Médicaments et jeûne - Pr KHABBAL Yousef

1. Médicaments et jeûne
Fès, le 20 Juillet 2013
Pr KHABBAL Youssef

2. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefGénéralités

3. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Deux approches
oImpact du RAMADAN sur la prise des médicaments
oImpact des médicaments sur RAMADAN

4. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Impact des médicaments sur Ramadan Voies d’administrationBut pharmacologique
Thérapeutique
Alimentaire

5. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Impact du ramadan sur la prise des médicaments
Interaction médicament et jeûne
Influence de la fréquence d’administration
Changement de l’horaire d’administration

6. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefInteraction jeûne et médicamentEstomac vide ou plein Le comportement alimentaire → teneur en graisse

7. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefInfluence de la fréquence d’administrationLes repères temporels: le lever, les trois repas et le coucherDurant ramadan: Deux repasMédicaments temps dépendants

8. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Horaire de prise médicamenteuseReport des prisesRythme circadien

9. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefPreuves tangibles que toutes les fonctions du corps y compris ceux qui influencent les paramètres cinétiques tels que le système cardio- vasculaires , hépatique et rénale sont organisés dans le temps et ont des variations quotidiennes importantes

10. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefLITTÉRATURE RÉCENTE

11. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
RÉSULTATS: un total de 192 articles de journaux, 41 L'hypothèse spécifique pour l’impact de la chronothérapie :
chronoeffectiveness (n = 34),
chronopharmacocinétique (n = 5),
chronopharmacodynamics (n = 2).
Les résultats de deux tiers (n = 27) des études examinées, appuient l'idée de la chronothérapie.

12. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Perspectives on the chronotherapy of hypertension based on the results of the MAPEC study. Portaluppi F,Smolensky MH.Chronobiol Int.2010 Sep;27(8):1652-67. AbstractAppreciation of chronotherapy in hypertension continues to lag, despite clear demonstrations by many studies of (i) clinically relevant dosing-time differences of the beneficial and adverse effects of most blood pressure (BP) medications and (ii) significant association between reduced sleep-time BP decline of non-dippers and their heightened risk of cardiovascular disease (CVD). The Syst-Eur and HOPE outcome trials showed evening administration of nitrendipine and ramipril in these respective studies impacts sleep-time BP, converting the 24-h BP pattern to a more dipper one and in the HOPE study decreasing CVD risk. The CONVINCE study intended to compare BP control and CVD protection afforded by conventional β-blocker and diuretic medications versus a special drug- delivery verapamil formulation as a bedtime hypertension chronotherapy; however, the trial was terminated prematurely, not based on inadequate performance of the chronotherapy but on a corporate business decision. The just completed MAPEC study is the first trial specifically designed to prospectively test the hypothesis that bedtime administration of ≥1 conventional medications exerts better BP control and CVD risk reduction than the traditional approach of scheduling all medications in the morning. The results of this 5.6-yr median follow-up study establish that bedtime chronotherapy more effectively improves BP control, better decreases prevalence of non-dipping, and, most importantly, best reduces CVD morbidity and mortality. This chronotherapeutic approach to hypertension is justified by the fact that BP is usually lowest at night as is sodium excretion, but when sodium intake is excessive or its daytime excretion hampered, nocturnal BP is adjusted higher, to a level required for compensation overnight, via the pressure/natriuresis mechanism, resulting in non-dipping 24-h BP patterning. In diurnally active persons, the entire circadian BP pattern may be reset to a lower mean level and to a "more normal" day-night variation, simply by enhancing natriuresis during the night-the time-of-day when it can be most effective. A modification as simple and inexpensive as switching ≥1 hypertension medications from morning to evening may be all that is needed to normalize nighttime BP, exerting an effect exactly like sodium restriction. Current clinical concepts such as "normotensive non- dipper" (with higher CVD risk than a hypertensive dipper), broad recommendation of pharmacotherapy with exclusively high "smoothness index" medications (without attention to individual patient needs defined by the features of the 24-h BP pattern), and reliance upon static daytime diagnostic BP thresholds based solely on single office cuff assessment necessitate urgent reconsideration.

13. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefCancer chronotherapeutics: experimental, theoretical, and clinical aspects. Ortiz-TudelaE,MteyrekA,BallestaA,InnominatoPF,LéviF.HandbExp Pharmacol.2013;(217):261-88. AbstractThe circadian timing system controls cell cycle, apoptosis, drug bioactivation, and transport and detoxification mechanisms in healthy tissues. As a consequence, the tolerability of cancer chemotherapy varies up to several folds as a function of circadian timing of drug administration in experimental models. Best antitumor efficacy of single- agent or combination chemotherapy usually corresponds to the delivery of anticancer drugs near their respective times of best tolerability. Mathematical models reveal that such coincidence between chronotolerance and chronoefficacy is best explained by differences in the circadian and cell cycle dynamics of host and cancer cells, especially with regard circadian entrainment and cell cycle variability. In the clinic, a large improvement in tolerability was shown in international randomized trials where cancer patients received the same sinusoidal chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed chronotherapy. However, sex, genetic background, and lifestyle were found to influence optimal chronotherapy scheduling. These findings support systems biology approaches to cancer chronotherapeutics. They involve the systematic experimental mapping and modeling of chronopharmacology pathways in synchronized cell cultures and their adjustment to mouse models of both sexes and distinct genetic background, as recently shown for irinotecan. Model-based personalized circadian drug delivery aims at jointly improving tolerability and efficacy of anticancer drugs based on the circadian timing system of individual patients, using dedicated circadian biomarker and drug delivery technologies.

14. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefChronopharmacology of anti-convulsive therapy. Ramgopal S,Thome-Souza S,Loddenkemper T.Curr Neurol Neurosci Rep.2013 Apr;13(4):339. AbstractApproximately one-third of patients with epilepsy continue to have seizures despite antiepileptic therapy. Many seizures occur in diurnal, sleep/wake, circadian, or even monthly patterns. The relationship between biomarkers and state changes is still being investigated, but early results suggest that some of these patterns may be related to endogenous circadian patterns whereas others may be related to wakefulness and sleep or both. Chronotherapy, the application of treatment at times of greatest seizure susceptibility, is a technique that may optimize seizure control in selected patients. It may be used in the form of differential dosing, as preparations designed to deliver sustained or pulsatiledrug delivery or in the form of 'zeitgebers' that shift endogenous rhythms. Early trials in epilepsy suggest that chronopharmacologymay provide improved seizure control compared with conventional treatment in some patients. The present article reviews chronopharmacologyin the treatment of epilepsy as well as future treatment avenues.

15. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Points communsUn médicament consommé avec la même dose et dans des conditions identiques présente un profil cinétique et dynamique différent entre le jour et la nuitPharmacologie phénomène circadien phase dépendant

16. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefFONDEMENT SCIENTIFIQUE

17. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefApproche chronobiologique de la pharmacologie

18. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefReconnaitre les paramètres pharmacologiques qui peuvent être influencer par ramadanExpliquer les mécanisme auxquels ils obéissent.

19. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef

20. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
1. Absorption = RésorptionPénétration du médicament dans le sang à partir de son lieu d’absorption. Le PA dissous traverse les membranes biologiques pour pénétrer dans le circulation sanguine. Cette étape n’existe pas lorsque le médicament est introduit directement dans la circulation par voie intraveineuse

21. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefVariations circadiennes de l’absorption des médicaments
Vidange gastrique et absorption intestinale
Substance dont la solubilité est faible
Indométacine, furosémide,
Autres facteurs:
Ph gastro-intestinal: délitement, ionisation
Motilité de l’intestin
Taux de perfusion d’organe: Circulation sanguine intestinale

22. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef2. DistributionJuste après l’absorption, le Mdt parvient dans le plasma où il se trouve sous deux formes:
Forme liée aux protéines plasmatiques –Sorte de réserve en PA
Forme libre seule responsable de l’action pharmacologiqueLiaison aux protéines plasmatiques
M+ PMP

23. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Variations circadiennes de la distribution des médicaments
La perméabilité membranaire
Erythrocyte: lidocaine, metformine
Barriere hematomeningé: valproate
La liaison aux protéine
Rôle de transport
Fraction libre active
L’albumine; l’alpha1-glycoproteine, globuline sérique
Chute nocturne
Différence de 20 % chez le sujet âgé
Effets indésirables Diazépam

24. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef3. Métabolisme
Les transformations métaboliques concernent la plupart des médicaments
Site de métabolisme:foie (+++), poumons, rein
Réactions:
M M-OHM-O-Conjugué
Élimination urinaire ou biliaire Phase IPhase II

25. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefVariations circadiennes du métabolisme des médicaments
Rythme circadien des enzymes hépatique
Le Vmaxet Kmaxenzymatique sont 4 fois plus grandes le jour, ex: sulfotransférase
Le jeûne ne modifie pas ces rythmes.
La circulation sanguine hépatique est plus grande à la fin de la journée

26. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
4. Elimination
1) Filtration glomérulaire:passage de substances du sang vers l’urine
2) Résorptionde substances de l’urine vers le sang
3) Excrétionfinale du plasma vers l’urineGloméruleArtériole AfférenteArtériole efférente
Urine définitive
1
23
NEPHRON

27. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefVariations circadiennes de l’élimination des médicamentsPh urinaire:
basique le matinFiltration glomérulaire pdt le jour en relation la tension artérielle.

28. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef

29. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef

30. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
ChronoesthésieChronoefficacité et ChronotoléranceSusceptibilité des système ciblesNombre de récepteur B max

31. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Circadianchangesinanticoagulanteffectofheparininfusedat a constant rate. Decousus HA,Croze M,Levi FA,Jaubert JG,Perpoint BM,De Bonadona JF,Reinberg A,Queneau PM. Six patients with venous thromboembolismwere treated withheparin, administered intravenously by a constant infusion pump. The initial daily dose ofheparinwas adjusted to keep the activated partial thromboplastintime, sampled at 0800, between 1.5 and 2.5 times the control level. Once that level was obtained, this dose was kept constant. Anticoagulation was thereafter measured, every four hours for 48 hours, by activated partial thromboplastintime, thrombin time, and coagulation factor Xainhibition assay. The results of all three coagulation tests showed acircadianvariation in the six patients. Maximum values were achieved at night and minimum values in the morning.Thesecircadianvariations were reproduced for two consecutive days. Differences between night and morning values reached almost 50% for activated partial thromboplastintime, 60% for thrombin time, and 40% for factor Xainhibition assay. Thiscircadianvariation resulted from two rhythms, acircadianrhythm lasting 24 hours and an ultradianrhythm lasting 12 hours, which were detected by cosinoranalysis for each coagulation test (p less than 0.01). Acircadianrhythm was detected individually in most of the patients for each coagulation test (p less than 0.05). All patients had a nocturnal peak in activated partial thromboplastintime on both days. In four patients this peak exceeded the upper desired limit of activated partial thromboplastintime. These rhythms should be taken into account when evaluating the dosage ofheparinto be administered.

32. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Comparison of once-daily evening versus morning sustained-release theophylline dosing for nocturnal asthma. Reinberg A,Pauchet F,Ruff F,Gervais A,Smolensky MH,Levi F,Gervais P,Chaouat D,Abella ML,Zidani R.
Eight diurnally active (approximately 0730-1100 hr) adults (41-61 yr) suffering from nocturnal asthma volunteered for a double-blind, cross-over randomized study of a once-daily dosing (600-900 mg/24 hr) of Armophylline (Rorer s.a., France), a sustained-release theophylline given either at 0800 hr or 2000 hr for 8-day durations. Study variables monitored daily were: (a) self-measured peak expiratory flow (PEF), heart rate, oral temperature and self-rated fatigue checked every 2 hr during the waking span as well as upon spontaneous nocturnal awakenings and (b) duration and subjective characteristics of sleep rated every morning. In addition, serum theophylline concentration (STC) plus the variables in (a) were sampled every 2 hr during the 24 hr of the eighth day of each timed treatment span. Rx at 0800 hr was associated with a nocturnal dip in PEF of 20 +/-2.8% (X +/- S.E.M.) from the level achieved at the time of the diurnal crest; Rx at 2000 hr moderated the nocturnal fall; it was only 10 +/-2.1% and within the physiologic limits of non-asthmatic persons. The STC peak height (Cmax) was greater (P less than 0.05) and time-to-peak (Tmax) shorter (P less than 0.005) with Rx at 0800 hr than at 2000 hr. With Rx at 2000 hr an STC plateau of approximately 12 hr resulted. A statistically significant correlation (r = 0.86; P less than 0.01) between PEF and the corresponding-in-time STC was observed with Rx at 2000 hr but not with Rx at 0800 hr. A small, but statistically significant, higher heart rate resulted from 2000 hr dosings in five out of eight subjects relative to the 0800 hr dosing. There were no differences in the sleep characteristics nor in oral temperature between dosing times. Once-daily (600-900 mg) SRT dosing at 2000 hr controlled the nocturnal dip of bronchial patency with no major side-effects in diurnally active adult patients with nocturnal allergic asthma.

33. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Circadianchangesof thedurationof action of local anaesthetic agents. ReinbergA,ReinbergMA. Abstract
A statistically significantcircadianrhythm of thedurationof local anaesthesiaproduced by lidocaineand betoxycainewas found in both human skin and teeth. In adult subjects with diurnal activity and nocturnal rest the longestdurationwas found around 15.00 (3 p.m.) with a large peak-trough difference amounting to more than 100% of the 24 h mean. Such chronopharmacologicrhythm might be related tocircadianrhythms in catecholamine secretion and/or incircadianchangesof cell membrane properties.

34. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Heure de l’injection
Durée de l’anesthésie
8 h
12 min
15h
30 min
18h
17 min
Méthodologie:
35 sujet
Anesthésie para apicale d’une dent
Intervention sur dent vivante
Ampoule de 2ml de lidocaine 2p100Résultats:

35. Fès, le 20 Juillet 2013
Pr KHABBAL YoussefTable des heures d’administration
molécule
effet
antihistaminique
Efficacité maximale le soir
Tolérance excellentequelque soit l’heure d’administration
Anesthésiqueslocaux
À15H dure 2 à FOIS Vs 7H
cancérologie
Adriamycine
Meilleure tolérance et meilleure efficacité en perfusion avec un maximum à 6H
Cisplatine
Meilleure tolérance et meilleure efficacité en perfusion avec un maximum à 18H
Antihypertenseurs:
•Bétabloquant
•Diurétique
•Inhibiteur du canal calcique
Meilleur activitédiurne que nocturne

36. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef
Conclusion
•Lareconnaissancedelastructuretemporelledel’organisme
•Impactduramadansurlesmédicamentsestimpactchronopharmacologique
•L’heuredelajournéedoitêtreinclusdanslastratégiethérapeutiquepouradapterlaposologie

37. Fès, le 20 Juillet 2013
Pr KHABBAL Youssef