psychopharmacology what you should know to survive the lmcc and internship
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Psychopharmacology What you should know to survive the LMCC and Internship. Kate Huntington, MD April 2008. Objectives. To review: indications for mechanism of action side effects (remember not everyone gets these) monitoring parameters for the major classes of psychotropic medications. - PowerPoint PPT PresentationTRANSCRIPT
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PsychopharmacologyWhat you should know to survive the
LMCC and Internship
Kate Huntington, MD
April 2008
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Objectives
To review:• indications for• mechanism of action • side effects (remember not everyone gets
these)• monitoring parameters
for the major classes of psychotropic medications
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SSRI’s: Indications
• MDD• GAD• Social phobia• PTSD• OCD• Augmentation in BD• Premenstrual Dysphoric Disorder• Panic Disorder
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SSRI: Mechanism of Action
• In depression, the serotonin neuron has a relative deficiency of serotonin and the autoreceptors and postsynaptic receptors are increased in number & sensitivity
• When the reuptake pump is blocked, the level of serotonin increases in the somatodendritic area, causing autoreceptors (the brakes) to decrease in number & sensitivity
• This turns off the brake on the serotonin neuron and electrical impulses flow down the axon, releasing more serotonin at the axon terminal
• Increased levels of serotonin in the synapse leads to down regulation (decreased number and sensitivity) of postsynaptic receptors & other downstream changes
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SSRI: Side Effect Profile
• Headache
• Anxiety (limbic projections) and Agitation (basal ganglia projections)
• Nausea (chemoreceptor trigger zone)
• Diarrhea (peripheral GI 5HT3 & 5HT4 receptors)
• Sexual dysfunction (spinal projections) and Sleep disruption or Somnolence (Brainstem sleep centre)
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SSRI: Rare but Dangerous Side Effects
• UGI bleeding (platelet dysfunction)
• SIADH
• SSRI discontinuation syndrome (slow taper)
• Serotonin syndrome
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Norepinephrine & Dopamine Reuptake Inhibitor:Mechanism of Action
(Bupropion/Wellbutrin)
• Blockade of norepinephrine and dopamine reuptake pumps, leads to similar cascade as with SSRI’s
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NDRI: Side Effect Profile
• Seizures (not with SR formulation & following correct dosing; contraindicated with Bulimia or electrolyte disturbances)
• Headache• Agitation (limbic cortex)• Rash• Emesis• Sleep disruption (limbic cortex) and Shaking (cerebellum)
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Serotonin & Noradrenergic reuptake Inhibitors: Mechanism of Action
(Venlafaxine/Effexor)
• Blockade of serotonin reuptake up to about 150 mg
• Blockade of serotonin and norepinephrine reuptake from about 150-225mg
• Blockade of serotonin, norepinephrine and dopamine reuptake above 225 mg
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SNRI: Side Effect Profile
• Same as SSRI up to 150 mg
• >150 mg, may also see sustained increase in diastolic BP & other noradrenergic-type side effects (see NDRI)
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SNRI: Rare but Dangerous Side Effects
• As with SSRI’s
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NaSSA: Mechanism of Action
• Blocks Alpha 2 autoreceptors on norepinephrine neurons & heteroreceptors on Serotonin neurons, causing more NE & 5HT to be released (puts the brakes on the brakes)
• NE neurons from the locus coeruleus innervate midbrain raphe 5HT neurons. Therefore, increased NE causes a further increase in 5HT release
• Blocks 5HT2 receptors, having an anxiolytic effect & blocking sleep & sexual side effects
• Blocks 5HT3, blocking GI side effects from peripheral receptors & from brainstem chemoreceptor trigger zone
• Blocks H1 histamine receptors, causing sedation & weight gain
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NaSSA: Side Effect Profile
• Weight gain (H1 blockade)
• Anticholinergic: constipation, urinary retention, dry mouth, blurred vision, drowsiness, sinus tachycardia, confusion/delirium, fever (red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare; bowel & bladder lose their tone & the heart goes off alone)
• Drowsiness (H1 blockade)
• Equilibrium
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NaSSA: Rare but Dangerous Side Effects
• Neutropenia
• Serotonin syndrome
• Hepatotoxicity
• Possibly SIADH
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SARI: Mechanism of ActionSerotonin 2A antagonists/reuptake inhibitors (Trazadone/Desyrel)
• Primarily blocks 5HT2A, reducing sexual dysfunction & sleep disruption & increasing effect of 5HT1A stimulation (5HT2A & 5HT1A oppose one another)
• Weak 5HT reuptake inhibitor, increasing 5HT stimulation of 5HT1A (therapeutic effects)
• H1 blockade causes sedation
• Alpha One blockade leads to orthostatic hypotension
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SARI: Side Effect Profile
• Orthostatic hypotension
• Sedation
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SARI: Rare but Dangerous Side Effects
