Principles for Principles for PharmacotherapeuticsPharmacotherapeutics

Rianto SetiabudyRianto SetiabudyLecture for the Regular Class FKUILecture for the Regular Class FKUI

August 25, 2008August 25, 2008

Objectives (1)Objectives (1)

To understand the following issues:To understand the following issues: Sources of interpatient variationSources of interpatient variation Steps to a rational therapySteps to a rational therapy Pharmacokinetic and pharmacodynamic Pharmacokinetic and pharmacodynamic

variationsvariations Relationship between drug concentration in Relationship between drug concentration in

plasma and its intensity of effectplasma and its intensity of effect Paediatric patientsPaediatric patients Pharmacogenetic factorsPharmacogenetic factors

Objectives (2)Objectives (2)

Patient with renal diseasesPatient with renal diseases Patient with hepatic diseasesPatient with hepatic diseases Pregnant womenPregnant women Drugs to be avoided in breast-feedingDrugs to be avoided in breast-feeding Drug interactionsDrug interactions Evaluating a possible drug interactionEvaluating a possible drug interaction Features of drug allergyFeatures of drug allergy Clinical trialsClinical trials

Seven key steps to a rational Seven key steps to a rational therapeuticstherapeutics

1. Make a specific diagnosis1. Make a specific diagnosis2. Understand the pathophysiology of the disease2. Understand the pathophysiology of the disease3. Select a therapeutic objective(s)3. Select a therapeutic objective(s)4. Select a drug of choice for that particular patient4. Select a drug of choice for that particular patient5. Determine the appropriate dosing regimen5. Determine the appropriate dosing regimen6. Devise a plan for monitoring the drug’s action and 6. Devise a plan for monitoring the drug’s action and

determine an end point for the therapydetermine an end point for the therapy7. Plan a program for patient education7. Plan a program for patient education

How to select a drug of choice for How to select a drug of choice for a patient?a patient?

1.1. Make a list of drugs which are potentially effectiveMake a list of drugs which are potentially effective2.2. Determine Determine oneone drug which is the best for the patient drug which is the best for the patient

by considering its: by considering its: EfficacyEfficacy SafetySafety Suitability (for this particular patient)Suitability (for this particular patient) CostCost

Note: for some diseases such as hypertension, Note: for some diseases such as hypertension, diabetes mellitus, tuberculosis, selection of more diabetes mellitus, tuberculosis, selection of more than one drug is necessarythan one drug is necessary

Sources of interpatient Sources of interpatient variations of drug effect (1)variations of drug effect (1)

Prescribed dose:Prescribed dose: Patient compliancePatient compliance Medication errorMedication error

Administered dose:Administered dose: Rate and extent of absorptionRate and extent of absorption Body size and compositionBody size and composition Distribution in body fluidsDistribution in body fluids Binding in plasma and tissuesBinding in plasma and tissues Rate of drug eliminationRate of drug elimination

Concentration at site of action:Concentration at site of action:

Sources of interpatient Sources of interpatient variation of drug effect (2)variation of drug effect (2)

Concentration at site of action:Concentration at site of action: Physiological variablesPhysiological variables Pathological factorsPathological factors Genetic factorsGenetic factors Drug-drug interactionDrug-drug interaction Development of toleranceDevelopment of tolerance

Intensity of effect:Intensity of effect: Drug-receptor interactionDrug-receptor interaction Functional stateFunctional state Placebo effectPlacebo effect

Pharmacokinetic and Pharmacokinetic and pharmacodynamic variationpharmacodynamic variation

Key pharmacokinetic steps include:Key pharmacokinetic steps include: Absorption of drugAbsorption of drug First pass metabolismFirst pass metabolism Overall bioavailabilityOverall bioavailability Drug distributionDrug distribution Urinary excretionUrinary excretion Hepatic biotransformationHepatic biotransformation

Relationship between drug concentration in Relationship between drug concentration in plasma and its intensity of effectplasma and its intensity of effect

