5th y dental special pk consideration in elderly
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5th y dental special pk consideration in elderly

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GUIDLINES TO CONSIDER WHEN PRESCRIPNING ANALGESICS AND ANTIBIOTICS FOR ELDERLY IN DENTAL PRACTICE

GUIDLINES TO CONSIDER WHEN PRESCRIPNING ANALGESICS AND ANTIBIOTICS FOR ELDERLY IN DENTAL PRACTICE

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  • * Chronic interstitial nephritis and papillary necrosis
  • The
  • FIRST PASS METABOLISM May render a drug ineffective by mouth e.g. lignocaine, insulin May mean that much higher dose needed orally to produce the same effect e.g. 5mg propranolol IV = 100mg propranolol PO Can use sub-lingual or rectal route e.g GTN get absorption directly into systemic circulation and bypass the liver initially LIVER DISEASE The liver has a large capacity and metabolism is only affected in extensive liver disease. Intravenous shunting in the absence of much hepatocellular damage can impair drug metabolism e.g. in liver cirrhosis HEPATIC BLOOD FLOW Liver receives blood from the portal vein and the hepatic artery. The hepatic clearance of a drug depends on hepatic blood flow and the hepatic extraction ratio. Free drug (dissociated from plasma proteins or partitioned out of blood cells) passes across hepatocyte membrane and undergoes either biliary excretion or metabolism by an enzyme. Drugs with a high extraction ratio (approaching 1) - none of these processes is slow or rate limiting. Hepatic clearance depends on the rate of hepatic blood flow. Drugs with a low extraction ratio - one of the processes is slow and rate limiting e.g. poor diffusion into hepatic cell, slow diffusion out of blood cell, tight binding to plasma proteins. Drug concentration is almost the same in venous and arterial blood and hepatic clearance is independent of blood flow .

5th y dental special pk consideration in elderly 5th y dental special pk consideration in elderly Presentation Transcript

