Prescribing in special situations
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Prescribing in special situations
- 1. PRESCRIBING IN SPECIAL SITUATIONS Dr. Pravin Prasad MBBS, MD Clinical Pharmacology Assistant Professor, Department of Clinical Pharmacology Maharajgunj Medical Campus, Kathmandu 10 July 2020(26 Asar 2077), Friday
- 2. Describe the factors governing drug use in: Physiological conditions like: Children Elderly Pregnancy Lactation Pathological conditions like: Renal disease Hepatic disease 2
- 3. Absorption: lower gastric acidity ad slow intestinal transit- altered absorption of drugs Faster transdermal absorption and faster rectal absorption – Diazepam Distribution: Blood brain barrier (BBB) is more permeable – Kernicterus Metabolism: Low hepatic drug metabolizing systems in newborns – gray baby syndrome After one year age, faster metabolism than adults – phenytoin, carbamazepine
- 4. Calculation of child dose Young’s formula Child dose = {Age/(Age+12)} x adult dose Dilling’s formula Child dose = (Age/20) x adult dose Clark’s formula Child dose = (Weight (kg) / 70) x adult dose
- 5. Absorption: Decreased gut motility and blood flow to intestines slower absorption Distribution: Lower plasma protein lesser plasma protein binding Altered volume of distribution Metabolism: Decreased hepatic microsomal enzyme activity Decreased first pass metabolism Overall effect on drug metabolism: not uniform Elimination: Decreased renal function 50 years 75%, 75 years 50%
- 6. Both pharmacokinetic and pharmacodynamic: Likely to be on multiple drugs Drug interaction Exaggerated effects (pharmacodynamic): Prone to develop cumulative toxicity on prolonged medication Enlarged prostate Intolerant to digitalis Decreased responsiveness to β adrenergic drugs More Likely to develop adverse drug reactions Postural hypotension, giddiness, mental confusion
- 7. Drugs during pregnancy: Affects mother Therapeutic Non-therapeutic Affects the developing foetus Not usually desired
- 8. When prescribed to a pregnant lady, can affect at three stages:Stage of pregnancy Description Example of drugs Fertilization and implantation (conception to day 17) Failure of pregnancy (often goes unnoticed) Misoprostol, Ergot alkaloids Organogenesis (weeks 2-8 intra- uterine life) Most vulnerable period Severe malformations occur Warfarin, Alcohol, Phenytoin Growth and development ( 9 week post intra- Developmental and functional abnormalities can ACE inhibitors (hypoplasia of lungs and kidney)
- 9. Teratogen: Teratos: monstor Teratogenicity: Capacity of a drug to cause foetal abnormalities when administered to a pregnant woman
- 10. Thalidomide tragedy: Occurred in Europe Pregnant lady suffering from morning sickness received thalidomide Child born to them had deformed limbs Phocomelia Drug withdrawn from market
- 12. Foetal Hydantoin Syndrome: • Upturned nose • Mid facial hypoplasia • Long upper lip with thin vermilion border • Cleft lip
- 14. Drug Category/ Clinical Condition Avoid using Safer drug Anti-emetics Ondansetron Domperidone Metoclopramide Promethazine Peptic ulcer/GERD Cimetidine Lansoprazole Ranitidine, Pantoprazole Analgesics Aspirin, NSAIDs Morphine Paracetamol Ibuprofen Antiallergics Cetirizine Fexofenadine Chlorpromazine Promethazine
- 15. Drug Category/ Clinical Condition Avoid using Safer drug Anti-helminthic Albendazole Piperazine Niclosamide Antihypertensives ACE inhibitors Angiotensin antagonists Methyldopa Beta blockers Antidiabetic Sulfonylureas Metformin Insulin Anticoagulants Warfarin Heparin
- 16. Lipid soluble Attain high concentration in maternal plasma Are low in protein binding Are in low molecular weight (<800 Da) Basic drugs
- 17. LipidMembrane For weak basic drug: Plasma (pH 7.5) H+ + B B + H+ BH+ Drug concentrated in breast milk Breast milk (pH 6.6) BH+
- 18. Basic Drugs: Morphine, Bromocriptine, Antihistamines Acidic Drugs: Sulfonamides, Ampicillin, Phenobarbitone Non-electrolytes: Ethanol Low molecular weight electrolytes: Lithium Drugs known to cause hemolysis in G-6-PD deficient individuals: Anti-malarials: quinine, primaquine Sulfa drugs: Dapsone, isoniazid
- 19. Alters the response to drugs Large hepatic reserve, severe liver disease only important Dose reduction is sufficient in several instances If drug is hepatotoxic, avoid its use 19
- 20. Influences drug pharmacokinetics Altered bioavailability of drugs Increased for high first pass metabolism drugs Decreased bioavailability for fat soluble drugs Altered distribution of drugs Less serum albumin: High concentration of free acidic drugs Altered distribution due to changes in body fluids Metabolism and elimination of drugs Decreased metabolism of drugs that are primarily metabolised by liver Activation of prodrugs affected Decreased biliary excretion 20
