Dr. Kate Huntington April 2011

Dr. Kate Huntington khunting@rohcg.on.ca April 2011
Psychopharmacology What you should know to survive the LMCC and Internship Dr. Kate Huntington April 2011

Objectives To review: indications for mechanism of action side effects (remember not everyone gets these) monitoring parameters for the major classes of psychotropic medications

Which of the following is not a common side effect of SSRI’s?
a. Nausea b. Headache c. Rigidity d. Anxiety e. Sleep disruption

Which of the following receptors does Mirtazepine not block?
a. Histamine b. 5HT1 c. 5HT2 d. 5HT3 e. Alpha 2

At which dose level does Venlafaxine typically begin to have a noradrenergic effect?
a. 75mg b. 150mg c. 225mg d. 300mg

Which is not an indication for the use of Benzodiazepines?
a. Catatonia b. Long term hypnotic c. Mania d. Alcohol withdrawal e. Anxiety

How are the novel hypnotics different from Benzodiazepines?
a. Do not cause falls b. Do not lead to tolerance c. Used as long term hypnotics d. More selective for the alpha one subtype of GABA-A receptor

Which of these is the most prominent side effect of atypical antipsychotics?
a. Rigidity b. Dystonia c. Dyskinesia d. Akathisia

Which of the following is an example of a low potency typical antipsychotic?
a. Haldol b. Pimozide c. Olanzapine e. Clomipramine f. Chlorpromazine

Which class of cognitive enhancers is indicated in mild to moderate Alzheimer’s Disease?
a. Cholinesterase inhibitor b. NMDA receptor antagonist

Which mood stabilizer can reduce the risk of suicide in Bipolar Disorder?
a. Valproic Acid b. Lamotrigene c. Lithium d. Carbamazepine

What is the most common excitatory neurotransmitter in the brain?
a. Serotonin b. Glutamate c. Norepinephrine d. GABA e. Dopamine

SSRI’s: Indications MDD Premenstrual Dysphoric Disorder GAD
Social phobia PTSD OCD Panic Disorder

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

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)

SSRI: Rare but Dangerous Side Effects
UGI bleeding (platelet dysfunction) SIADH SSRI discontinuation syndrome (slow taper) Flu like symptoms Insomnia Nausea Imbalance Sensory disturbance Hyperarousal (anxiety/agitation) Serotonin syndrome

Norepinephrine & Dopamine Reuptake Inhibitor:Mechanism of Action (Bupropion/Wellbutrin)
Blockade of norepinephrine and dopamine reuptake pumps, leads to similar cascade as with SSRI’s

NDRI: Side Effect Profile
Seizures (not with extended release formulations & following correct dosing; contraindicated with Bulimia or electrolyte disturbances) Headache, Hypertension (SNS activation) Agitation (frontal and limbic projections) and Anticholinergic (relative decrease in parasympathetic tone) Rash Emesis, decreased appetite and weight loss (SNS activation) Sleep disruption, Shaking and Sweating (sleep center and cerebellar projections and SNS activation)

Serotonin & Noradrenergic reuptake Inhibitors: Mechanism of Action (Venlafaxine/Effexor, Desvenlafaxine/Pristiq, Duloxetine/Cymbalta) Blockade of serotonin reuptake at lower dose range Blockade of serotonin and norepinephrine reuptake in mid dose range Blockade of serotonin, norepinephrine and dopamine reuptake at very high dosages

SNRI: Side Effect Profile
As with SSRI’s in lower to mid dose range As with NDRI in mid to high dose range

SNRI: Rare but Dangerous Side Effects
As with SSRI’s

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

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

NaSSA: Rare but Dangerous Side Effects
Neutropenia Serotonin syndrome Hepatotoxicity SIADH

SARI: Mechanism of Action Serotonin 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

SARI: Side Effect Profile
Orthostatic hypotension Sedation

SARI: Rare but Dangerous Side Effects
Serotonin syndrome

TCA: Mechanism of Action Tricyclic 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

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)

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

MAOI: Mechanism of Action Monoamine 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

MAOI: Side Effect Profile
Side effects related to increase in serotonin norepinepherine & dopamine (see SSRI’s & NDRI’s) Orthostatic hypotension

MAOI: Rare but Dangerous Side Effects
Hyperthermia i.e.Serotonin Syndrome even more susceptible than with other serotonergic antidepressants; need to avoid anything that has serotonergic effects such as such as antidepressants and opioids) 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 aged cheeses and wines or tap beer) and any medications with noradrenergic effects (cold remedies, stimulants etc) Hepatotoxicity Teratogenicity Blood dyscrasias

Serotonin Syndrome: HARMED
Hyperthermia Agitation/Autonomic instability Rigidity/Reflexes increased MyoClonus/tremors Encephalopathy Diaphoresis

