pmcol hallucinogens

besides hallucinations, what else is associated with hallucinogens

substantial changes in thoughts, emotions, and conciousness

what do most hallucinogen drugs alter

the function of monoaminergic (esp. serotonin) or glutamatergic systems

4 classes of hallucinogens

1. classical psychedelics (serotonin systems)

2. dissociative agents

3. deliriants

4. oneirogens

drugs included in classical psychedelics (3)

1. lysergic acid diethyl amide (LSD)

2. psilocybin

3. dimethyltryptamine (DMT)

common mechanism of action of classical psychedelics

serotonin 5HT2a receptor (Gq coupled protein)

discovery of LSD

fungus growing on rye produced ergot alkaloids → unstable = break down to LSD

ergot alkaloids

good vasoconstrictors from fungus that grows on rye

not stable in solution

mechanism of LSD

has over 50 targets (many 5HT + monoamine)

LSD at 5HT2a receptor

high affinity partial agonist

proof that 5HT2a activation causes hallucinogens (2)

1. modified mouse models lacking these receptors do not show hallucinogenic like behavior to LSD

2. humans with 5HT2a antagonist (ketanserin) pretreatment block LSD hallucinogen affects

T of F: all 5HT2a agonists are hallucinogenic and why

false due to biased agonism

LSD (+other hallucinogenic serotonin agonists) activates phospholipase C while non-hallucinogenic agonists activate beta-arrestin signaling over PLC signalling

effects of 5HT1 receptor activation (3)

1. dilated pupils

2. increased heart rate

3. increased blood pressure

5HT1 are Gi coupled

effects of 5HT2b receptor activation

valvulopathies over long time use (changes in heart valves) → lethal

hallucinogenic persisting perception disorder

distressing visual hallucinations/ disturbances that appear following drug use

LSD tolerance

1 dose of LSD can lead to tolerance that lasts for several days by downregulation of only 5HT receptors

cross tolerance with other serotonin hallucinogens

psilocybin

indole + amine group → homologous to serotonin (bind with high affinity to serotonin receptors)

origin of psilocybin

naturally occurring in psilocybin mushrooms used for years

what happens pharmocokinetically after ingestion of psilcybin

psilocybin (prodrug) rapidly dephosphorylated to psilocin in body

psilocybin at 5HT receptors

partial agonist at 5HT receptors

high affinity at: 5HT2b + 5HT2c

lower affinity at: 5HT2a → hallucinogenic effects (higher doses needed)

dissociative hallucinogens

distort perception of sight and sound and produces feelings of detachment from environment or self → can lead to depersonalization

analgesia

phencyclidine

(aka angel dust)

NMDA receptor antagonist (like ketamine) + dopamine transporter inhibitor (abuse liability)

datura

deliriant hallucinogen containing tropane alkaloids (scopolamine + atropine)

that is lethal @ higher doses

atropine + scopolamine

competitive antagonists at muscarinic cholinergic receptors (loss of cognition + conciousness (brain) + ANS effects)

deliriant hallucinogens

characterized by extreme confusion and inability to control ones actions

highly susceptible to anterograde amnesia

low lucidity

low lucidity

part of deliriant hallucinations where hallucinations are perceived as real and users may not be aware they are in a state of drug-induced consciousness

oneirogen

substance that produces dreamlike state of consciousness similar to REM state +low lucidity

salvia divinorum

sage plant that includes active ingredient salvinorin A

salvinorin A

active ingredient in salvia that is an agonist at the kappa opioid receptor

produces short acting hallucinogens

4 key interventions to treatment of addiction emergnecies

1. reversal agents

2. downstream effects on body

3. alternative pathways

   1. chronic changes

what are the more serious presentations of alcohol consumption in ER

trauma, suicide ideation, alcholoic ketoacidosis, panreatitis

what drugs to give to patient who is agitated and swinging widlly in ER

sedating agents (minimal effect on respiratory drive): benzodiazepines + first gen antipsychotic drugs (haloperidol)

what drugs to give patient who has chronic alcohol use

chronic use = depletion of:

thiamine (vitamin B1) → reduction thiamine related enzymes

folic acid (Vitamin B12) → increased urinary excretion

magnesium → increased urinary + bowel excretion

what happens during alcohol withdrawl

down regulation of GABA and increases glutamatergic signaling, removal will lead to increase in glutamate

seizures

what to give patient who comes into ER for withdrawl symptoms

GABA enhancing drugs to resotre GABA:glutamate imbalance

IV benzodiazepines + phenobarbital to open GABA + ketamine

diazepam vs lorazepam

diazepam most commonly use benzodiazepine but lorazepam used for history of liver disease

