1/23/2014 TOPICS PHARMACOLOGY: UPDATES AND REVIEW. Elizabeth Reeve MD HealthPartners Medical Group Gillette Children s Specialty Heath Care

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1 PHARMACOLOGY: UPDATES AND REVIEW Elizabeth Reeve MD HealthPartners Medical Group Gillette Children s Specialty Heath Care TOPICS General pharmacology concepts when prescribing for children and adults When to start, stop, or change? New medications and safety updates Tips for specific diagnoses and medications ADHD Depression Anxiety Psychosis Sleep Genomics 1

2 GENERAL CONCEPTS The choice of medication is not specific to the diagnosis Some antidepressants may be used for anxiety, depression, pain management, ADHD, sleep, bedwetting Choose a target symptom before the medication is started Communicate with all providers what the target symptom is and how it will be monitored Choose a measurable target symptom when possible Hours of sleep, frequency of panic attacks, hours doing compulsions For many patients medications should NOT be the first line of treatment Mild to moderate depression of anxiety GENERAL CONCEPTS Some patients are not able to explain/discuss side effects Side effects may mimic the symptoms you are trying to treat Agitation, anxiety, restlessness Doses in children are generally higher in mg per kg calculations than in adults Consideration must be given to the ability of the patient to be compliant with the medication schedule Ability to swallow a pill, frequency of dosing etc. must be considered WHO studies estimate that medication comlpiance for persons with chronic conditions is about 50% WHEN TO START Quality of life is impaired/functional impairment The presence of a symptom alone does not require that treatment be started There is a spectrum of tolerance for symptoms that depends on the individual, the family, and the other supports in place Assess developmentally appropriate spheres of activity in order to assess impairment Family, friends, work, school, hobbies Use collaborative information sources 2

3 WHEN TO START Recurrence of symptoms/illness that previously responded to medications Patient has tried alternatives to medications and is still not doing well Appropriate therapy has been utilized For example CBT for OCD Lifestyle changes have been implemented and have not resulted in enough benefit Sleep hygiene, decreased alcohol, exercise Medical evidence suggests efficacy for the chosen treatment Stimulants for ADHD, antipsychotics for psychosis WHEN TO STOP Change in the risk/benefit ratio Patient develops a new medical issue New side effects from the medication Tardive dyskinesia Side effects are not tolerated Lack of clear benefit that the treatment improves quality of life Symptoms have resolved and the treatment has been used for an appropriate amount of time Noncompliance or lack of supervision WHEN TO STOP Noncompliance/lack of supervision 15 year old with ADHD on atomoxetine 80 mg (60 kg wt) FU appt reveals recent worsening and mom is convinced the medications are not working. She would like a dose increase Interview reveals that the patient is responsible for taking medications and he misses about 2 days a week (M-F) and never takes the medications on weekends 3

4 WHEN TO CHANGE Lack of efficacy of the chosen treatment Correct dose for the correct amount of time Formulary issues Inability to adhere to dosing schedule Noncompliance Side effects not tolerated 4

5 NEW MEDICATIONS ON THE MARKET:ADHD Kapvay Approved for ADHD Extended release clonidine Needs to be given in twice daily dosing Start at 0.1 mg at night Increase in 0.1 mg increments as clinically indicate Maximum dose is 0.2 mg twice a day NEW MEDICATIONS ON THE MARKET:ADHD Quillivant XR Liquid methylphenidate product No better efficacy then other products already on the market 25 mg/5 ml Intuniv Extended release guanfacine Single daily dosing No efficacy advantage over short acting but compliance may improved NEW MEDICATIONS ON THE MARKET: ANTIPSYCHOTICS Three new antipsychotics Asenapine (Saphris ) Iloperidone (Fanapt ) Lurasidone (Latuda ) No FDA indications for children or adolescents Not on most formularies 5

6 SAPHRIS Generic Name Asenapine Dosages available Sublingual tablets: 5 mg and 10 mg Target dose For acute treatment of schizophrenia in adults, recommended dose 5 mg twice daily; maximum dose 10 mg twice daily; For treatment of bipolar disorder in adults, 10 mg twice daily Average cost $676 for one month at target dose Advantages over existing antipsychotics: Seems to cause fewer metabolic problems than other atypicals SAPHRIS Must be sublingual or no bioavailability Must not eat/drink at all for 10 minutes and then avoid food for 4 hours or bioavailability decreases by 20% Metabolized by 1A2 and inhibits 2D6 so has drug interactions Increased sedation May cause reflex tachycardia which can be frightening to patients FANAPT Generic Name Iloperidone Dosages available 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg Target dose 12 to 24 mg/day administered twice daily, achieved by daily dosage adjustments, alerting patients to symptoms of orthostatic hypotension Average cost $515 for one month target dose Advantages over existing antipsychotics Lower risk of EPS than Haloperidol, less akathisia than ziprasidone 6