For reference only

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

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

Treatment choices in children
Concerns were raised about the safety of antidepressants (Paroxetine and Venlafaxine) in children and youth in 2004 Further metaanalyses and epidemiologic studies now confirm that antidepressants in children and youth are safe with close (weekly) monitoring. Problems with Venlafaxine and Paroxetine may have been related to poor adherence and discontinuation symptoms

Choice of Initial Treatment in children/youth
Mild to moderate depression: Start with psychotherapy or non-medication interventions as first line Second line is to add medication; best evidence is for Fluoxetine; other SSRI’s could be considered next Moderate to severe depression: First line is to consider medication but depending on patient/family preference, may also start with psychotherapy or monitoring Note that the clinical presentation in children and youth can change quickly; they may appear severely depressed one week then by the next week be in a new relationship and everything is better…

Choice of Initial Antidepressant in Adults
There is comparable efficacy between and within classes of medication, therefore, initial selection is based on: Symptom profile Side effect profile in relation to the individual patient Patient preference Cost History of previous response of the patient or family members Comorbid psychiatric or medical illnesses Potential drug-drug interaction The BEST antidepressant is the one that a patient will actually take acutely and for the long haul

Course of Recovery From Depression
Response 2-3 weeks: Improved sleep, appetite, vegetative shifts 3-4 weeks: objective improvement energy suicidal ideation may  6-8 weeks: subjective improvement

Goals of antidepressant therapy
REMISSION of symptoms and maintaining that level of improvement in order to prevent relapse and recurrence Rate of relapse is significantly less for patients who achieve full remission of symptoms Patients who have been ill longer tend to be more treatment resistant; there is also evidence of hippocampal atrophy with prolonged illness, leading to the concept of disease progression and the hope that this can be modified by treating all mood episodes to the point of remission

Stimulants: Indications
ADHD Narcolepsy (treatment resistant depression)

Stimulants: Mechanism of action (1)
Increases dopamine and NE actions by blocking their reuptake and facilitating their release Improving the efficiency of information processing in the frontal subcortical circuits by targeting the arousal neurotransmitters dopamine and NE can relieve frontally mediated symptoms of inattention, hyperactivity and impulsivity.

Stimulants: Mechanism of action (2)
Action in DL prefrontal cortex improves attention, concentration, executive function and wakefulness Action in supplementary or prefrontal motor cortex may improve hyperactivity Action in the orbital frontal cortex may improve impulsivity Action in medial prefrontal cortex may improve depression, fatigue and sleepiness

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

Stimulants: Rare Side Effects
Psychosis

Stimulants: Ongoing Monitoring
Blood pressure at baseline and with dose increases In children, ongoing monitoring of height and weight

ECT: Indications Common MDE Mania Mixed state Catatonia
Schizophenia with prominent affective symptoms Schizoaffective disorder Uncommon Delirium NMS Parkinson’s Disease

ECT: Indications (cont.)
Indications for First Line Use: Need for rapid improvement (suicide, malnutrition, catatonia, severe psychosis or agitation) When other treatments are more risky (elderly) Patient preference Psychotic depression (gold standard – 95% response)

ECT: Relative Contraindications (weigh pros & cons)
Space occupying cerebral lesions Increased ICP Recent MI Recent CVA Aneurysm Retinal detachment Pheochomocytoma

ECT: Mechanism of Action
Neurotransmitter theory Enhances DA, 5HT & NE neurotransmissiom Neuroendocrine theory Increased release of neurohormones including prolactin, TSH, ACTH & endorphins Neurogenesis theory Increased neuroplasticity Release of BDNF Anticonvulsant theory Increase in seizure threshold during course of ECT; CSF of animals receiving ECS is anticonvulsant when given IV to recipient animals

ECT: Side Effect Profile
Common Headache Muscle ache Nausea Memory impairment Delirium Amnesia (anterograde & retrograde) No longterm deficits

ECT: Side Effect Profile
Rare: Mortality 2 / Cardiovascular initial vagal stimulation Bradycardia / asystole / ectopic activity sympathetic stimulation during tonic clonic phase of seizure Increased HR & increased BP Sometimes parasympathetic rebound with second phase of bradycardia Prolonged apnea Pseudocholinesterase deficiency Prolonged seizure Treat with IV benzo

Mood Stabilizers: Indications
Bipolar Affective Disorder (BPAD) Migraine or cluster headaches Chronic aggression or impulsivity Lithium reduces suicidal risk in BPAD and augments antidepressants in MDD and OCD

What is a “mood stabilizer”?
Originally , these medications treated mania and prevented its recurrence, thus treating and stabilizing the manic pole of bipolar disorder More recent medications can be thought of as treating one of the following phases: Acute bipolar depression Acute bipolar mania Maintenance