propofol

hyperpolarize GABA → inhibit NMDA receptors → stop respiratory drive → intubation

symptoms from opioid overdose

hypoxia, pneumonia, arrythmias

symptoms of opioids withdraw

dehydration, pain, electrolyte imbalance

Narcan

used in ER to treat opioids overdose

3 opioids agonists in Alberta

methadone: full agonist at mu opioids

suboxone

sublocade: injection buprenorphine

methamphetamine pharmacology

causes large dopamine surges particulary in reward systems

inhibits dopamine reuptake + triggers dopamine vesicle release

aura

preceeds migraines

visual disturbances consisting of flashing lights or zigzag lines moving acroos field of vision

what are auras thought to be driven by

cortical spreading depression: wave of neuronal depolariztion followed by desensitization (depression) that propagates across cortex

what are migraines causes by

mix of genetic and environmental factors

increases in women after puberty (hormones?)

familial hemiplegic migraine

genetic autosomal dominant inheritance that infludes weakness in half of the body

what are the 3 known genetic mutations associated with familial hemiplegic migraines

1. P/Q-type calcium channel

2. Na+/K+ ATPase

3. Na+ channel subunit

what do the mutations that cause familial hemiplegic migraines do

they lower the threshold for cortical spreading depression

trigeminal nerve

largest cranial nerve that:

sense pain + temp in head region

innervate dura mater

control cerebral blood vessels (trigminovascular system)

what are the three branches of peripheral processes of the trigeminal nerve

ophthalmic, maxillary and mandibular

how is the pain of a migraine detected

by the ophthalmic branch of trigeminal nerve innervating dura mater and blood vessuls

steps of migraine

1. extracerebral vessels dilate during migraine attack

2. cranial blood vessel stimulation provokes headaches

3. vasoconstrictor drugs alleviate pain

what is the vasoconstricotr of migraines

5HT (particularily 1B), migraineurs have low levels of this between attacks and is released during attacks

calcitonin gene-related peptide

located in and released by trigeminal peripheral afferents in response to pain

leads to vasodilation

(elevated elvels in those with migraine)

treatment strategies of migraine

1. prophylactic: taken daily to prevent

2. abortive: taken when attack occurs

both used

what are the prophylactic non-pharmacological interventions of migraines

identifying triggers (diet, excercise, sleep, etc.)

what are the prophylactic pharmacological interventions of migraines (3)

1. beta blockers (propanolol): decrease bp

2. anticonvulsatns (gabapentins): block pain transmission

3. antidepressants (amitriptyline): serotonin reuptake inhibitor

rare treatments

what are the abortive treatments of migraine + risk

non-specific analgesics

risk: medication overuse headahce (chronic use makes ur headaches worse over time)

caffeine

adenosine receptor antagonist (on vessles of trigenimal system) → vasoconstriction in migraines

increases abosorption of some analgesics

may trigger headaches of rebound vasodilation headache (withdrawal)

ergot alkaloid

like LSD, binds 5HT-1b.d receptors → inhibit neurogenic inflammation

downsides of ergot alkaloid

low degree of receptor selectivity (bind to other 5HT receptors and adrenergic receptors) → increases drug induced side effect risk

ex. is coronary vasoconstriction

pharmacokinetics (absorption, distribution, metabolism and excretion) of ergotamines

abs + dist: large first pass metabolism = low bioavailibility (caffeine helps improve rate and extent of absorption)

metabolism: poorly metabolized by liver (2 hr half life)

excretion: in bile

triptans

Sumatriptan

first line migraine therapy

selective 5HT 1b/d agonist → vasoconstriction + inhibition of trigeminal nerve = less pain

no ergotamine like side effects

CGRP inhibitors

small molecule of CGRP antagonists or antibodies

monoclonal antibodies

sent to CGRP receptor of CGRP itself to inhibit CGRP signaling → vasoconstriction

BIBN4096

Olcegepant, a CGRP inhibitor that has good efficacy in treating migraines

poor bioavailibitliy (abandoned at phase II)

MK-0974

Telcagepant (CGRP inhibitor)

had serveral phase III trials showing anti-migraine efficacy + safety

problems: elevation of liver aminotransferease = abandoned

Rimegepant (Nurtek)

small molecule CPRP receptor antagonist that is effective in migraine treatment and less effect on liver aminotransferease levels

gepants

small moleculr antagonists at CGPR receptor

biologics

antibodies made naturally in lab

easier to make but expensive + less stable