NOP test 2 Flashcards
SSRIs
Fluoxetine and Sertraline
SNRIs
Duloxetine
Tricyclics
Amitriptyline
MAOIs
Phenelzine and Selegiline
Which types of depression do you use antidepressants with?
- Major depression and maybe bipolar depression
- Use only with reactive depression if necessary
Fluoxetine: MOA, Uses, and PK
- SSRI
- MOA: Highly selective inhibition of 5HT repute
- Uses: Major depressive disorder., OCD, Bulimia nervosa, Panic Disorder, and PMDD
- PK: Inhibits 2D6 and requires 5-6 wks to reach steady state and to wash out.
Fluoxetine: Adverse effects
-AE: Black box warning for suicide
-5HT2 receptor effects: (tolerance develops to most SD) agitation, akathesia, initial anxiety, panic, insomnia and SEXUAL DYSFUNCTION
-5HT3 (tolerance develops)
nausea, gi distress, diarrhea, headache, wt loss
-LONG TERM WEARING of efficacy
Fluoxetine: Contraindications
- Pregnancy (3rd trimester pulmonary HTN)
- Tamoxifen uses 2D6
- Drugs that increase 5HT levels (MAOI) due to Serotonin syndrome
Sertraline
- SSRI very similar to fluoxetine with less side effects
- may be more efficacious in severe depression
- approved for PTSD and bulimia is off label
Duloxetine: MOA, Uses, and PK
- SNRI ( same mech as tricyclics with less side effects
- MOA: Blocks 5HT and NE reuptake but more selective of SERT
- USES: MDD, generalized anxiety disorder, and several pain disorders (peripheral myopathy, fibromyalgia, and chronic pain)
- PK: Blocks 2D6 (tamoxifen) metabolites are inactive w/ half life of 11-12 hrs (shorter than fluoxetine)
Duloxetine: AE and contraindications
- AE: Suicide risk, sexual dysfunction, HTN crisis or MI
- Contraindication: don’t take w/ other drugs that increase [Serotonin], and narrow angle glaucoma, don’t take with drugs that need NET for their action (methyldopa)
Tricyclic Antidepressants
- Amytriptyline
- Side effects limit patient compliance and overdose can be lethal due to CV effects
Amytriptyline: Uses, MOA, and PK
USES: MDD, and off-label for some pain disorders
-MOA: inhibit 5HT and NE reuptake (more selective for SERT)
PK: Metabolized by 2D6, half –> nortriptyline. Other metabolites are active –> long half life (30 hrs)
Amytriptyline: Adverse effects and Toxicity
ADVERSE EFFECTS
-Suicide risk
-Anticholinergic (tachycardia)
-Alpha 1 antagonist (ortho Hypo and drowsiness)
-Antihistamine (Sedation and Wt gain)
-Sexual dysfunction and transition to mania in bipolar patients
TOXICITY
-Acute poisoning is common and potentially life threatening (Cardiotoxic treat with Na Bicarb if QR widening)
Amytriptyline: Drug interactions and contraindications
DRUG INTERACTIONS:
-MAOIs or other drugs that increase serotonin.
-Drugs that prolong QT (thioridazine)
-Can reverse Anti-HTN effects of some drugs.