Choice of Treatment in BPAD (Bipolar Affective Disorder)
First line for acute mania: Lithium, Valproic Acid atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole) taper and discontinue antidepressants First line for acute bipolar depression: Lithium lamotrigine quetiapine do not use antidepressant monotherapy First line for maintenance therapy: Valproic acid Lamotrigine Atypical antipsychotics quetiapine, risperidone LAI and Olanzapine

Goals of treatment in BPAD
Again, the goal is to treat to complete remission of all mood symptoms It has been theorized that under-treated discrete depressive and manic episodes may progress to mixed and dysphoric episodes, rapid cycling and treatment resistance The hope is that recognition and full treatment of mood episodes may prevent progression to more difficult mood states

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 Works in acute bipolar mania, depression and maintenance phases Decreases suicide, deliberate self harm and death from all causes in patients with mood disorders

Lithium: Side Effect Profile
Lethargy Insipidis Tremor/Teratogen (increased risk Ebstein’s anomaly (0.1% vs 0.005%) in first trimester) Hypothyroid Increased weight Vomitting, nausea, GI Miscellaneous: EKG changes (T wave flattening or inversion), acne, hair loss

Lithium: Toxicity Narrow therapeutic index!!!
Anything that affects water and electrolyte imbalance can contribute to Lithium toxicity (CAUTION with flu, dehydation, meds) Levels are increased by NSAIDS, thiazide diuretics, ACEI, tetracycline, anticonvulsants Levels are decreased by osmotic diuretics (mannitol), carbonic anhydrase inhibitors, caffeine, increased salt

Lithium: Toxicity There is delayed distribution and elimination in the brain relative to serum therefore early signs are peripheral and later signs are central unless high level is chronic, in which case peripheral and central symptoms will occur simultaneously Peripheral symptoms: nausea, vomitting, cramping, diarrhea Central symptoms: tremulousness, hyperreflexia, ataxia, mental status changes, coma, seizures Can lead to irreversible neurotoxicity including cognitive impairment, peripheral neuropathy and cerebellar dysfunction Hospitalize for levels >2.0 or based on clinical symptoms

Lithium: Initial Work-up
Lytes, BUN, Cr (renally excreted) TSH (5% hypothyroidism) EKG with rhythm strip (contraindicated with sick sinus syndrome) Metabolic baseline including baseline weight , BMI, waist circumference , BP, fasting glucose and lipid profile Personal and family history of obesity, dyslipidemia, hypertension and cardiovascular disease

Lithium: Ongoing Monitoring
Lithium level every five days until steady state is reached then at months, with signs of dehydration or toxicity or with change in medications or salt intake Repeat kidney functions, TSH and EKG every 6-12 months BMI monthly for three months and then q4mths Waist circumference at the umbilicus, BP, fasting glucose and lipid profile repeat at 3 months and then annually

Lithium : Rx Adult Dosing 600 – 1500 mg/d (bid dosing) Level 0.5 – 1.2
Geriatric Dosing 150 – 600 mg/d (bid dosing) Level 0.4 – 0.8

Why Use an Anticonvulsant as a Mood Stabilizer: The Kindling Hypothesis
Term first coined by Graham Goddard in 1967 while studying learning in rats using low intensity electrical brain stimulation Over time the rats became sensitized to this and began to have seizures when they received this low intensity signal Likened to kindling in starting a fire in that the stimulus is not enough to cause the event on its own but when repeated enough leads to an episode

Why Use an Anticonvulsant as a Mood Stabilizer: The Kindling Hypothesis
Robert Post drew the parallel to BPAD where the initial episode is often precipitated by a stressor but when cycles continue untreated, the brain can become “kindled” and future episodes can occur with little or no precipitant Dysfunctional cation (Na &Ca) pumps leading to an imbalance between excitatory (glutamate) & inhibitory (GABA) neurotransmitters may contribute to this kindling phenomenon Anticonvulsants are thought to prolong inactivation of cation channels during activity, preventing spread of activity & leading to downstream changes in GABA & glutamate

MedTech to change to Valproic acid

Valproic Acid: treatment effects
Treats bipolar mania First line for bipolar depression in combination with lithium or SSRI/bupropion Second line monotherapy for bipolar depression Indicated for maintenance phase

Valproic Acid: Acute Side Effect Profile STUN
Sedation (31%) Tremor (10-29%) Unsteadiness (dizziness) Nausea (20%) /GI

Valproic Acid: longer term side effect monitoring
On the surface: Acne , hair loss Under the surface: weight gain, edema Systemic: blood dyscrasias (esp plt dysfn) liver dysfunction =/- elevated ammonia levels reproductive changes incl menstrual irregularities (up to 45%), PCOD, teratogenicity (5-15%)

