Exam 2 Semester 2 Chand CNS

Statins cause

rhabdomyolysis

Chochliomyia Hominivorax

“school worm”- maggots

Primary/endogenous depression

no known cause of depression can be declared

Affective disorders

Depression and bipolar disorders

• Affective disorder: patient’s mood; sad, anxious, empty, hopeless, worried, worthless, guilty irritable, hurt, restless; may lose interest in activities that were once enjoyable

Loss of executive function

Losing the ability to make a decision on one’s own

• can be due to mental disorders

Typical depression

depressed mood or loss of interest and four other depressive symptoms

• antidepressants and psychotherapy

Atypical depression

Overeating/weight gain, oversleeping rejection sensitivity, mood reactivity

• antidepressant: SSRI, MAOI, TCAs

Anxious depression

prominent anxiety in addition to major depressive symptoms

• SSRIs, MAOIs

Seasonal depression

fall onset, spring offset and recurrent

• SSRIs, phototherapy

Dysthymia

chronic or depressive illness for 2 or more years, fewer and less severe symptoms than major depression

• SSRIs

Bipolar depression

Prior history of mania, mixed episodes may occur

• Mood stabilizers preferred: lithium, valproate, carbamazepine

Monoamines

Epi, norepinephrine, serotonin, dopamine

• MAO: breaks down above (if overactive will have low levels of these in the brain)

Antidepressant categories

• MAOI: block breakdown of MAO

• TCAs: non-selective reuptake inhibitors (epi, norepinephrine, serotonin, dopamine)

• SSRI: selectively inhibit reuptake of serotonin

• Atypical→ SNRIs: selective serotonin norepinephrine reuptake inhibitor

• Alpha 2 adrenoceptor blockers (pre-synaptic)

Serotonin

5-Hydroxy tryptamine (5-HT)

Impulse causes

release of serotonin into the synaptic cleft to get the post-synaptic receptors to function

• MAO exists in the synaptic cleft to break down the serotonin so it’s not sitting there

• some of the 5-HT released gets recycled back into the pre-synaptic cleft (reuptake)

TCAs (non-selective reuptake inhibitors)

A DIC (amytriptyline, clomipramine- DOC OCD, desipramine, imipramine- DOC enuresis; bed wetting)

• MOA: non-selective reuptake inhibitor (NE, 5HT, DA); increase the synaptic concentration of neurotransmitters and increase stimulation of pre and post synaptic receptors

• 2-3 weeks for clinical effects→ increased post-synaptic receptors to pick up the most amount of available neurotransmitters (up-regulation of receptors), after a while using the meds the body will decrease the amount of receptors (down-regulate) which is what takes 2-3 weeks

  • long term effect is down-regulation

Pharmacokinetics in TCAs

• Incomplete absorption d/t significant first pass effect (extensively metabolized)

• High protein binding and lipid solubility→ not much present in blood

• Active and inactive metabolites

  • Amytriptyline→ Nortryptyline

  • Impramine→ Desipramine

SE of TCAs

High SE profile

• Drowsiness/sedation, sympathomimetic effects (tremor, insomnia), Ach effects (blurred vision, constioption, dry mouth), CV (ortho HoTN, tachycardia, arrhythmias), psych (withdrawal syndrome→ needs a taper), lower seizure threshold (increasing monoamines in synaptic cleft), metabolic endocrine (weight gain, sexual disturbance)

DI of TCAs

• CNS depressants- additive effects (alcohol, antidepressants)

• Symapathomimetics (NE, EPI): arrhythmia

• Prolong QT intervals (azole antifungal and macrolide antibiotics)

• Antihypertensives (additive hypotensive effects)

SSRI- selective serotonin reuptake inhibitors

Some People Can’t Eccept Feeling Fine- Sertraline, paroxteine, citalopram, escitalopram, Fluoxetine, Fluvoxamine

