Small Molecule NTs Cholinergic Catechols Biogenic amines Indole Imidazole AA - Excitory AA- Inhibitory Adenine NT

Neurotransmitter Acetylcholine Dopamine Norepinephrine Epinephrine (adrenergic) Serotonin Histamine Glutamate Aspartate GABA Glycine Purine/Adenosine

Precursor(s) Acetly CoA and Choline Tyrosine --> L-Dopa Dopamine Norepinephrine Tryptophan --> 5-hydroxytryptophan --> Histidine Glutamine Glutamate (vice-versa) Glutamate serine

Large Molecule NTs Opiates

Methionine enkephalin endorphins

proopiomelanocortin (POMC) proopiomelanocortin (POMC)

Substance P Somatostain-14 Thyrotropin releasing hormone (TRH) Cholecystikinin (CCK) Vasoactive intestinal p. (VIP) Leutinizing h. releasing h. (LHRH) Oxytocin

Enzyme/Location Vesicular transport Receptor choline acetyltransferase (CHAT) transporter Transmitter-gated Ion Channel vesic. Ach Tyrosine hydroxylase --> aromatic aa decarbxylase Dopamine hydroxylase/NE vesicle vesicular monoamine transporter Phenylethanol-amine N-methyl-transferase Tryptophan-5-hydroxylase --> aromatic aa decarbxylase Transmitter-gated Ion Channel Histidine decarboxylase Glutaminase/mitochondria VGLUT Transmitter-gated Ion Channel glutamic acid decarboxylase (GAD) serine transhydroxymethylase ATPase/ECS Transmitter-gated Ion Channel Transmitter-gated Ion Channel Transmitter-gated Ion Channel

Degrading Enzyme/Speed acetylcholinesterase (synpase)/fast

reuptake; Monoamine oxidase(pre-syn) Cateo reuptake; Monoamine oxidase(pre-syn) Glu synthetase (glial cells)/fast

G-Protein Coupled

Location Projections NMJ, ENS, SNS, PNS, CNS Substantia nigra and ventral tegmental area (midbrain) throughout cortex and striatal complex (hippo) Locus coeruleus (midbrain) throughout cortex, hippocampus, cerebellum raphe nucleus (midbrain) and and subcortical features cortical brainstem Tuberomammillary nucelus ofregions cortical hypothalamus Brain, Spinal cord Brain, Spinal cord spinal cord

CNS CNS CNS CNS

ANTIDEPRESSANTS Mechanism Iproniazid Phenelzine (Nardil) Tranylcypromine (Parnate) isocarboxazid (Marplan) Selegeline (Emsam) Impramine Clomipramine Norptriptyline Fluoxetine (Prozac/Serafem) Paroxetine (paxil) Sertraline (Zoloft) Fluvoxamine (Luvox) Citalopram (Celexa) Escitalopram (Lexapro) MAO-A inhibitor MAO-A/B inhibitor MAO-A/B inhibitor MAO-A/B inhibitor MAO-A/B inhibitor Tricyclic AntiD Tricyclic (OCD only) Tricyclic AntiD SSRI SSRI SSRI SSRI SSRI SSRI

Buproprion (Wellbutrin, Zyban)

NE and DA Reuptake Blocker

Mirtazapine (Remeron) Nefazodone (Serzone)

NaSSA SARI

Trazodone (Desyrel)

SARI

Class

Indications atypical depression, MDD, dysthmia, panic disorder, bulimia, tx resistant depression

MAOI - second line

MDD, Panic disorder, enuresis, OCS (clompramine only), Pain (Migraine, chronic pain), Tricyclic Antidepressants - second line Uticaria, pruritis

SSRI

MDD, dysthymia, minor depressoin, OCD, Generalized anxiety disorder, panic disorder, PTSD, pre-menstrual dysphoric disorder, bulimia nervosa, premature ejaculation, pain syndrome Depression, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Diabetic Neuropathy, Pain

SNRI (5HT-NE reuptake inhib)

NDRI (NE and DA reuptake Inhib) NRI (NE reuptake Inhib)

