Alterazioni farmacocinetiche e farmacodinamiche (PK/PD) associate all età

Transcription

1 Alterazioni farmacocinetiche e farmacodinamiche (PK/PD) associate all età Dario Cattaneo, U.O. Farmacologia Clinica Az. Ospedaliera Polo Universitario L. Sacco, Milano Bergamo, città alta

2 ..ma è davvero importante parlare di alterazioni PK/PD nell anziano?

3 - Garrasco, BMC Health Service Res

4 Total ADR hospitalizations by age Age 2001 (%) 2008 (%) total (%) Drug groups most frequently associated with ADRs Drug class frequency (n) % (95%CI) - Garrasco, BMC Health Service Res

5 perché il paziente anziano ha una frequenza cosi elevata di ADR???

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7 290 admission to the Emergency Department Age Polypharmacy yrs yrs yrs Yes No Medication-related admission 18,9% 21,8% 35,4% 28,2%* 10,7% *Odd Ratio 3.3 [1,5-6,9], p= Laatikainen, Frontiers Pharmacol

8 ..e che succede dopo la dimissione??? 70 Italian internal medicine and geriatric wards (2765 pts >65 yrs) DDI: drug-drug interaction - Pasina, Pharmacoepidemiol Drug Safety

9 e nel paziente anziano complesso?? Più comorbidità Più farmaci Più DDIs ma c è di più

10 Metabolismo DOSE ORALE DOSE I.V. Farmacocinetica Assorbimento TRATTO G.I. FEGATO CIRCOLAZIONE SISTEMICA DISTRIBUZIONE PERIFERICA Distribuzione CLEARANCE Eliminazione ORGANO BERSAGLIO RECETTORE L età influenza diversamente le fasi ADME EFFETTO

11 Assorbimento - Klotz, Drug Metab Rev

12 In base alle stime attuali*, circa il 30% degli ultraottantenni italiani assume farmaci inibitori della pompa protonica (PPIs) water coke water+ esomeprazole coke + esomeprazole * Franchi et al. Changes in drug prescribing to Italian community-dwelling elderly people: the EPIFARM-Elderly Project Eur J Clin Pharmacol Apr;70(4):437-43

13 L inibizione dell attività della P-gp mediata dai PPI potrebbe determinare un aumentato assorbimento di alcuni antibiotici - Pea, AAC

14 Distribuzione - Klotz, Drug Metab Rev

15 Physiologic change Result PK parameter PK effect Reduced muscle mass and total water Accumulation of hydrophilic drugs Volume of distribution Increase of drug plasma concentrations Increased body fat Accumulation of lipophilic drugs Volume of distribution Increase of drug half-life - Klotz, Drug Metab Rev

16 Changes in drug clearance for highly bound antibacterials in critically ill patients with hypoalbuminemia - Roberts, Clin Pharmacokinet

17 Metabolismo - Klotz, Drug Metab Rev

18 Daptomycin AUC [linezolid], mg/l 500 ** Age quartiles [Linezolid] trough < 40 yrs 4.6 ± 4.9 mg/l yrs 6.1 ± 4.5 mg/l yrs 10.0 ± 7.0 mg/l** > 80 yrs 12.6 ± 9.3 mg/l** young (18-30 yr) geriatric (>75 yr) - Dvorchik, J Clin Pharmacol n= Patients age, yrs - Cattaneo, IJAA 2016-

19 The PCR analysis showed that, with advancing age, expression of CYP2A6 and CYP3A4 decreased in female liver, while PXR* decreased in male liver *Pregnane X receptor is a nuclear receptor that controls inducible expression of biotransformation enzymes and drug transporters

20 Quali farmaci sono più a rischio di accumulo e di DDIs nel paziente anziano? Il 50% dei farmaci oggi in commercio viene metabolizzato dal citocromo 3A (CYP3A4/5)

21 Eliminazione Decreased renal function results in decreased elimination of drugs excreted by the kidney Even in the absence of kidney disease, renal clearance may be reduced by 35-50% in healthy elderly vs healthy younger men Reduced renal clearance of active metabolites may enhance therapeutic effect or increase risk of toxicity Need to reduce dose and/or increase dosing intervals - Klotz, Drug Metab Rev

22 egfr: Use CKD-EPI formula; the abbreviated modification of diet in renal disease (amdrd) or the Cockcroft-Gault (CG) equation may be used as an alternative; see

23 qui allora è semplice se conosco la funzione renale del paziene posso stimarmi la clearance di ogni farmaco!!! - Mistry, J Clin Pharmacol

