Download Psychopharmacology Antipsychotics Ameliorate symptoms of psychosis

Psychopharmacology
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Antipsychotics
o Ameliorate symptoms of psychosis – hallucinations, delusions, bizarre behavior, disordered
thinking, and agitation
o Uses: schizophrenia, psychotic d/o, psychotic mood d/o, medically or drug induced
psychoses, control aggressive behavior in MR, autistic and borderline, and pts w/ delirium or
dementia, tourette’s
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MOA: potency positively correlates with level of D2 antagonism.
 SGA are weaker D2 antag but more potent 5HT2a antag  incr antichol and
antihistamine SE & decr EPS
 Antipsychotics exert influence at mesocortical and mesolimbic dopaminergic pwys
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Pharmacokinetics:
 PO  absorption is variable, peak plasma levels in 1-4 hrs
 IM  effects w/in 15 mi, high bioavail
 Metabolized by liver by oxidation from lipid soluble to water soluble
 CYP450,2D6,1A2,3A4
o **Watch levels in those w/ poor CYP2D6 metab mutation
 Conventional antipsychotics are protein bound
Acute Psychosis:
 High potency conventional (haloperidol) or SGA (risperidone, olanzapine,
quetiapine, ziprasidone) for at least 4-6wks before changing regimen
 Clozapine is 2nd line b/c of propensity for agranulocytosis and white cell montoring
req
 Emergently  IM antipsych + benzo
Maintenance:
 Prevention of relapse is more impt than risk of SE
 At least 1-2 yrs of tx are recommended following initial episode b/c of high risk of
relapse and deterioration
 At least 5yrs tx for multiepisode tx
 Chronic ongoing tx for those a danger to self or others
 SGA tend to provide both mood stabilization and control of psychotic symp
AE:
 potency positively correlates with level of D2 antagonism.
 SGA are weaker D2 antag but more potent 5HT2a antag  incr antichol and
antihistamine SE & decr EPS
 Tardive dyskinesia (TD) – abnormal involuntary movements (usually of mouth and
tongue)
 Caused by postsynaptic supersensitivity to dopamine
 Vitamin E can help alleviate abnl movements
 Pseudoparkinsonism & Akathesia –
 Pseudoparkinsonism- tremor, rigidity, hypokinesia – seen in 3+ weeks
 Akathesia- restlessness, snake like wringing of hands – MC form of EPS—
seen in first few weeks
 Both can be treated by reducing dose or adding an antiparkinsonian (ie.
Benztropine-Cogentin)
 Akathesia can be treated w/ B-blockers or amantadine (potentiates release
of dopamine from basal ganglia), or benzos or clonidine (a2 agonist  decr
NE, sympatholytic)
 Acute dystonic reaction
 Seen in first 4 days
 MC in younger pts, cocaine users and those getting high potency IM
 Sustained contraction of neck mm, mouth, tongue, etc.
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 Often don’t recur – can be treated w/ short course benztropine
 Anticholinergic SE
 Dry mouth, urinary ret, blurry vision, constipation, exacerbation of narrow
angle glaucoma
 Mc in low potency antipsychotic (ie. Chlorpromazine)
 Benztropine can make worse!
 Orthostatic hypotension
 Mc cv se b/c of alpha block
 Mc in low potency antipsych
 QT prolongation – chlorpromazine, thioridazine, pimozide, & aripiprazole,
iloperidone
 Agranulocytosis  seen w/ clozapine
 Hyperprolactinemia  seen w/ conventional antipsy, less so w/ SGA
 Quetiapine or aripiprazole favored for low EPS and low prolactin effect
 Metabolic problems
 SGAs can affect glucose regulation, lipids, and cause wt gain
 Clozapine and olanzapine MC to cause wt gain
 Aripiprazole and ziprasidone  wt neutral
 NMS
 Less likely w/ SGAs
 Medical emergency- rigidity, fever, delirium, autonomic instability, incr
levels of CPK and liver enzymes
 Tx – dantrolene (mm relaxant) and bromocriptine
o Pregnancy  All are C except clozapine which is B
Antidepressants
o Uses: acute and maintenance tx of major depression, dysthymia, bipolar, panic d/o,
agoraphobia, OCD, PTSD, GAD, social phobia, bulimia nervosa
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SSRIs
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Safer and better tolerated than TCAs
 Lack SE of TCAs caused by blockade of muscarinic, histaminic, and alpha rec
