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The Influence of Age and Disease on PK and PD

The Influence of Age and Disease on PK and PD. Matthew Walters. Influence of Disease on PK/PD. Influence of age Influence of disease: Impaired renal function Impaired hepatic function Congestive cardiac failure Gastrointestinal disease Thyroid disease. Influence of Age: Pharmacokinetics.

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The Influence of Age and Disease on PK and PD

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  1. The Influence of Age and Disease on PK and PD Matthew Walters

  2. Influence of Disease on PK/PD • Influence of age • Influence of disease: • Impaired renal function • Impaired hepatic function • Congestive cardiac failure • Gastrointestinal disease • Thyroid disease

  3. Influence of Age:Pharmacokinetics • Decrease in total body water (due to decrease in muscle mass) and increase in total body fat affects volume of distribution • Water soluble drugs: lithium, aminoglycosides, alcohol, digoxin • Serum levels may go up due to decreased volume of distribution • Fat soluble: diazepam, thiopental, trazadone • Half life increased with increase in body fat

  4. Influence of Age:Pharmacokinetics • Absorption: Not highly impacted by aging • Variable changes in first pass metabolism due to variable decline in hepatic blood flow (elders may have less first pass effect than younger people, but extremely difficult to predict)

  5. Influence of Age: the Liver • Acetylation and conjugation do not change appreciably with age • Oxidative metabolism through cytochrome P450 system does decrease with aging, resulting in a decresed clearance of drugs • Hepatic blood flow extremely variable

  6. Influence of Age:Excretion and Elimination • GFR generally declines with aging, but is extremely variable • 30% have little change • 30% have moderate decrease • 30% have severe decrease • Serum creatinine is an unreliable marker • If accuracy needed, do Cr Cl

  7. The Cockroft and Gault Equation • Cr Cl = 140-age(yrs) X wt (kg) X .85 for women • Cr (mg/100ml)X72 • May overestimate Cr Cl, especially in frail elders • Useful equation, but must be aware of its limitations

  8. Influence of Age:Pharmacodynamics • Some effects are increased • Alcohol causes increase is drowsiness and lateral sway in older people than younger people at same serum levels • Fentanyl, diazepam, morphine, theophylline • Some effects are decreased • Diminished HR response to isoproterenol and beta -blockers

  9. Undertreatment of the Elderly • CAD • Beta blockers • ASA • Anticoagulation in AF • HTN, especially systolic HTN • Pain • Particular fear of narcotics in the elderly

  10. Adverse Drug Reactions in the Elderly • About 15% of hospitalizations in the elderly are related to adverse drug reactions • The more medications a person is on, the higher the risk of drug-drug interactions or adverse drug reactions • The more medications a person is on, the higher the risk of non-adherence

  11. Drug-drug Interactions • Common cause of ADEs in elderly • Almost countless – good role for pharmacist and computer or on-line programs • Some common examples • Statins and erythromycin and other antibiotics • TCAs and clonidine or type 1Anti-arrythmics • Warfarin and multiple drugs • ACE inhibitors increase hypoglycemic effect of sulfonylureas

  12. Drug-disease Interactions • Patient with PD have increased risk of drug induced confusion • NSAIA (and COX-2’s) s can exacerbate CHF • Urinary retention in BPH patients on decongestants or anticholinergics • Constipation worsened by calcium, ahticholinergics, calcium channel blockers • Neuroleptics and quinolones lower seizure thresholds

  13. The “Prescribing Cascade” • Common cause of polypharmacy in elderly • Some common examples • NSAIA ->HTN->antihypertensive therapy • Metoclopromide ->parkinsonism ->Sinemet • Dihydropyridine -> edema ->furosemide • NSAIA ->H2 blocker ->delirium ->haldol • HCTZ ->gout->NSAIA ->2nd antihypertensive • Sudafed ->urinary retention ->alpha blocker • Antipsychotic ->akithesia ->more meds

  14. Influence of Disease on Kinetics and Dynamics

  15. Renal Disease • Pharmacokinetics: • Decreased elimination • Decreased protein binding • Decreased hepatic metabolism • Pharmacodynamics: • Altered sensitivity to drug effect • Adverse effects

  16. Decreased Elimination • Aminoglycosides • Lithium • Digoxin • Methotrexate • Penicillins • Which drugs? • Plasma concentration? • Time to steady state? • Effect on:

  17. Decreased Elimination • Determination of renal function • Alteration of dosing schedule • Monitoring drug concentrations

  18. Protein Binding • Renal failure leads to acid retention • “Acidic” drugs less bound to albumin: • Conformational change in albumin • Less ionised drug to bind • Increased free (active) drug in plasma • Binding of basic drugs unchanged

  19. Protein Binding • Usually of little clinical relevance, but… • Phenytoin (acidic) • Less bound drug (more free drug) • Target concentration lower in renal failure • Effect of HD? • Effect of transplantation?

  20. Hepatic Metabolism in Renal Failure • Hepatic metabolism of some drugs is slower in renal failure • ? Endogenous inhibitor in uraemic plasma • Normalised by HD

  21. Pharmacodynamics in Renal Failure • Increased sensitivity to sedatives • ? BBB permeability

  22. Other Considerations • Nephrotoxins • Fluid retention • Increasing uraemia • Electrolyte disturbances Amphoteracin, gentamicin NSAIDS Tetracyclines Amiloride, digoxin

  23. Hepatic Impairment

  24. Hepatic Impairment • Pharmacokinetics • First pass metabolism • Activation of prodrugs • Decreased protein binding • Decreased elimination • Pharmacodynamics • Altered drug effect

  25. First Pass Metabolism • Profound changes in bioavailability: • Chlormethiazole (1000% increase) • Verapamil (140% increase) • Paracetamol (50% increase) • First pass activation reduced: • Enalapril, perindopril etc

  26. High and Low Extraction Drugs • High extraction • Metabolised at high rate by liver • Rate varies with delivery • Affected by changes in blood flow • Morphine, verapamil, lignocaine

  27. High and Low Extraction Drugs • Low extraction: • Metabolised at low rate by liver • Independent of blood flow • Sensitive to changes in liver enzyme activity • Chloramphenicol, theophylline

  28. Effect on PK • Difficult to predict • Many factors involved • No simple test (cf renal impairment) • Start with low dose • TDM

  29. Effect on PD • Sensitivity to sedatives • Sensitivity to oral anticoagulants • Precipitation of encephalopathy • Fluid retention • Hepatorenal syndrome

  30. Congestive Cardiac Failure Mucosal oedema  Blood flow •  Absorption • Altered V of D •  Hepatic elimination •  Renal elimination ECF (oedema) Tissue perfusion Perfusion Hypoxia Congestion Perfusion Tubular reabsorption

  31. Gastrointestinal Disease • Achlorhydria • Coeliac disease • Crohn’s More ionised acidic drug in stomach Absorption of aspirin Variable effects Gut SA Gut permeability Variable effects Gut wall thickened Altered bacterial flora Gut SA

  32. Thyroid Disease • Digoxin • Increased sensitivity in hypothyroidism • Decreased sensitivity in hyperthyroidism • Lithium • May precipitate hypothyroidism • Check TFT’s regularly

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