• MOA: selectively block serotonin reuptake, well absorbed and extensively metabolized by p450 enzymes

• SE: male sexual dysfunction, less act effects and sedation, nervous/dizzy/insomnia, may increase suicidal tendencies in younger patients, less problems of OD, does not decrease the seizure threshold

DI SSRIs

• CNS depressants

• Cytochrome p450

  • inhibit CYP2D6 (responsible for b.d. of opioids)

  • inhibit CYP2C and CYP3A4 (almost everything else)- increase concentrations of everything else

• MAO-I: concurrent use may lead to serotonin syndrome (myoclonus, hyperreflexia, agitation, psychosis→ need a 2-5 week washout period)

  • Cognitive effects (HA, agitation, hypomania), autonomic effects (shivering, hyperthermia, HTN), somatic effects (myoclonus)

Atypical Antidepressants

Heterocyclics→ 2nd, 3rd, SNRIs

• 2nd: amoxapine, trazodone, bupropion

• 3rd: nefazadone, mirtazapine

• SNRI: venlafaxine

Bupropion (Wellbutrin, Zyban)

• MOA: weak uptake of dopamine, NE, serotonin (2nd generation)

• SE: few anticholinergic effects, rare CV or sexual dysfunction

• SMOKING CESSATION- Zyban

Nefazodone (Szerzone)

MOA: inhibit 5HT receptors, 3rd gen atypical

• NOT associated with sexual dysfunction

Venlafaxine (Effexor)

• MOA: blocks the reptile of NE and serotonin

• SE: similar to SSRIs (can have sexual dysfunction), no anticholinergic effects, minimal sedative or CV effects

Trazodone

Selectively inhibits serotonin reuptake

• SE: considerable sedation and orthostatic hypotension (depression and aggression)

Alpha 2 antagonist

Mirtazapine

• Increase amine release from presynaptic nerves

BPD

Alternate depression and mania

• BPD1: full mania

• BPD2: hypomania

• Cyclothymia: chronic moodiness up and down

DOC BPD

• Lithium- mood stabilizer

• Valproic Acid- anti epileptic

• Carbamazepine- anti epileptic

• Clonazepam- benzodiazepines

• Gabapentin- anti epileptic

Lithium

Mood stabilizer that reduces manic and depressive symptoms

• MOA: electrolyte and ion transport (Na), NT and receptor biding, signaling pathways following the NT receptor binding

  • suppress IP3 and DAG (important in amine neurotransmission)→ excess of these causes the mania

• Well absorbed, high levels in thyroid and bone and some areas of the brain, not metabolized→ volume of distribution is high

• NARROW THERAPEUTIC WINDOW

Pharmacokinetics of lithium

• excreted in the urine, good for therapeutic drug monitoring (therapeutic window); clearance increased during pregnancy

• neurotoxicity and cardiotoxicity, extreme SE (convulsions, etc.)

• sodium competes for renal tubule reabsorption

DI of lithium

• NSAIDs

• Thiazide diuretics (decreased lithium clearance by 25%)

• Antipsychotic drugs- more extrapyramidal effects

• Antidepressants and antipsychotic durgs

Alzheimer’s Disease

MC form of dementia; progressive disease until death, no cure

• Patho: loss of neurons in the cerebral cortex and subcortical regions; causes gross atrophy of the affected regions and degeneration of parts of the lobes

  • can see amyloid plaque and neurofibrillary tangles (Tau protein)

Hypothesis for Alzheimer’s

• Cholinergic: decreased levels of acetylcholine

• NDMA: increased NDMA activity in grey matter of cerebral hemispheres (MSG excitatory stimulant)

• Tau: hyperphosphorylated tau begins to pair with other threads of tau and form the neurofibrillary tangles

Anti-Alzheimers Agents

• Acteylcholinesterase inhibitors: Donepezil (only FDA approved)

• NMDA: Memantine (acts on glutamatergic (glutamate-msg) by inihibiting overstimulation)