Modulate Mood, sleep-wake cycle, motivation, and pain 

1. Serotonin/5HT
2. Norepi-bind to a2 can be broken down my MAO

1. Decrease serotonin/ or norepi transmission
2. But immediate increase in Serotonin/norepi does not always alleviate depression
3. Delayed onset of action of medication *long-term treatment is key (8 wks. to see response)

Ueses: increase in NE will increase interest, energy, concentration, cognition, mood. 

SE: increase NE will increase HR, BP, Anxiety

Off Target: Histamine=drowsiness, M1=Dry, A1=antagonisim so Hypotension

At least one of the following that interfered with the person's life: 

1. Depressed mood for 2 weeks
2. loss of interest and pleasure for 2 weeks
3. <18 irritable mood for 2 weeks

Bipolar 1: Presence of only one manic episode and no past major depressive episodes. 

Bipolar 2: Major depressive episodes, least on hypomanic episode, never full manic episode. the symptoms cause distress, impairment in social, occupationla, or ther important areas of functioning. 

Antidepressants, Anxiolytics, Mood Stabilizers- 

Inhibitors of Serotonin Degradation

MAOI's 

• Nonselective, irreversible-not as safe: Phenelzine (nardil), Isocarboxazid (Marphan)
• Nonselective, reversible: tranylcypromine (parnate)
• Selective, reversible (serotonin, norepi, epi): used for depression inhibits RIMA. Meclobemide, befloxatone, brofaromine.
• Irreversible agonist, MAOB antagonized : selegiline & rasagiline. Transdermal patch

MAOI's

nardil, Marplan, Parnate, Selegiline, Rasagiline

Action: Inhibition of MAO, inhibits degredation of monoamines so increase available serotonin and NE.

PK: well absorbed, hepatically metabolized, renal excreted (watch liver function), CYP450 drug interactions (TCA, SSRI, Pseudoephedrine, dextrometho) 

AE: Tyramine toxicity. Tyramine displaces catecholamines (norepi) leading to hypertensive crisis! 

Watch with red meats, cheeses, red wine

FYI: wont happen with Selegiline! Transdermal patch decreases tyramine toxicity. 

Antidepressants, Anxiolytics, Mood Stabilizers 

Reuptake Inhibitors

TCA's

Tricyclics: 

Secondary Amine-less SE, more effects on NE than 5HT, no H1,M,A

     Nortriptyline (Pamelor), Desipramine (Norpramine)

Tertiary Amine-more SE, more effects on 5HT than NE, unwanted H1 & A effects.

      Amitriptyline-metabolized to nortiriptyline

      Imipramine-metabolized to desipramine

      Doxepin (Sinequan)

      Clomipramine (Anafranil) 

TCA's

Secondary: nortiriptyline, desipramine

Tertiary: Amitriptyline, Imipramine, Doxepin, clomipramine

Action: Antagonize 5HT and NE so increase levels of both in synaptic cleft. 

No effect on dopamine

Used to treat pain at lower doses

AE: AV block, bundle branch block

Unwanted Effects: Tertiary prominent (amytriptylin)

Antagonize Muscarinic causing N/V, Anorexia, Dry, Confusion, urinary retention, Tachycardia

Antagonize histamine which causes dedation, wt. gain, confusion.

Antagonize adrenergic receptors which causes orthohypo, reflex tachycardia, drowsiness, dizziness. 

Antidepressants, Anxiolytics, Mood Stabilizers 

Reuptake Inhibitors

SSRI's (COMMON)

Fluoxetine (Prozac),Citalopram (Celexa)-least SE,Fluvoxamine, Paxil, Zoloft, Lexapro

First Line due to higher selectivity and less SE

Different agents work for different patients

Selective for 5HT transporters so increase serotonin levels

They lose selectivity at heigher dosed and will bind NE as well

AE: Sexual disfunciton (5HD2), Serotonin Syndrome=hyperthermia, muscle regidity, myoclonus, rapid fluctuations of mental status and vital signs. 

PK: Inhibitors of CYP2D6 so lots of CNS Meds. 

Antidepressants, Anxiolytics, Mood Stabilizers 

Reuptake Inhibitors

SNRI's

Effexor, Cymbalta

Blockage of 5HT and NE

Concentration dependant

Metabolized by CYP2D6- so watch with Pristiq. 