  • ‫’’“بسم ال الرحمن الرحيم‬ ‫غافر‬
  • Clinical PK consideration in elderly By Dr. Ahmed Shaker Ali Dept of pharmacology Faculty of medicine Ahmedshaker21@ yahoo. com Bl 7. G751 Ex. 223305th yr dental 11 -2-1434
  • An elderly with renal impairment , what the appropriate regimen of Augmentin ? Leaflet of the drug mentioned Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Severely impaired patients with a glomerular filtration rate of <30 mL/min. should not receive the 875-mg tablet. Patients with a glomerular filtration rate of 10 to 30 mL/min. should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a less than 10 mL/min. glomerular filtration rate should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.
  • How about Voltaren ? Special Populations Hepatic Insufficiency: Hepatic metabolism accounts for almost 100% of Voltaren elimination, so patients with hepatic disease may require reduced doses of Voltaren compared to patients with normal hepatic function. Renal Insufficiency: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and < 30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects. BUT elderly are more predisposed for ADE specially renal impairment
  • OBJECTIVES – To optimize use of drugs in elderlyTOPICS – Introduction – Reduced renal function with aging – Assessment of renal function – Dose adjustment in renal impairment – Liver disease – Other PK variables
  • Elderly may suffer one or more chronic diseaseMultiple Diseases – ASHD – CHF – Diabetes Mellitus – COPD – Osteoporosis – CRF – DJD – Chronic liver disease – Dementia – Others
  • Aging is associated with normal changes Relative increased in fat ? Decreased bone density Decreased muscle Decreased water content – Ref: Cefalu CA. Clinical Pharamcology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p. 90.
  • Normal Physiological Changes of the Organ Systems Liver- decreased blood flow; Decreased Phase I Metabolism Kidney- decreased creatinine clearance with advanced age CNS-increased risk of confusional states primarily secondary to anti-cholinergic agents Intestinal tract-- malabsorption-- not clinically significant in absence of disease
  • Normal Changes of Aging-Hepatic Phase I Metabolism-rate of metabolism slows (oxidation, reduction, hydroxylation) Phase II Metabolism-rate stays the same (conjugation with glucronic acid, sulfation methylation, acetylation) – Examples-benzodiazepines » Short acting-Phase II only-appropriate » Long acting-Phase I and II-inappropriate, long half-lives Reference: Beers MH. Medication Use in the Elderly. In: Calkins , Ford & Katz, 1992, p. 40.
  • Normal Changes of Aging :-Renal Age-related reduction in renal blood flow and creatinine clearance in the face of a normal BUN and serum creatinine: Implications- – Adjust dose of renally excreted drugs with age according to creatinine clearances (Clcr ) for certain drugs
  • Degree of renal impairments for prescribing purposesGFR : Ml/min renal impairment 20-50 mild 10-20 moderate < 10 severe
  • Nephrotoxic drugs 1) Pre-renalNSAIDs even short courses– renalunder- perfusionACE inhibitors ( angiotensin converting enzyme ) in patient with compromised renal perfusion
  • Nephrotoxic drugs cont 2) Intrarenal damage : Glomerunephritis : Captopril, antibiotics including pencillins , sulphonamides and Rifampicin Interstitial nephritis : Penicillin, cephalosporines, NSAIDs and Rifampicin Direct toxicity to renal tubules : aminoglycosides, amphotercin, Cyclosporine A
  • Nephrotoxicity Cont3-Biochemical changes :Excessive vit D replacement : hypercalcemia –precipitates or exacerbate renal impairmentOther : Cefixime rare cases NSADs ; AnalgesicAnalgesics :nephropathyAnalgesic nephropathy have been mostcommonly seen with combination analgesics thatcontain aspirin and or Paracetamol
  • GFR & CKDGFR is a direct measurement of kidneyfunction and reduced before the onset ofsymptoms of kidney failure.A decrease in GFR correlates with thepathogenic severity of kidney disease.Replacement therapy with dialysis ortransplantation becomes necessary whenthe GFR decrease below 15mL/min/1.73m2.
  • (GFR tests). Serum Creatinine : (Scr) Simple.Χ Misleading .Χ Scr may remain constant although GFR decline specially in elderly.Χ Several variables : age, diet ,muscle mass etc
  • (GFR tests).Urine collection (24h) [Urine Cr] X Volume (ml)24Cr Cl= [Serum Cr] X Time 1440 min?
  • Disadvantages of 24 hr urine collectionΧTime consumingΧErrors in collection time / volumeΧTroublesome to both patients & LabΧMay over estimate GFR by 10-30 %ΧEffect of drugs ??
  • Estimating creatinine clearance Cockcroft & Gault equation (modified )Men: CrCl = 1.23 x (140 – Age) x Wt SrCrWomen: CrCl = 1.04 x (140 – Age) x Wt x SrCrCrCl = Creatinine clearance (ml/min)Age (Years)Wt = Weight (kg) SrCr = Serum creatinine (micromole/L l)Ref: Ref: Cefalu CA. Clinical Pharmacology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p. 92.
  • Adjust Dose: GFR < 50 ml/min*Antimicrobials Cardiovascular Acyclovir Methyldopa Amantidine Most ACE Inhibitors* Aminoglycosides Atenolol, Nadolol, Sotalol Amphotericin Digoxin Aztreonam Procainamide* Cephalosporins (many) Others Imipenem Lithium Penicillins (most) Meperidine* Quinolones (most) Acetaminophen** Sulbactans H2 Blockers (most) Sulfonamides Albuterol Tetracycline** Glyburide Vancomycin Insulin *Refer to Methotrexate detailed protocols
  • Clinical significance of renal impairmentProlonged half life (T1/2) is commonT1/2 = 0.693 x Vd Cl Longer dosing interval should be considered for drugs which depends mainly on renal elimination Longer time is required to 1. Attain steady state 2. Or until body is drug-free in case of toxcicity