7 LATUDA Generic Name Lurasidone Dosages available 20 mg, 40 mg, 80 mg Target dose Average cost Max recommended dose 80 mg $536 for one month at target dose Advantages over existing antipsychotics Does not seem to cause weight gain, increase lipids or glucose, increase prolactin, or cause QTC prolongation NEW MEDICATIONS ON THE MARKET: ANTIDEPRESSANTS NEW MEDICATIONS ON THE MARKET: ANTIDEPRESSANTS Silenor Branded version of doxepin Tricyclic, very sedating Marketed for sleep, not depression One month is about $200, generic doxepin is on the $4 list at many stores Marplan Re-release of isocarboxazid, and MAOI Generic not available, two other generic SSRI s are available 7

8 NEW MEDICATIONS ON THE MARKET: ANTIDEPRESSANTS Brintellix Vortioxetine SSRI and also an antagonist of 5_HT3A and 5-HT7, and partial agonist of 5_HT1B and agonist of 5-HT1A No added Benefit in trials that included paxil and duloxetine Not covered by most insurance NEW SAFETY UPDATES Cardiovascular effects of stimulants negligible New research suggests no greater risk for cardiac rhythm issues for children on stimulant medications Citalopram increases the risk for arrhythmias if used in doses over 40 mg Suicide link to antidepressants refuted Arch Gen Psych 2/6/12 8

9 BASIC FACTS Decide between stimulant versus nonstimulant medications History of not tolerating side effects of stimulants Baseline severe anxiety that could get worse with stimulants Substance abuse Tics that have worsened in the past with stimulants The presence of tics is not an absolute contraindication Lack of appropriate supervision Need for extended full day symptom coverage BASIC FACTS All stimulants have an equal chance of being efficacious Choice should be based on cost Duration of action desired Risk for abuse Formulary options Supervision at home 9

10 BASIC FACTS All stimulants have the same potential risk for side effects Individuals may have individual reactions Obtain baseline height and weight before starting medications and at every visit EKG is not usually necessary Consider obtaining baseline rating scales from teachers Not always needed and may depend on the reliability of the caregiver BASIC FACTS Doses can be changed frequently No need to wait for weeks on each dose. Give the family a schedule at the first visit to increase the dose or have them call within the first 3-4 days of use to get instructions for an increase If a nonstimulant is chosen remind the family that it will take weeks to work All the nonstimulants must be given every day, seven days a week in order to have benefit BASIC FACTS Stimulants can be stopped without any type of taper Remember, they are washed out everyday by the end of the day Nonstimulants may need to be tapered Clonidine/tenex products decrease every 2-3 days to avoid rebound hypertension Strattera is not dangerous to stop all at once but patient may have a sense of discomfort and withdrawal Buproprion can be stopped all at once Tricyclics should be tapered for the comfort of the patient and to prevent issues such as severe rebound insomnia 10

11 BASIC FACTS Stopping medications will result in ADHD symptoms returning unless the patient is now quite a bit older and has truly outgrown the symptoms Between 30-40% of patients will continue to have significant symptoms into adulthood There is not way to know when to stop medications You cannot predict who will outgrow the symptoms Consider family history If a parent still has symptoms it may impact the outcome for the child BASIC FACTS Most ADHD patients will respond to any stimulant you choose. However, if you have side effects or lack of efficacy then change from the first family you chose to another MAS/dexedrine methylphenidate MAS/dexedrine If you fail both main classes of stimulants then change to a nonstimulant such as guanfacine/clonidine or atomoxetine Keep in mind that % of ADHD patients may not be stimulant responders Consider using both a nonstimulant with a stimulant for partial responders THE DRUGS: STIMULANTS Methylphenidate products Long, short and mid acting Mixed amphetamine salt products Long and short acting Dexedrine products Long and short acting 11

12 STIMULANT SIDE EFFECTS Decreased appetite and resulting possible decreased weight Decreased height velocity Tics Sleep disturbance Headaches GI upset HEIGHT CHANGES Height can change independent of weight changes May of may not recover lost height Make sure you assess pubertal status Constitutional delay in growth If the choice is to continue stimulants have a clear discussion with the family and document well TICS Tics are not a contraindication to a trial of stimulants About a third get better, a third get worse and a third stay the same Consider changing to another stimulant but it may not help Tics that occur with stimulants stop when the stimulant is stopped and do not get worse if the stimulant is continued 12

