Fumo attivo, fumo passivo e farmaci

Centro Antifumo (interdipartimentale) AOU Policlinico di ModenaStruttura Complessa di Farmacologia e Tossicologia Clinica

(Direttore: Prof. A. Tomasi)

Maria Michela Cainazzo, Ilaria Tiraferri

Modena, 24 Maggio 2011

La nicotina (C10H14N2) è una sostanza dotata di forte lipofilia e ciò le consente, indipendentemente dalla via di assunzione, di attraversare la b.e.e. e di raggiungere rapidamente il Sistema Nervoso Centrale (SNC) a livello del quale esplica le sue funzioni eccitatorie.

N

N

CH3

si accumula prevalentemente a livello cerebrale, epatico, renale e nel tessuto adiposo

Struttura e metabolismo della nicotina nell’uomo

La principale via di metabolizzazione della nicotina è la C-ossidazione epatica; circa il 70-80% della dose di nicotina inalata viene metabolizzata a cotinina; quest’ultima è ulteriormente metabolizzata a trans-3’idrossicotinina. Ambedue le reazioni sono catalizzate dal CYP2A6.

esposizione regolare al fumo passivo aumenta del 99% il rischio di sdr coronarica acuta

aumento del 20-30% del rischio di insorgenza di neoplasie polmonari

peggiora le patologie polmonari preesiste

aumento del 40% di sviluppare il diabete

sindrome da distress respiratiorio infantile

riacutizzazione di asma e patologie orecchio medio (otite media) nei bambini

aumento del rischio di eventi cardiaci fatali e non fatali

Rischi associati al fumo passivo

Per interazione tra farmaci si intende il fenomeno che si realizza quando gli effetti (tossici o terapeutici) di un farmaco A sono modificati dalla precedente o concomitante assunzione di uno o più agenti farmacologici (B, C...)

Il fenomeno può divenire clinicamente significativo qualora la risposta globale successiva alla somministrazione ravvicinata o simultanea di due o più composti è marcatamente diversa dalla semplice somma degli effetti che ciascun composto avrebbe esercitato se dato individualmente o dagli effetti che il composto principale avrebbe avuto se somministrato da solo.

Interazioni tra farmaci

Sono intese come una modifica o un’alterazione dell’assorbimento, della distribuzione (trasporto), del metabolismo o della escrezione di un farmaco (A) sotto l’influenza di un secondo farmaco (B). Le interazioni farmacocinetiche sono quelle con maggiore significato clinico.

Interazioni farmacocinetiche

Interazioni farmacodinamiche

Le interazioni farmacodinamiche sono definite come una modifica della risposta farmacologica di un farmaco A in seguito all’azione diretta o indiretta di un farmaco B a livello del recettore o della funzione, senza modifica concomitante delle concentrazioni dei farmaci in causa.

CYP3A4

CYP2D6

CYP2B6

CYP2C9

CYP2C19

Sono i principali enzimi appartenenti al complesso enzimatico del citocromo P450 responsabili del 90% del metabolismo ossidativo dei farmaci

Gli enzimi del citocromo P450 sono presenti in quasi tutti i tessuti, il contenuto enzimatico maggiore, espresso in nmol/mg di proteine microsomiali, è nel fegato; i CYPs si localizzano, anche, in intestino, polmone, rene, ghiandole surrenali, cervello, cuore, gonadi, mucosa tracheale e cute. Nel genoma umano sono stati individuati 57 geni codificanti per i CYP; sono geni polimorfi, le cui numerosi varianti alleliche possono codificare enzimi funzionalmente inefficaci; la conseguenza della ridotta attività enzimatica si manifesta con la comparsa di reazioni avverse nell’individuo (elevate concentrazioni plasmatiche).

Relative abundance of individual CYP forms in the liver and some examples of substrates, inhibitors and inducers. CYPs with clinically significant genetic polymorphism in gray. Phenob. phenobarbital, TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin, nk not known

Pelkonen O. et al, 2008

Le interazioni clinicamente evidenti tra fumo di sigaretta e farmaci possono essere interazioni di tipo farmacocinetico oppure interazioni di tipo farmacodinamico

Gli idrocarburi aromatici policiclici, potenti induttori del citocromo P450, sono responsabili delle interazioni farmacocinetiche

La nicotina può causare le interazioni farmacodinamiche

Il fumo di sigaretta ha effetto variabile sulla concentrazione plasmatica di amitriptilina e nortriptilina; non ha nessun effetto sul clordiazepossido; modifica poco la concentrazioni plasmatica della carbamazepina per le proprietà specifiche di autoinduzione epatica del farmaco.