MOA: serotonin reuptake inhib – incr serotonin
Metab by liver – only fluoxetine and sertraline have active metabolites
 Fluoxetine has longest t1/2 (2-3 days) rest of ssris have t1/2 of 15-35hrs
AE:
 dose related – nausea, loose stool, anxiety/hyperstimulation (ha, insomnia,
jitteriness)
o Sometimes – wt gain/loss, vivid dreams, bruxism, rash, amotivation
 SEXUAL DYSFXN – tx w/ lower dose, changing to a non-ssri (ie. duloxetine,
buproprion), or an antidote drug (bupropion or cyproheptadine)
 Fluoxetine – most likely for SE, escitolopram – least likely
 Discontinuation Syndrome –
o Nausea, ha, irritability, vivid dreams
o Avoided w/ tapering
o Not seen w/ fluoxetine  self tapers
 Serotonin Syndrome –more likely among pts taking more than 1 drug
boosting serotonin
o Lethargy, restlestness, confusion, flushing, diaphoresis, tremor,
myoclonic jerks
o Can progress to hyperthermia, hyperonicity, rhabdomyolysis, renal
failure and death
o Classic ex is SSRI + MAOI
SSRIs inihibit various CYP450 enzyme  DI
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SSRI (cont)
 Pregnancy C, except paroxetine (D)
 Avoid w/ breast feeding
Buproprion
 Inhibits reuptake of D and NE
 Tx for major depression and smoking cessation
 Also, seasonal aff d/o, ADHD
 Rapidly absorbed PO  peak conc in 2hrs
 Biphasic elimination (1st phase 1.5hrs, 2nd phase 14 hrs)
 SE: ha, nausea, anxiety, tremors, insomnia, diaphoresis
 Risk of seizure w/ high dose
Duloxetine
 Selective serotonin-NE reuptake inhibitor along with venlafaxine and desvenlafaxine
 Tx: major depression, GAD, diabetic neuropathy, fibromyalgia
 Well absorbed in the gut, t1/2 8-17hrs
 Metabolized in liver CYP540 2D6 and 1A2  prone to DI
 SE: insomnia, asthenia (weakness), nausea, dry mouth, constipation
 Potential for hepatotoxicity
 Serotonin Synd w/ MAOI
 Fatal w/ overdose
Mirtazapine
 Enhances both serotonergic and noradrenergic neurotransmission – but is NOT a
reuptake inhib
 Also an antagonist at histamine, alpha, and muscarinic rec
 Tx: major depression
 Well absorbed in gut, 85% protein bound, t1/2 20-40hrs
 Se: somnolence, wt gain, incr appetite
 Serotonin Synd w/ MAOI
 Not fatal w/ overdose
 Rare cases of agranulocytosis
 NO CYP metab = less DI
 Early effect on anxiety and sleep disturbances
Nefazodone
 Blocks 5HT2 rec and weakly inhibits serotonin reuptake
 Tx: major depression
 Se: nausea, somnolence, dry mouth, dizziness, constipation, blurred vision, asthenia
 Inhibits CYP450 3A4/3 = DI
 Black box warning – hepatic failure
Trazodone
 Weak inhibitor of serotonin and blocks 5HT2 rec
 Shares structure w/ alprazolam and is similar structurally to nefazodone
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Trazodone (cont)
 Tx: major depression – Very sedating  insomnia
 Absorbed in gi, peak plasma in 1-2hrs, t1/2 6-11hrs
 Metabolized by the liver and 75% excreted in urine
 AE: usually related to alpha antag and antihistaminic
 Sedation, ortho hypotn, dizziness, ha, nausea, dry mouth
 Priapism
 Serotonin synd w/ MAOIs
Venlafaxine and Desvenlafaxine
 SNRIs
 Venlafaxine- major depression, GAD, social anxiety, panic d/o
 Rapidly absorbed in gut, 98% bioavail, t1/2 4hrs
 Desvenlafaxine – major depression
 Well absorbed PO, t1/2 10rs
 Both metabolized in liver and renally excreted
 SE: hyperstimulation, sexual dysfxn
 BP monitoring recommended
 Serotonin syndrome w/ MAOIs
TCAs
 Block reuptake of NE and serotonin at presynaptic nerve ending
 Tertiary amines (amitriptyline, imipramine, doxepin)
o Primarily serotonin reuptake blocking
 Secondary amines (desipramine, nortyptyline, protriptyline)
o Primarily block NE reuptake
 Clomipramine – exception – relatively ssri
 TCAs all block muscarinic, histaminic, and alpha rec
 Well absorbed orally, undergo enterohepatic cycle and reach peak plasma in 2-4hrs
 Highly protein bound and fat soluble
 Metabolized in liver and excreted in kidneys
 Blood levels increased by drugs that inhib CYP (ie. Ssris, antipsychotics)
 AE:
 sedation, orthostatic hypotn, anticholinergic
o Tertiary amines have rougher SE
 Misc SE: tremors, pedal edema, myoclonus, seizures, hyperstimulation,
insomnia, n/v, confusion, eeg changes, allergic rxns
 CV SE: prolonged cardiac conduction
