1. Principles for Pharmacotherapeutics Rianto Setiabudy Lecture for the Regular Class FKUI August 25, 2008

2. Objectives (1) To understand the following issues: Sources of interpatient variation Sources of interpatient variation Steps to a rational therapy Steps to a rational therapy Pharmacokinetic and pharmacodynamic variations Pharmacokinetic and pharmacodynamic variations Relationship between drug concentration in plasma and its intensity of effect Relationship between drug concentration in plasma and its intensity of effect Paediatric patients Paediatric patients Pharmacogenetic factors Pharmacogenetic factors

3. Objectives (2) Patient with renal diseases Patient with renal diseases Patient with hepatic diseases Patient with hepatic diseases Pregnant women Pregnant women Drugs to be avoided in breast-feeding Drugs to be avoided in breast-feeding Drug interactions Drug interactions Evaluating a possible drug interaction Evaluating a possible drug interaction Features of drug allergy Features of drug allergy Clinical trials Clinical trials

4. Seven key steps to a rational therapeutics 1. Make a specific diagnosis 2. Understand the pathophysiology of the disease 3. Select a therapeutic objective(s) 4. Select a drug of choice for that particular patient 5. Determine the appropriate dosing regimen 6. Devise a plan for monitoring the drug’s action and determine an end point for the therapy 7. Plan a program for patient education

5. How to select a drug of choice for a patient? 1.Make a list of drugs which are potentially effective 2.Determine one drug which is the best for the patient by considering its:  Efficacy  Safety  Suitability (for this particular patient)  Cost Note: for some diseases such as hypertension, diabetes mellitus, tuberculosis, selection of more than one drug is necessary

6. Sources of interpatient variations of drug effect (1) Prescribed dose:  Patient compliance  Medication error Administered dose:  Rate and extent of absorption  Body size and composition  Distribution in body fluids  Binding in plasma and tissues  Rate of drug elimination Concentration at site of action:

7. Sources of interpatient variation of drug effect (2) Concentration at site of action: Concentration at site of action:  Physiological variables  Pathological factors  Genetic factors  Drug-drug interaction  Development of tolerance Intensity of effect:  Drug-receptor interaction  Functional state  Placebo effect

8. Pharmacokinetic and pharmacodynamic variation Key pharmacokinetic steps include: Absorption of drug Absorption of drug First pass metabolism First pass metabolism Overall bioavailability Overall bioavailability Drug distribution Drug distribution Urinary excretion Urinary excretion Hepatic biotransformation Hepatic biotransformation

9. Relationship between drug concentration in plasma and its intensity of effect Maximal effect variability Concentration slope Intensity of effect

10. Pediatric patients Renal and hepatic functions in neonates are significantly inadequate Renal and hepatic functions in neonates are significantly inadequate Glucocorticoids are more likely to inhibit bone growth and premature epiphyseal maturation Glucocorticoids are more likely to inhibit bone growth and premature epiphyseal maturation Small quantity of bile  absorption lipid-soluble vitamins (A, D, E, K) decreases Small quantity of bile  absorption lipid-soluble vitamins (A, D, E, K) decreases Free fraction of drug in plasma is relatively high because protein bound fraction is low Free fraction of drug in plasma is relatively high because protein bound fraction is low

11. Elderly patients (1) Decreased cardiac output, decreased blood flow to the liver, and decreased blood flow to the kidneys  results in decreased clearance of many drugs. Decreased cardiac output, decreased blood flow to the liver, and decreased blood flow to the kidneys  results in decreased clearance of many drugs. E.g., lidocaine, theophylline, gentamicin, diazepam, etc. E.g., lidocaine, theophylline, gentamicin, diazepam, etc. Pharmacodynamic effects of certain drugs (e.g., heparin, warfarin, benzodiazepins) may increase due to: Pharmacodynamic effects of certain drugs (e.g., heparin, warfarin, benzodiazepins) may increase due to:

12. Elderly patients (2) –Increased number of receptors –Increased function of second messengers (cAMP, Ca ++, IP3, DAG) –Increased cellular response to second messenger

13. Elderly patients (3) Additional principles in drug prescribing for the elderly: Make extra effort to establish a correct diagnosis Make extra effort to establish a correct diagnosis Obtain a drug history Obtain a drug history Know the clinical pharmacology of drugs prescribed Know the clinical pharmacology of drugs prescribed Re-evaluate drug use at frequent interval Re-evaluate drug use at frequent interval

14. Elderly patients (4) Use non-pharmacologic approach whenever appropriate Use non-pharmacologic approach whenever appropriate Individualize treatment (e.g., loading dose, maintenance dose) Individualize treatment (e.g., loading dose, maintenance dose) Inform the patient about the potential side effects Inform the patient about the potential side effects Increase compliance (e.g. give fewer drugs, simple drug regimens) Increase compliance (e.g. give fewer drugs, simple drug regimens)

15. Pharmacogenetic factors (1) Should be suspected in the following cases: Should be suspected in the following cases: –Unexpected drug toxicity despite low doses of drugs are being administered –Unexpected drug-drug interaction –Novel drug effects not seen in average patients Caused by inheritance of abnormal gene  synthesis of an abnormal protein or decreased synthesis of a normal protein Caused by inheritance of abnormal gene  synthesis of an abnormal protein or decreased synthesis of a normal protein

16. Pharmacogenetic factors Examples: Examples: –G6PD deficiency  hemolysis when exposed to nitrofurantoin, sulfonamides, etc –Inability to metabolize succinylcholine –Reduced activity of the enzyme thiopurine methyltransferase (TPMP)  reduced ability to metabolize azathioprine  myelosuppresion 

17. Patients with renal disease (1) Renal clearance and muscle mass decline with age  the decline of renal function is not apparent in the elderly Renal clearance and muscle mass decline with age  the decline of renal function is not apparent in the elderly Pharmacokinetic alteration in RF: Pharmacokinetic alteration in RF: –In severe azotemia  serum albumin concentration   free fraction of drugs may  –Vd of many drugs may  due to ascites, edema or pleural effusion

18. Patients with renal disease (2) Pharmacodynamic alteration in RF: Pharmacodynamic alteration in RF: –Drugs (e.g., ACE inhibitors, NSAIDs) are more likely to produce hyperkalemia –Diuretics: efficacy  –NSAIDs : more likely to cause GI bleeding

19. Patients with renal disease (3) Principle to use drugs in severe renal diseases: Choose drugs mainly excreted through the liver, not through the kidneys Avoid giving tetracyclines, potassium-sparing diuretics, thiazides, aspirin, and oral hypoglycemic agents Avoid giving tetracyclines, potassium-sparing diuretics, thiazides, aspirin, and oral hypoglycemic agents Give drugs in low dose, especially those excreted through the kidney Give drugs in low dose, especially those excreted through the kidney

20. Patient with hepatic disease (1) Negative impacts of severe hepatic diseases: Negative impacts of severe hepatic diseases: –Drug metabolism  –Synthesis of albumin and blood clotting factors  –Sensitivity of receptors for CNS depressants  –Edema and ascites may be aggravated by fluid retaining drugs such as NSAIDs, corticosteroids

21. Patient with hepatic disease (2) Principle to use drugs in severe hepatic diseases: Choose drugs eliminated mainly through the kidney Choose drugs eliminated mainly through the kidney Avoid prescribing CNS depressants, thiazides, oral contraceptives, and oral anticoagulants Avoid prescribing CNS depressants, thiazides, oral contraceptives, and oral anticoagulants Give drugs in low dose, especially those excreted through the liver Give drugs in low dose, especially those excreted through the liver

22. Pregnant women Drugs that are small, uncharged, and highly lipid soluble crosses placenta rapidly Drugs that are small, uncharged, and highly lipid soluble crosses placenta rapidly During pregnancy the mother’ s cardiac output increases upto 40% During pregnancy the mother’ s cardiac output increases upto 40% Glomerular filtration  Glomerular filtration  Plasma volume  Plasma volume  Plasma albumin  Plasma albumin 