  • Methods of dose adjustment in renal impairment If mild , drug has wide therapeutic range usually no need to adjust the dose • If moderate or severe , or the drug has narrow therapeutic range , appropriate adjustment is essential • A- reduce the dose keep dosing interval as normal • B- normal dose but Longer dosing interval
  • Factors affecting drug metabolismMain site of drug metabolism = LIVER Drug metabolism can be affected by: 1. First pass effect 2. Hepatic blood flow 3. Liver disease 4. Drugs which alter liver enzymes
  • Factors affecting drug metabolismI. Genetic factors e.g acetylation statusI. Other drugs o hepatic enzyme inducers o hepatic enzyme inhibitorsI. Age Impaired hepatic enzyme activity o Elderly o Children < 6 months (especially premature babies)
  • Enzyme Inducing Drugs Phenytoin Phenobarbitone Carbamazepine Rifampicin Griseofulvin Chronic alcohol intake Smoking
  • Enzyme Inhibiting Drugs Inhibit the enzymes which break down drugs Decreased rate of drug breakdown Smaller dose of affected drug needed to produce the same clinical effect
  • Enzyme InhibitorsErythromycin Oral contraceptivesCiprofloxacin Sodium valproateMetronidazole CimetidineChloramphenicol OmeprazoleSulphonamides Calcium channel blockersAcute alcohol AmiodaroneAllopurinol DextropropoxyphenePhenylbutazone FluconazoleIsoniazid
  • Drugs subjected to Hepatic Metabolism NSAIDs; Aspirin Ca channel blockers Acetaminophen Alpha blockers Erythromycin Statins Ketoconazole Dilantin Tetracyclines Valproic acid Lidocaine Carbamazepine Metoprolol Tricyclic Antidepres SSRIs Neuroleptics
  • Pharmaceutical Agents That Require Hepatic Metabolism Benzodiazepines Cimetidine Ranitidine Famotidine Terfenadine Proton pump inhibitors Schwartz JB. Clinical Pharmacology. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4th Ed., 2000, p. 309- 319.
  • The Cytochrome System CYP1A2 CYP2C CYP2D6 CYP3A – Involves Model Compounds, Drug Substrates, Inducers, and Inhibitors – Ref: Schwartz JB. Clinical Pharmacology. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4th Ed., 2000, p. 308.
  • Particular Agents of Concern in the Elderly-highly bound to protein Phenytoin Carbamazepine Barbiturates Warfarin Malnutrition or hypoproteinemia is associated with increased free fraction of drug and increased toxicity Ref: Physicians Desk Reference, Medical Economics- Thomson Healthcare,55th Edition, 2001, p. 2427.
  • Physiological changes of the GI Tract Stomach- little change in gastric acidity with aging. In presence of dsyphagia and H2 blocker therapy, may increase risk of morbidity and mortality from pneumonia (bacteria more viable after aspiration due to reduced acidity) Decreased GI motility and blood flow-- increased frequency of constipation – Ref: In: Hall KE, Wiley JW. Age-Associated Change in Gastrointestinal Function. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4th Ed., 2000, p. 835-842. –
  • NSAIDs*: Can Worsen HBP- removal of NSAID can affect mean blood pressure control Fluid retention Worsen CHF Cause confusion GI bleeding Newer Cox-2 agents, gastric sparring Less risk of Alzheimers and cognitive decline*In high doses or used chronically Ref: Carson JL & Strom BL. Use of Nonsteroidal Anti-Inflammatory Drugs. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p. 1113-1119; Stewart WF et al. Risk of Alzheimer’s disease and duration of NSAID use. Neurology, 48, 1997, p. 626-632.
  • “Tips” for Safe Traditional NSAID Use Substitute acetaminophen when possible instead of NSAID Guide the patient to avoid misuse of acetaminophen. Use PRN when possible Use lowest dose possible Use for acute flare for 7-10 days then d/c When necessary for chronic use, insist on routine q 3 month. RFT &LFT & and CBC Consider institutional changes to allow relatively safe analgesics
  • ‫.‬ ‫المقامة اليمانية لصفات الصادقين‬ ‫ال صا دق في إيمانه‬ ‫ّ ِ‬ ‫يؤمن بالله وملئكته وكتبه ورسله واليوم الخر والقدر خيره‬ ‫وشره‬‫يحب الرسول ويطيعه فيما أمر ويحب أصحاب رسول ا جميعا‬ ‫وكذلك أمهات المؤمنين وأهل بيته أجمعين . يعتقد أنهم خير‬ ‫القرون ويعرض عما يروجه أهل الضلل من شبهات وظنون .‬ ‫عقيدته التباع وترك البتداع . يؤمن بان ا أتم نوره وأكمل‬ ‫دينه ورضي السلم دينا‬ ‫وان القوانين الوضعية منبوذة وضيعه وانه ل يصح إيمان من‬ ‫عادى أو عطل الشريعة .‬ ‫يوقن إن الشرك أعظم الظلم وان ا ل يغفر أن يشرك به‬ ‫ويغفر ما دونه من الذنوب .‬ ‫ل يدعو مع ا أحدا ول يستعن بسواه ول يسال غيره قضاء‬ ‫الحوائج وتفريج الكروب .‬ ‫يحب في ا المؤمنين ويبغض في ا الكفار والمنافقين .‬ ‫يكثر من النوافل ويحافظ على الفرائض - يشهد الجماعات -‬ ‫ويسارع في الخيرات .‬ ‫يعظم القرءان ف يتعلم ه ويعلمه – ويتدبره ويعمل بمحكمه‬
  • ‫.‬‫المقامة اليمانية لصفات الصادقين‬ ‫نظره اعتبار وصمته فكر وكلمه خير وذكر -ل ينشغل بما ل‬ ‫يعنيه ول يطلب فوق ما يكفيه .‬ ‫أ ذا ابتلى صبر و إذا أعطي شكر و إذا س ئ ل بذل و إذا عز تواضع‬ ‫َِ‬ ‫ُِ َ‬ ‫َِ‬ ‫َِ‬ ‫َ‬ ‫و إذا تولى أمرا رفق .‬ ‫َِ‬‫موقر للكبير رحيم بالصغير – يوف بالعهد أمين – ويسعى على‬ ‫اليتيم والمسكين‬ ‫تراه دوما حليما وإذا مر باللغو مر كريما .‬‫يحرص على هدى وسنة محمد صلى ا عليه وسلم خير النام –‬‫ويصل الرحام ويفشى السلم – ويطعم الطعام ويصلى والناس‬ ‫نيام .‬ ‫– يأمر بالمعروف وينهى عن المنكر ويجاهد بماله ونفسه في‬ ‫سبيل ا متبعا للشريعة - ول يسب أهل الكفر والضلل‬ ‫والجاهلين سدا للزر يعه .‬ ‫علم أن صلح القلب هو أصل صلح الجسد - فلم يحمل في‬ ‫قلبه حقدا ول حسد –‬ ‫و علم إن العمال بالنيات - فتحرى الخلص وداوم على‬ ‫سؤال ا العون على الثبات .‬ ‫لم تغره زخارف دار ا لغ رور عن أحوال القبور و أهوال ي وم‬ ‫َ ْ‬ ‫َ‬ ‫ْ ُ‬ ‫َ‬