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Flashcards in Psych Meds Deck (45):
1

Lithium: MOA, uses

Classical mood stabilizer
- Effective, cheap

Works on multiple neurotransmitters (5-HT, NE, Glu, GABA, DA)
- Modifies 2nd messenger system

Efficacy:
- Bipolar mania
- Prophylaxis
- Adjunct to antidepressants
- Acute tx of mania/agitation
- Better at preventing mania than depression

2

Lithium: Interactions/AEs

Side effects:
- Tremor
- Polyuria +/- polydipsia
- Weight gain
- Cognitive slowing/memory problems
- Hypothyroidism
- **Decreased renal function**
- Dermatologic side effects (eg acne)
- Nausea/vomiting/diarrhea

Pregnancy: category D
- Avoid in 1st trimester (Ebstein's abnormality, birth defects= congenital defect in heart, septal leaflet of tricuspid valve towards apex of R ventricle)
* can use after 1st trimester if benefits > risks
- Do NOT use breastfeeding

Med interactions:
1. Decreased Li Levels:
- Urinary alkalinizers
- Sodium-Bicarb
- Verapamil
2. Increased Li Levels:
- Diuretics
- NSAIDs
- Antipsychotics (increased toxicity)
- Verapamil
3. Other side effects:
- Iodide Salts --> inc hypothyroidsim
- Bupropion--> increased seizure risk

Food interactions: Decreased Li levels from:
- sodium, caffeine, green tea
levels
* Must monitor thyroid function (TSH) b/c can get hypothyroid which is reversible if d/c Li

3

Lithium: clinical points

Key clinical points:
* Narrow therapeutic window
- Maintain blood level 0.8 – 1.2 mmol/liter
* Li Toxicity
- Coarse tremor, muscle fasciculations, confusion, stupor
- Slurred speech, ataxia, vomiting, arrhythmia & seizures
* Kidneys – Li is excreted through kidneys
- Monitor kidney fnct
- Pt with kidney disease may have inc Li

4

Anticonvulsants (mood stabilizers): MOA

Act on sodium, potassium and calcium ion channels in cell
- This modulation changes both excitatory (GLU) and inhibitory (GABA) neurotransmission
- Augment synthesis/release of GABA
- Inhibit reuptake and breakdown of GABA
- Decrease release of Glu

5

Valproic acid

MOA: Increases GABA, decreases NMDA

Uses:
Anticonvulsant

- Acute mania
- Seizure disorder
- Bipolar prophylaxis

Side effects:
- Weight gain
- Sedation
- GI upset (take with food)
- Dizziness
- Hair Loss
- Maybe be associated with polycystic ovaries
- Thrombocytopenia*
More common in children
- Pancreatitis *
- Hepatitis *

Pregnancy:
- Category D: neural tube defects

Levels:
- Check levels (50-100 g/mL)
- OD effects seen at ideal 20x blood level

Drugs increasing serum level: CAFE Pi (OTC stuff)
- Cimetidine
- Aspirin
- Fluoxetine
- Erythromycin
- Phenothiazines
- ibuprofen

Drugs reducing serum level: CREP (Antiseizure meds)
- Carbamazepine
- Rifampin
- Ethosuximide
- Phenobarbital

Drugs with metabolism inhibited by VPA: I sAW LAND
- Amitriptyline
- Warfarin --> increase risk of bleeding b/c VPA displaces it
- Lamotrigine
- AZT
- Nortriptyline
- Diazepam

6

Carbamazepine

Acts on Na and K channels to enhance GABA availability

NOT FDA APPROVED for bipolar d/o
- Except for carbamazepine XR
- FDA approved for acute mania
- Used off label for mixed & rapid-cycling bipolar d/o

** Not used 1st line b/c interacts with SO MANY MEDS**
- used for pts who have failed other meds

FDA approved for siezure d/o

Side effects:
- Sedation
- Dizziness
- Fatigue
- Nausea/vomiting/constipation/diarrhea
- Ataxia
- Thromboycytopenia* & aplastic anemia*
- Hepatitis*
- Exfoliative dermatitis*, toxic necrolysis* (aka Stephens-Johnson syndrome)

