reasons why the absorption, metabolism and excretion of drugs might vary.
---------------------------------------------------------------
also:
1. Alteration in the amount of drug that reached the receptor. This is usually due to changes in the total absorption of the drug and the rate that this occurs, the volume of distribution and the clearance of the drug (PHARMACOKINETIC FACTORS). This may sometimes be predicted in terms of age, race, weight, physiological or pathological state (especially lung function, renal and hepatic funtion) and specifc genetic factors which may be predicted with a careful history and genetic testing if indicated ( 2nd example).
2. Differences in the presence of endogenous and exogenous ligands This mechanism contributes signiffcantly to antagonist response. In patients with phaeochromocytoma (high endogenous ligand) propanolol will have a large effect, in marathon runners the response will be negligble (low catecholamines)
3. Variation in the number or function of receptors This may be due to both genetic and environmental factors, hormone responses (eg thyroid hormone up regulates beta adrenoceptors in the heart and response to catecholamines), or as a specifc response to drug therapy. In particular agonists may reduce the number of receptors (down regulation) or coupling e ciency (desensitisation). Antagonists may prevent endogenous down regulation of recpetors leading to a relative increase in receptors (PHARMACODYNAMIC FACTORS).
These mechanisms contribute to the concept of tolerance, tachphylaxis, dependence and importantly withdrawal (discussed below).
4. Changes in components of the response distal to the receptor Although a drug initiates a response by binding to receptors, the response is dependent on the functional integrity of the biological system and associated cellular and physiological responses.
Physiological and pathological states may lead to variability of response.
1. Absorption Effect site equilibrium Volume of Distribution Clearance 3. Receptor number and function
4. Downstream effects and response to receptor activation 2. Other endogenous and exogenous ligands A B Pharmacogenetics is the study of the molecular mechanisms that underlie the individual differences in drug metabolism, efficacy and side effiects. Important genes with respect to anaesthetics are RYR1 mutations which are associated with malignant hyperthermia syndrome and the gene that codes for butyrylcholinesterase, a precursor to pseudocholinesterase which hydrolyses suxmethonium.
Neonates:
An important generality is that pharmacokinetic variability is likely to be greatest at times of physiological change (e.g., the newborn or premature baby or at puberty) such that dosing adjustment, often aided by drug monitoring for drugs with narrow therapeutic indices, becomes critical for safe, effective therapeutics.
Most drug-metabolizing enzymes are expressed at low levels at birth, followed by an isozymespecifc postnatal induction. CYP2E1 and CYP2D6 appear in the first day, followed within 1 week by CYP3A4 and the CYP2C subfamily. CYP2A1 s not expressed until 1–3 months after birth.
Some glucuronidation pathways are decreased in the newborn, and an inability of newborns to glucuronidate chloramphenicol was responsible for the “gray baby syndrome”. Renal elimination of drugs also is reduced in the neonatal period. Neonates at term have markedly reduced GFR (2–4 mL/min/1.73 m2), and prematurity reduces renal function even further. As a result, neonatal dosing regimens for a number of drugs (e.g., aminoglycosides) must be reduced to avoid toxic drug accumulation. GFR (corrected for body surface area) increases progressively to adult levels by 8–12 months of age.
Elderly:
As adults age, gradual changes in pharmacokinetics and pharmacodynamics increase the interindividual variability of doses required for a given effect. Pharmacokinetic changes result from changes in body composition and the function of drug-eliminating organs. The reduction in lean body mass, serum albumin, and total-body water, coupled with the increase in percentage of body fat, alters drug distribution in a manner dependent on lipid solubility and protein binding. The clearance of many drugs is reduced in the elderly. Renal function variably declines to ~50% of that in young adults.
Hepatic blood ow and drug metabolism also are reduced in the elderly but vary considerably. In general, the activities of hepatic CYPs are reduced, but conjugation mechanisms are relatively preserved. Frequently, the elimination half-lives of drugs are increased as a consequence of larger apparent volumes of distribution of lipid-soluble drugs and/or reductions in the renal or metabolic clearance.