 Withdrawl syndrome w/o tapering – ha, myalgia, chills, malaise, nausea
o Can be tx w/ anticholinergic (ie. Diphenhydramine)
MAOIs
 Inhibit monamine oxidase which is responsible for degradation of tyramine,
serotonin, dopamine, and NE
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MAOI (cont)
 MAO-A found in brain, liver, gut and sympathetic nerves
 Acts primarily on serotonin and NE
 MAO-B found in brain, liver and platelets
 Acts primarily on phenylethylamine
 Both A and B act on dopamine and tyramine
 4 MAOIs used in US – isocarboxazid, phenelzine, tranylcypromine, selegiline
 Readily absorbed PO, renally excreted
 MAO is irreversibly inhibited and max inhibition is reached in 5-10 days
 Platelet MAO reduced by 80% = antidep activity
 Tx: depression accomp by anxiety, agoraphobia, panic d/o, social phobia, PTSD,
bulimia nervosa, atypical depression
 SE:
 MAOIs are alpha blockers  ortho hypotn
o May need to add salt or salt retaining steroids like fludrocortisone
to counteract
 Sedation, hyperstimulation, insomnia, dry mouth, wt gain, edema, sex
dysfxn
 Concomitant ingestion of tyramine substance  htn, stroke, death
o **No need for tyramine free diet w/ Selegeline (MAO-B inhib)
o Tyramine foods: meats, cheese, fruits, fermented items, wine/liquor
 Serious interaction w/ amphetamines  htn crisis
o Tx w/ IV phentolamine (alpha blocker)
 DI w/ meperidine (opioid)
 Serotonin Syndrome when combined w/ another serotonin boosting drug
Use of antidepressants
 Start w/ ssri
 Safer for those w/ CV history and suicidal intentions (not fatal OD)
 For TCAs nortriptyline, imipramine, and desipramine are DOC because plasma
levels can be measured
 After 1st depressive episode  4-9 mos tx
 Chronic tx for:
 3 or more depressive episodes
 Depression + dysthymia
 2+ severe episodes in last 5yrs
 Depressive d/o complicated by substance abuse or anxiety
 Age of onset >60
 Drug trials should last at least 4-8 weeks
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Mood Stabilizers
o Lithium, valproate, carbamazepine, and lamotrigine can all be used to treat Bipolar
o Lithium Carbonate
 MOA unknown
 Inhibits inositol-1-phosphatase w/in neurons  decr response to NT using
phosphatidylinositol 2nd messenger system
 Onset of action – 5-7 days
 Blood level
 Acute mania: .9-.14 mEq/L
 Maintenance: .5-.7 mEq/L
 Tx: 1st line for bipolar depression, prophylaxis of manic and depressive episodes in
BP pts, schizoaffective d/o, aggression w/ dementia, MR, borderline & antisocial
personality d/o
 Pkinetics
 PO admin and rapidly absorbed in gut  peak plasma in 2hrs
 T1/2 8-12hrs in manic pts, 18-36hrs in euthymic pts
 NOT protein bound
 Renally excreted
 Blood levels should be checked 12hrs after admin
o Levels checked monthly for 1st three and every three thereafter
 Watch kidney and thyroid
 AE
 Polyuria, tremor, diarrhea, wt gain, edema  all appear early and tend to
diminish w/ time
 Hypothyroidism
o Thyroid fxn should be checked before initiating tx
o Tx w/ thyroid hormone replacement
o Reversible
 Long term  incr Ca2+, PTH
o Incr Ca2+ can cause lethargy, ataxia, dysphoria  may falsely be
attr to depression
 Reabsorbed in PT of kidney w/ Na and H2O  risk of Li toxicity w/
hyponatremia
o NSAIDs can also incr Li levels
 Nephrogenic Diabetes Insipidis
o Tx w/ amiloride (K sparing diuretic) or HCTZD to paradoxically decr
urine output
 Decr GFR
 Sinus node dysfxn, T wave changes
 Acne, hair loss, psoriasis
 Reversible leukocytosis
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 Parkinsonian like symptoms
Lithium (cont)
 AE (cont)
 Cognitive effects (poor memory, confusion, etc)
 CI
 Sever renal dx
 Pts w/ recent MI (D/C for 10-14 days post MI)
 Myathenia Gravis – Li blocks release of ACh
 Caution w/ DM, UC, psoriasis, cataracts
 1st trimester and breast feeding
o Ebseteins anomaly –CV malformation
Valproate
 An anticonvulsant commonly used to treat acute mania
 First line for bipolar, as are lithium and carbamazepine
 MOA: unknown – enhances CNS levels of GABA
 PKinetics: rapidly absorbed PO, nearly 100% bioavail, 90% protein bound and peak
conc in 1-4hrs
 T1/2 8-17hrs
 Metab by liver through glucuronide conjugation
