Smoking Cessation and psychotropic drug interactions

1. Smoking Cessation and psychotropic drug interactions Hazel Sharp Lead Directorate Pharmacist Clatterbridge Hospital introduce self/lisa days of work.introduce self/lisa days of work.

2. Objectives Background-Smoking in the MH patient Pharmacokinetic and Pharmacodynamic drug interactions Effect of smoking cessation on drugs Factors to consider when prescribing drugs during cessation Recommendations for prescribing during cessation Specific drug interactions

3. Smoking in the Mental Health Patient Estimated rate over double of general population Highest in those diagnosed with psychotic disorders Negative effect on physical, mental and financial well-being Aggravate symptoms, affect handling of medication, contribute to relapse Sure this comes as no surprsie to any of you and apologies if going over old ground.Sure this comes as no surprsie to any of you and apologies if going over old ground.

4. Pharmacokinetic interactions(what smoking does to the body) Affect the absorption, distribution, metabolism and elimination of drugs Cause an altered pharmacological response Induce (speed up and increase) hepatic enzymes Smoking increased plasma clearance, decreased absorption or enzyme inductionSmoking increased plasma clearance, decreased absorption or enzyme induction

5. Enzyme Induction Cigarette smoke contains polycyclic aromatic hydrocarbons (PAHs) (and it is these not nicotine) that induce the hepatic cytochrome enzymes CYP1A1, 1A2 and 2E1. Induce means (increase the amount and/or activity of) It is unclear how quickly the CYP enzymes are induced on commencing smoking. The inducing agent (PAHs in cigarette smoke) causes the synthesis of new enzymes however; it generally takes more than a week before maximal enzyme induction is seen. The extent or magnitude of induction varies according to the bioavailability of the cigarette smoke components (unfiltered cigarettes produce higher levels of some PAHs than filtered) and the extent of inhalation. Induce means (increase the amount and/or activity of) It is unclear how quickly the CYP enzymes are induced on commencing smoking. The inducing agent (PAHs in cigarette smoke) causes the synthesis of new enzymes however; it generally takes more than a week before maximal enzyme induction is seen. The extent or magnitude of induction varies according to the bioavailability of the cigarette smoke components (unfiltered cigarettes produce higher levels of some PAHs than filtered) and the extent of inhalation.

6. Pharmacodynamic Interactions(what the body does to the psychotropic drug) Hepatic enzymes metabolise (break down) some psychotropic drugs Enzyme induction increases metabolism of these drugs = decreased plasma concentration Higher doses may be required to achieve the same plasma level +therapeutic effect.  Heavier smokers have the greatest increase in drug clearance. In one study (Chetty et al, 1994 - 47), the combination of cigarette and cannabis smoking produced a greater increase in drug clearance than cigarette smoking alone.  Heavier smokers have the greatest increase in drug clearance. In one study (Chetty et al, 1994 - 47), the combination of cigarette and cannabis smoking produced a greater increase in drug clearance than cigarette smoking alone.

7. Effect of smoking cessation on psychotropic drugs Approximately 1 week for CYP1A2 activity to decrease Increased levels of drugs metabolised via CYP1A2 (eg: clozapine) Important if narrow therapeutic index In a study investigating the time frame for CYP1A2 changes on smoking cessation it was found that on stopping smoking there was a rapid decrease in activity of CYP1A2 with a new steady state being reached after approximately one week (Faber et al, 2004). In a study investigating the time frame for CYP1A2 changes on smoking cessation it was found that on stopping smoking there was a rapid decrease in activity of CYP1A2 with a new steady state being reached after approximately one week (Faber et al, 2004).

8. Effect of smoking cessation on psychotropic drugs Change in dose may be necessary Recommend stepwise daily dose reduction of approx 10% until the 4th day after smoking cessation Clear guidelines for clinical practice are not available Few reports on actual pharmacokinetic changes Limited data is available for most drugs. Few reports on actual pharmacokinetic changes Limited data is available for most drugs.

9. Factors to consider when prescribing during cessation  Smoking status Amount of tobacco smoked Expected changes to smoking status on leave/discharge i.e. light, moderate, or heavy smoker. This may correlate with the level of nicotine dependence. has the patient actually stopped smoking?) (will the patient resume smoking on leave or on discharge?) i.e. light, moderate, or heavy smoker. This may correlate with the level of nicotine dependence. has the patient actually stopped smoking?) (will the patient resume smoking on leave or on discharge?)

10. Factors to consider when prescribing during cessation Changes to drugs for other reasons Time delay for changes to CYP1A2 levels Age Liver dysfunction - less induction of CYP1A2 enzyme with increasing age . Liver dysfunction e.g. acute hepatitis following alcohol binge - less induction of CYP1A2 enzyme with increasing age . Liver dysfunction e.g. acute hepatitis following alcohol binge

11. Recommendations for prescribing during smoking Cessation  Ascertain pre-admission smoking status Determine effect on specific psychotropic medication (see table) Adjust dose side effects due to raised serum levels (or for lack of efficacy due to reduced serum levels – usually only the case when a patient is smoking without the knowledge of the treating team).change in smoking status on leaveside effects due to raised serum levels (or for lack of efficacy due to reduced serum levels – usually only the case when a patient is smoking without the knowledge of the treating team).change in smoking status on leave

12. Recommendations for prescribing during smoking Cessation Monitor for side effects Monitor for change in smoking status Predict smoking status on discharge

