الرحيم الرحمن الله ’’“بسم

غافر

Clinical PK consideration in elderly

By

Dr. Ahmed Shaker AliDept of pharmacology

Faculty of medicine

Ahmedshaker21@ yahoo. com

Bl 7. G751 Ex. 22330

5th 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 elderly

TOPICS– 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 disease

Multiple Diseases– CHF– COPD– CRF– Chronic liver disease– Dementia

– ASHD

– Diabetes Mellitus– Osteoporosis– DJD– 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 purposes

GFR : Ml/min renal impairment

20-50 mild

10-20 moderate

< 10 severe

Nephrotoxic drugs 1) Pre-renal

NSAIDs even short courses– renal

under- perfusion

ACE 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 Cont 3-Biochemical changes : Excessive vit D replacement : hypercalcemia –

precipitates or exacerbate renal impairment Other : Cefixime rare cases

Analgesics : NSADs ; Analgesic nephropathy

Analgesic nephropathy have been most commonly seen with combination analgesics that contain aspirin and or Paracetamol

GFR & CKD GFR is a direct measurement of kidney

function and reduced before the onset of symptoms of kidney failure.

A decrease in GFR correlates with the pathogenic severity of kidney disease.

Replacement therapy with dialysis or transplantation becomes necessary when the GFR decrease below 15mL/min/1.73m2.

Renal function evaluation

(GFR tests). Serum Creatinine : (Scr)Simple. Misleading . Scr may remain constant although GFR decline

specially in elderly. Several variables : age, diet ,muscle mass etc

Urine collection (24h)

24Cr Cl=[Urine Cr]

[Serum Cr]

X Volume (ml)

X Time 1440 min?

(GFR tests).

Disadvantages of 24 hr

urine collection

Time consumingTime consumingErrors in collection time / volume Errors in collection time / volume Troublesome to both patients & LabTroublesome to both patients & LabMay over estimate GFR by 10-30 %May over estimate GFR by 10-30 %Effect of drugs ??Effect of drugs ??

Estimating creatinine clearance

Cockcroft & Gault equation (modified )

Men: CrCl = 1.23 x (140 – Age) x Wt SrCr

Women: CrCl = 1.04 x (140 – Age) x Wt x SrCr

CrCl = 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 Acyclovir Amantidine Aminoglycosides Amphotericin Aztreonam Cephalosporins (many) Imipenem Penicillins (most) Quinolones (most) Sulbactans Sulfonamides Tetracycline** Vancomycin

Cardiovascular Methyldopa Most ACE Inhibitors* Atenolol, Nadolol, Sotalol Digoxin Procainamide*Others Lithium Meperidine* Acetaminophen** H2 Blockers (most) Albuterol Glyburide Insulin Methotrexate

*Refer to detailed

protocols

Clinical significance of renal impairment

Longer dosing interval should be considered for drugs which depends mainly on renal elimination

Longer time is required to 1. Attain steady state2. Or until body is drug-free in case of toxcicity

Prolonged half life (T1/2) is common

T1/2 = 0.693 x Vd

Cl

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 metabolism

Drug metabolism can be affected by:

1. First pass effect

2. Hepatic blood flow

3. Liver disease

4. Drugs which alter liver enzymes

Main site of drug metabolism = LIVER

Factors affecting drug metabolism

I. Genetic factorse.g acetylation status

II. Other drugso hepatic enzyme inducerso hepatic enzyme inhibitors

III. AgeImpaired 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 Inhibitors Erythromycin Ciprofloxacin Metronidazole Chloramphenicol Sulphonamides Acute alcohol Allopurinol Phenylbutazone Isoniazid

Oral contraceptives Sodium valproate Cimetidine Omeprazole Calcium channel blockers Amiodarone Dextropropoxyphene Fluconazole

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 toxicityRef: 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 Alzheimer's 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, 4th 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

الصادقين لصفات اإليمانية .المقامة

إيمانه في اد2ق الص3 وشره خيره والقدر اآلخر واليوم ورسله وكتبه ومالئكته بالله يؤمن ويحب يحب أمر فيما ويطيعه وكذلك الرسول جميعا الله رسول أصحاب

أجمعين بيته وأهل المؤمنين أنهم .أمهات ويعرض يعتقد القرون خيروظنون شبهات من الضالل أهل يروجه . عما

. االبتداع وترك اإلتباع دينه عقيدته وأكمل نوره أتم الله بان يؤمندينا اإلسالم ورضي

أو عادى من إيمان يصح ال وانه وضيعه منبوذة الوضعية القوانين وانالشريعة . عطل

ما ويغفر به يشرك أن يغفر ال الله وان الظلم أعظم الشرك إن يوقنالذنوب . من دونه

الحوائج قضاء غيره يسال وال بسواه يستعن وال أحدا الله مع يدعو الالكروب . وتفريج

. والمنافقين الكفار الله في ويبغض المؤمنين الله في يحب - ويسارع - الجماعات يشهد الفرائض على ويحافظ النوافل من يكثر

. الخيرات في ف القرءان ويؤمن – هيتعلميعظم بمحكمه ويعمل ويتدبره ويعلمه

مو عن الكلم يحرف وال ضعه ابمتشابهه والرجاء الخوف بين متقلب في - حاله ورزقه مقدر اجله بان موقن

السماء.

الصادقين لصفات اإليمانية .المقامة - يطلب وال يعنيه ال بما ينشغل ال وذكر خير وكالمه فكر وصمته اعتبار نظره

. يكفيه ما فوقأمرا أ تولى إ2ذا pو تواضع عز إ2ذا pو بذل pِئ2ل sس إ2ذا pو شكر أعطي إ2ذا pو بر pص ابتلى ذا

رفق. – بالصغير رحيم للكبير بالعهد موقر اليتيم – يوف على ويسعى أمين

والمسكين . كريما مر باللغو مر وإذا حليما دوما تراه – ويصل األنام خير وسلم عليه الله صلى محمد وسنة هدى على يحرص

نيام – . والناس ويصلى الطعام ويطعم السالم ويفشى األرحام –متبعا الله سبيل في ونفسه بماله ويجاهد المنكر عن وينهى بالمعروف يأمر

أهل- يسب وال والجاهلين للشريعة والضالل . الكفر يعه للزر سدا - وال حقدا قلبه في يحمل فلم الجسد صالح أصل هو القلب صالح أن علم

حسد – العون - علمو الله سؤال على وداوم اإلخالص فتحرى بالنيات اإلعمال إن

. الثبات على.. النشور يpوzم أهوال و القبور أحوال عpن ور sغرzال دpار زخارف تغره لم وأوالدها زوجها حق ترعى الصادقة مكان– وجيرانها والمؤمنة خير وترى

فال – – تعرف أن ادني فذلك والحياء الحجاب لزمت لحاجة خرجت وان بيتهاالسفهاء إليذاء تتعرض

. اإلصالح إال أردت وما العلماء كالم من وفهمت علمت بما اال شهدت وما هذااستطعت على – ما الله وصلى أنيب واليه توكلت عليه بالله إال توفيقي وما

العالمين . رب لله الحمد أن دعوانا وأخر وصحبه واله محمد سيدنا