Lecture 13+ Flashcards
Psychosis
refers to mental disorders in which there is a loss of contact with reality, affecting a persons ability to think, feel, and act
Core clusters of schizophrenia
- positive symptoms: mental phenomena that are absent in healthy individuals (hallucinations and delusions)
- negative symptoms: loss or impairment of normal psychological function (ex: loss of motivation and social withdrawal)
Cognitive symptoms of Schizophrenia
poor concentration, disorganized thinking, poor memory, etc.
Dopamine hypothesis
- symptoms of schiz due to hyperactivity of dopamine system
- inferential evidence: drugs that increase synaptic dopamine (amphetamine, cocaine, cannabis) can cause delusions and hallucinations at high doses; drugs that block dopamine receptors are effective antipsychotics (first gen antipsychotics)
largest population of dopamine neurons are located in the …
midbrain (ventral segmental area and substantial nigra)
Mesocortical/mesolimbic system
dopamine neurons located in the ventral tegmental area project to striatum and the PFC
Dopamine receptors
GPCR; two classes:
- D1: stimulate adenylate cyclase via Gs… (although target for drugs, they are unlikely to contribute to the therapeutic action of many antipsychotics)
- D2: Gi (inhibit adenyl cyclase); blocking D2 directly related to clinical antipsychotic potency
Serotonin Hypothesis
symptoms of schizophrenia due to increased serotonin signalling
5HT-2A antagonists
block glutamate release in cortex = reduces hallucinations and other positive symptoms
First generation antipsychotics
- typical
- targets both D1 and D2 (D2 antagonism = efficacy!)
- haloperidol, chlorpromazine
Second generation antipsychotics
- atypical
- antagonists at both 5HT and D2 receptors
- bind looser (lower affinity) to dopamine receptors than first gen = produce less dopamine related side effects
- clozapine, risperidone
This has a unique affinity for D4 receptors ad causes a serious side effect called agranulocytosis (WBC loss)
Clozapine ; not considered a first line therapy bc of the rare side effects
Alcohol distribution
- throughout tissues
- leaner ppl = there’s more water to dissolve into = lower BAC
- larger people = larger body vol = lower BAC
- alcohol seems to favour water than adipose tissue (doesn’t retain alcohol well)
T or F. Females have a greater BAC
T, they tend to be smaller (small size allows passage into brain) and less lean
Acute effects of ethanol consumption
- inhibited decision making
- unstable mood/heightened emotions
- decreased anxiety
- increased aggression
- increased addiction
- less REM sleep
- impaired memory
- impaired balance and coordination, vision impeded and taste and smell too
- reduced perception of pain
- dilated blood vessels of skin
- reduced blood clotting
- increased HDL levels
Acute effects of ethanol
- Biphasic*
- BAC rises = stimulant
- BAC declines = depressant
- metabolism causes phases
- increased sociability, decreased anxiety
Why does alcohol affect perception?
interacts with brain receptors!
- ethanol modulates glutamate and GABA receptor activity
- tilts balance of neuronal activation towards hyper-polarization => inhibition
Heteropentameric receptors of GABA receptors
most have 2 alpha and 2 beta and one other
- conduct negative chloride current into neurons
Heterotetrameric receptors of NMDA receptors
- all contain 2 NRI subnuits and either 2 NR2 or 2 NR3 subunits
- conduct positive currents into neurons; depolarizing
Physiological effects of EtOH
- vasodilation (warm skin but low core temp = autonomic brainstem nuclei)
- loss of stomach mucosal lining = ulcers
- spins (endolymph and cupula)
Metabolic tolerance of alcohol
due to liver adaptation
- up-regulation of enzymes, especially in heavy drinkers
Congener
minor chemical constituent, especially one that gives a distinctive character to a wine or liquor or is responsible for some of its physiological effects
Beer belly
- ethanol is calorie-dense so problem if also malnutrition
- 50% of caloric intake; complex carbs, especially beer!!!
- metabolic changes in E usage -> brain metabolizes acetate not glucose
Acetate
calorie-dense product of ehtanol; can enter CAC and generate energy (not nutritional)
FASD
3rd trimester most vulnerable; affects synaptogenesis, facial development
Affected liver function due to disease
- Steatosis (fatty liver) = lipid buildup in liver = yellow colour
- Cirrhosis = nodules, fatty deposits, essentially all fibrous
- scar tissue = liver has lost its ability to properly filter blood and metabolize toxins
Brain health after excessive alcohol consumption
- acetaldehyde (ethanol metabolite) is reactive
- modifies proteins = dysfunction = affects glucose metabolism, protein synthesis and myelin formation
- damages neurons and cause cell death
Acetaldehyde
carcinogen; impairs DNA synthesis
- especially upper GI tract bc microflora metabolizes ethanol too ; can reach 10-100x higher conctns than in the blood
Disinhibition
release a neuron from inhibition - you’re activating it!!