Pregnancy: Category D
- Associated with Spina Bifida

Clinical points:
- Avoid in patients with cardiac, hematological, liver or kidney disease
- Think of it as a drug that interacts with almost everything
- If you ever rx must check it doesn’t interact with other meds pt is taking
- Must have 14 day washout period before initiate MAOI

7

Lamotrigine

MOA – dec the excitatory actions of Glu via interference with Na channels
- Effective for bipolar d/o: Mania, hypomania & depression

Side effects:
- Sedation
- Dizziness
- Ataxia
- Decreased coordination
- Headache
- Nausea/vomiting
** Toxic epidermal necrolysis* (aka Stevens-Johnson syndrome)
- 10% will get rash
- Subset will go on to S-J
- Must d/c if ANY rash

Pregnancy:
- Avoid in first trimester
- Use after first trimester if other meds don’t work
- Avoid in breast feeding – risks unknown

8

Use of Antipsychotics

1. Psychotic illness – unable to distinguish unreality from reality
- Schizophrenia, Bipolar Mania, Depression w/psychosis
2. Augmentation of antidepressant (eg SSRI)
- Aripiprazole & Quetiapine
3. Mood Stabilizer – Acute Mania
- Quetiapine, olanzepine, aripiprazole, ziprasidone & risperidone
4. Mood Stabilizer – Maintenance
Olanzapine & aripiprazole

9

Typical antipsychotics (1st generation)

Dopamine antagonists
- Chlorpromazine
- Thiordazine
- Prochlorperazine (compazine)*
- Trifluoperazine
- Haloperidol

MOA:
1. Competitively block Da receptors (D2, D3 & D4 subtypes)
- D2 receptors located in limbic, extrapyramidal & endocrine structures
- D3 & D4 subtypes located primarily in limbic structures
2. Receptors linked to enzyme adenyl cyclase via G protein which inhibits activation of enzyme
3. Blocking receptors decreases +sx (mesolimbic pathway)
4. Bind to D2 receptors 10-50x more avidly than D3 receptors

Potency:
- Drug's ability to bind to DA receptor
1. High potency:
- Low anticholinergic & low sedating properties
- Fewer CV abnormalities
- Higher rate of EPS (extrapyramidal symptoms): ex. haloperidol & fluphenazine
2. Low potency: opposite profile

10

Atypical antipsychotics (2nd generation antipsychotics)

Serotonin/Dopamine antagonist
- Clozapine
- Risperidone
- Olanzapine
- Quetiapine
- Ziprasidone

Partial Dopamine agonist:
- Ariprazole

MOA:
1. More selective for mesolimbic Da pathway (origin + symptoms)
2. Less active on nigrostriatal pathway (origine EPS)
3. Competitively block serotonin receptors (5-HT2 subtype)
4. Have >5x binding affinity for 5-HT2 than D2 : 5-HT2 located in cortical structures where neg sx thought to originate
5. Higher degree of binding/blockade of D4 & D3 receptors vs D2
- D4 & D3 receptors located in limbic structures where + sx thought to originate
6. Blockade of 5-HT receptors therefore:
- Improves negative & positive sx
- Dec EPS

11

Dopaminergic Pathways in Brain

1. Mesolimbic Pathway: Midbrain ventral tegmental area (VTA= vestibule to addiction) --> nucleus accmbens (pleasure pathway)
- Pathway of all things pleasurable
- Pathways for drugs of abuse to create “high” feeling
- Pathway of delusions and hallucinations of pscyhosis

2. Mesocortical Pathway: Midbrain ventral tegmental area --> limbic cortex
- May have role in mediating +/- psychotic symptoms
- May have role in cognitive side effects of 1st gen antipsychotics