 SE: gi issues, elevated hepatic transaminase, tremor, sedation, wt gain
 Can cause hematologic abnl and hepatotoxicity
 NTD w/ pregnancy
 Coma or death w/ overdose
 Must get CBC and liver enzymes before beginning
Carbamazepine
 Anticonvulsant structurally similar to TCAs used to treat complex partial and tonic
clonic seizures
 Used as an alternative to lithium and valproate for acute mania
 Also used to tx bipolar
 MOA: unknown
 Takes 5-7 days to see affect for mania
 Can be combined with antipsychotics
 More effective for rapid cyclers w/ poor lithium response
 SE: transient skin rash, impaired coordination, drowsiness, dizziness, slurred speech,
ataxia
 Transient Leukopenia
 Aplastic anemia
 Vasopressin agonist  can induce hyponatremia
 Need CBC and EKG before starting
 Linked with malformations in pregnancy and not rec. for breast feeding
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Mood Stabilizers
o Lamotrigine
 Anticonvulsant approved for the maintenance treatment of bipolar I d/o
 Most effective in delaying the time to occurrence of depressive episodes
 MOA: unclear – known to block Na channels which inhibits release of presynaptic
glutamate, aspartate, and GABA and weakly inhibit 5HT3
 Pkinet: bioavail 98%, two peak concentrations at 1-3hrs & 4-6 hrs, 60% protein
bound
 Metabolism – hepatic glucuronidation
 T1/2 25-35hrs
 SE: usually minor
 Occasionaly SJS and TEN
 Do not combine w/ valproate (risk of SJS)
 Pregnancy category C
Anxiolytics
o Most widely prescribed psycotropic drug -- include benzos, barbs, nonbarb sedatitive
hypnotic, and buspirone  only benzos and buspirone are recommended
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Benzodiazepines
 Uses: anxiety d/o, sleep disturbances, MSK problems, seizures d/o, etoh w/d, and
anesthesia
 MOA: bind to benzo rec in brain linked to GABA rec  potentiate actions of GABA
 anxiolytic effect on limbic system
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Benzos (cont)
 Indications: GAD, panic d/o (2nd line after ssri), social phobia, coadministered w/
antidepressant for dep+anxiety, situational anxiety (adjustment d/o w/ anxiety), s/t
tx of insomnia, etoh w/d (usu. Chlordiazepoxide), akathesia, catatonia, acute
agitation, and mania
 Pkinetics:
 rapidly absorbed in gut (except lorazepam) and poorly absorbed IM
o lorazepam is widely avail parenterally
 metab by hepatic oxidation and have active metabolites
o Lorazepam, Oxazepam, & temazepam are metab by glucuronide
conjugation short acting w/ no active metabolites  good for the
elderly
 Drug selection
o Rapid onset drugs tend to be lipophilic (rapid crossing BBB)
o Longer t1/2 take longer to accumulate, reach steady state, be
eliminated, and tend to have active metabolites
o Determine drug selection: t1/2, metabolites, route of elimination
 AE:
o CNS depression – avoid etoh
o Potential for abuse and addiction
o Discontinuation can lead to tremulousness, sweating, light and
sound sens, insomnia, abdominal probs, syst htn
 Pregnancy Cat D or X
 Rarely fatal w/ o/d
Buspirone
 Uses: GAD, panic attacks, phobias, obsessions, compulsions
 5HT1A rec agonist and does not interact w/ benzo rec  no sedation, etoh
interaction, or abuse potential
 Well absorbed orally and metab by the liver, t1/2 2-11hrs
 SE: drowsiness, ha, dizziness
ECT
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Electric current through scalp to induce grand mal seizure
MOA: unknown
Almost exclusively for the tx of mood d/o non-responsive to other tx, also -- suicidal
depression, depression w/ refusal of food or fluids, depression and pregnancy, catatonic
syndromes, acute schizophrenia, mania unresponsive to meds, psychotic or melancholy
depression refractory to tx
Effective w/ antidepressants
Pre ECT workup
 Physical exam, ekg, cbc, electrolytes
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Relative CI
 MI w/in 1mo, uncompensated CHF, uncontrolled htn cv dx, venous
thrombosis
 Absolute CI
 Space occupying brain lesions and incr ICP
Can use bilateral nodes or unilateral nodes
AE:
 Hypo/hypertn, bradyarrythmias, tachyarrythmias, prolonged seizures,
laryngospasm, prolonged apnea b/c of pseudocholinesterase deficiency
 Most troublesome is memory impairment