Depression, Dysthymia, Smoking cessation, ADHD Depression (in EU), ADHD Major depression, anxiety, insomnia, sedation or weight gain can be useful) esp in elderly) Depression, Anxiety, Insomnia acts like MAOI for all 3 nts! target glucocorticoid sys abortion pill

NaSSA (Noradrenergic and specific 5HT Antidepressant) SARIs (5HT Antagonist and Reuptake Inhib) SDNRIs (triple reuptake inhib) Substance P antagonists CRF antagonists RU486

anti-histamine anticholinergic anti-alpha adrenergic Serotonin Receptors - 5HT1A - 5HT2A - 5HT2C - 5HT3

Effects of antogonism: weight gain constipation, blurred vision, dry mouth, drowsiness dizziness, decreased BP anxiolytic, anti-depressant anxiolytic, sleep restoring, no sexual dysfunction anxiolytic, weight gain no GI problems, no nausea

Result Side Effect More NE in the pres-synN --> more NE in the cleft

NE and 5HT reuptake transporter inhibition-> more NE and 5HT in cleft

5HT reuptake inhibitor

NE and DA reuptake pump inhibitor --> inc NE and DA in synapse anti-alpha-2 blockade --> inc both 5HT and noradrenergic transmission (esp at 5HT1A) 5HT2A blockade inc 5HT to therapeutic

Sedation, Orthostatic No weight gain, no sex dysfunction, mild sedatoin, rare fatal hepatotoxicity

Side Effects HT crisis (lethal; requires tyraminerestriction), orthostatic HT, weight gain, sexual dysfunction,

Pros

No anticholinergic sideeffects

significant overdose potential, cardiovascular toxicity, also has anti-histamine, anti-alpha1, and anti-cholinergic

5HT side effects (GI, nausea, vomitting, diarrhea), 5HT syndrome ( diarrhea, sweating, fever, tachycardia, HT, delerium, myoclonus; hyperpyrexia, death), Discontinuation Sydrome (when SSRI stopped appruptly; headaches, dizziness, irritability, fatigue), Suicidality (mania, akathesialinked?), Sexual dysfunction (esp. anorgasmia), weight gain, myoclonus,

No NE uptake inhibition and anti-histamine, anti-alpha1, and anti-cholinergic action; wide therapeutic index, better tolerated

5HT side effects: GI, nausea, vomitting, diarrhea, activation, sexual dysfunction; NE side effects: Tremor agitation, sustained HT Increased seizure risk (esp bulemics); Avoid: daily dose >450mg, clinical indicators for seizure, history of eating disorders Tremor, agitation, HT, Tachycardia Little or no 5HT action, so no sexual dysfunction or weight gain

antihistaminergic effects; weight gain (2C, real inc. in appetite), sedation (H1, 2A), (see specific 5HT receptor effects)

due to 5HT-2A, 2C and 3 blockade: anxiolytic, antidepression, no nausea, no GI issues, sleep restoring

vision, dry mouth, drowsiness

oring, no sexual dysfunction

Drug Interactions Narcotics (Merperidone/Demerol), Antidepressants (Tricyclic and SSRI), many OTC cold medications,

MAO A MAO B

NE and serotonin dopamine

Drug/Class

Mechanism

Lithium Anticonvulsants

modulates phosphatidyl inositol second messenger system

- Valproic Acid (Depakote/Depakene)

Inhibition of Na/Ca channels, thereby boosting GABA inhibition and decr. glutamatergic excitation

- Carbamazepine (Tegretol)/ Oxcarbazapine (Trileptal, somewhat safer)

Inhibition of Na/K channels, thereby boosting GABA inhibition and decr. glutamatergic excitation

- Lamotrigine - Gabapentin (Neurontin), Topiramate (Topamax) Other Bipolar Agents - typical and atypical antipsychotics, omega 3 fatty acids, Ca channel blockers, benzodiazepines

unclear, inhibits Na and glutamate

Indications

Toxicities Hypothyroidism, renal polyuria and polydipsia (nephrogenic diabetes insipidus), nephrotoxicity, cardica arrhythmias, teratogenicity, overdose; Neuro: cognitive dulling, decr creativity, tremor, decr memory and concentration; GI: abdominal cramps, nausea, vomiting, diarrhea; Metabolic: weight gain, inc thirst and urination; Derm: psoriasis, acne, benign leukocytosis