AE: Effexor will increase BP, Cymbalta will increae transaminases, slight chance of increase BP. 

Antidepressants, Anxiolytics, Mood Stabilizers 

Atypical Antidepressants

Wellbutrin, Rameron, Serzone, Trazodone

Atypical Antidepressants

Bupropion (Wellbutrin)

Inhibits dopamine and NE reuptake

Least sexual side effects

Can keep people from sleeping so give early in day 

Contraindications: Seizure disorders, eating disorders

PK: hepatically metabolized by CYP2B6- if fiven with Effafirins (HIV) can cause decrease of CYP2B6 so increase levels of wellbutrin. 

Atypical Antidepressants

Mirtazapine (Rameron)

Unknown mechanism of antidepressant

Antagonizes histamine receptors (greater at lower doses)

Less sexual disfunction

SE: increase appetite, sedation

so to decrease SE increase dose 

Atypical Antidepressants

nefazodone (Serzone)

Antagonizes 5HT2 so less secual disfunction, antianxiety properties

Antagonizes histamine and A1 so cause sedation and orthostasis. 

Substrate and inhibitor of CYP3A4 so increase drug interaction

SE: Hepatotoxicity and fulminant liver failure (2nd and 3rd line)

Atypical Antidepressants

Trazodone

Antidepressant effects at very high doses

Mostly used as sleep agent at lower doses

SE: priapism (erect penis)

Metabolized by CYP3A4

Antidepressants, Anxiolytics, Mood Stabilizers

Serotonin Receptor Agonists 

Buspirone (Buspar)

Buspirone (Buspar) 

Anxiety only/ not depression

Non sedating, non benzo, non addictive

SE: Dizziness, Nausea

Antidepressants, Anxiolytics, Mood Stabilizers

Increase in Neurotransmission by less well described mechanisms 

Amphetamine, Meth, Methylphenidate (Ritalin, Concerta, Provigil, Nuvigil) 

may interere with ability of synaptic vesicles to store monamines, may displace 5HT, DA, NE 

Second Line Agents

SE: Induction of psychosis, alertness (Can be used in Narcolepsy) 

Lithium: 

MOA not well understood, interference with formation of cAMP & IP3

Controls Mania and Depression

Long half life 12-72 hours

Narrow Therapeutic Index (0.7-1.2)

PK: Lithium is secreted and reabsorbed in the renal tubules. Interferes with diurtics, probenecid (gout), renal insufficiency can increase lithium levels! 

SE: N, Thirst, Polyuria, hypothyroidism, tremor, weakness, mental confusion, teratogenisis:(

Antidepressants, Anxiolytics, Mood Stabilizers

Mood Stabilizers for Bipolar Disorder

Carbamazepine & Valproic Acid

Valproic acid mainly used for seizures. MOA in bipolar siorder is unknown 

Antimigraine Drugs

Triptans

Imitrex, Maxalt-fastest onset of action, Axert, Frova, Relpax, Zomig, Amerge-slowest onset of action, lowest recurrence rate. 

used early on in attack most the time can be used otherwise

MOA: Seratonin agonists in vasculature

         Potent vasoconstriction in intracranial blood vessels

         inhibit vasoactive peptides, interuption of pain 

"Specific for Migraine Thereapy" 

Maxalt-fastest onset of action, dose adjust with propanolol, decrease dose. 

Amerge-slowest onset of action, lowest recurrence rate. 

Relpax: CYP3A4 do not admin within 72 hourse of HIV pts. taking Ketoconazl, drythoromycin. 

Contraindications: ishemic heart desease, HTN, Stroke, Pregnancy. Not w/ MAOI's Except Frova, Relpax, Amerge. Risk of Serotonin syndrome in combination with SSRI's and SNRI's 

Antimigraine Drugs

Erogots

Ergotamine, DHE45

MOA: same as triptans, serotonin agonists, mixture agents most effect

Ergotamine: Poor bioavailability with oral and rectal formas. Poor tolerability incrase N/V. Dose dependent rebound HA. NOT USED VERY MUCH. Never in CAD, PVD, HTM,Hepatic or renal disease. 

May be used in patients with prolonged duration of attacks (>48 hours)

DHE 45: Fewer side effects, no rebound HA. Use with anitemetics. Never use in HTN, ischemic heart disease, with MAOI's, and elderly. 