Valproic Acid: Initial Work-up & Ongoing Monitoring
CBC + LFT’s Epival level weekly until steady state reached Metabolic baseline including baseline weight and calculate BMI Baseline personal and family history of obesity, dyslipidemia, hypertension and cardiovascular disease Baseline waist circumference at the umbilicus, BP, fasting glucose and lipid profile Ongoing Repeat tests monthly x 6 months then Q6mos or if symptoms develop BMI monthly for three months and then q4mths Waist circumference at the umbilicus, BP, fasting glucose and lipid profile repeat at 3 months and then annually

Valproic Acid: Rx Reference only
Starting dose: 250 qhs (geriatrics) 250 bid-tid (adults) Dose range: 750 – 3000 mg/d (bid dosing) Levels: 350 – 800 umol/l

Lamotrigine: Treatment effects
Treats bipolar depression First line maintenance treatment

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

Lamotrigene: Rx Start with 25-50 mg/d
Increase every 2 weeks by mg Usual maintenance dose is 200 mg in 2 divided doses

Atypical Antipsychotics: Olanzapine and Quetiapine
All atypical antipsychotics are indicated to treat bipolar mania Quetiapine is first line monotherapy for bipolar depression Both olanzapine and quetiapine are first line maintenance treatments

Anxiolytics: Indications eg. Benzodiazepines (lorazapam)
Short term hypnotic (But decrease REM, Stages 3 & 4 sleep) Anxiolytic Acute mania Alcohol withdrawal Catatonia

Anxiolytics: Mechanism of action
↑ Affinity of GABA a receptor for GABA (a positive allosteric modulator) GABA-A receptors with alpha one subunits most important for sleep GABA-A receptors with alpha two or three subunits are most important for anxiety (but all available at this time are non-selective and therefore also sedating)

Anxiolytics: Side effects
Memory decline Addiction(dependency &withdrawal) Ataxia/Falls Drowsiness/dizziness/disinhibition

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

Novel hypnotics (e.g. Zopiclone/Imovane)
Indications: short term hypnotic agents Mechanism of action: Some are selective for the alpha one subtype of GABA-A receptor (sedating effects) and not the alpha 2 (anxiolytic, muscle relaxant and alcohol potentiating) or alpha 5 (linked to memory) Side Effects: Reported to be less tolerance, dependence and withdrawal on discontinuation than BZD

Antipsychotics: Indications
Psychotic illness Delirium Mood disorder with psychosis Severe agitation or aggression

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)

Typical Antipsychotics: Side effects
High potency EPS Haldol Chlorpromazine Loxapine Perphenazine Low potency Antihistamine AntiAlpha-Adrenergic Anticholinergic QT prolongation with pimozide, CPZ

Atypical Antipsychotics: Indications
Same as typicals Agitation/aggression in dementia NOT responding to adequate non-pharmacological interventions

Features of Atypical Antipsychotics
Block both D2 and 5HT2A Cause less EPS than typical antipsychotics Improve positive symptoms as well as typical antipsychotics

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

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.

Atypical Antipsychotics: Side 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

Atypical Antipsychotics: Monitoring
Baseline personal and family history of vascular risk factors Obtain baseline weight and calculate BMI; BMI monthly for three months and then 3x per year Baseline waist circumference at the umbilicus, BP, fasting glucose and lipid profile; repeat at 3 months and then annually

Neuroleptic Malignant Syndrome
Antipsychotic use (+) fever (+) rigidity (+) 2 others of: Fever Encephalopathy (neuro s/s or change in mental status) Vital signs unstable Elevated CPK/ WBC Rigidity

Cognitive Enhancers Cholinergic Agents NMDA Antagonist Rivastigmine
- Donepezil Rivastigmine Galantamine NMDA Antagonist Memantine

Cognitive Enhancers: Indications
AChEI: early to moderate AD Lewy Body Dementia Galantamine in Mixed Dementia Donepezil in Vascular Dementia Memantine: Moderate to severe AD

Cholinesterase Inhibitors: Indications
Abilities Behaviour Cognition Decrease in caregiver time Entry into Nursing Home

Cholinesterase Inhibitors Mechanism of Action
Inhibits centrally-acting acetylcholinesterase, making more acetylcholine available This compensates in part for degenerating cholinergic neurons that regulate memory

AChEI: Common Side Effects
Muscle Cramps Insomnia/ incontinence Nausea Diarrhea Diarrhea Urination Miosis/muscle weakness Bronchorrhea Bradycardia Emesis Lacrimation Salivation/sweating

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

Memantine: Indications
Socialization Household tasks ADL Persecutory ideation Excessive activity (agitation)

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

Memantine: Common Side Effects
Confusion Headache Equilibrium (dizziness) Constipation Kidney function (But in large studies had a similar rate of treatment emergent side effects as placebo)

Cognitive enhancers: monitoring
Response may be seen 1 month, typically 3 months Realistic expectation is to “maintain”