Alterations in renal function may lead to impairment of renally exceted drugs. Drug dosage should be adjusted according to the estimation of GFR. Patients with cirrhosis, hepatitis and other hepatic disease also have impairment of drug metabolising enzymes particularly microsomal oxidases, but unlike the kidneys there is no quantative basis for dose adjustment beyond plasma levels and clinical response. Cardiac disease may result in an reduction of blood ow to the liver, modifying clearance of ow dependent drugs. In patients with circulatory shock neuroendocrine response may drastically reduce renal and hepatic blood ow reducing the clearance of many drugs. Pulmonary disease may also affect drug metabolism as indicated by impaired hydrolysis or procanamide and procaine in patients with COPD. Finally disease states may lead to reductions in circulating protiens and in drugs with high protien binding this may lead to an increase in free drug and therefore potency. In this case measurement of free drug is more accurate that total drug. Christopher Andersen 2012
Therapeutic drug monitoring
Prescribers choose treatment regimens on the basis that the benefits that accrue will outweigh the adverse effects. However, that outcome is never certain for individual patients even if the best evidence suggests that it is likely. The uncertainty arises for many of the reasons outlined in previous sections (e.g. pharmacodynamics, pharmacolkinetics, pharmacogenetics). For this reason, whenever possible, prescribers should try to measure the effects of the drug, beneficial and harmful. This will help to inform decisions about dose titration (up or down) or discontinuation of treatment. Monitoring can be achieved in several different ways. It might be achieved subjectively be asking the patient about their symptoms. More objective approaches might be to measure the actual clinical effect. If this is not possible then alternatives are to measure a biomarker that acts as a surrogate for the clinical endpoint. Alternatively, if the pharmacodynamic effects of the drug are difficult to assess then it may be possible to measure the plasma drug concentration on the basis that it will be closely related to the effect of the drug.
reasons for the variebility
pharmacodynamic reasons
Variation in the response to equivalent drug concentrations arises because of various factors, such as differences in receptor number and structure, receptor-coupling mechanisms and physiological changes in target organs resulting from differences in genetics, age and health. For example, the beneficial natriuresis produced by the loop diuretic furosemide is often significantly reduced at a given dose in patients with renal impairment while confusion caused by opioid analgesics is more likely in the elderly.
pharmacogenetic reasons
Tolerance to the effect of opioids or other drugs simply means that the drug loses its effectiveness over time and an increased dose is required to produce the same physiological response. When a drug rapidly loses it responsiveness it is termed tachyphylaxis (”fast guarding”). Dependence refers to a complex and poorly understood set of changes in the homeostasis of an organism that causes a disturbance of the homeostatic set point of the organism if the drug is stopped. This disturbance often is revealed when administration of an opioid is stopped abruptly, resulting in withdrawal. Withdrawal is the pathological repsonse to the removal of a drug. An example is the agonist clonidine used to lower blood pressure by potentiating alpha-2 adrenoceptors. Administration of this medication leads to down regulation of these receptors and acute withdrawal may lead to a hypertensive crisis. Addiction is a behavioral pattern characterized by compulsive use of a drug and overwhelming involvement with its procurement and use. Tolerance and dependence are physiological responses seen in all patients and are not predictors of addiction. Four general mechanisms contribute to variability in responsiveness to drugs.
pharmacokinetic reasons :
Variation in the drug concentrations achieved by equivalent doses is a much more important cause of the inter-individual variation in drug response encountered in clinical practice. There are many reasons why the absorption, metabolism and excretion of drugs might vary.
---------------------------------------------------------------
also:
1. Alteration in the amount of drug that reached the receptor. This is usually due to changes in the total absorption of the drug and the rate that this occurs, the volume of distribution and the clearance of the drug (PHARMACOKINETIC FACTORS). This may sometimes be predicted in terms of age, race, weight, physiological or pathological state (especially lung function, renal and hepatic funtion) and specifc genetic factors which may be predicted with a careful history and genetic testing if indicated ( 2nd example).
2. Differences in the presence of endogenous and exogenous ligands This mechanism contributes signiffcantly to antagonist response. In patients with phaeochromocytoma (high endogenous ligand) propanolol will have a large effect, in marathon runners the response will be negligble (low catecholamines)
3. Variation in the number or function of receptors This may be due to both genetic and environmental factors, hormone responses (eg thyroid hormone up regulates beta adrenoceptors in the heart and response to catecholamines), or as a specifc response to drug therapy. In particular agonists may reduce the number of receptors (down regulation) or coupling e ciency (desensitisation). Antagonists may prevent endogenous down regulation of recpetors leading to a relative increase in receptors (PHARMACODYNAMIC FACTORS).