3. Nigrostriatal Pathway (nigrostride)
- Substantia nigra --> basal ganglia
- Controls movement

4. Tuberoinfundibular Pathway
- Hypothalamus --> anterior pituitary gland
- Controls prolactin secretion
- Dopamine & prolactin have an inversely proportionate relationship (i.e. inc of one --> dec of the other)

12

Dopamine hypothesis of Schizophrenia

1. Hyperdopaminergic activity in mesolimbic system --> positive sx
- Delusions
- Hallucinations
- Catatonia
- Thought disorder

2. Hypodopaminergic activity in mesocortical system --> neg sx
- Apathy
- Motor retardation
- Social withdrawal

13

Aripirazole

Second Generation Antipsychotic: partial DA agonist

1. Establishes balanced dopamine availability
2. Acts as antagonist when there is xs Da
- Mesolimbic pathway
3. Acts as agonist when there is too little Da
- Nigrostriatal pathway & frontal lobes
- Serotonin 2A antagonist
- Partial serotonin 1A agonist
4. Aripiprazole only drug in this class

14

AEs of Antipsychotics

Antipsychotics act on other recptors--> Results in MORE side effects:
1. Anticholinergic (M1)
- Dry mouth
- Mydriasis
- Urinary retention
- Constipation
2. Antihistaminergic (H1)
- Weight gain (can be VERY significant): Olanzapine, Risperidone, Quetiapine
- sedation
3. Alpha Adrenergic Blockade
- Orthostatic (postural) hypotension
- sedation
4. Dopaminergic Blockade
- EPS

15

Extrapyramidal symptoms of Antipsychotics

Due to Da blockade or depletion in basal ganglia

Parkinsonian Syndrome:
- Due to blocking D2 receptors in striatum
- Muscle rigidity, slowed movements, shuffling gate
- Resting tremor, mask-like facial expression
- Cogwheel rigidity
- Acute Dystonia
- Prolonged muscular spasm tx’d with diphenhydramine or benztropine

Tardive Dyskinesia:
- Abnormal writhing movement of tongue, face, limbs or trunk
- Theory caused by D2 blockade in hypthalamus & striatum causing upregulation of D2 receptors
- More common with FGA’s
- May not EVER go away (50%)

Neuroleptic Malignant Syndrome
- Life threatening must recognize and tx ASAP!
- More common in men
- Hyperthermia, hypertension, tachycardia
- Tremor, seizures, dyskinesia
- Must stop antipsychotic

Akathisia
- Absolutely awful subjective feeling of motor restlessness
- Give pt diphenhydramine, propanolol or benzodiazepine

16

Other clinical side effects of antipsychotics

1. Endocrine:
- Blockade of D2 in hypothalamus &/or anterior pituitary
- Inc prolactin --> gynecomastia in men and galactorrhea in women
- Dec gonadotropin --> amenorrhea
- Dec growth hormone, Luteinizing hormone & ACTH

2. Cardiovascular
- Prolongation of QT interval on EKG (Torsades)
- Can result in potentially lethal cardiac arrhythmia

3. Metabolic Syndrome:
- MONITOR: weight, waist circumference, fasting glucose, fasting lipids, blood pressure
- Risk of heart disease, stroke, diabetes (increased BP, insulin, abdominal fat, cholesterol
** INCREASED risk for Second generation antipsychotics

17

Antipsychotic prescribing: clinical guidelines

Choose based on past response and side effects

1. SGA’s generally 1st line, especially if past tardive dyskinesia
2. Avoid SGA’s for behavioral disorders in patients with dementia --> inc mortality
3. Pregnancy category C
- FGA’s – slight inc in anomalies
- SGA’s – need inc data
4. Smoking increases metabolism of antipsychotics
5. Must adjust dose for patients with liver or kidney disease

18

Clozapine

2nd gen antipsychotic (Serotonin/Dopamine Antagonist)