Contraindications: CV problems and pre-exisiting CV conditions
Phenelzine: MOA, USES, and PK
MOA: Irreversible inhibition of MAO (A&B) = drug action continues after drug has been cleared
USES:
-MDD: onset is faster than w/ other anti-depressants
-Agoraphobia, Bulimia, Panic Disorder, Social phobia
PK:
-Transformed by acetylation in liver with 50% slow acetylators
Phenelzine: AE, Toxicity
AE:
-Increased suicide
-Ortho Hypo and sedation common
-Central stimulation, wt gain, and insomnia/euphoria
Toxicity: CNS stimulation –> hallucinations, delirium, convulsions, coma, (USUALLY NOT LETHAL)
Phenelzine: Food and Drug Interactions
- Cheese RXN: Large amounts of tyramine –> NE release –> HTN crisis
- Sympathomimetic Amines: potentiates amphetamines –> HTN. L-DOPA should be withdrawn 2-4 weeks prior to MAOI
- DO NOT COMBINE WITH OTHER ANTI-DEPRESSANTS
- DO NOT COMBINE WITH CNS DEPRESSANTS IN GENERAL
Phenelzine: Contraindications
- Drugs that increase 5HT
- Drugs that increase NE or EPI
- Dextromethorphan (5HT syndrome of pyschosis)
- Meperidine (Death)
Selegiline: MOA, USE, and PK
-MOA: irreversible inhibition of MAO A&B
-USES: MDD and Parkinson’s at low doses
PK: 2B9–> active metabolites
-Regen or new enzymes is required
Selegiline: AE
AE:
- Increased risk of suicide
- Same food and drug interactions as phenelzine
Bupropion: USES, MOA
USES:
-MDD (treat sexual dysfunction due to other meds but not as effective in presence of anxiety)
-SAD
-When other ADs produce cognitive slowing
MOA:
-Inhibits DAT and NET, with greater specificity for DAT
Bupropion: AE,
AE:
- Suicide
- WT Loss
- Tachycardia
- Lowers seizure threshold
- inhibits 2D6
- Serotonin syndrome w/ MAOIs or other drugs that elevate 5HT
Mirtazapine: MOA
- Antagonist at presynaptic alpha 2 antagonist –> increase release of 5HT and NE
- Antagonist at presynaptic 5HT2 –> increase release of DA and NE
- Inhibition of postsynaptic 5HT3 –> antiemetic effects
- Antagonist at H1 receptor –> sedation and wt gain.
Mirtazapine: Uses
-MDD: Patients with insomnia, no ortho hypo, lower incidence of sexual dysfunction
Mirtazapine: AE
- Increase Suicide
- Somnolence (H1 Blockade)
- Weight gain
- No significant affect on CYPs
- increase triglycerides and cholesterol.
Mirtazapine: Toxicity and Drug interactions
-Toxicity: Overdose drowsiness, disorientation, ataxia, nausea and vomiting
Drug Interactions: Drugs that elevate 5HT levels Serotonin syndrome
Which anti-psychotics are most effective?
-They are all equally effective (with the exception of clozapine) so selection depends more on patient tolerability
Typical Anti-Psychotics
- First generation
- associated with EPSE and Tardive dyskinesia
- Cheaper
Atypical Anti-Psychotics
- Lower risk of EPSE/TD and more effective for negative symptoms, but more adverse metabolic side effects.
- More expensive
Typical and atypical anti-psychotics MOA
- D2 receptor antagonist
- requires 60% occupancy for effect
- Atypical drugs differ in that serotonin receptor affinity is higher than D2 receptor affinity (accounts for higher efficacy with neg symptoms and lower EPSE risk)
Neuroleptic Malignant Syndrome
- Side effect of neuropsychotic
- Life threatening
- More common with typical
- Mental status change, Hyperthermia, extreme muscle rigidity, and autonomic dysfunction
- Tx: drug withdrawal and supportive therapy
Antipsychotic side effects
-QT interval prolongation
-Adverse metabolic effects
-Increased mortality in elderly with dementia related psychosis
Autonomic effects: Anticholinergic, anti-adrenergic, anti histaminergic
EPSE
- Akathisia: Feeling of restlessness difficulty sitting still (Dose reduction, beta, or BZD)
- Parkinsonism: Tremor, rigidity, shuffling gait, bradykinesia (anti-parkinsonian, anti-cholinergic)
- Dystonias: Acute muscle spasms of neck, back, and eyeballs (anti parkinsonism, anti-cholinergic)