1st line: classic euphoria mania, pure bipolar depression, bipolar maintenance; 2nd line: mized mania, rapid cycling; suicide prevention

thrombocytopenia, hepatoxicity, pancreatitis, polycystic ovarian syndrome, teratogenicity (neural tube defects), overdose; Dyspepsia and diahhrea, sedation, dizziness, inc appetie and weight gain, 1st line: mized (dysphoric) mania, rapid cycling; 2nd tremor, edema, neurotoxicity (cog blunting & ataxia), line: pure depressive states, classic euphoric mania hair loss Hematologic side effects (thrombocytopenia, agranulocytosis, aplastic anemia), hepatotoxicity, allergic reactions, rash, Teratogenicity (nerual tube defects, craniofacial abnormalities), overdose; Nausea, anorexia, vomiting, sedation, dizziness, cog dulling, electrolyte abnormalities, anticholinergic effects, 10% rash, 1% Steven Johnson Syndrome; generally less serious; nausea, vomiting, diarrhea, sedation, lightheadedness, tremor, cog blunting, weight gain

bipolar disorder (mixed mania, rapid cycling)

softer' bipolar disorders

Drug Interactions

NSAIDs, Thiazide diuretics, ACEi, Ca channel blockers

Induces Cyt p450 system; causes decr levels of many other medications, including itself

ANXIETY DISORDERS Drug Antidepresants - SSRI - Venlafaxine - Mirtazapine - Nefazodone - TCAs, MAOIs Atypical Antipsychotics Beta-Blockers Anticonvulsants Antihistamines

INSOMNIA Drugs Antidepresants - Mirtazapine - Trazodone - TCAs Anticonvulsants Antihistamines Atypical Antipsychotics

Barbituates

GABA-ergic; allosteric binging to GABAR --> inc duration of opening upon GABA binding --> leading to enhanced Cl- flow into cell (hyperpolarization) GABA-ergic; allosteric binging to GABAR --> inc frequency of opening upon GABA binding --> leading to enhanced Cl- flow into cell (hyperpolarization); work in 1-2 weeks high potency/long half-life high potency/short half-life

Benzodiazepines - Clonazepam (klonopin) - Alprazolam (Xanax) - Diazepam (Valium)

- Lorazepam Ativan), Oxazepam (Serax), Temazepam (Restoril)

Glucoronidated BZs, avoid Phase 1 metab (liver oxidation) and get glucoronidated and excreted through the liver --> no liver-metabolism

Hypnotics/Sedative BZs Benzodiazepine Receptor Agonists - BZ-1 (Omega 1) - BZ-2 - BZ-3 work on BZ receptor but not BZ selective BZ-1 agonist selective BZ-1 agonist selective BZ-1 agonist 5HT 1A receptor agonist that cuases upregulation of autoreceptors on pre/postsynaptic neuron; req 2-3 weeks for effect

Buspirone

Ramelteon

Melatonin Receptor agonist; binds receptors in the hypothalamus, pituitary and retina to increase melatonin secretion that is implicated in drowsiness

2nd line

depressed all levels of CNS, dec respiratory drive, narrow therapuetic index, overdose (Jimmi Hendrix and Marilyn Monroe!) Anxiolytic (short vs long-term) for GAD, OCD, Panic Disorder, adjustment disorder, nonpathologic anxiety, insomnia, anticonvulsant, muscle relaxant, alcohol withdrawl combination with alcohol is dangerous

rapid discontinuation leads to problems; sedation, ataxia, cog effects, paradoxical disinhibition, respiratory depress, tolerance, dependance, abuse potential insomnia anxiolysis and sleep muscle relaxant unsure

GAD, other anxiety disorders? Augmentation dizziness, drowsiness, headaches, nausea, for depression tx? contraindicated with MAOI

more subtle effect

BZ on it's own will not cause Cl to flow!! safer and more efficacious than barbituates; broader therapeutic index, no respiratory or cardiac effects, less lethal overdose, alcohol tolerant

more specific; less overdose, addiction, withdrawl and seizures

non-sedating; no abuse potential, tolerance or withdrawl; few drug interactions

no risk of addiction, tolerance, etc