AEs:
- Risk of agranulocytosis & neutropenia must monitor CBC : This is 1+ times/mn depending how long pt has been on
- Risk seizures on doses > 600mg/day
- Myocarditis – rare
- Low association with TD
- Sedation, orthostatic hypotension & hypersalivation

Use:
- For patients who have failed 2+ other antipsychotic agents
- Decreased risk of suicide in patients with schizophrenia

19

Delivery systems for antipsychotics

All come as a pill or capsule
1. Immediately dissolving oral tablet
- M-Tab risperdal (risperidone)
- zydus (olanzapine)

2. Intramuscular Preparations – short acting (hours)
- Haloperidol
- Chlorpromazine
- Droperidol
- Ziprasidone
- Olanzapine

3. Intramuscular Preparations – long acting (weeks)
- Haloperidol
- Fluphenazine
- Risperdal Consta

20

Clinical effect of antidepressants

Clinical remission of depression requires 3-6 weeks of treatment
Down-regulates:
- Beta-1
- 5HT2
- 5HT1a receptors in CNS

21

Fluoxetine
Sertraline
Paroxetine
Citalopram/Escitalopram
Fluvoxamine

SSRI= selective serotonin reuptake inhibitors
- Varied chemical structures
- Similar PK to tricyclics
- More benign side effect profile

MOA:
- Inhibits selective inhibition of serotonin reuptake (pre-synaptically)
- Longer contact of serotonin with postsynaptic receptor site (5-HT1A)--> downregulation of post-synaptic receptor sites--> resolution of depression

Uses:
- Depression
- OCD
- Panic disorders
- PTSD
- Eating disorders
- Generalized anxiety disorder (higher dosing)
- PMS

- Lack H1 receptors (less sedation) and alpha1-adrenergic blocking action
- No Quinidine action on heart
- No weight gain
- Safety margins higher in overdose
- Do not need blood monitoring

AEs:
- Nervousness /irritability/insomnia (Transient)
*Nausea/diarrhea/dyspepsia (Transient)
*Sexual dysfunctions (Persistent)
!! Serotonin syndrome characterized by confusion, fever, altered consciousness, myocolonus.

Drug interactions:
- Can inhibit CyP450 enzymes
- Potentiate toxicity of warfarin, theophylline, etc.

22

Venlafaxine
Duloxetine

NE and Serotonin reuptake inhibitor (SNRI)

Venlafaxine= metabolized prodrug
Duloxetine= similar to Venlafaxine but liver transaminase elevation; indicated in diabetic neuropathy tx

MOA:
- With increasing doses Serotonin reuptake--> NE reuptake--> DA reuptake

AAEs:
- Dose dependent sustained HTN (Venlafaxine)
- Significant withdrawal syndrome with abrupt discontinuation

Uses:
* Depression
* Generalized anxiety disorder
* Social Anxiety Disorder
* Panic disorders
*Posttraumatic stress disorder
*Premenstrual syndrome

23

Bupropion

Norepinephrine and dopamine reuptake inhibitor (NDRI)
- Wellbutrin, Zyban (smoking cessation)

MOA:
- Blocks active reuptake of NE and DA--> higher levels of neurotransmitters--> downregulation of receptors

AEs:
- Agitation, insomnia, headache, nausea, blurred vision. Dose dependent risk of seizures.
- False positive amphetamine screen
- Inhibits 2D6

Uses:
- Depression (fewer sexual side effects than SSRI)
- Cessation of smoking
- ADHD

24

Mirtazapine

Noradrenaline and specific serotonin agent (NaSSA)

25

Nefazodone
Trazadone

Serotonin antagonist reuptake inhibtors
- Nefazodone= too many contraindications
- Trazadone= sedative, not therapeutic for depression at lower doses (Priapism!)