- Tardive Dyskinesias: Oral-Facial dystonias, chorioathetosis (no treatment, permanent)
Halperidol
- Typical anti-pyschotic
- High potency (higher risk of EPSE but less sedating)
- Approved for schizophrenia, severe behavioral problems in kids, tourettes
Chlorpromazine
- Lower potency (lower risk of EPSE but more sedating)
- approved for psychosis, and nausea/vomitting and severe behavioral problems in kids
- Off label control behavior in elderly children with dementia
Clozapine
- Atypical Anti-psychotic
- Recalcitrant schizophrenia and suicidal behavior in patients with schizoaffective disorder (6 mos. for full response)
- Usually last line due to agranulocytosis
- Virtually no risk of EPSE/TD
Other atypical antipsychotics
-Risperidone -olanzapine -quetiapine, ziprasidone
Apiprazole
-Partial D2 agonist
Drug selection for Schizophrenia
- Mono therapy of Aripiprazole, risperidone, quetiapine, ziprasidone (atypical agents)
- One not really better than another, but olanzapine usually reserved due to its metabolic side effects
- Typical agents can be used when effective in patients and absence of EPSE
Refractory Schizophrenia
- failure of at least 2 mono therapy trials
- Clozapine is effective in 30-60% patients
Drugs used to treat Mania
- LITHIUM
- Anticonvulsants (valproate, carbamazepine)
- Antipsychotics
- Benzodiazepines: used mostly as adjunct for agitation, insomnia, or anxiety
Drugs use in Severe acute mania
-Combo of lithium or valproate & antipsychotic
Drugs used in Hypomania
-Monotherapy with atypical antipsychotic is recommended
Lithium: MOA
- Prototype mood stabilizer
- MOA: Unknown for most part
- Inhibits neuronal signaling pathways IP3 –> reducing GPCR synaptic transmission activity and glycogen synthase kinase-3 pathway
- Reduces Manic symptoms and stabilizes mood in bipolar pts (no affect on regular individuals
Lithium: PK
- Serum levels must be monitored to prevent toxicity (0.8-1.2)
- Renal elimination with dosage based on CrCL
Lithium Adverse effects: (acute, long term, and overdose)
- Acute: tremor, mild nausea, polyurea/dipsia, wt gain, mild cog impairment
- Long-Term: Nephrogenic Diabetes insipidus, thyroid dysfunction, hypercalcemia, arrhythmias in pots with preexisting CV dz
- Overdose: Increase risk with renal impairment, dehydration and sodium depletion,
- Present with nausea, vomiting, diarrhea, arrhythmias, lethargy ataxia, confusion, and seizures
- Thiazides, NSAIDS, ACEIs increase lithium levels
Mechanisms of Action of Anti-Seizure Drugs
- Block Neuronal gated Na+ Channels: Limited repetitive firing by promoting inactivated state, but action is voltage (greater effect if depolarized) and use dependent (mostly affects repetitive firing neurons). Great of FOCAL and SECONDARILY GENERALIZED SEIZURE
- Block Ca 2+ channels: T-Type channels inhibits absence seizures and HVA Ca ++ suppresses glutamate release (FOCAL SEIZURES)
- Enhance GABAergic transmission
- Antagonize Glutaminergic Transmission: suppress glutamate mediated synaptic excitation by antagonizing neuronal NMDA and AMPA receptors
Traditional Agents
- Older drugs that all block Na+ channels
- Phenytoin
- Valproic Acid
- Carbamazepine
- Ethosuximide
- Lorazepam
Phenytoin (Traditional): MOA and PK
-MOA: blocks Na+ channels
PK:
-Oral formulation
-IV: Fosphenytoin
-Non-linear elimination, plasma protein binding and hepatic CYP metabolism
-Plasma drug conc. increases disproportionately as dose is elevated (toxicity)
Phenytoin (Traditional): Therapeutic use and Drug interactions
- Therapeutic Use: Focal and tonic clonic seizure and status epilepticus, NOT effective against absence seizures, Cardiac arrhythmia
- Drug Interactions: Increases CYP 3A4 clearance –> ineffective birth control
- Decrease CYP2C9 clearance which leads to increased bleeding with warfarin
Carbamazepine (Traditional): MOA and PK