- 21. Influences drug pharmacodynamics Increased sensitivity Increased depressant action of morphine and barbiturates Mental changes due to brisk diuresis by diuretics in hepatic encephalopathy Prolonged prothrombin time due to warfarin Accentuated fluid accumulation due to NSAIDs 21
- 22. Medicine Comment Allopurinol Reduce dose Amitriptyline Sedative effect increased (avoid in severe liver disease) Amlodipine Half-life prolonged — may need dose reduction Amoxicillin + clavulanic acid Monitor liver function in liver disease Azithromycin Avoid; jaundice reported Carbamazepine Metabolism impaired in advanced liver disease 22
- 23. Reduced renal function may lead to: Failure to excrete a drug or its metabolites producing toxicity Increased in sensitivity to some drugs Impaired tolerance to adverse effects Diminished efficacy of some drugs Doses of drugs need to be adjusted to: To avoid adverse reactions To ensure efficacy 23
- 24. Adjustment is based on: Renal impairment status of the patient Usually dose reduced as: 24 Reduction in GFR (ml/min) Reduction in dose 50-70 70% 30-50 50% 10-30 30% 5-10 20%
- 25. Adjustment is based on: Toxicity of the drug/metabolite Avoid nephrotoxic drugs Use safer alternatives Relative excretion from kidneys Drugs excreted as active drug/metabolite: reduce dose Drugs excreted as inactive drug/metabolite: dose reduction not required Drugs mainly excreted from kidneys: reduce dose Drugs partially excreted from kidneys: lesser reduction in 25
- 26. Loading dose in not changed (especially for long half life drugs) Changes in maintenance dose: Change the dose, leaving the frequency: steady plasma concentration Change the frequency, leaving the dose: decreased cost, improved compliance Assess renal function before starting the treatment as well as during the treatment 26
- 27. 27
Editor's Notes
- Young’s: for children less than 12 yrs of age Dilling’s: for child 4-20 yrs. Age/20 fraction is very close to the weight curve of the infant
- Lipophilic drug increased Vd Hydrophilic drug decreased Vd
- Liver disease may alter the response to drugs. However, the hepatic reserve appears to be large and liver disease has to be severe before important changes in drug metabolism take place. The ability to eliminate a specific drug may or may not correlate with the liver’s synthetic capacity for substances such as albumin or clotting factors, which tends to decrease as hepatic function declines. Unlike renal disease, where estimates of renal function based on creatinine clearance correlate with parameters of drug elimination such as clearance and half-life, routine liver function tests do not reflect actual liver function but are rather markers of liver cellular damage. The altered response to drugs in liver disease can include all or some of the following changes: Impaired intrinsic hepatic eliminating (metabolizing) capacity due to lack of or impaired function of hepatocytes. Impaired biliary elimination due to biliary obstruction or transport abnormalities (for example, rifampicin is excreted in the bile unchanged and may accumulate in patients with intrahepatic or extrahepatic obstructive jaundice). Impaired hepatic blood flow due to surgical shunting, collateral circulation or poor perfusion with cirrhosis and portal hypertension. Altered volume of distribution of drugs due to increased extracellular fluid (ascites, oedema) and decreased muscle mass. Decreased protein binding and increased toxicity of drugs highly bound to proteins (for example phenytoin) due to impaired albumin production. Increased bioavailability through decreased first-pass metabolism. Decreased bioavailability due to malabsorption of fats in cholestatic liver disease. In severe liver disease increased sensitivity to the effects of some drugs can further impair cerebral function and may precipitate hepatic encephalopathy (for example, morphine). Oedema and ascites in chronic liver disease may be exacerbated by drugs that cause fluid retention (for example, acetylsalicylic acid, ibuprofen, prednisolone, dexamethasone). Usually drugs are metabolized without injury to the liver. A few drugs cause dose-related hepatotoxicity. However, most hepatotoxic reactions to drugs are rare but tend to be unpredictable. In patients with impaired liver function, the dose-related hepatotoxic reaction may occur at lower doses and the unpredictable reactions seem to occur more frequently. Both should be avoided. Information to help prescribing in hepatic impairment is included in the following table. The table contains only those drugs that need dose adjustment. However, absence from the table does not automatically imply safety as for many drugs data about safety are absent; it is therefore important to also refer to the individual drug entries.