24 - Ryzner, Annals Pharmacother

25 E poi c è la frailty.

26 Frailty and aging are associated with altered PK, polypharmacy and increased risk of DDIs Impact of fall-risk increasing drugs (FRIDs), polypharmacy and DDIs in elderly patients (80,5±8,3 yrs) Frail patients Robust patients Patients (n) FRIDs 3,4±2,2 1,6±1,5* Medications (n) 9,8±4,3 4,4±3,3* DDI exposure 35% 5%* Prevalence of statin-drug interactions in 180 elderly patients (median age 78 [71-85] yrs) Frail patients - Bennett, Drugs Aging Thai, Drugs Aging Robust patients Patients (%) 35% 65% Potential DDIs 12,7% 8,5%* Clinically relevant DDIs 9,5% 6,8%*

27 Metabolismo DOSE ORALE DOSE I.V. Assorbimento TRATTO G.I. FEGATO CIRCOLAZIONE SISTEMICA DISTRIBUZIONE PERIFERICA Distribuzione ORGANO BERSAGLIO CLEARANCE Eliminazione L età influenza anche la PD??? Farmacodinamica (PD) RECETTORE EFFETTO

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29 Age-related changes in the affinity of some medications to receptor sites or in the number of receptors may reduce drug efficacy or increase drug sensitivity

30 PD changes in the elderly: main clinical challenges and issues The cardiovascular system The CNS system The cholinergic system The immune system

31 There is a linear change in blood pressure (BP) with the advancement of age from predominantly diastolic BP in the young to predominantly systolic BP in the old (replacement of the elastic fibers with collagen fibers). An inverse relationship with stroke risk was noted when the DBP was <70 mm Hg in persons older than 60 years. Accordingly, when treating SBP in the elderly, care should be taken not to lower the DBP below this level in order to minimize the risk for CVD and stoke Drugs that block the renin-angiotensin-aldosterone system and calcium channel blockers (alone or in combination) are preferable as first-line treatment of HP in elderly patients, compared with old b-blockers and thiazide diuretics

32 Target INR: The pk characteristics of warfarin do not explain the lower dose requirements, because the distribution and elimination half-lives of warfarin change very little with advancing age. We, therefore, hypothesize increased warfarin sensitivity due to unknown mechanisms

33 Coagulation potential Hemostatic potential

34 Age-related changes in pharmacodynamics: focus on drugs acting on central nervous systems Elderly patients are particularly susceptible to the effects of frequently prescribed drugs acting on central nervous system, such as benzodiazepines, antidepressants, antipsychotics and lithium, with high potential for adverse drug reactions. - Trifirò Curr Drug Metab

35 Older adults displayed less activation than young people in some elements of the typical left-hemisphere semantic network Semantic processing in later life is associated with a shift from semanticspecific to domain-general neural resources, consistent with the theory of neural dedifferentiation, and a performance-related reduction in prefrontal lateralisation, which may reflect a response to increased task demands

36 The issue of anticholinergic burdern

37 Di quali farmaci stiamo parlando??

38 Anticholinergic burden is associated with recurrent and injurious falls in older individuals Conclusion The association between recurrent and injurious falls and the use of any medications listed in the anticholinergic burden (ACB) scale was mediated through gait and balance impairment but not by muscular weakness, providing a novel insight into the potential mechanistic link between ACB and falls - Zia, Maturitas

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42 whereas in the majority of elderly the NK cell compartment appears to be highly stable in terms of function and phenotype, in a minority of subjects a breakdown of NK cell repertoire diversity is observed that might influence immune surveillance and healthy aging

43 Age-related decline in innate and adaptive immune reactivity? Overuse of immunosuppressive agents in elderly patients?

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45 Quali strumenti abbiamo per prevenire DDI e ADR nel paziente anziano? The 2015 American Geriatrics Society (AGS) Beers Criteria are presented. New to the criteria are lists of select drugs that should be avoided or have their dose adjusted based on the individual s kidney function and select drug drug interactions documented to be associated with harms in older adults. The 2015 AGS Beers Criteria are applicable to all older adults with the exclusion of those in palliative and hospice care.

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47 c è anche l app (i-geriatrics)

48 uno strumento utile per le medicine

49 Quali strumenti abbiamo per prevenire DDI e ADR nel paziente anziano?

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51 PPOs: potential prescribing omissions; PIMs: potentially inappropriate medications..ma questa è un altra storia..