• Serotonin syndrome
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TCA: Mechanism of ActionTricyclic antidepressants: 3° amines (eg amitriptyline, imipramine, doxepine) 2°
amines (eg nortriptyline, desipramine)
• Therapeutic effects and side effects from blocking Serotonin, Norepinephrine & Dopamine Reuptake
• Some also have 5HT2 blocking ability (blocks sex & sleep side effects)
• Side effects from blocking H1 histamine receptors, muscarinic receptors, alpha one adrenergic receptors & sodium channels in the heart & brain
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TCA: Side Effect Profile
• Antihistamine – weight gain & sedation
• Anticholinergic – (remember toxidrome from NaSSA)
• Anti-alpha adrenergic – dizziness, orthostatic hypotension
• Blockade of fast sodium channels – prolongation of QTc (risk of Torsades)
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TCA: Rare but Dangerous Side Effects
• Torsades de Pointes
• EKG – rule out bradycardia and prolonged QTc
• Lytes – rule out electrolyte imbalance
• Make sure not on type 1 or 3 antiarrythmic drugs
• SIADH
• Serotonin Syndrome
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MAOI: Mechanism of ActionMonoamine oxidase inhibitors:
“the classics” (phenylzine/nardil, tranylcypromine/parnate)Reversible inhibitor: (moclobemide/mannerix)
• Irreversibly bind MAO (2 wks) & destroy its function, therefore decrease monoamine breakdown, increasing 5HT, NE & DA
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MAOI: Side Effect Profile
• Side effects related to increase in serotonin norepinepherine & dopamine (see SSRI’s & NDRI’s)
• Orthostatic hypotension
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MAOI: Rare but Dangerous Side Effects
• Blood dyscrasias• Hepatotoxicity• Teratogenicity• Serotonin Syndrome - (even more susceptable than with other
serotenergic antidepressants)• When you see an MAOI, get a pharmacy consult, the patient
should consult their pharmacist about any over - the – counter medications
• Hypertensive crisis• Consult the dietician Re: MAOI diet• Patients need to avoid all foods with tyramine (aged foods such as
cheese and wine)
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Serotonin Syndrome
Major Criteria Minor Criteria
Mental Symptoms
impaired consciousness,
elevated mood,
coma/semicoma
restlessness,
insomnia
Autonomic
Symptoms
fever, sweating Tachycardia, dyspnea,
diarrhea
Neurological
Symptoms
myoclonus, tremor, shivering, rigidity, hyperreflexia
uncoordination, dilated pupils, akathisia
Co-incidence with the addition or increase of a serotenergic agentDevelopment of at least 4 major or 3 major plus 2 minor criteria
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Hypertensive Crisis
• Norepinephrine is the amine most closely linked with control of blood pressure
• MAO normally inactivates norepinepherine
• Tyramine, an amine present in aged foods, causes release of norepinepherine
• In the presence of MAOI, this increased NE cannot be broken down, resulting in a hypertensive crisis
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Starting Antidepressants: General Guidelines
• Start with a reuptake inhibitor or mirtazepine (not a TCA or MAOI)
• Start at lowest possible dose (half of this with anxiety and in the elderly and medically frail)
• Increase by this increment about every five half lives (or about once a week) until one of the following endpoints:
• Intolerable side effects
• Full response
• Maximum dose
• Continue to monitor for therapeutic effects, side effects and safety
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Course of Recovery From Course of Recovery From DepressionDepression
Response
2-3 weeks:
Improved sleep,
appetite, vegetative
shifts
3-4 weeks:
objective improvement
energysuicidal
ideation may
6-8 weeks:
subjective improvement
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Stimulants: Indications
• ADHD
• Narcolepsy
• (treatment resistant depression)
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Stimulants: Mechanism of action
• Increases dopamine and NE actions by blocking their reuptake and facilitating their release
• Action in DL prefrontal cortex improves attention, concentration, executive function and wakefulness
• Action in Basal Ganglia may improve hyperactivity
• Action in medial prefrontal cortex may improve depression, fatigue and sleepiness
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Stimulants: Common Side Effects
• Headaches and Heart concerns(palpitations, tachycardia and hypertension)
• Insomnia, Irritibility and Increased stimulation• Dizziness• Exacerbation of tics, tremor• Stomach: anorexia, nausea, abdo pain, weight
loss, possibly slowing of normal growth in children
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Stimulants: Rare Side Effects
• Psychosis
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Stimulants:Ongoing Monitoring
• Blood pressure at baseline and with dose increases
• In children, ongoing monitoring of height and weight
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ECT: Indications
• Common
• MDE
• Mania
• Mixed state
• Catatonia
• Schizophenia with prominent affective symptoms
• Schizoaffective disorder
• Uncommon
• Delirium
• NMS
• Parkinson’s Disease
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ECT: Indications (cont.)
