Physiological and Pathological Factors Influencing Drug Response PDF

BIOPHARM REVIEVER PHYSIOLOGICAL AND PATHOLOGICAL Dosing Guidelines FACTORS INFLUENCING DRUG  For children over 2 years: Dosing can actually be adjusted using mg/kg of b...

BIOPHARM REVIEVER PHYSIOLOGICAL AND PATHOLOGICAL Dosing Guidelines FACTORS INFLUENCING DRUG  For children over 2 years: Dosing can actually be adjusted using mg/kg of body weight. RESPONSE  Newborns require special care in dosing due to FACTORS underdeveloped organ functions. PHYSIOLOGICAL/ PATHOLOGIC AGED ENVIRONMENTAL Body Composition Changes with Age: Body weight Cardiovascular diseases Newborn/Children Renal Diseases  Lead body mass decreases, and fat tissues Aged Liver Diseases increases (even if body weight stays the same). Temperature Physiological Changes: Gastric Emptying time  Blood flow to organs and tissues decreases Blood Flow Rates  Renal function and metabolic rate decline Environment: Smoking, Drug Elimination: Exposures to chemicals,  In general, the elimination half-life increases with etc., age Nutrition  However, dosage adjustments should be based Pregnancy Genetics solely on half-life because: Circadian Rhythm-Diurnal o Volume of distribution (Vd) may also Rhythm change (increase or decrease) Effects of Volume Distribution (Vd) PHYSIOLOGICAL/ ENVIRONMENTAL FACTORS  Increase Vd: BODY WEIGHT o May compensate for prolonged half-life, Standard Dose Size: keeping drug clearance unchanged  Designed for an average adult body weight of 70 o No dosage change needed, but steady kg state takes longer to reach Impact of Body weight:  Decrease Vd:  Higher body weight: Leads to lower drug o Smaller dose sizes may be required concentrations Key Consideration  Lower body weight: Results in higher drug  Monitor drug concentrations carefully and adjust concentration based on individual response. Dose adjustment  Typically adjusted based on mg per kg of body TEMPERATURE weight. Hypothermia (Decrease body temperature): Special case-Obesity  Can affect all phases of the LADMER system.  Adjustment not valid for obese individuals (if Hyperthermia (Increased body temperature) & High actual body weight exceed 20% above ideal humidity weight).  Leads to body water and salt depletion  Other factors must be considered for accurate  Reduces extracellular fluid volume (ECF), which dosing in obesity. can impact the volume of distribution (Vd) Key considerations NEWBORNS AND CHILDREN  Both temperatures extremes can alter drug Newborn vs. Adults absorption, distribution, and clearance, requiring  Body composition differs (amount/distribution of careful monitoring and potential dose fluids and fat). adjustments.  Immature liver and kidneys affect drug metabolism and elimination. GASTRIC EMPTYING TIME Development Milestones → Directly affects the rate and extent of drug  By 6 months (in terms infants): Liver and kidney absorption function is similar to adults.  In premature infants, full maturation takes longer. Factors Influencing Gastric Emptying 1. FoodType and amount of solid or fluids consumed. 2. GI content: Viscosity and pH BIOPHARM REVIEVER 3. Patients Position: Slowest empting occurs in the High Altitude Effects: left supine position.  Reduces cardiac output, which may delay all 4. Stress: May delay gastric empting. phases of the LADMER system. 5. Concomitant Drugs: Can alter emptying rate. 6. Temperature: NUTRITION a. Ice-cold water (5°C): Accelerates gastric Impact on Hepatic Enzymes: emptying (as fast as 15 minutes)  Nutritional status affects the activity of hepatic b. War fluids: Delay stomach emptying enzyme systems.  Undernutrition and vitamin deficiencies: Special Note for Enteric-Coated and Gastric-Sensitive o Common in both developing and Drugs: industrialized countries.  Should be taken with 250 mL of ice-cold water to Effects of Protein Deficiency: ensure rapid empting and protection from gastric  Reduces protein synthesis can lead to: fluids. o Hypoalbuminemia: Lowers levels of albumin in plasma. BLOOD FLOW RATES o Reduced metabolism rates of drugs Drug Distribution Process: Consequences for Drug Behavior:  Drug leaves the systemic circulation via  Volume of distribution (Vd) may change: capillaries to reach interstitial fluids and tissue o Higher free drug fraction in plasma- cells. increased drug effects and toxicity.  