Idrocarburi aromatici policiclici

Desai HD, et al., 2001

Role of human UGT2B10 in N-glucuronidation of tricyclic antdeprassant, amitripyline, imipramine, clomipramine, and trimipramine

Zhou D, Guo J, Linnenbach AJ, Booth-Genthe CL, Grimm SWDrug Metab Dispos 38(5):863-70, 2010

Nicotine was found to selectivity inhibit UGT2B10 but not UGT1A4 activity. At a low tricyclic antideprassant concentration, nicotine inhibited their glucuronoconidation by 33 to 50% in human liver microsomes. Our results suggest that UGT2B10 is a high-affinity enzyme for tricyclic antidepressant glucuronidation and is likely to a major UGT isoform responsible for the glucuronidation of these drugs at therapeutic concentration in vivo

Effects of nicotine on cytochrome P4502A6 and 2E1 activities Hukkanen J et al.

British J of Clinical Pharmacol 2009; 69:152-159

Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone; nicotine is a useful probe for CYP 2A6 activity; chlorzoxazone is a frequently used probe for CYP 2E1 activity; the tobacco smoke constituents responsible of those modifications are unknown

Human CYP2A6 and CYP2E1 are not affected by nicotine. High-dose nicotine treatment has a low potential for interaction with CYP2A6 CYP 2 E1 substrates

Chronic smoking inhibits CYP 2A6-mediated metabolism; there are substances in tobacco smoke, as yet unidentified, that inhibit the metabolism of nicotine

INITIATION

PROPAGATION

CLOT FORMATION

ANTHITROMBIN

Il fumo di sigaretta accelera la clereance dell’eparina; si riduce, pertanto la quota di eparina che potenzia l’attività dell’antitrombina (ATIII); l’eparina normalmente incrementa l’intensità della reazione trombina-antitrombina, che porta alla formazione di un complesso ATIII-T inattivato in grado di inibire il fattore Xa e IIa. L’aumentata eliminazione dell’eparina può causare trombofilia.

EPARIN

Median C-peptide-corrected insulin concentratio-time profiles in the presence and absence of passive smoke exposure. EXU, inhaled human insulin (Exubera). Passive smoke + EXU ( ); EXU 3 mg alone ( ).

Acute passive cigarette smoke exposure and inhaled human insulin pharmacokineticsFountaine R. et al.

British J of Clinical Pharmacol 2007; 65:864-870

Acute passive cigarette smoke exposure and inhaled human insulin pharmacokineticsFountaine R. et al.

British J of Clinical Pharmacol 2007; 65:864-870

Active cigarette smoking is associated with increased permeability of the pulmonary alveolar epithelium, resulting in faster absorption of inhaled drugs such as inhaled human insulin; its absorption is increased approximately twice to four times as much in chronic smokers compared with nonsmokers

Passive smoke exposure causes a decrease in lung permeability, an effect opposite to that of active smoking

Acute passive smoke exposure results in a decrease in inhaled human insulin bioavaibility and does not create a risk of hypoglicemia

Effect of smoking cessation, acute re-exposure and nicotine replacement in smokers on AIR inhaled insulin pharmacocokinetics and glucodynamicsPan A.X. et al.

British J of Clinical Pharmacol 2007; 65: 480-187

Effect of Cigarette Smoking and Cytochrome P450 2D6 Genotype on Fluvoxamine Concentration in Plasma of Japanese PatientsKatoh Y. et al.

Biol. Pharm. Bull. 2010; 33:285-288

Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine-alprazolam interaction in patients with psychosomatic diseaseSugahara H. et al.

Eur. J. Pharmacol 2009; 65:699-704

Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and distrupt blood-brain barrier integrity

Manda V.K. et al.

J of Neurochemistry 2010; 115:515-525

Chronic administration of nicotine, saquinavir and ritonavir or the combination of drugs create ROS in vivo in brain tissue, measured by fluorescence emitted by DHE. The upper panel in (a) shows the qualitative images for the ROS generated in control and treatment groups. The fluorescent quantification of the ROS was shown in lower panel. *** indicate p < 0.001. To see whether ROS is associated with blood vessels, brain sections were stained with CD31 and the representative pictures both at lower and higher magnification were shown in panel (b).

Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 espressione and distrupt blood-brain barrier integrityManda V.K. et al.

J of Neurochemistry 2010; 115:515-525

Chronic administration of saquinavir, ritonavir in presence of nicotine and cigarette smoke extract at pharmacological doses results in BBB disruption as evidenced by an increased brain distribution volume of the vascular impermeant marker [14C]-sucrose. In this experiment, concurrent exposure to nicotine and the protease inhibitor resulted in a significantly greater volume of distribution for [14C]-sucrose than control animals and or the chronic administration of either alone. This data strongly suggests the BBB is disrupted during chronic nicotine and protease inhibitor administration. All data represent the mean ± SEM, n = 4–6 independent experiments. *** indicates significance at a value of p < 0.001.

Carbamazepina but not valproate induces CYP2A6 activity in smokers with mental illnessWilliams JM et al. Cancer Epidemiol Biomarkers Prev 2010; 19: 2582-9

CONCLUSIONS Carbamazepine likely induces hepatic metabolism via CYP2A6 and is associated with increased 3HC/cotinine ratios. Increased nicotine metabolism in individuals using AED has implications for increased smoking behavior and exposure to more tobacco toxins

3HC/cotinine ratios in smokers taking carbamazepine (CBZ; n= 14) versus those not taking it (n= 135) in total sample and mental health subgroups. OCB, oxcarbazepine; SCZ, schizophrenia; BPD, bipolar disorder. **P < 0.001; *P < 0.05, Mann-Whitney test.

3HC/cotinine ratios in smokers taking valproic acid (n = 40) versus those not taking it (n= 109) in total sample and mental health subgroups

Interazioni farmacodinamiche della nicotina

Contraccettivi ormonali Steroidi Beta-bloccanti Benzodiazepine Oppioidi

DATA SYNTHESIS: The summary risk estimates associated with current use of low-dose OCs were 1.84 [95% confidence interval (CI) = 1.38, 2.44] for myocardial infarctions and 2.12 (95% CI = 1.56, 2.86) for ischemic strokes. The overall summary odds ratio for both outcomes was 2.01 (95% CI = 1.63, 2.48). Second generation OCs were associated with a significant increased risk of both myocardial infarction and ischemic stroke events [1.85 (95% CI = 1.03,3.32) and 2.54 (95% CI = 1.96,3.28), respectively]; and third-generation OCs, for ischemic stroke outcome only [2.03 (95% CI = 1.15,3.57)].

CONCLUSIONS: In conclusion, a rigorous meta-analysis of the literature suggests that current use of low-dose OCs significantly increases the risk of both cardiac and vascular arterial events, including a significant risk of vascular arterial complications with third generation OCs

Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis.Baillargeon JP, McClish DK, Essah PA, Nestler JE.

J Clin Endocrinol Metab, 2005; 90: 3863-3870

Dexamethasone attenuation of the cortisol response to nicotine in smokersPomerleau OF, Pomerleaau CSPsychopharmacology 1990; 101:284-6

The dexamethasone condition was characherized by a pronunced suppression of baseline plasma cortisol, as expected and by a significant dampening of cortisol response to nicotine, indicating diminished sensitivity to nicotine under contiditions of enhaced corticosteroid activity.

Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthmaChaudhuri R et al.AM J Respir Crit Care Med, 2003; 168:1308-1311

Il fumo di sigaretta si associa ad aumento dei neutrofili nell’espettorato e ad una riduzione della risposta bronchiale agli steroidi assunti per via orale perchè nei fumatori si ha

TNF-α β recettori per i glucocorticoidi sulla superficie bronchiale attivazione di NF-kB

attività della deacetilasi a livello dell’istone; aumento dell’espressione genica dei mediatori della flogosi

Inhaled steroid/tobacco smoke particle interactions: a new light on steroid resistanceInvernizzi G. et al.Respiratory Research 2009; 10, 48-57

CONCLUSION: Our data suggest that particle interaction between inhaled BDP-HFA (beclomethasone-hydrofluoralkane) pMDI and ETS takes place in the first few seconds after drug delivery, with a decrease in smaller particles and a concurrent increase of larger particles. The resulting changes in aerosol particle profile might modify regional drug deposition with potential detriment to drug efficacy, and represent a new element of steroid resistance in smokers. Although the present study does not provide any functional or clinical assessment, it might be useful to advise smokers and non smokers with obstructive lung disease such as asthma or COPD, to avoid to act inhaled drugs in the presence of ETS in order to obtain the best therapeutic effect

Particles frequency of BDP-HFA pMDI delivered in ambient air (open columns) and in ETS (black columns). Particles sized 0.3–1.0 μm, which predominated in ambient air, were again no longer measurable in ETS, particles in the range of 1.0 to 3.0 μm in diameter being mostly represented.

Interazioni tra fumo di tabacco e farmaci

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