• Indications for First Line Use:
• Need for rapid improvement (suicide, malnutritian, catatonia, severe psychosis or agitation)
• When other treatments are more risky (elderly, pregnant)
• Patient preference
• Psychotic depression (gold standard – 95% response)
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ECT: Relative Contraindications(weigh pros & cons)
• Space occupying cerebral lesions
• Increased ICP
• Recent MI
• Recent CVA
• Aneurysm
• Retinal detachment
• Pheochomocytoma
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ECT: Mechanism of Action
• Neurotransmitter theory
• Enhances DA, 5HT & NE neurotransmissiom
• Neuroendocrine theory
• Increased release of neurohormones including prolactin, TSH, ACTH & endorphins
• Anticonvulsant theory
• Increase in seizure threshold during course of ECT; CSF of animals receiving ECS is anticonvulsant when given IV to recipient animals
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ECT: Side Effect Profile
• Common
• Headache
• Muscle ache
• Nausea
• Memory impairment
• Delirium
• Amnesia (anterograde & retrograde)
• No longterm deficits
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ECT: Side Effect Profile
• Rare:
• Mortality 1/10,000-0.2 / 100 000
• Cardiovascular
• 2° initial vagal stimulation
• Bradycardia / asystole / ectopic activity
• 2° sympathetic stimulation
• Increased HR & increased BP
• Prolonged apnea
• Pseudocholinesterase deficiency
• Prolonged seizure
• Treat with IV benzo
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Mood Stabilizers: Indications
• Bipolar Affective Disorder (BD)
• Migraine or cluster headaches
• Chronic aggression or impulsivity
• Lithium reduces suicidal risk in BD and augments antidepressants in MDD and OCD
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Choice of Treatment in BD (Bipolar Disorder)
• For first onset acute manic or mixed episodes, start lithium, epival or an atypical antipsychotic; taper and discontinue antidepressants if possible
• For acute bipolar depression, initiate either lithium or lamotrigene
• For rapid cycling (more than four episodes per year), initiate either lithium, epival or lamotrigene; taper and discontinue antidepressants
• For maintenance therapy, lithium and epival are most supported. Alternatives include lamotrigene, carbamazepine, oxcarbazepine and M-ECT
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Lithium: Mechanism of Action
• MOA is unclear• Thought to be involved in:
• Modulating second messenger systems (ie G protein-coupled receptors, through which most hormones and neurotransmitters mediate their effects) which leads to:
• Increasing GABA activity• Reducing glutamate activity• Stabilizing catecholamine receptors• Blocking the effects of some hormones (eg. ADH and TSH) on end
organs
• Effective in treating classic, euphoric mania & BD with M-D-E pattern
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Lithium: Side Effect Profile(THE MAGIC WAND)
• Tremor
• Hypothyroid (5%)
• EKG changes (bradycardia, reversible T-wave flattening or inversion; contraindicated in sick sinus syndrome, can lead to sinus node dysfunction)
• Muscle weakness
• Alopecia
• GI upset
• Increased WBC (transient)
• Cardiac abnormality: increased risk Ebstein’s anomaly
(0.1% vs 0.005%) in first trimester
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Lithium: Side Effect Profile (cont.)(THE MAGIC WAND)
• Weight gain (50%)• Acne (rashes in general)• Neurological (in toxicity)• Diabetes insipidus/Drinking more
• Early Toxicity GI distress, hand tremor, fatigue, thirst, headache, decreased concentration
• Late Toxicity AtaxiaStupor Comamyoclonic jerking increase DTR’s seizure
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Lithium: Initial Work-up
• CBC ( can increase WBC)
• Lytes, BUN, Cr (renally excreted)
• TSH (5% hypothyroidism)
• EKG with rhythm strip(contraindicated with sick sinus syndrome)
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Lithium: Ongoing Monitoring
• Lithium level every five days until steady state is reached then at 3-6 months, with signs of dehydration or toxicity or with change in medications or salt intake
• Levels are increased by NSAIDS, thiazide diuretics, ACEI, tetracycline, anticonvulsants
• Levels are decreased by osmotic diuretics (mannitol), carbonic anhydrase inhibitors, caffeine, increased salt
• Repeat kidney functions, Li level, TSH and EKG every 6-12 months
• Target Li level is 0.5-1.2 in adults and 0.4-0.8 in the elderly
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Why Use an Anticonvulsant as a Mood Stabilizer: The Kindling Hypothesis
• Underlying pathophysiologic mechanisms in BD are poorly understood