13 SLEEP If given too late in the day stimulants may cause sleep problems Assess sleep hygiene Change to a shorter acting stimulant Change to a different stimulant Add a medication for sleep AFTER SCHOOL Rebound irritability Make sure there is time to transition Consider adding a short acting after school dose Change to twice daily dosing of a mid acting agent DIVERSION/ABUSE Short acting stimulants are highly sought out on college campuses and on the street Discuss supervision of medications at home Make a clear plan for college age patients 13

14 THE DRUGS: NONSTIMULANTS Alpha-2 adrenergic antagonists Clonidine and guanfacine products Short and long acting are available In general, guanfacine is less sedating Most be given 7 days a week Take 4-6 weeks for full benefit Atomoxetine Titrate to a dose of 1.4 mg/kg/day Must use of 6-10 weeks at an adequate dose to see the response THE DRUGS: COMBINATIONS OK to use a stimulant with a nonstimulant Alpha-2 plus stimulant Atomoxetine plus a stimulant Ok to use two nonstimulants Alpha -2 plus atomoxetine 14

15 BASIC FACTS Make sure that the patient has had an adequate trial of therapy if mild-moderate symptoms are present The benefit of medications for depression is only 50-60% Most likely first choice for anxiety or depression is an SSRI Always add therapy to medication when treating depression or anxiety All SSRI s have the same liklihood for efficacy but individuals may have varying responses. SSRI s may differ somewhat in side effects but all have the same possible side effects BASIC FACTS All SSRIs should be tapered EXCEPT fluoxetine. Because of a long half life it can just be stopped Stop treatment for depression after 9-12 months of effective treatment Anxiety is often a chronic long term condition and the decision to stop medications is very individualized 15

16 THE DRUGS SSRI s Fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, paroxetine SNRI s Venlafaxine, duloxetine Buproprion Mirtazapine Trazodone The really old ones Tricyclics and MAOI s The new ones SSRI SIDE EFFECTS Akathesia/restlessness fluoxetine Insomnia GI upset sertraline Sexual dysfunction Headache Weight gain paroxetine SPECIAL SSRI SIDE EFFECT ISSUES Possible increased muscle stiffness in at risk population CP In developmentally disabled kids restless may come across as increased aggression 16

17 VENLAFAXINE Increased blood pressure Weight gain Restlessness May be hard to taper off, some patients seem to be very sensitive to dose reductions Comes in long acting once a a day formulation DULOXETINE Has an FDA indication for peripheral neuropathy No added antidepressant effect Increased risk of cardiomyopathy at high doses BUPROPRION Slight increase in seizure risk Do not use in a patient with know clear history of seizures or current seizures Headaches Restlessness Sleep disturbance Poor choice for anxiety 17

18 MIRTAZAPINE Excessive sedation Marked increase in appetite and weight gain Comes in a dissolvable tablet Often used as a sleep aid 18

19 BASIC FACTS Does the prescriber have the expertise to prescribe this medication? Baseline labs must be drawn before or very shortly after starting antipsychotics Most patients should have fasting lipids and glucose at baseline and then every 6 months Educate patients about weight gain Behavioral strategies to prevent weight gain and increase exercise should be implemented BASIC FACTS Check weight and BMI before starting medications Discuss side effects thoroughly with families Weight gain can be managed better if families know weight gain is very likely to happen BASIC FACTS Withdrawal dyskinesias are very common when stopping or decreasing antipsychotics, especially in children Slow decrease can minimize dyskinesias They may last for weeks but do resolve If you have had a partial response to one antipsychotic and you are changing to another then taper the first and add the second 19

20 THE DRUGS The old drugs The second generation atypicals Risperidone Aripiprazole Olanzapine Quetiapine Ziprasidone The new drugs THE USES Psychosis and severe mood disorders such as bipolar disorder Adjunctive treatment in partial repsonders OCD, major depression and severe anxiety Aggression and explosive behavior Autism, developmental disabilities Severe temper tantrums? SIDE EFFECTS Weight gain Sedation or activation Aripirazole and ziprasidone tent o be more activating Metabolic syndrome Sexual dysfunction Menstural irregularity Elevated prolactin Risperidone: usually returns to normal in the first year of treatment 20