- MOA: Blocks Na+ channels
- PK: Linear Kinetics and more reliable blood levels
- Met: by CYP3A4 and induces its own metabolism
Carbamazepine (Traditional): Therapeutic Uses and Adverse effects
- Therapeutic Uses: Generalized tonic clonic seizures, simple and complex focal seizures, trigeminal neuralgia, and bipolar disorder
- Adverse Effects:
- Most frequent: Drowsiness, ataxia, vertigo, diplopia, and blurred vision, nausea/vomiting and diarrhea
- Hyponatremia (SIADH)
- Rash (Black box warning test for allele in asians)
- Blood Dyscrasias (boxed warning for aplastic anemia and agranulocytosis
Valproic Acid (Traditional): MOA and USE
- MOA: Blocks Na+ Channels, Blocks T-Type Ca++ Channels, Stimulates GABA synthesis while inhibiting degradation
- USES: Absence Seizure, Myoclonic, focal and tonic clonic seizures
- Bipolar disorder
- Migraine prophylaxis
Valproic Acid (Traditional): Adverse Effects and Drug Interactions
AE:
-GI solved by using enteric coated divalproex
-CNS: Sedation, Ataxia, tremor, and weight Gain
-Hepatic Toxicity and Pancreatitis: Boxed warnings especially in children under 2 years
-Teratogenic: Boxed warning for neural tube defects
Drug Interactions:
-Phenytoin displaces Valproic acid from albumin and decreases it metabolism
Ethosuximide (Traditional): MOA and Uses
MOA:
-Blocks T-Ca++
Uses:
-Uncomplicated Absence seizures
Ethosuximide (Traditional): Adverse Effects
AE:
- GI Complaints and CNS complaints
- Rare: SLE, Leucopenia, aplastic Anemia, and SJS
Status Epilepticus treatment
- IV Lorazepam to terminate seizure episode due to longer duration of action
- IV Phenytoin for prolonged control after termination
Gabapentin (newer): PK, Uses and Adverse Effects
- PK: Excreted unchanged in Urine
- Uses: Add on of focal and generalized seizure, Postherpetic myalgia, tons of off label uses
- Adverse effects: Sedation, dizziness, but mostly well tolerated
Lamotrigine (NEWER): MOA, and PK
MOA: blockade of Na+ channels –> less glutamate release, Ca++ Channel block and 5-HT3 antagonist
-PK: Glucuronidation which is increased by enzyme inducers
Lamotrigine (NEWER): USES and ADVERSE EFFECTS
USES: Lennox-Gastaut Syndrome, Monotherapy for partial and secondarily generalized tonic-clonic seizures in adults, alternative to ethosuximide for absence, Bipolar maintenance
ADVERSE EFFECTS: Dizziness, ataxia, blurred vision, nausea, and vomiting, Rash SJS, Teratogen
Levetiracetam (NEWER): PK, Therapeutic Uses, and Adverse effects
PK:
-Mostly devoid of drug interactions
USES: Add-on for partial or generalized tonic-clonic and myoclonic seizures
ADVERSE EFFECTS: Fatigue, dizziness, can cause HTN, Behavioral symptoms
Tiagabine (NEWER): MOA, USE, and Adverse Effects
MOA: Blocks glutamate reuptake (GAT-1) thus prolongs inhibitory effect
USES: Add-on for refractory partial seizure w/wo secondary generalization (may promote seizures in those who don’t have epilepsy)
AE:
-Dizziness, somnolence, tremor, and enhance absence seizure activity
Topiramate (NEWER): MOA, and PK
MOA:
-Blocks Na chan., Neuronal hyperpolarization, Carbonic anhydrase inhibitor
PK:
-Excreted unchanged in urine
Topiramate (NEWER): USES and ADVERSE EFFECTS
USES: -Monotherapy for partial and generalized tonic-clonic seizures, -Adjunct for lennox-gaustaut syndrome -Prophylaxis for migraines AE: -Renal calculi from CA inhibition -Cog impairment
Felbamate (Newer): MOA, USE, and ADVERSE EFFECTS
MOA:
-Antagonist of NMDA
-Postive modulator of GABA receptors
USE:
-Monotherapy of poor control severe focal and second. gen. seizures that are refractory
-Adjunct for Lennox-Gastaut
AE: Life threatening aplastic anemia and liver failure
Vigabitrin: MOA, USE, and ADVERSE EFFECTS
MOA: -Irr. inhib. of GABA transaminase USE: Refrac. complex partial seizures Mono therapy for infantile spasms ADVERSE EFFECTS: Progressive and permanent bilateral vision loss