• Mania and epilepsy may share the underlying mechanism of kindling (repeated subthreshold stimuli generating an action potential leading to seizure in epilepsy or mood states in BD)
• It is hypothesized that both disorders may be caused by dysfunctional cation (Na &Ca) pumps, which leads to an imbalance between excitatory (glutamate) & inhibitory (GABA) neurotransmitters
• Anticonvulsants are thought to prolong inactivation of cation channels during activity such as seizure(or mood episode), preventing spread & leading to downstream changes in GABA & glutamate
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Epival: Side Effect Profile(TURN SO BALD & FAT)
• Tremor (10-29%)
• Unsteadiness
• Rashes (incl. S-J-S)
• Nausea (20%) / GI upset
• Sedation (31%)
• Oligomenorrhea/PCO (menstral irregularity in 45%)
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Epival: Side Effect Profile (cont.)(TURN SO BALD & FAT)
• Blood dyscrasia • thrombocytopenia (always ask about bruising and bleeding)• Anemia (macrocytic)• Agranlocytosis(ask about symptoms of infection)• Coagulopathies
• Alopecia (treat with Zn & selenium)• LFT elevation (up to 44%) (always ask re.: nausea, vomiting, edema,
malaise)• Dysarthria• Fat (weight gain) / insulin resistance• Ammonia levels can rise (can cause confusion, stupor, coma)• Teratogen (5-15%)
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Epival: Initial Work-up & Ongoing Monitoring
• Initial
• CBC + LFT’s
• Epival level weekly until steady state reached
• Ongoing
• Repeat tests monthly x 6 months then Q6mos or if symptoms (bruising/bleeding/infection/general malaise) develop
• Target range 350-800 umol
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Lamotrigene: Side Effect Profile
• Rash – 0.3% adults / 1% in children. With slow titration risk was reduced to 0.01% comparable to other anticonvulsants.
• Activation (3-8%), Ataxia
• Spaced out (cognitive slowing), Sedation, Sleep disturbances
• H/A, Hypersensitivity reactions
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Lamotrigene: Rx
• Start with 25-50 mg/d
• Increase every 2 weeks by 25-50 mg
• Usual maintenance dose is 100-500 mg in 2 divided doses
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Anxiolytics: Indicationseg. Benzodiazepines (lorazapam)• Short term hypnotic (But decrease REM,
Stages 3 & 4 sleep)
• Anxiolytic
• Acute mania
• Alcohol withdrawal
• Catatonia
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Anxiolytics: Mechanism of action
• ↑ Affinity of GABA a receptor for GABA (a positive allosteric modulator)
• Two main receptor types• BZ1 – Located mostly in the cerebellum
– Anxiolytic and sedative-hypnotic actions• BZ2 – Located mostly in the spinal cord,
striatum and limbic system– Muscle relaxant actions
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Anxiolytics: Side effects
• Memory decline
• Addiction(dependency &withdrawal)
• Ataxia/Falls
• Drowsiness/dizziness/disinhibition
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Anxiolytics:Contraindications
• With COPD or sleep apnea
• Avoid in the elderly; with long term use taper by 25 % q-monthly after treating the underlying anxiety disorder with an SSRI as indicated
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Novel hypnotics (e.g. Imovane)
Indications: short term hypnotic agents Mechanism of action:• Higher affinity for BZ1 than BZ2 therefore
less side effects• More specific to CNS vs. peripheral
receptors therefore less side effectsSide Effects: Same as benzodiazepines but
reported to be less
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Antipsychotics: Indications
• Psychotic illness
• Delirium
• Mood disorder with psychosis
• Severe agitation or aggression
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Typical Antipsychotics: Mechanism of action
• D2 blockade
• Produces antipsychotic effect in the mesolimbic pathway• Causes worsening of negative and cognitive symptoms in
the mesocortical pathway, where a dopamine deficit is thought to cause these symptoms
• Causes EPS (dystonia, dyskinesia, akathesia, parkinsonism)in the nigrostriatal pathway
• Causes increased prolactin in the tuberoinfundibular pathway (gynecomastia, galactorrhea and sexual dysfunction)
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Typical Antipsychotics: Side effectsTypical Antipsychotics: Side effects
High potencyHigh potencyEPSEPS
HaldolPimozide
MellarilChlorpromazine
Loxapine
Perphenazine
QT prolongation with pimozide, CPZ
Low potencyLow potencyAntihistamineAntihistamineAntiAlpha-AntiAlpha-AdrenergicAdrenergicAnticholinergicAnticholinergic
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Atypical Antipsychotics: Indications
• Same as typicals
• Agitation/aggression in dementia NOT responding to adequate non-pharmacological interventions