26

Imipramine
Desipramine
Amitriptyline
Nortriptyline

Tricyclic antidepressants
- Closely resemble phenothiazines
- More efficacious than SSRIs, but more side effects

MOA:
- Affect multiple receptors (NE, 5-HT= serotonin)
- Blocks active reuptake of NE, Serotonin--> higher levels in synaptic celft--> longer contact with post-synaptic sites
** GOLD STANDARD efficacy
- Used for treatment-resistant depression (due to side effect burden)

Uses:
* Depression
* Enuresis in childhood (e.g., Imipramine)
* Chronic pain, neuralgias, migraine, diabetic neuropathy (e.g., Amitriptyline, Imipramine and Desipramine)

AEs:
- * Sedation
- * Anticholinergic (constipation dry mouth, urinary hesitancy, blurry vision, impaired memory)
- * Orthostatic hypotension/ falls
- * ECG changes (e.g. QRS, PR and QT prolongation)
- * Weight gain
- * Headache, tremor & seizures
- *Obstructive jaundice
- *Sexual side effects (impotence)
- *Class 1a anti-arrhythmic (avoid in BBB, post MI arrhythmias)
- *More likely than SSRI to precipitate mania (MAKE SURE IT'S UNIPOLAR DEPRESSION)

Can be fatal in overdose (1 week supply)
- Medical emergency: Cardiac monitoring, gastric lavage, lidocaine, phenytoin, bicarb need STAT administration

Drug interactions:
- Metabolism affected by race, sex (slower in AA, Asians, higher in women)
** Nortriptyline is only TCA that doesn't require drug monitoring

27

Phenelzine
Tranycypromine

MAO-inhibitors
- MAO-A enzyme deaminates NA/5-HT/Tyramine
- MAO-B deaminates DA/histamine/tyramine

MOA:
- Inhibits intraneuronal MAO type A isoenzyme--> higher levels of NE, serotonin release

Uses:
- Superior to TCA for bipolar and atypical depression, dysthymia
- Phobic anxiety states
- Migraine
- neurodermatitis

AEs (Phenelzine):
- Hydrazine derivative
- More weight gain
- More orthostatic hypotension
- More hepatotoxicity potential
- More anxielytic
- Slower onset of action
- Sexual dysfunction

AEs (Tranylcypromine):
- Non-hydrazine
- Related to amphetamine structure (cyclopropyl ring)
- Faster onset of action, some abuse potential
- Sexual dysfunction

Drug interactions:
- Tyramine containing food (aged food, chianti wine, fava beans)--> dangerous rise in BP--> stroke
- Amphetamines, demerol, sympathomimetics--> HTN crisis
- Must be discontinued 2 weeks prior to surgery (interaction with anesthetics)
- MAOI/ SSRI combination--> serotonin syndrome (need 2 week washout)

28

Noradrenergic tracts

Cell bodies in Locus Coeruleus. Project to:
- Caudate
- amygdala
- Thalamus
- Hypothalammus
- Limbic cortex

29

Serotonergic tracts

Cell bodies in Raphe nuclei. Project to:
- Limbic system (hippocampus, hypothalamus, amygdala)
- Cortex

30

Fluoxetine

SSRI
Prodrug with v. long half-life (2.5 days)
- 4-5 week steady state

31

Sertraline

SSRI
Short half-life than Fluoxetine
- Time to achieve steady state= 1 week
- Short wash-out period
Fewer drug interactions than Fluoxetine

32

Paroxetine

SSRI
Some anticholinergic action= more sedating
- Early relief of anxiety and insomnia
- Can cause constipation
- Short half-life, severe discontinuation syndrome if stopped abruptly= akasthesia, restlessness, GI upset, dizziness, tingling, dysesthesias, nausea

33

Sedatives

reduce daytime anxiety, decrease excessive excitement, promote calm state.

34

Hypnotics

produce drowsiness and promote onset and maintenance of sleep.

35

Benzodiazepines

MOA: bind to specifc site on GABA(A) receptor
- Enhance GABA effect without directly activating GABA receptor or opening Chloride channel
- GABA needs to be present for benzos to work
- alpha-1 subunit appears to mediate both sedation and memory effects of benzodiazepines.

