Pharm III: L4

Drug Classes to treat Schizophrenia (2)

- First Generation Antipsychotics "Typical" (FGA)

- Second Generation Antipsychotics "Atypical (SGA)

First Gen Antipsychotics "Typical" (3)

- Haloperidol

- Chlorpromazine

- Fluphenazine

High Potency FGAs "Typical"

- Haloperidol

- Fluphenazine

Low Potency FGAs "Typical"

Chlorpromazine

Main ADEs for FGAs

increased movement and prolactin ADE

2nd Gen Antipsychotics "Atypical": 'pines' (3)

- Clozapine

- Quetiapine

- Olanzapine

2nd Gen Antipsychotics "Atypical": dones (3)

- Risperidones

- Ziprasidone

- Lurasidone

2nd Gen Antipsychotics "Atypical": 3rd Generations (4)

- Aripiprazole

- Brexpoprazole

- Cariprazine

- Lumateperone

Main ADEs for SGAs

Metabolic problems

Greatest risk for metabolic ADE:

Clozapine and Olanzapine

If there is only a minimal response to a antipsychotic drug in the first 2 weeks, will the patient have a good response to that drug?

Unlikely

SGA: Metabolic syndrome monitor (7)

- weight/BMI/waist circumference

- fasting glucose/A1c

- lipids

- increased prolactin

- QTc prolongation

- sedation

- EPS throughout tx course

Class with greatest risk of Extrapyramidal sx (EPS)

FGAs

EPS AE: Acute Dystonia

- painful, sustained contractions causing complete paralysis

- common in young males

- onset: hours to days

- reversible

How to treat Acute dystonia

- IM/IV Benztropine or Diphenhydramine

- airway emergency risk

EPS AE: Akathisia

- inner restlessless with pacing, shifting; inability to stay still

- mc EPS sx

- onset: days to weeks

- usually reversible

EPS AE: Akathisia tx (3)

- reduce dose of offending drug or switch

- propranolol (1st)

- consider benzodiazepine short term

EPS AE: Parkinsonism

- usually reversible

- takes weeks to months

EPS AE: Parkinsonism sx

- bradykinesia

- rigidity/cogwheeling

- resting tremor

- mask-like facies (lack expresson

- shuffling gait

EPS AE: Parkinsonism tx (3)

- reduce dose of offending drug or switch

- benxtropine (anticholinergic): 1st

- amantadine (dopaminergic): 2nd

EPS AE: Tardive Dyskinesia

- onset: months to years

- can be irreversible

- involuntary choreoathetoid movements

- oro-facial dyskinesias (lip smacking, tongue protrusion, chewing)

- choreoathetoid limn/trunk movements

EPS AE: Tardive Dyskinesia - what drug is it most common with?

FGAs

EPS AE: Tardive Dyskinesia

Which antipsychotic has the lowest risk of TD?

Clozapine

EPS AE: Tardive Dyskinesia tx

- stop offending agent and switch

- VMAT2 inhibitors (Valbenazine) for sx management

EPS AE: Tardive Dyskinesia can you use anticholinergics?

No will worsen TD

All antipsychotics BBW

Increased risk of mortality when used to tx dementia-related psychosis in older adults

What antipsychotic works the best?

Clozapine

Clozapine benefits

- tx tx-resistant schizophrenia

- reduces suicide risk

- lowest risk of TD

Clozapine ADE

- agranulocytosis

- myocarditis

- seizures

- severe constipation/ileus

- metabolic AE

Clozapine Monitor

- ANC: weekly x6mo, then q2wk x 6mo, then monthly

- troponin and CRP: first 4wk then weekly

Clozapine ANC: when to hold and discontinue

- Hold: ANC < 1000

- Discontinue: ANC < 500

Novel Drug for Schizophrenia

Xanomeline-Trospium

Xanomeline-Trospium MOA

- xanomeline: selective muscarinic M1/M4 receptor agonist

- Trospoim: peripherally acting muscarinic antagonist that mitigates the peripheral cholinergic ADRs of xanomeline

What ADE has an increased risk with high potency FGAs?

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS)

- usually follows initiation or dose escalation

- life threatening emergency

Neuroleptic Malignant Syndrome (NMS) sx (FALTERED)

- fever

- autonomic instability

- leukocytosis

- tremer

- elevated CPK

- rigidity

- excessive sweating

- delirium

Neuroleptic Malignant Syndrome (NMS) tx (3) 1st and 2nd

- stop drug + supportive care

- +/- Dantrolene (severe rigidity/hyperthermia)

- bromocriptine (2nd)

Acute Agitation: 1st line oral meds (3)

- Lorazepam

- Haloperidol + Lorazepam

- Oranzapine

Which oral med for acute agitation is spaced further apart in women due to slower metabolism than men?

Oranzepine

Oranzepine ADE with Benzodiazepine

potentially life threatening sedation and hypotension when co-administered

Acute Agitation: 1st line injectable meds (2)

- Haloperidol + Promethazine

- Olanzapine

Bipolar: Mood stabilizers (2)

- Lithium

- Anticonvulsants (antiepileptics)

Antiepileptic Drugs (3)

- Valproic acid

- Carbamazepine

- Lamotrigine

Bipolar: Antipsychotics (2)

- SGAs

- can use FGAs

Bipolar: Antidepressants (2)

- Bupropion

- SNRI/SSRI

Can you use monotherapy in bipolar?

No never

What combination of pharmacotherapy do you use for bipolar?

Combine mood stabilizers, antipsychotics, and possible antidepressants

How are medications used to treat bipolar disorder?