23. Diseases and recommended treatments for pregnant women (1) Diabetes Diabetes –Use: insulin –Avoid : sulfonylureas (risk of hypoglycemia) Hypertension: Hypertension: –Use: methyldopa, nifedipine –Avoid : »Diuretics  exacerbates volume depletion »ACE inhibitors, reserpine  affect fetal growth

24. Diseases and recommended treatments for pregnant women (2) Urinary tract infections Urinary tract infections –Use: ampicillin, cephalosporins –Avoid : sulfonamides, fluoroquinolones Thrombophlebitis Thrombophlebitis –Use: heparin –Avoid : warfarin Hyperthyroidism: Hyperthyroidism: –Use: PTU –Avoid : radioactive iodine, surgery

25. Categories of drug risk to the fetus Category A: risk of fetal harm appears to be remote Category A: risk of fetal harm appears to be remote Category B: animal studies showed some risk, but not confirmed in human data Category B: animal studies showed some risk, but not confirmed in human data Category C: no data of animal or human studies Category C: no data of animal or human studies Category D: evidence of human fetal risk, but the benefits of the drugs still outweigh risks in certain situation Category D: evidence of human fetal risk, but the benefits of the drugs still outweigh risks in certain situation Category X: evidence of animal and human fetal risk, and this risk outweighs the potential benefits to the mother Category X: evidence of animal and human fetal risk, and this risk outweighs the potential benefits to the mother

26. Drugs to be avoided during breast-feeding Endocrine drugs: PTU, methimazole, iodine Endocrine drugs: PTU, methimazole, iodine Radiopharmaceuticals: iodine, technetium Radiopharmaceuticals: iodine, technetium Cytotoxic agents: methotrexate, cyclophosphamide Cytotoxic agents: methotrexate, cyclophosphamide Antibiotics: sulfonamides, chloramphenicol Antibiotics: sulfonamides, chloramphenicol Hormones: estrogens, androgens Hormones: estrogens, androgens Psychoactive drugs: lithium, ethanol, barbiturates Psychoactive drugs: lithium, ethanol, barbiturates Opioids: morphine, heroin Opioids: morphine, heroin

27. Common examples of pharmacokinetic drug interactions Drug ADrug BEffect of drug B on drug A Estrogensrifampicinmetabolism  Phenytoincimetidinemetabolism  SalicylateNaHCO3renal excretion  Penicillinprobenecidtubular secretion  Digoxinquinidineclearance  and Vd 

28. Some examples of pharmaco- dynamic drug interactions Drug ADrug BInteraction EthanolbenzodiazepineCNS depression  PhenothiazinesopioidsCNS depression  Atropinephysostigmineantichol. effect  Propranololnitroglycerinanginal pain  Midazolamfentanyl sedation  Prochlorperazinedexamethasoneantiemetic effect 

29. Key points to consider for evaluating a possible adverse drug reaction Previous report in literature Previous report in literature Time of onset after starting the drug Time of onset after starting the drug Other possible etiologies are absent Other possible etiologies are absent Previous similar response in the patient Previous similar response in the patient Improvement with dechallange Improvement with dechallange Recurrent with rechallange Recurrent with rechallange

30. Key features of drug allergy No relationship to usual or toxic pharmacologic effects No relationship to usual or toxic pharmacologic effects Not dose related Not dose related Common patterns of organ or systemic toxicity Common patterns of organ or systemic toxicity Appearance usually delayed after first exposure to drug Appearance usually delayed after first exposure to drug Re-exposure often but not always results in allergy again Re-exposure often but not always results in allergy again Allergy on re-exposure may appear more quickly or be more severe Allergy on re-exposure may appear more quickly or be more severe Desensitization is sometime possible, but risky Desensitization is sometime possible, but risky

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