21 METABOLIC SYNDROME In my clinical experience most patients will have some change in their metabolic profile Decreased HDL first followed by increased triglycerides and finally increased LDL Reduce dose to minimal effective dose Use this class of medications only when absolutely needed Work to get them off meds when possible Change to a lower risk antipsychotic if appropriate METABOLIC SYNDROME All antipsychotics may cause metabolic syndrome Patients with schizophrenia have an increased risk for death even before treatment with antipsychotics Changes in lipids and glucose can occur even without any change in weight Quality of life can be highly impacted with a significant weight gain 21

22 BASIC FACTS Start medications only after extensive sleep hygiene efforts have been made Electronic restrictions None in the room Stop all exposure about an hour before bed Keep a regular schedule for going to and getting up from bed Make sure the patient is not hungry ADHD meds have worn off and appetites go up Avoid caffeine High fat/protein snack Snack at the bedside for the night BASIC FACTS Consider stopping medications only after a period of successful sleep and time to put in place good sleep hygiene practices Stop if side effects outweigh the benefit Excessive day time hangover effect Excessive weight gain Lack of efficacy Most sleep medications work right away, no need for build up Melatonin may be the exception 22

23 THE DRUGS Melatonin Trazodone May cause daytime sedation Clonidine So short acting that may have rebound insomnia when it wears off Mirtazapine Weight gain WILL occur Tricyclics Remember to get an EKG sleeping pills Quetiapine: last resort due to side effects Must get fasting labs even at a low dose GENOMICS Increased interest in choosing medications based on individual genetic inheritance Cytochrome P450 system is a family of liver enzymes used to metabolize many medications P450 2D6, 1A2, 2C19, 2C9 are the most commonly tested You can be a poor, intermediate, extensive, or ultrarapid metabolizer Extensive is normal GENOMICS Most insurance providers do not currently pay for genomic testing Some practitioners question practical aspects For example, slow 2D6 metabolizers may get increase side effects from fluoxetine Others feel the time savings may be crucial in successful treatment 23

24 CYTOCHROME P450 SYSTEM Drug metabolizing enzymes (DME) There is one specific gene for each enzyme. There is extensive variability in allele distribution of these genes. There is considerable variability in the distribution of these polymorphisms across different ethnic groups. FOUR COMMONLY TESTED DME GENES Cytochrome P450 2D6 (CYP2D6) Cytochrome P450 2C19 (CYP2C19) Cytochrome P450 2C9 (CYP2C9) Cytochrome P450 1A2 (CYP1A2) FOUR CLINICAL PHENOTYPES Poor Metabolizers (PM) Intermediate Metabolizers (IM) Extensive Metabolizers (EM) Ultra rapid Metabolizers (URM) 24

25 POOR METABOLIZER PHENOTYPE Poor Metabolizers (PM) range in severity of their ability to produce functional enzyme. Most patients with this phenotype have a serious inability to clear medications. These patients can suffer serious side effects. INTERMEDIATE METABOLIZER PHENOTYPE Intermediate Metabolizers (IM) may have a wide range of levels of enzyme activity. Some intermediate metabolizers have fairly adequate capacity to produce sufficient enzymes while others are more vulnerable. Inhibition by other medications of intermediate metabolizers is a more serious concern. EXTENSIVE METABOLIZER PHENOTYPE Extensive Metabolizers (EM) are normal Molecular biologists refer to them as wild types Current dosing schedules assume that the patient is an extensive metabolizer 25

26 ULTRA RAPID METABOLIZER PHENOTYPE Ultra rapid Metabolizers (URM) rapidly clear 2D6 substrate medications. This can minimize or eliminate the therapeutic response. These patients are almost always non-responders to 2D6 metabolized psychotropic medications. CYP2D6 Initially named the debrisoquine hydroxylase gene The most frequently genotyped psychiatric pharmacogenomic gene Highly variable with over 100 described variants Important psychotropic substrates include paroxetine, fluoxetine, venlafaxine, risperidone, and haldoperidol CHROMOSOME 22 26

27 CYP2C19 Initially named mephenytoin hydroxylase The second most frequently genotyped psychiatric pharmacogenomic gene Important psychotropic substrates include citalopram, escitalopram, amitriptyline, and diazepam Somewhat less variable than 2D6 CYP2C9 CYP2C9 can play a clinically significant role in the metabolism of amitriptyline, fluoxetine, and sertraline, if their primary metabolic pathway is not functional. CYP2C9 plays an important role in the metabolism of phenytoin and warfarin. CYP1A2 Originally named the phenacetin-0-de-ethylase gene Involved in the metabolism of caffeine Some variants can be induced by smoking Important psychotropic substrates include fluvoxamine, duloxetine, imipramine, clozapine and olanzapine 27

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