Medications target specific phases of treatment to stabilize mood and prevent recurrence of acute mood episodes

Bipolar: Acute Mania tx (2)

- Lithium

- Valproate

When treating mania, what should you discontinue

Destabilizers (antidepressants and stimulants)

Bipolar: Acute Bipolar Depression tx

Lamotrigine

Bipolar: maintenance tx

Lithium

Lithium MOA

- eneuroprotective properties

- modulation of phosphoinosital pathway

- dampens excessive neuronal excitability primary by reducing excitatory neurotransmitters and increase inhibitory activity

Lithium: unique pharmokinetics (4)

- not metabolized

- rapidly absorbed and widely distributes

- excreted by kidneys unchanges

- excretion affected by Na levels

Lithium: caution in

Renal impairement

Lithium: hyponatremia

hyponatremia increases Lithium levels

Lithium: reduces risk of

Suicide

Lithium ADE (5)

- GI: N/D/bloating/anorexia

- fatigue/HA

- muscle weakness

- confusion/sedation

- thirst

Lithium BBW

Lithium Toxicity

Lithium Toxicity

- Tremor

- Polyuria

- Renal toxicity

- Goiter and hypothyroidism

- hypercalcemia

- teratogenic

Lithium: acute mania trough levels

0.8-1.1 mmol/L

Lithium: maintenance/depression trough level

0.6-0.8 mmol/L

Lithium: narrow therapeutic index when to treat (interrupt and hemodialysis)

- interrupt dosing: >1.2 mmol/L

- hemodialysis: > 2.5 mmol/L

Plasma Lithium < 1.5 sx (6)

- N/V/D

- thirst/polyuria

- lethargy

- slurred speech

- muscle weakness

- fine hand tremor

Plasma Lithium 1.5-2 sx (3)

- confusion

- sedation

- incoordination

Plasma Lithium 2-2.5 sx (5)

- seizures

- stupor

- severe hypotension

- coma

- death

When should you check serum Lithium level after initiation/dose change?

Every 5-7 days

Can you use Lithium in pregnancy?

Small increased risk of congenital cardiac malformations - use shared decision making

Bipolar: Antieleptic drugs active agent

Valproate ion

Drugs with Valproate ion (3)

- Valproic Acid

- Sodium Valproate

- Divalproex Sodium

Valproate ion MOA

increase GABA, inhibiting Na/Ca channels and modulate gene expression and neuroplasticity

Valproate ion BBW (3)

- hepatotoxicity with liver failure

- pancreatitis

- teratogenic NTDs

Valproate ion rare but serious ADR (3)

- thrombocytopenia

- DRESS

- activation of SI and suicidal behavior

Valproate ion common ADR (7)

- N/V/D/C

- abdominal pain

- dyspepsia

- weight gain

- sedation

- dizziness

- HA

does Valproate ion have drug interactions

Yes a lot

does Valproate ion require baseline and periodic lab monitoring?

Yes

Valproate ion trough levels

50-100 mcg/mL

how is Valproate given for acute mania vs seizures

- loaded rapidly for acute mania

- titrated slowly for seizures

Valproate ion: what should you check if unexplained mental status change

Check ammonia

Carbamazepine MOA

inhibits Na+ channels to reduce high frequency neuronal firing and synaptic transmission in the brain

Carbamazepine BBW (3)

- SJS and TEN

- aplastic anemia

- agranylocytosis

Carbamazepine rare but serious ADR (3)

- hyponatremia/SIADH

- activation of SI and suicidal behavior

- hepatotoxicity: increase LFT, jaundice, failure

Carbamazepine common ADR (8)

- N/V/D

- HA

- sedation

- vertigo

- ataxia

- blurred vision

- rash

- transient benign leukopenia

Carbamazepine drug interactions

Yes its a very potent hepatic enzyme inducer CYP3A4 and increases clearance

Carbamazepine D/I (4)

- valproate

- lamotrigine

- many antidepressants

- contraceptive hormones

Carbamazepine in pregnancy?

No its a teratogenic

Valproic acid and carbamazepine in pregnancy?

No can cause severe birth defects

Lamotrigine MOA

inhibition of Na+ channels to reduce excessive neuronal excitability and decreases release of excitatory neurotransmitters

Lamotrigine BBW

SJS and TEN

Lamotrigine SJS/TEN risk factors (4)

- coadministration with valproate

- exceeding recommended starting dose

- exceeding recommended dose-escalation schedule

- presence of HLA-B 1502 allele

Lamotrigine discontinue

at first sign of a rash

Lamotrigine rare but serious ADR (3)

- hyponatremia/SIADH

- activation of SI/behavior

- hepatotoxicity: increase LFT, jaundice, failure

Lamotrigine mc ADRs (4)

- dizziness

- HA

- nausea

- benign rash

What can double Lamotrigine levels?

Valproic acid

How should you change dosing of Lamotrigine when taken with Valproic acid

Reduce Lamotrigine dose by 1/2

Lamotrigine caution when using

Hormonal contraceptives - can decrease Lamotrigine levels and vice versa

What monotherapy medication is preferred for pregnant patients with bipolar disorder?

SGA or lamotrigine

Psychotropic Agents: CNS Stimulants 2 classes

- Amphetamine class

- Methylphenidate class

1st line for ADHD

- monotherapy of amphetamine or methylphenidate (70% response)

- duel therapy of amphetamine or methylphenidate (90% response)

Amphetamine class MOA

- dopamine and NE reuptake block and increased release into cytoplasm

- reversal of transporter to pump the neurotransmitter out of synaptic cleft