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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

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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

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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

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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

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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

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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

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LATUDA®

Generic Name Lurasidone

Dosages available 20 mg, 40 mg, 80 mg

Target dose Max recommended dose 80 mg

Average cost $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

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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

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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

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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

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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 10-15 % 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

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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

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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

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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

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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

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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

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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

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MIRTAZAPINE

Excessive sedation

Marked increase in appetite and weight gain

Comes in a dissolvable tablet

Often used as a sleep aid

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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

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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

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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

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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

High fat/protein snack

Snack at the bedside for the night

Avoid caffeine

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

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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

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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)

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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

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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

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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

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