13. Antipsychotics Olanzapine - May ? olanzapine levels (? ? by 5mg ) Haloperidol - ? haloperidol level Chlorpromazine - Possible ? in level, clinical significance unclear. Fluphenazine - ? in plasma levels Olanzapine - in smokers olanzapine clearance higher and t 1/2 shorter in smokers than non smokers ,probably via CYP1A2 induction.Maudsley-takeplasma level? On stopping reduce dose by 25%.Then after 1 week repeat plasma level. Haloperidol -Maudsley-reduce plasma level by about 20%-reduce dose by 10% Fluphenazine- Maudsley- on stopping smoking reduce dose by 25%,monitor carefully over 4-8 weeks.Consider further dose reduction. Olanzapine - in smokers olanzapine clearance higher and t 1/2 shorter in smokers than non smokers ,probably via CYP1A2 induction.Maudsley-takeplasma level? On stopping reduce dose by 25%.Then after 1 week repeat plasma level. Haloperidol -Maudsley-reduce plasma level by about 20%-reduce dose by 10% Fluphenazine- Maudsley- on stopping smoking reduce dose by 25%,monitor carefully over 4-8 weeks.Consider further dose reduction.

14. Antipsychotics Flupenthixol, Trifluoperazine, Zuclopenthixol - limited data no interaction expected. Amisulpiride, Aripiprazole, Quetiapine, Risperidone - Limited data no interaction expected. Need to monitor patient for increase in adverse effects

15. Clozapine Plasma levels increase on stopping - may ? levels by as much 72%. Nomograms predict what dose of clozapine to use in smokers/non smokers.

16. Clozapine Formula: Using plasma level Non-smoking level=45.3 +(1.474 x smoking level) Take clozapine plasma level before stopping. Monitor level throughout(where useful). Assess for clinical efficacy and adverse-effects Process complicated ask Pharmacist for advice. Maudsley- Smoking reduces level by 50% (depends on number and type of cigareette smoked. Take plasma level before .On stopping reduce dose gradually over 1 week until abou 75% of dose .Repeat plasma level after1 week.Consider further reductions.If starts smoking increase dose back to normal dose over 1 week. Bazire-formula 80% of cases can be predicted.But if plasma level high formula may not be so effective.ie clozpine doses above 700mg or plasma level >700ng/ml.This is because CYP1A2 enzyme may become saturated with the substrate clozapine causing greater reduction in the rate of metabolism.Nomogram-difficult need clear copy Faber et al -recommend stepwise daily reduction of 10% until day 4 post smoking cessation as well as therapeutic monitoring.On cessation of smoking,reversal or decay of the induction of CYP1A2 occurs resulting in a 30% reduction of CYP1A2 acivity in approx 4 days.Serum clozapine levels riseand probably achieve steady state approx 7-10 after stopping smoking..Maudsley- Smoking reduces level by 50% (depends on number and type of cigareette smoked. Take plasma level before .On stopping reduce dose gradually over 1 week until abou 75% of dose .Repeat plasma level after1 week.Consider further reductions.If starts smoking increase dose back to normal dose over 1 week. Bazire-formula 80% of cases can be predicted.But if plasma level high formula may not be so effective.ie clozpine doses above 700mg or plasma level >700ng/ml.This is because CYP1A2 enzyme may become saturated with the substrate clozapine causing greater reduction in the rate of metabolism.Nomogram-difficult need clear copy Faber et al -recommend stepwise daily reduction of 10% until day 4 post smoking cessation as well as therapeutic monitoring.On cessation of smoking,reversal or decay of the induction of CYP1A2 occurs resulting in a 30% reduction of CYP1A2 acivity in approx 4 days.Serum clozapine levels riseand probably achieve steady state approx 7-10 after stopping smoking..

17. Antidepressants SSRIs - Citalopram, Escitalopram, Fluoxetine, Paroxetine+Sertraline - limited data no interaction expected. Fluvoxamine- possible ? levels, may need ? to the dose. TCAs - Amitriptyline, Clomipramine, Dothiepin, Imipramine - possible increase in levels , may need to reduce the dose. Nortriptyline - Conflicting reports may need to reduce the dose. TCAs -plasma levels reduced by 25-50%.Monitor closely consider reducing the dose by 10-25% over 1 week. Bazirre-serum levels fall in smokers,free level rise, minimising the clinical significance TCAs -plasma levels reduced by 25-50%.Monitor closely consider reducing the dose by 10-25% over 1 week. Bazirre-serum levels fall in smokers,free level rise, minimising the clinical significance

18. Antidepressants Others Duloxetine- possible plasma level ? by 50%, may need ? to the dose. Mirtazepine- possible plasma level ?, may only have to ? high doses. Reboxetine and Venlafaxine- limited data, no interaction expected Duloxetine- smokers may have plasma levels 50% lower than than non smokers.Bazirre Duloxetine- smokers may have plasma levels 50% lower than than non smokers.Bazirre

19. Mood Stabilisers Carbamazapine-interaction unlikely but possible Lamotrigine- Levels may be ?. Consider dose reduction Lithium- no interaction but monitor caffeine intake Sodium Valproate-limited data. Monitor patient. If patient taking caffeine levels will rise on smoking cessation which will cause lithium levels to fall. May need to increase lithium levels.Do weekly bloods and monitor for adverse effects. Patient may need to reduce caffeine intake.If patient taking caffeine levels will rise on smoking cessation which will cause lithium levels to fall. May need to increase lithium levels.Do weekly bloods and monitor for adverse effects. Patient may need to reduce caffeine intake.

20. Other Drugs Benzodiazepines - Possible ? in plasma levels-consider reducing dose (doses should be reviewed regularly anyway) Insulin- May ? insulin levels. Monitor BMs and reduce dose if necessary.