Maximal effect

variability

Concentration

slope

Inte

nsity

of e

ffect

Pediatric patientsPediatric patients

Renal and hepatic functions in neonates are Renal and hepatic functions in neonates are significantly inadequatesignificantly inadequate

Glucocorticoids are more likely to inhibit bone Glucocorticoids are more likely to inhibit bone growth and premature epiphyseal maturationgrowth and premature epiphyseal maturation

Small quantity of bile Small quantity of bile absorption lipid-soluble absorption lipid-soluble vitamins (A, D, E, K) decreasesvitamins (A, D, E, K) decreases

Free fraction of drug in Free fraction of drug in plasma is relatively high plasma is relatively high because protein bound fraction is lowbecause protein bound fraction is low

Elderly patients (1)Elderly patients (1)

Decreased cardiac output, decreased blood flow Decreased cardiac output, decreased blood flow to the liver, and decreased blood flow to the to the liver, and decreased blood flow to the kidneys kidneys results in decreased clearance of results in decreased clearance of many drugs.many drugs.

E.g., lidocaine, theophylline, gentamicin, E.g., lidocaine, theophylline, gentamicin, diazepam, etc.diazepam, etc.

Pharmacodynamic effects of certain drugs (e.g., Pharmacodynamic effects of certain drugs (e.g., heparin, warfarin, benzodiazepins) may increase heparin, warfarin, benzodiazepins) may increase due to:due to:

Elderly patients (2)Elderly patients (2)

– Increased number of receptorsIncreased number of receptors– Increased function of second messengers Increased function of second messengers

(cAMP, Ca(cAMP, Ca++++, IP3, DAG), IP3, DAG)– Increased cellular response to second Increased cellular response to second

messengermessenger

Elderly patients (3)Elderly patients (3)Additional principles in drug prescribing for the Additional principles in drug prescribing for the

elderly:elderly: Make extra effort to establish a correct diagnosisMake extra effort to establish a correct diagnosis Obtain a drug historyObtain a drug history Know the clinical pharmacology of drugs Know the clinical pharmacology of drugs

prescribedprescribed Re-evaluate drug use at frequent intervalRe-evaluate drug use at frequent interval

Elderly patients (4)Elderly patients (4)

Use non-pharmacologic approach whenever Use non-pharmacologic approach whenever appropriateappropriate

Individualize treatment (e.g., loading dose, Individualize treatment (e.g., loading dose, maintenance dose)maintenance dose)

Inform the patient about the potential side effectsInform the patient about the potential side effects Increase compliance (e.g. give fewer drugs, Increase compliance (e.g. give fewer drugs,

simple drug regimens)simple drug regimens)

Pharmacogenetic factors (1)Pharmacogenetic factors (1)

Should be suspected in the following cases:Should be suspected in the following cases:– Unexpected drug toxicity despite low doses of Unexpected drug toxicity despite low doses of

drugs are being administereddrugs are being administered– Unexpected drug-drug interactionUnexpected drug-drug interaction– Novel drug effects not seen in average Novel drug effects not seen in average

patientspatients Caused by inheritance of abnormal gene Caused by inheritance of abnormal gene

synthesis of an abnormal protein or decreased synthesis of an abnormal protein or decreased synthesis of a normal proteinsynthesis of a normal protein

Pharmacogenetic factors Pharmacogenetic factors

Examples:Examples:– G6PD deficiency G6PD deficiency hemolysis when exposed hemolysis when exposed

to nitrofurantoin, sulfonamides, etcto nitrofurantoin, sulfonamides, etc– Inability to metabolize succinylcholineInability to metabolize succinylcholine– Reduced activity of the enzyme thiopurine Reduced activity of the enzyme thiopurine

methyltransferase (TPMP) methyltransferase (TPMP) reduced ability reduced ability to metabolize azathioprine to metabolize azathioprine myelosuppresion myelosuppresion

Patients with renal disease (1)Patients with renal disease (1)

Renal clearance and muscle mass decline with age Renal clearance and muscle mass decline with age the decline of renal function is not apparent in the decline of renal function is not apparent in the elderlythe elderly