Capillary Network  Reduced metabolic capacity: o Total length in the human body: 95,000 o Leads to greater drug accumulation, km raising the risk of adverse effects. o No cell is more than 0.125 mm away from capillary in perfused tissue. PREGNANCY Body Composition Changes: Impact of Perfusion on Distribution  Increased fat tissue affects the distribution of  Reduce perfusion (e.g., due to temporary lipophilic drugs. capillary closure): Hormonal Changes: o Slows down the rate and extent of drug  Alter drug metabolism, potentially modifying drug distribution. clearance rates. Renal Function: Factors Affecting Tissue Perfusion  Increases renal blood flow enhances renal  Depends on blood flow rates, which are influence elimination of drugs. by cardiac output. Fetal Compartment:  Decrease perfusion: Caused by bed rest,  The fetus acts as an additional pharmacokinetic hypothermia, shock, heart failure, etc. compartment, influencing drug distribution.  Increased perfusion: Caused by physical exercise. GENETICS Genetic Variations: ENVIRONMENT  Caused by mutations in DNA, leading to changes Enzyme Activity: in the structure of proteins involved in  Induction of metabolic enzyme can be influenced pharmacokinetics (absorption, distribution, by: metabolism, elimination) and drug-receptor o Smoking interactions. o Living in cities or industrial areas Drugs Affected by Genetic Variations: o Exposure to insecticides 1. Antipyrine Chemical Toxicity: 2. Bishydroxycoumarin  Certain industrial chemical (e.g. halogenated 3. Ethanol hydrocarbons) can cause renal and hepatic 4. Halothane damage, leading to: 5. INH (Isoniazid) o Prolonged elimination half-life (t1/2) of 6. Hydralazine drugs. 7. Nortriptyline 8. Phenylbutazone BIOPHARM REVIEVER 9. Succinylcholine 6. Quinidine 10. Warfarin Hepatic Clearance: Impact:  Prolonged hepatic clearance for drugs such as  These drugs show differences in response and/or lidocaine and theophylline in patients with disposition due to genetic control. congestive heart failure. Volume of Distribution: CIRCADIAN RHYTHM- DIURNAL RHYTHM  A reduce volume of distribution has been Biological Clock and Rhythms: observed for digoxin and other drugs in  The biological clock influences all phases of the congestive heart failure LADMER system (Liberation, Absorption, Distribution, Metabolism, Excretion, Response) RENAL DISEASES  Circadian rhythm: Controlled by endogenous Accumulation of drugs rhythms (e.g., hormones)  Diurnal rhythm: Controlled by external Impaired Metabolism in Renal Drugs synchronizers (e.g., light-dark cycles, sleep-wake  Reduction: hydrocortisone – undergo reduced cycles) metabolic breakdown Drugs Affected by Rhythms  Acetylation: The metabolism of drugs such as  Differences in blood concentration-time curves isoniazid (INH), hydralazine, sulfisoxazole, and found for: para-aminosalicylic acid (PAS) may be reduced. o Acetaminophen, aminopyrine,  Ester hydrolysis: Metabolism of clindamycin amphetamine, antipyrine, phosphate, erythromycin estolate, indanyl carbamazepine, and others. carbenecillin, and prednisone hemisuccinate can o Cortisol, ethanol, lithum, meperidine, etc. be affected. Pharmacologic Response: Reduce volume of distribution:  Response to drugs may follow a circadian or 1. Ampicilline diurnal rhythm 2. Cephacetrile  Example: Antihistamines, local anesthetics, 3. Cephalexin chlorpromazine. 4. Digoxin Receptor Sensitivity 5. Insulin  Variations in drug response may be due to 6. Lincomycin changes in receptor sensitivity rather than 7. Methicillin changes in blood concentration-time curves. 8. Metolazone 9. Quinidine PATHOLOGIC FACTORS 10. Propranolol CARDIOVASCULAR DISEASES Increased filling pressure in congestive heart failure LIVER DISEASES lead to: Liver Disease Overview:  Increased stroke volume, which can cause 1. Cirrhosis: Amobarbital, Ampicillin, Antipyrine, congestion of vital organs Chloramphenicol, Diazepam, Isoniazid (INH),  This congestion, coupled with sodium retention, Lidocaine, Meperidine, Phenobarbital, results in the formation of edema. Phenylbutazone Reduce Cardiac output leads to: 2. Acute Viral Hepatitis: Antipyrine, Diazepam,  Decreased perfusion of key organs, such as the Hexobarbital, Meperidine liver, kidneys, splanchnic area, muscle tissue, o No change: Lidocaine, Phenobarbital, and skin. Phenylbutazone, Phenytoin, Warfarin  This reduced blood flow can result in pulmonary 3. Chronic Active Hepatitis and Obstructive edema, hypoxia, and systemic acidosis. Jaundice: Absorption Rates in congestive heart failure: Impact of Liver Disease on Drug synthesis and Albumin  Decreased absorption for drugs such as Production 1. Aprindine Volume Distribution (Vd): 2. Digoxin 3. Hydrochlorthiazide  Cirrhotic patients: Amobarbital, Ampicillin, 4. Metolazone Diazepam, Lidocaine, Propranolol, Thiopental 5. Procainamide Metabolism and Hepatic Enzyme Function BIOPHARM REVIEVER  Acute hepatitis can cause changes in the metabolism of certain drugs Effects of Liver Diseases on Extrahepatic Drug Metabolism  Pseudocholinsterase Activity: reduced activity  Altered Blood Flow and First-Pass Metabolism: