Capsaisin (chilli peppers)

H+ < 7.0

Temperature increase

Enkephaline

Endorphine

Dynorphine

Mnemonic: Pain in the END because he DYN-ed (dined) on ENK (ink) EF (of) the pen.

-Supraspinal and spinal analgesia

-Parasympathetic nervous system activation including ...

--euphoria, respiratory depression, bradycardia, obstipation (failure to pass stool/gas), urinary retention, mitosis (constricting of pupils), also addiction due to europhoria

-analgesia

-dysphoria (therfore not addictive)

-psychotomimetic effects (delusions, delirium, etc)

Morphine

-Mode of action

-Effects

-Side Effects

-Metabolism, half-life, analgesic potency

-μ opioid receptors

-μ mediated effects (analgesia, PNS stimulation, addiction)

-itching (histamine release due to mast cell stimulation, emesis (D receptor agonist)

-Phase 2 in liver, t_1/2 = short 3 hr, 1.0 Mo

Piritramid (Dipidolor)

-Mode of action

-Effects

-Side Effects

-analgesic potency

-μ opioid receptors

-μ mediated effects (analgesia, PNS stimulation, addiction)

-LESS THAN morphine: itching (BUT LESS histamine release than morphine), emesis (D receptor agonist)

-0.8 Mo

Codeine (Methyl-morphine)

-Mode of action

-Effects

-Side Effects

-metabolism, analgesic potency

-10% converted to morphine which acts on μ opioid receptors

-μ mediated effects (analgesia, PNS stimulation, addiction)

-itching (histamine release), emesis (D receptor agonist)

-hepatic (3A4 & 2D6), 0.1 Mo

Tramadal

-Mode of action

-Effects

-MIXED: 1) metabolism by 2D6 to agonist that acts on μ opioid receptors; 2) Inhibition of norephinephrine (NA: noradrenaline) and Serotonin (5-HT) reuptake i.e. they are NASRI's (Noradrenaline-Serotonin Reuptake inhibitors) 3) central α₂ agonist (Clonidine-like) which slows release of SNS neurotransmitters

-1) μ mediated effects (analgesic: especially for acute pain) 2) relieves chronic pain 3) slows SNS

Pentazocine (Fortral)

-Mode of action

-Effects

-Side effects

-MIXED opioid: κ receptor agonist; μ receptors weak antagonist

-analgesia

-dysphoria, can cause withdrawal syndrone in mophine abusers

Methadone

-Mode of action

-Effect

-Side effects

-half-life; analgesic potency

-MIXED: opioid μ receptors agonist; NMDA antagonist

-analgesia, used to reduce opioid abuse/sedation (because long acting)

-unpredictable effects

-slow acting, variable half life (6-8 hr), but active metabolite t_1/2 = 55 hr leading to accumulationand sedation; 4-12 Mo

Remifentanil

-Mode of action

-Half life and potency

-Delivery method

-Opioid μ receptor agonist

-Ultra-short (stays in blood and requires continuous infusion because metabolized by esterases); 100 Mo

-Intravenous (IV)

Pethidin/Meperidine

-Mode of action

-Effect

-Side effects

-Half life and potency

-Delivery method note

-MIXED: 1) anti-cholinergenic; 2) SSRI; 3) alpha-blocker; 4) interaction with MAO-I

-1) atropine-like effects e.g. causes mydriasis (pupil dilation)...Only opioid that does this (usually stimulates PSN...ALSO prevents post-anesthetic shivering; 3) vasodilation; 4)increase catelcholamines

-Normeperidine is neurotoxic and can accumulate with renal insufficiency

-short t_1/2= 2hr, 1/20 Mo

Noloxone

-Mode of action

-Effect

-Opioid competitive antagonist

-Stops respiratory depression

Causes of emesis

--Treatment

-GI tract afferent stimulation of 5-HT₃ (Serotonin) receptor in CRTZ

-Stimulation of dopamine receptors in CRTZ (chemoreceptor trigger zone in medulla)

-Vestibular nucleus release of Ach which stimulates Muscarinic receptors in CRTZ

--Commonly treat with 5-HT₃ and D₂ (dopamine receptor) blockers...muscarinic blocker only for motion sickness

setron (ending)

-Mode of action

-Effect

-5HT₃ antagonist

-anti-emesis

Droperidol (DHB)

Metoclopramid (Pasertin)

-Mode of action

-Effect

-D₂ antagonist (also 5-HT₃ antagonist and 5HT₄ agonist)

-Anti-emetic

Scopolomine

-mode of action

-effect

-muscarinic antagonist (affecting vestibular nucleus and CRTZ)

-for motion sickness only

Diphenhydramine (Benadryl)

-Mode of action

-Effect

-Side effect

-H₁ blocker (antimuscarinic agent like those in vestibular nucleus)

-anti-emesis (motion sickness only)

-makes sleepy (but hard to wake up)

-ROSA (rapid onset, short acting)

-normally raises HR, but in low doses, inhibits pre-synaptic Ach receptors (which when activated, stop the release of Ach). This leads to an increase in Ach (which stimulates PNS) and causes bradycardia

-Central anti-cholinergenic syndrome

--dry as a bone (can't sweat because Ach in SNS stimulates sweat glands)

--red as a beet (vasodilation to release heat, because Ach in PNS causes vasoconstriction)

--hot as a hare (body heat increases, Ach in PNS thru thalamus causes response to heat)

--blind as a bat

--mad as a hatter (CNS effect)

5 HT receptors

-endogenous agonist

-tropic types

-Serotonin receptors influencing metabolic processes

-5-HT₃ are ionotropic, all others are metabotropic

5-HT

-Receptor type, mode of action for each, effect for each (Example for each)

1) 5-HT 1A, agonist->G_i -> inhibit AC (adrenylyl cyclase, anxiety (pirones) and hypertension (pidil)

2) 1D/1F, agonist, migrane (triptans)

3) 2, antagonist, psychosis

4) 3, antagonist: blocking afferent pathways from GI tract, emesis (setrons)

5) 4, agonist, gastroparesis (prides, esp. to help diabetics with vagus nerve damage)

6) RI, ..., depression

Urapidil

-Mode of action

-Effect

-DUAL: 5-HT 1A agonist (α₁ adrenoreceptor antagonist)

-vasodilation, BP down

Buspirone

-Mode of action

-Effect

-Onset

-5-HT _IA partial agonist (also D₂ and weak 5-HT₂ affinity)

-anti-anxiety (for chronic anxiety; as opposed to benzodiazepines for acute anxiety)

-slow onset (4-6 weeks), effect may be delayed for several months

Triptans (e.g. Sumatriptan)

-Mode of action

-Effect

-Metabolism

-Example with long half life

-Delivery method with best theraputic gain

-Contraindication

-5-HT_{1 B or D}

-agonists

-1B: arterial (cerebral) vasoconstriction; 1D: reduce nociceptive transmission (inflammatory soup)

-anti-migrane (vasodilation and inflammation cause pain...for acute migrane only)

-usually Monoamine oxidase aka MAO-A (except Naratriptan: CYP only), causes interaction with NE which is MAO-A metabolized too...dopamine is MAO-B metabolized

-Frovatriptan: t_1/2 = 25 hr

-subcutaneous

-cardiovascular disease: vasoconstriction bad for those with coronary artery disease, impared infusion etc

Moclobemide (Aurorix)

-Mode of action, effect

Selegeline (Antiparkin)

-Mode of action, effect, side effect

-MAO-A inhibitor which increases serotonin, anti-depressant

-MAO-B inhibitor which increases dopamine, anti-Parkinson Disease but in high amounts psychotic effect

St. John's wort (Hyperforin)

-MAO interaction
-CYP interaction

-MAO-A inhibitor = antidepressant

-CYP450 3A4 inducer

5-HT₂

-tropic type

Pizotifen( Sanomigran, Pizofen)

-Mode of action

-Effect

-5-HT₂ antagonist (and 5-HT₁ antagonist)

-prophylaxis of migraines (prevents vasodilation)

Mianserin and Ritanserin

-Mode of action

-Effect

-5-HT₂ antagonist

-CNS drug for anxiety and depression (tricyclic-esque)

Ketanserin

-mode of action

-effect

-side effect

-5-HT₃ antagonist (and α₁ blocker)

-Anti-hypertensive (vasodilator)

-Raynaud disease: mostly females get, spasms of finger arteries controlled by α₁ receptors.