Pharmacokinetic alteration in RF:Pharmacokinetic alteration in RF:– In severe azotemia In severe azotemia serum albumin serum albumin

concentration concentration free fraction of drugs may free fraction of drugs may – Vd of many drugs may Vd of many drugs may due to ascites, edema due to ascites, edema

or pleural effusionor pleural effusion

Patients with renal disease (2)Patients with renal disease (2)

Pharmacodynamic alteration in RF:Pharmacodynamic alteration in RF:– Drugs (e.g., ACE inhibitors, NSAIDs) are Drugs (e.g., ACE inhibitors, NSAIDs) are

more likely to produce hyperkalemiamore likely to produce hyperkalemia– Diuretics: efficacy Diuretics: efficacy – NSAIDs : more likely to cause GI bleedingNSAIDs : more likely to cause GI bleeding

Patients with renal disease (3)Patients with renal disease (3)

Principle to use drugs in severe renal diseases:Principle to use drugs in severe renal diseases:Choose drugs mainly excreted through the liver, Choose drugs mainly excreted through the liver, not through the kidneysnot through the kidneys

Avoid giving tetracyclines, potassium-sparing Avoid giving tetracyclines, potassium-sparing diuretics, thiazides, aspirin, and oral diuretics, thiazides, aspirin, and oral hypoglycemic agentshypoglycemic agents

Give drugs in low dose, especially those Give drugs in low dose, especially those excreted through the kidneyexcreted through the kidney

Patient with hepatic disease (1)Patient with hepatic disease (1)

Negative impacts of severe hepatic diseases:Negative impacts of severe hepatic diseases:– Drug metabolism Drug metabolism – Synthesis of albumin and blood clotting factors Synthesis of albumin and blood clotting factors – Sensitivity of receptors for CNS depressants Sensitivity of receptors for CNS depressants – Edema and ascites may be aggravated by fluid Edema and ascites may be aggravated by fluid

retaining drugs such as NSAIDs, corticosteroidsretaining drugs such as NSAIDs, corticosteroids

Patient with hepatic disease (2)Patient with hepatic disease (2)

Principle to use drugs in severe hepatic Principle to use drugs in severe hepatic diseases:diseases:

Choose drugs eliminated mainly through the Choose drugs eliminated mainly through the kidneykidney

Avoid prescribing CNS depressants, thiazides, Avoid prescribing CNS depressants, thiazides, oral contraceptives, and oral anticoagulantsoral contraceptives, and oral anticoagulants

Give drugs in low dose, especially those Give drugs in low dose, especially those excreted through the liverexcreted through the liver

Pregnant womenPregnant women

Drugs that are small, uncharged, and highly lipid Drugs that are small, uncharged, and highly lipid soluble crosses placenta rapidlysoluble crosses placenta rapidly

During pregnancy the mother’ s cardiac output During pregnancy the mother’ s cardiac output increases upto 40%increases upto 40%

Glomerular filtration Glomerular filtration Plasma volume Plasma volume Plasma albumin Plasma albumin

Diseases and recommended Diseases and recommended treatments for pregnant women (1)treatments for pregnant women (1)

DiabetesDiabetes– Use: insulinUse: insulin– Avoid : sulfonylureas (risk of hypoglycemia)Avoid : sulfonylureas (risk of hypoglycemia)

Hypertension:Hypertension:– Use: methyldopa, nifedipineUse: methyldopa, nifedipine– Avoid :Avoid :

» Diuretics Diuretics exacerbates volume depletion exacerbates volume depletion» ACE inhibitors, reserpine ACE inhibitors, reserpine affect fetal growth affect fetal growth

Diseases and recommended Diseases and recommended treatments for pregnant women (2)treatments for pregnant women (2)

Urinary tract infectionsUrinary tract infections– Use: ampicillin, cephalosporinsUse: ampicillin, cephalosporins– Avoid : sulfonamides, fluoroquinolonesAvoid : sulfonamides, fluoroquinolones