AEs:
- Potential for Abuse including Intoxication
- can be associated with behavioral disinhibition
** Withdrawal--> Seizures, death
- short term use (< 6 weeks) of long-acting benzos unlikely to have withdraw
- Year or longer use= careful monitoring
- Discontinuation needs slow taper (50%, then 10% per week)

Side effects:
- Daytime drowsiness
- Dangerous in combination with other sedatives esp. ETOH--> drowsiness, disinhibition, respiratory depression.
- Dizziness and ataxia (< 2%)
- Avoid in COPD, sleep apnea patients
- Avoid in pts with cognitive defects (amnesia, memory impairment)
OVERDOSE: lethal to effective dose: 200:1

Drug interactions:
- Decreased absorption: antacids
- Increased CNS depression: antihistamines, barbiturates, TCAs, EtOH
- CYP450 competition--> increased BZD levels (cimetidine, erythromycin, estrogens, fluoxetine, isoniazid, fluvoxamine, cisapride, grapefruit juice)
** Lorazepam, oxazepam, temazepam can be used in liver disease patients

36

Barbituates

MOA: increase duration of channel openings
- May directly activate Cl-channel opening
- Can also directly depress excitatory neurotransmitters
- More powerful CNS suppression, low margin of safety
** Potential for drug interactions, abuse, use in suicide attempts make them obsolete as routine meds for insomnia

37

Short-acting Benzodiazepines

Alprazolam,
Triazolam,
Lorazepam,
Oxazepam

38

Long-acting Benzodiazepines

Flurazepam,
Clorazepate,
Prazepam

39

Chloral hydrate

Barbituate-like effect at GABA receptor
- Prodrug
- Lethal dose (3x therapeutic dose)
- Liver injury
- Only used in pediatrics, limited use

40

Antihistamines

Antagonists of CNS H-1 receptors- need to penetrate BBB to produce sedation
- Diphenhydramine used at 25-50 mg
- Anticholinergic and serotonergic properties
- Frequently used, effects on sleep not well-documented

Side effects:
= Cognitive impairment
- Confusion
- Sedation
- Delirium, urinary retention

41

Benzos used for insomnia

Estazolam
Flurazepam (t1/2= 100 hours, not ideal)
Quazepam
Temazepam
Triazolam

42

Non-benzo hypnotics

Benozodiazepine receptor agonists:
1. Zolpidem (Ambien®): t ½ - 2.5 hrs
- Liver metabolizm
- XR tablets-- longer action, longer onset
2. Zaleplon (Sonata®): t ½ - 1 hr
-useful for middle of the night insomnia, less likely to cause next-day impairment
3. Eszopiclone (Lunesta): t ½ - 6 hrs
- Act on Alpha subunit of GABA-A type receptor
- Better specificity to produce hypnotic effect

*AEs:
- daytime sedation, psychomotor/cognitive impairment
- Rebound insomnia
- Respiratory depression
- Abuse

Melatonin receptor agonists:
1. Ramelteon= melatonin receptor agonist
AEs:
- HA, somnolence, fatigue, dizziness
- Prolactin elevation in females, testosterone elevation in older males
- No abuse

43

Pramipexole, Ropinorole

DA Agonists used for Restless Legs syndrome

Side effects:
- Nausea, orthostatic hypotension (gradual dose increase)
- Insomnia (Benso)
- Fatigue (reduce dose, switch to L-dopa)
- Hallucinations (discontinue)
- Tolerance (Rx holiday)
- Augmentation (daytime dose, discontinue if severe)

44

Pharmacotherapy for sleepiness

1. Modafinil
2. Methylphenidate (ritalin)
3. Dextroampetamine/Methamphetamine
4. Pemoline (NOT used any more- hepatotoxic)

45

Treatment of Cataplexy

1. Tricyclic antidepressants
2. SSRIs
3. Misc: Venlafaxine, gamma hydroybutyrate