Nefazadone (Serzone)

-mode of action

-effect

-side effect

-MIXED: 5-HT₂ antagonist and SSRI (Selective seretonin reuptake inhibitor)

-antidepressant

-liver damage (removed from market)

Trazodone (-zodone)

-mode of action

-effect

-side effect?

-MIXED: 5-HT₂ antagonist and SSRI (Selective seretonin reuptake inhibitor)

-antidepressant

-without liver toxicity of Nefazodone

Quetiapine, Olanzapine, Ziprasidone

-mode of action

-effect

-side effects

-1) D₂ ≈ 5-HT₂ 2) D₂ < 5-HT₂ 3) D₂ << 5-HT₂

-antipsychotic

-the less it relies on D₂ blockage, the less D₂ blocker effects e.g. Parkinson-like effects.

Aripiprazole

-Mode of action

-effect

-side effects?

-5HT_1A agonist, 5-HT₂ antagonist (inbitory and blocked excitatory

-dopamine-serotonin system stabilizer

-no associated with significant weight gain or prolonged QT

Setrons

-mode of action

-effects

-Important examples

-5-HT₃ blocker (closes Na⁺, Ca ²⁺ and K⁺ channels)

-anti-emesis

-Palonosetron (long acting, single IV dose before chemotherapy), Alosetron (causes IBS/diarrhea)

5-HT₄ receptor activation causes the release of this.

-ending?

Acetylcholine (through G_s protein-coupled receptor and production of cAMP)

-pride

Metoclopramide

-mode of action

-effects

-side effects

-5-HT₄ agonist, D₂ antagonist, weak 5-HT₃ antagonist, ChE inhibitor

-increase Acetylcholine, promoting gastric emptying

-tardive dyskinesia (abnormal movements which are Parkinson-like that have a late onset; occur with antipsychotic drugs also as a result of D₂ blockade.)

Cisapride

-Mode of action

-Effect

-Side effects

-5-HT₄ antagonist

-increases Ach release

-doesn't effect D₂ receptors and so no tardive dyskinesia, however caused arrhythmias and death due to interference with the metabolism of K⁺ channel blockers which cause hyperpolarization and prolonged QT

Mosapride

-Mode of action

-Effect

-Side effects?

-5-HT₄ antagonist

-increases Ach release which promotes gastric emptying (esp. prescribed to diabetics with neuropathy)

-doesn't interfere with the metabolism of K⁺ channel blockers

-Acetylcholine esterase inhibitor, D₂ antagonist

-prevents Ach metabolism (effects PNS and sweating)

Tegaserod

-mode of action

-effect

-side effect

-5-HT₄ agonist; 5-HT_2A antagonist

-increase Ach, vasoconstriction

-angina, heart attack, stroke, serious cases of diarrhea, ischemic colitis

Selective Serotonin Reuptake inhibitors

-mode of action

-effect

-side effects

-examples

-increases 5-HT (can inhibit reuptake of NE if not selective)

-anti-depressant

-Rare and almost never lethal (as opposed to TCAs), hyperthermia, autonomic dysfunction

-Fluoxetine (Prozac), Sertralin (Zoloft), Citalopram (Cipramil): most selective

Dapoxetine (Priligy)

-mode of action

-effect

-side effect?

-SSRI

-anti-depressant

-delayed ejaculation

SSRI

-metabolism

-interaction

-metabolized by mainly CYP 450 2D6 except Citalopram (3A4)

-Sertraline (Zoloft) and Citalopram do not interact with any CYP 450 enzyme

Venlafaxin (Effexor)

-mode of action

-effect

-NASRI that increases NE(NA) and 5-HT

-anti-depressant ("clean TCA": effect of TCA without side effects or structure), for chronic pain

Duloxetine (Cymbalta)

-Mode of action

-Effect

-NASRI that increases NE(NA) and 5-HT

-anti-depressant ("clean TCA": effect of TCA without side effects or structure), for chronic pain