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Features of Atypical Antipsychotics
• Block both D2 and 5HT2A
• Cause less EPS than typical antipsychotics
• Improve positive symptoms as well as typical antipsychotics
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Atypical Antipsychotics: Mechanism of action
• 5HT2A, when stimulated, normally stops dopamine release; when this is blocked, it causes dopamine release
• The different dopamine pathways have varying amounts of D2 and 5HT2A receptors
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Atypical Antipsychotics: Mechanism of action cont…
• In pathways with more 5HT2A receptors to block, SDA’s lead to dopamine release(i.e. the mesocortical pathway, reducing negative and cognitive symptoms)
• In pathways with more D2 receptors to block, SDA’s cause dopamine blockade (i.e.the mesolimbic pathway, with antipsychotic effects)
• In pathways where receptor numbers are relatively equal, there is no change in the amount of dopamine (i.e. in the tuberoinfundibular pathway, preventing increased prolactin)
• In the nigrostriatal pathway, there are just enough 5HT2 receptors to bring the D2 blockade down below 80%, the critical number to prevent EPS.
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Atypical Antipsychotics:Atypical Antipsychotics:Side EffectsSide Effects
Less effects on:• EPS, negative symptoms and cognition
A different set of concerns:• Weight gain (get baseline weight)• Akathisia • Sedation• Hyperglycemia/Hyperlipidemia(baseline fasting
lipids and glucose)• Dizziness (orthostatic hypotension; check BP)• In dementia increase mortality and risk of
cardiovascular events• Risk of agranulocytosis and seizure (dose
dependent) with Clozapine
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Atypical Antipsychotics: Monitoring
• Obtain baseline weight and calculate BMI; BMI monthly for three months and then q4mths
• Baseline personal and family history of obesity, dyslipidemia, hypertension and cardiovascular disease
• Baseline waist circumference at the umbilicus, BP, fasting glucose and lipid profile; repeat at 3 months and then annually
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Neuroleptic Malignant Syndrome
• Antipsychotic use (+) fever (+) rigidity (+) 2 of: • ↑ WBC • Lab evidence muscle injury (CK or myoglobinuria)• Diaphoresis• ↑ HR • ↑ or labile BP• Dysphagia• Tremor• Incontinence• Change in MS• Mutism
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Cognitive EnhancersCognitive Enhancers
Cholinergic Agents- Donepezil
- Rivastigmine
- Galantamine
NMDA Antagonist- Memantine
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Cognitive Enhancers: Cognitive Enhancers: IndicationsIndications
AChEI: early to moderate AD
Lewy Body Dementia
Mixed Dementia
Memantine: Moderate to severe AD
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Cholinesterase Inhibitors: Indications
• AAbilities
• BBehaviour
• CCognition
• DDecrease in caregiver time
• EEntry into Nursing Home
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Cholinesterase InhibitorsMechanism of Action
• Inhibits centrally-acting acetylcholinesterase, making more acetylcholine available
• This compensates in part for degenerating cholinergic neurons that regulate memory
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Cholinesterase Inhibitors: Common Side Effects
Muscle Cramps Insomnia Nausea Diarrhea
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Cholinesterase Inhibitors: use caution or consultation with:
• History of seizures
• History of bradycardia, sinus node dysfunction or other serious conduction abnormality
• History of PUD or other risk factors for GI bleeding
• History of COPD or asthma
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Memantine: Indications
SocializationHousehold tasksADLPersecutory ideationExcessive activity (agitation)
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Memantine: Mechanism of action
• A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer’s disease
• Memantine binds the NMDA receptor with a higher affinity than Mg2+ (which are normally there), inhibiting a prolonged influx of Ca2+ (thereby preventing excitotoxicity)
• The receptor can still be activated by the relatively high concentrations of glutamate released following depolarization of the presynaptic neuron
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Memantine: Common Side Effects
Confusion
Headache
Equilibrium (dizziness)
Constipation
Kidney function
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Cognitive enhancers: Cognitive enhancers: monitoringmonitoring
• Response may be seen 1 month, typically 3 months
• Realistic expectation is to “maintain”
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