These mechanisms contribute to the concept of tolerance, tachphylaxis, dependence and importantly withdrawal (discussed below).
4. Changes in components of the response distal to the receptor Although a drug initiates a response by binding to receptors, the response is dependent on the functional integrity of the biological system and associated cellular and physiological responses.
Physiological and pathological states may lead to variability of response.
1. Absorption Effect site equilibrium Volume of Distribution Clearance 3. Receptor number and function
4. Downstream effects and response to receptor activation 2. Other endogenous and exogenous ligands A B Pharmacogenetics is the study of the molecular mechanisms that underlie the individual differences in drug metabolism, efficacy and side effiects. Important genes with respect to anaesthetics are RYR1 mutations which are associated with malignant hyperthermia syndrome and the gene that codes for butyrylcholinesterase, a precursor to pseudocholinesterase which hydrolyses suxmethonium.
Neonates:
An important generality is that pharmacokinetic variability is likely to be greatest at times of physiological change (e.g., the newborn or premature baby or at puberty) such that dosing adjustment, often aided by drug monitoring for drugs with narrow therapeutic indices, becomes critical for safe, effective therapeutics.
Most drug-metabolizing enzymes are expressed at low levels at birth, followed by an isozymespecifc postnatal induction. CYP2E1 and CYP2D6 appear in the first day, followed within 1 week by CYP3A4 and the CYP2C subfamily. CYP2A1 s not expressed until 1–3 months after birth.
Some glucuronidation pathways are decreased in the newborn, and an inability of newborns to glucuronidate chloramphenicol was responsible for the “gray baby syndrome”. Renal elimination of drugs also is reduced in the neonatal period. Neonates at term have markedly reduced GFR (2–4 mL/min/1.73 m2), and prematurity reduces renal function even further. As a result, neonatal dosing regimens for a number of drugs (e.g., aminoglycosides) must be reduced to avoid toxic drug accumulation. GFR (corrected for body surface area) increases progressively to adult levels by 8–12 months of age.
Elderly:
As adults age, gradual changes in pharmacokinetics and pharmacodynamics increase the interindividual variability of doses required for a given effect. Pharmacokinetic changes result from changes in body composition and the function of drug-eliminating organs. The reduction in lean body mass, serum albumin, and total-body water, coupled with the increase in percentage of body fat, alters drug distribution in a manner dependent on lipid solubility and protein binding. The clearance of many drugs is reduced in the elderly. Renal function variably declines to ~50% of that in young adults.
Hepatic blood ow and drug metabolism also are reduced in the elderly but vary considerably. In general, the activities of hepatic CYPs are reduced, but conjugation mechanisms are relatively preserved. Frequently, the elimination half-lives of drugs are increased as a consequence of larger apparent volumes of distribution of lipid-soluble drugs and/or reductions in the renal or metabolic clearance.
Alterations in renal function may lead to impairment of renally exceted drugs. Drug dosage should be adjusted according to the estimation of GFR. Patients with cirrhosis, hepatitis and other hepatic disease also have impairment of drug metabolising enzymes particularly microsomal oxidases, but unlike the kidneys there is no quantative basis for dose adjustment beyond plasma levels and clinical response. Cardiac disease may result in an reduction of blood ow to the liver, modifying clearance of ow dependent drugs. In patients with circulatory shock neuroendocrine response may drastically reduce renal and hepatic blood ow reducing the clearance of many drugs. Pulmonary disease may also affect drug metabolism as indicated by impaired hydrolysis or procanamide and procaine in patients with COPD. Finally disease states may lead to reductions in circulating protiens and in drugs with high protien binding this may lead to an increase in free drug and therefore potency. In this case measurement of free drug is more accurate that total drug. Christopher Andersen 2012
My husband was diagnosed with early onset Parkinson's disease at 57.his symptoms were shuffling of feet,slurred speech, low volume speech, degradation of hand writing, horrible driving skills, right arm held at 45 degree angle, things were tough for me, but now he finally free from the disease with the help of total cure ultimate health home, he now walks properly and all symptoms has reversed, he had trouble with balance especially at night, getting into the shower and exiting it is difficult,getting into bed is also another thing he finds impossible.we had to find a better solution for his condition which has really helped him a lot,the biggest helped we had was ultimatehealthhome they walked us through the proper steps,am highly recommended this ultimatehealthhome@gmail.com to anyone who needs help.
ReplyDelete