- High first pass metabolism: Propanolol, morphine, pethidine, GTN, Lidocaine Acidic drugs: barbiturates, BZDs, NSAIDs, Penicillin, phenytoin, warfarin Drugs primarily metabolised by liver: morphine, lidocaine, propanolol Prodrugs: bacampicillin- ampicillin, prednisone- prednisolone, levodopa-depamine Impaired biliary elimination due to biliary obstruction or transport abnormalities (for example, rifampicin is excreted in the bile unchanged and may accumulate in patients with intrahepatic or extrahepatic obstructive jaundice).
- Increased sensitivity:
- Failure to excrete a drug or its metabolites producing toxicity: penicillin- convulsions, pethidine (active metabolite- norpethidine)- seizures Increased in sensitivity to some drugs: Alcuronium- prolonged duration of block, BZDs, barbiturates- increased CNS depression, anti-hypertensives- postural hypertension Impaired tolerance to adverse effects: acetazolamide- metabolic acidosis Diminished efficacy of some drugs: thiazide diuretics
- Reduced renal function may need drug or its dose adjustment because of problems with drug therapy for the following reasons: 1. The failure to excrete a drug or its metabolites may produce toxicity. 2. The sensitivity to some drugs is increased even if the renal elimination is unimpaired. 3. The tolerance to adverse effects may be impaired. 4. The efficacy of some drugs may diminish. The dosage of many drugs must be adjusted in patients with renal impairment to avoid adverse reactions and to ensure efficacy. The level of renal function below which the dose of a drug must be reduced depends on how toxic it is and whether it is eliminated entirely by renal excretion or is partly metabolized to inactive metabolites. A loading dose equivalent to the usual dose in patients with normal renal function should be considered for drugs with a particularly long half-life In general, all patients with renal impairment are given a loading dose which is the same as the usual dose for a patient with normal renal function. Maintenance doses are adjusted to the clinical situation. The maintenance dose of a drug can be reduced either by reducing the individual dose leaving the normal interval between doses unchanged or by increasing the interval between doses without changing the dose. The interval extension method may provide the benefits of convenience and decreased cost, while the dose reduction method provides more constant plasma concentration.
- Drugs excreted unchanged: Aminoglycosides, digoxin, phenobarbitone
- Reduced renal function may need drug or its dose adjustment because of problems with drug therapy for the following reasons: 1. The failure to excrete a drug or its metabolites may produce toxicity. 2. The sensitivity to some drugs is increased even if the renal elimination is unimpaired. 3. The tolerance to adverse effects may be impaired. 4. The efficacy of some drugs may diminish. The dosage of many drugs must be adjusted in patients with renal impairment to avoid adverse reactions and to ensure efficacy. The level of renal function below which the dose of a drug must be reduced depends on how toxic it is and whether it is eliminated entirely by renal excretion or is partly metabolized to inactive metabolites. A loading dose equivalent to the usual dose in patients with normal renal function should be considered for drugs with a particularly long half-life In general, all patients with renal impairment are given a loading dose which is the same as the usual dose for a patient with normal renal function. Maintenance doses are adjusted to the clinical situation. The maintenance dose of a drug can be reduced either by reducing the individual dose leaving the normal interval between doses unchanged or by increasing the interval between doses without changing the dose. The interval extension method may provide the benefits of convenience and decreased cost, while the dose reduction method provides more constant plasma concentration.