Antimigraine Drugs

Fist-Line Agents for Acute Migraines

NSAID's-high dose

Aspirin 650-1000mg

Acetaminophen 1,000 mg

Combination Meds (acetaminophen, aspirin, caffein)

Antimigraine Drugs

Monotherapy or Adjunct Therapy

Antiemetics: parenteral-metoclopramide, chlorpromazine, prochlorperazine- used with triptans

Benzo: Opiods, barbituates (not for chronic)

Pervention of Migrains and Tension HA: 

Beta Blockers

Calcium channel blockers

Tricyclic antidepressants

Anticonvulsants-phenytoin, carbamazepine, valproate, gabapetine, topiramate

Ergot Derivatives 

Midbrain cotains high concentrations of emetogenic receptors. 

Dopamine D2

Muscarinic-Cholinergic Receptors

Histaminic Receptors

5HT3 receptors (Histamine)

MOA:

Highest binding to dopamine-benzamides, butyrophenones, phenothiazines

Serotonin receptors act centrally and peripherally. 

Phenothiazine: cheap but cause sedation and dry. (compazine, phenergan) 

Corticosteroids: (Dexamethasone, Bethamethasone)used for chemo N/V due to membrane stabilizing and anti-intlammatory 

Anticholinergics: (Scopolamine, Meclizine)  block cholinergic muscarinic receptors. Great for motion sickness

Antihistamines: (Cyclizine, Atarax, Benadryl) act directly on the vomiting center and vestibular pathways.

Benzamides: (Reglan)

Serotonin Antagonist: (Zofran) used for chemo and many others. Really Expensive 

Sometimes Haldol is used in gastroerisis. 

Anticonvulsants

Sodium Channel Inhibitors

Phenytoin (Dilantin)

Fosphenytoin (Cerebyx)Narrow-simple partial, complex partial, generalized seizures

MOA: Reduces activation of channels and rapid firing. Only inhibition of channels that open and closed rapidly. 

Albumin bound so only a little bit of free drug is able to attach. so Watch with Albumin Levels. 

SE: CNS decrease, N/V/C, hirsutism (facial gair), Bleeding!!, AOsteoporosis. 

TDM: 10-20=total-normal 1-2=free-low

Anticonvulsants

Sodium Channel Inhibitors

Carbamaazepine (Tegretol)-Narrow-simple partial, complex partial, generalized seizures

MOA: similar to phynytoin. 

Protein bound. It induces its own metabolisim so dose decreases over time. 

Potent inducer of CYP3A4-lowers the level of drugs metabolized by this. 

SE: CNS, Deression, Hyponatremia, Jaundice, Rash, Leucopenia, Aplastic Anemia

TDM: 6-12

Oxcarbazepine (Trileptal)-dirivative of Carbamazepine with less drug interaction and SE. But is MoRe Expensive. 

Anticonvulsants

Sodium Channel Inhibitors

Oxcarbazepine (Trileptal)-Narrow-simple partial, complex partial, generalized seizures

Dirivative of carbamazepine with less drug interaction and SE. 

EXPENSIVE

Anticonvulsants

Sodium Channel Inhibitors

Lamotrigine (Lamictal)-Broad spectrum-all seizures

MOA: same as phynytoin, 55% protein bound, hepatically metabolized

SE: CNS depression, N/V, benign rash, serious rash associated with rapid titration. 

START LOW and GO UP over several weeks. 

Anticonvulsants

Calcium Channel Inhibitors

Ethosuximide-Absense Seizure

ABSENT Seizure USE. 

Long half life

No protein binding

SE: GI upset, anorexia, sleep terrors, aggressiveness, psychosis, mania, levopenia, eosinophilia. CNS :(

Anticonvulsants

Calcium Channel Inhibitors

Valproic ACID (Depakote, Depakene)

MOA: increase GABA activity, slows rate of Na+ channel recovery. Hepatically metabolized

SE: CNS depression, tremor, GI Upset, LFT elevations, thrombocytopenia, alopecia

TDM: 50-120

Anticonvulsants

Calcium Channel Inhibitors

Gabapentin (Neurontin)-narrow spectrum (simple partial, complex partial, generalized seizures)

Not used much for seizures. 