ThrombophlebitisThrombophlebitis– Use: heparinUse: heparin– Avoid : warfarinAvoid : warfarin

Hyperthyroidism:Hyperthyroidism:– Use: PTUUse: PTU– Avoid : radioactive iodine, surgeryAvoid : radioactive iodine, surgery

Categories of drug risk to the fetusCategories of drug risk to the fetus

Category ACategory A: risk of fetal harm appears to be remote: risk of fetal harm appears to be remote Category BCategory B: animal studies showed some risk, but not : animal studies showed some risk, but not

confirmed in human dataconfirmed in human data Category CCategory C: no data of animal or human studies: no data of animal or human studies Category DCategory D: evidence of human fetal risk, but the : evidence of human fetal risk, but the

benefits of the drugs still outweigh risks in certain benefits of the drugs still outweigh risks in certain situationsituation

Category XCategory X: evidence of animal and human fetal risk, : evidence of animal and human fetal risk, and this risk outweighs the potential benefits to the and this risk outweighs the potential benefits to the mothermother

Drugs to be avoided during Drugs to be avoided during breast-feedingbreast-feeding

Endocrine drugs: PTU, methimazole, iodineEndocrine drugs: PTU, methimazole, iodine Radiopharmaceuticals: iodine, technetiumRadiopharmaceuticals: iodine, technetium Cytotoxic agents: methotrexate, cyclophosphamideCytotoxic agents: methotrexate, cyclophosphamide Antibiotics: sulfonamides, chloramphenicolAntibiotics: sulfonamides, chloramphenicol Hormones: estrogens, androgensHormones: estrogens, androgens Psychoactive drugs: lithium, ethanol, barbituratesPsychoactive drugs: lithium, ethanol, barbiturates Opioids: morphine, heroinOpioids: morphine, heroin

Common examples of Common examples of pharmacokinetic drug interactionspharmacokinetic drug interactions

Drug ADrug A Drug BDrug B Effect of drug B on drug AEffect of drug B on drug AEstrogensEstrogens rifampicinrifampicin metabolism metabolism PhenytoinPhenytoin cimetidinecimetidine metabolism metabolism SalicylateSalicylateNaHCO3NaHCO3 renal excretion renal excretion PenicillinPenicillin probenecidprobenecid tubular secretion tubular secretion DigoxinDigoxin quinidinequinidine clearance clearance and Vd and Vd

Some examples of pharmaco-Some examples of pharmaco-dynamic drug interactionsdynamic drug interactions

Drug ADrug A Drug BDrug B InteractionInteractionEthanolEthanol benzodiazepinebenzodiazepine CNS depression CNS depression PhenothiazinesPhenothiazines opioidsopioids CNS depression CNS depression AtropineAtropine physostigminephysostigmine antichol. effect antichol. effect PropranololPropranolol nitroglycerinnitroglycerin anginal pain anginal pain MidazolamMidazolam fentanylfentanyl sedation sedation ProchlorperazineProchlorperazine dexamethasonedexamethasone antiemetic effect antiemetic effect

Key points to consider for evaluating a Key points to consider for evaluating a possible adverse drug reactionpossible adverse drug reaction

Previous report in literaturePrevious report in literature Time of onset after starting the drugTime of onset after starting the drug Other possible etiologies are absentOther possible etiologies are absent Previous similar response in the patientPrevious similar response in the patient Improvement with dechallangeImprovement with dechallange Recurrent with rechallangeRecurrent with rechallange

Key features of drug allergyKey features of drug allergy No relationship to usual or toxic pharmacologic effectsNo relationship to usual or toxic pharmacologic effects Not dose relatedNot dose related Common patterns of organ or systemic toxicityCommon patterns of organ or systemic toxicity Appearance usually delayed after first exposure to drugAppearance usually delayed after first exposure to drug Re-exposure often but not always results in allergy Re-exposure often but not always results in allergy

againagain Allergy on re-exposure may appear more quickly or be Allergy on re-exposure may appear more quickly or be

more severemore severe Desensitization is sometime possible, but riskyDesensitization is sometime possible, but risky

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