100% renal eliminated so not as hepatic toxic

Short half-life (dosed several times a day)

SE: CNS depression, Wt. gain, NOT VERY EFFECTIVE

Anticonvulsants

Enhancement of GABA Mediated Inhibition

Benzos and Barbituates

Very habit forming so try not to use if so for acute seizure than put on another. 

Anticonvulsants

Glutamate Receptor Inhibitor

Felbamate (Felbatol)-all seizure types

Also enhances GABA and limits NA firing

Renally eliminated 50% inactive metabolite and 50% unchanged. 

Inducer of CYP3A4 and Inhibitor of CYP2C19

SE: BLACK BOX WARNING acute hepatic failure and aplastic anemia-So limited use. 

Anticonvulsants

OTHER

Tiagabine (Gabitril), Topiramate (Topamax), Keppra (levetiracetam), Zonisamide (Zonegran)

SE: CNS Depression, N, Wt. Loss, Kidney stones, gluacoma

Keppra: is a fantastic drug, very well tolerated, but remember you need to titrate up, not many drug interactions. 

Zonegran: cant give with sulfa allergies. 

Parkinson's

DOPAMINE!

D1-stimulation of D1 receptors=excititory increase secondary messanges

D2-stimulation of D2 receptors=inhibatory decrease secondary messangers, Ca, Na so depolarization of cells. 

Parkinson's: Degeneration of dopaminergic neurons. Decrease dopamine or release 

SX: bradykinesia, rigidity, impaired postural balance, tremor. 

Anti-Parkinson's Drugs

Symptoms treatment only

Increase dopamine activity in brain

No change in the underlying degenerative process. 

Parkinsons decrease Dopamine

Schitzophrenia increase Dopamine

Why drugs for each can cause symptoms of others. 

Anti-Parkinson's Drugs

Dopamine Precursors

Levodopa

Most Effective Treatment

Transported across BBB unlike dopamine

Have to admin with Carbidopa (Sinemet combination drug) which does not cross BB. 

Continued use results in decensitization. Require Higher doses. will have On and off periods. use other class first and add this seocond. But dont wait tell symptoms are way bad 

SE: Dyskinesia, uncontrolled rhythmic movements of trunk and head. 

Anti-Parkinson's Drugs

Dopamine Receptor Agonists

Mirapex, Requip, Parlodel

Directly target postsynaptic Dopamine Receptors

Adjuvan to Levodopa

No enzymatic conversioon required. Longer half-life, less blood level sluctuations. 

SE: sedation, vivid Dreams, hallucinations. 

Anti-Parkinson's Drugs

Inhibitors of dopamine and or L-DOPA metabolism

Selegiline (Eldepryl), Rasagiline (Azilect)-MAOA inhibitors

Tolcapone (Tasmar), Entacopone (Compan)-COMT inhibitors so will increase levadopa to reach CNS. 

MAOB-Potentially toxic metabolite so no Amphetamine. 

SE: sleeplessness, confusion.

COMT-incrase levels of levodopa, hepatotoxicity, entacapone works peripherally only. 

Psychosis/Schizophrenia

+ symptoms of psychosis/schizophrenia

Delusions, hallucinations, disorganized speach, catatonic behavior, hyperacivity of mesolimbic dopaminergic pathway

-symptoms of psychosis/schizophrenia

Flat affect, alogia (lack of speech, avolition)

Hypoactivity of mesocortical dopaminrgic pathway

Dopaminergic Pathways

• mesolimbic: excess dopamine contributes to +symptoms
• Mesocortical: insufficient dopamine contributes to - symptoms. Also reason for ADHD
• Nigrostriatal: insufficient dopamine causes EPS, motor symptoms. 
• Tuberinfundibular: insufficient dopamine increase prolactin levels. (sexual dysfunction, gynecomastia, milk secretions, menstrual cycle disturbances)
• Norepi: insufficincy in frontal cortex also results in ADHD. 

Antipsychotics

Typical Antipsychotics: 

Thorazine, Mellaril, Serentil, Haldol, Prolixin, Thiothixene, Trilaphon, Loxitane

MOA: Decrease + Symptoms

SE:

On-target effects (D2 Antagonism) EPS, Tardive Dyskinesia, NMS, Increase prolactin amenorrhea, galactorrhea, false psitive pregnancy, gynecomastia, decrease libido. 

Off-target effects (muscarinic and a-antagonism) DRY, Orthohypo, failure to ejaculate, sedation

More off target effects when dose is lower. 

Antipsychotics

Atypical Antipsychotics

Abilify, Zyprexa, Seoquel, Risperdal-Q2wks IM, Geodon, clozapine, Haldol

More effective in treating - symptoms

MOA: Seratonin, and D2 Antagonism, D4 Antagonism, Fast dissociation form D2 so less EPS

SE: Dedation, cholinergic, 40% D2 saturation will cause akathisia, 60% D2 saturation will improve + symptoms, 80% D2 saturation will cause dystonia. 

Antipsychotics

EPS

EPS Acute: 

Dystonia: use anticholinergics to restore balance. benzos to relax muscles. 

Akathisia (restlessness): beta-blockers (propanolol), benzos

Pseudoaprkinsonism (rigidity, bradykinesia, tremor): anticholinergics (amantadine)

EPS Chronic: pseudoparkinsonism, tardive dyskinsia

NMS: analogous to serotonin syndrome but more severe. Fever, Regidity, renal failure, delirium. 

Antipsychotics

Atypical Antipsychotics: 

Clozapine

Last Line Atypical Antipsychotic. Reserved for treatment resistant patients. 

Risk of Life threatening: strict monitoring of CBC weakly *6, biweekly *6, then Q4 weeks. 

SE: Orthohypo, wt.gain, hyperglycemia, sedation, constipation

CYP2D6=SMOKING increases metabolism. 

Antipsychotics

Paliperidone (Insega)

Primary active metabolit of risperidone

Osmotic delivery capsule: do not cruse or chew. 

NO DRUG INteractions

Antipsychotics

Fanapt

SE: Ortho Hypo, QT prolongation

CYP2D6-metabolises many CNS drugs

Antipsychotics

Abilify

Antipsychotics

Zyprexa, Seroquel

Zyprexa: CYP1A2: Smoking increase metabolism, particularly in pts. who are stable on a dose while in a non-smoking hospital and then resume smoking once discharged. 

Seroquel: sedation at lower doses, wide dosing range makes drug interactions less significant. 

Anti-Alzheimer's/ Anti-Dementia

Acetylcholinestrerase Inhibitors: 

Cognex, Aricept, Exelon, Razadyne

MOA: Centrally acting, reversible inhibition of Ach esterase which increase the amount of Ach available to post-synaptic neurons. 

SE: GI

   Cognex: Not used much because of increase LFTS

   Aricept: Fewest SE. ONLYDRUG APPROVED FOR ALL STAGES OF ALZHEIMERS

    Exelon: HA, dizziness, with skin patch avoid giupsot

   Razadyne: high incidence of N/V. 

DI: Synergistic effects with cholinergic aganists, antagonistic effects with anticholinergics, Decrease levels of dovepezil

Antipsychotics

NMDA Receptors/Glutamate: important in targeting memory

Memantine (Namenda)

MOA: NMDA receptor antagonist-helps regulate glutamate, which is increased in alzheimers patients. 

SE: GI intolerance, hypertension, dizziness, HA

Only drug in its class can use in combination w/ acetylchnesterase inhibitors. 

Multiuse CNS Drugs

GABAA Receptor Modulators

Benzodiazepines

Medazolam, Clorazepate, Lorazepam, Clonazepam, -PAM

Used for Anxiety, SEizures, Phobial, Insomnia

SE: FATAL CNS depression when used in combination with alcohol, cns depressants, opioid analgesics, and TCAs. 

Overdose can be reversed with Flumazeniil. Also used to precipitate severe withdrawl. 

Multiuse CNS Drugs

Barbituates

Uses: Anesthesia induction, emergency seizure treatment, status epilepticus, insomina. 

CYP450: drug interactions

High doses can cause fatal CNS depression. 

Withdrawl symptoms: tremors, anxiety, insomnia, and CNS exitability, seizures, cardiac arrest. 

Multiuse CNS Drugs

Sleep Aids

Ambien, Lunesta, Sonata, Rozerem (non addictive)

SE: memory impairment, amnesia, impaired judgement, reasoing, sleep walking. 

H1 Antagonists

M1 Antagonist

thorazine, Mellaril, Serentil, Haldol, Prolixin, Thiothixene, Trilaphon, Loxitane.