Explain how the cupula affects brain’s position in space
whichever way the cupula deflects in the endolymph, it tells brain position in space ; ethanol leaves cupula first ( cupula a lot denser than endolymph); if lying down, cupula will be deflected but it’s supposed to be straight up ; brain perceives deflection as movement
the Limbic brain
- circles the brainstem
- ‘old’ neocortex that includes amygdala, hippocampus basal ganglia, and cingulate gyrus
- connections to FC and hypothalamus
monoaminergic neurotransmitters
dopamine, norepinephrine ,and serotonin
Depression results from inadequate monoamine neurotransmission especially…
serotonin and noradrenaline in the brain
inadequate monoamine neurotransmission may be due to: (3)
- fewer receptors
- less neurotransmitter release
- impaired signal transduction
Reserpine
antihypertensive drugs that block transporter necessary for moving dopamine into vesicles = depression symptoms
Ipronazid
anti-tubercular drug that alleviated depression by inhibiting MAO
Problems with amine hypothesis
- drugs that restore
monoaminergic levels are only moderately effective - inconclusive evidence that serotonin and noradrenergic systems are disrupted in depression
- antidepressants = several weeks before effect is seen despite immediate effects on synaptic neurotransmitter levels
Monomine antidepressants
- increase synaptic levels of monoamine neurotransmitters (ser and norepi)
- MAO inhibitors
Tyramine cheese reaction
- tyramine is a sympathomimetic monoamine (acts like noradrenaline)
- naturally found in aged cheese
- also degraded by MAO
- combo with antidepressant = acute hypertension rxn caused by tyramine binding to adrenergic receptors on blood vessels and in heart
Transporters
move neurotransmitters from the synapse to the intracellular space
SSRIs
- inhibit SET and NET
- blocking transporters increase the extracellular concentration of neurotransmitters
- inhibit both NET and SET = SNRI
- fluoxetine
limitations of Monamine antidepressants
- moderately effective in 30-50% of patients
- several weeks before clinical effect is seen
- MAOIs, SSRIs, and SNRIs affect levels throughout body = side effects such as nausea, indigestion, dizziness, dry mouth, weight loss, etc.
Ketamine
noncompetitive NMDA receptor antagonist
- dissociative anesthetic w/ hallucinogenic properties
- also possibly antidepressant
- binds to an allosteric binding site ; within pore of the glutamate (NMDA) receptor ; blocks its ability to open and pass positively charged ions; acts as an antagonist
Glutamate antidepressant
- ketamine
- causes transient burst in glutamate resulting from blockage of NMDA receptors on GABA interneurons
- glutamate burst = synaptic remodeling and resetting of systems
Ketamine clinical trials and limitation
- showed promise in patients with treatment-resistant depression
- very narrow therapeutic index
- administered intravenously within hospital setting
SSRI vs Ketamine
- SSRI = ~15% improvement after 8 weeks
- Ketamine = ~25% improvement after 1 day
Future treatments for Depression
- targeting downstream effects
- to increase cAMP, inositol, and CREB
- ex: Rolipram
Heterogenous disease with multiple overlapping mechanisms
Depression
Transient alteration of behaviour due to abnormally excessive and synchronous neuronal activity in the brain
Seizures
Epilepsy
disorder of brain function characterized by the periodic and unpredictable occurrence of seizures
Occurrence of spontaneous, unprovoked seizures
Epilepsy
Other things that can look like seizures which are not
movement and sleep disorders, migraines (often predicted by aura - also seen in seizures)
T or F. Normally neurons fire asynchronously n the brain
T, spread of electrical activity is maintained by changes in membrane potential following depolarization (refractory period) and surround inhibition
Surround inhibition
physiological mechanism that focuses neuronal activity in the CNS
Three steps of seizures
initiation
propagation
termination
Seizure initiation characterized by two events:
- high-frequency bursts of action potentials
- hyper-synchronization of a neuronal population
**sustained neuronal depol = burst of APs driven by Ca influx through NMDA receptors
(SEIZURES) With sufficient activation, can overcome intact hyperpolarization and surround inhibition by: (3)
- increasing extracellular potassium = blunts hyperpolarizing outward potassium
- accumulation of Ca in presynaptic terminals = enhances neurotransmitter release
- depolarization induced activation of the NMDA receptor = more Ca influx and neuronal activation
Mechanism that terminate a seizure are not well known but likely involve: (4)
- loss of ionic gradients
- depletion of ATP
- depletion of neurotransmitters like glutamate
- activation of inhibitory circuits (GABA)
Status epilepticus
- seizure lasting longer than 5 mins
- OR more than 1 seizure within a 5 minute period
- life-threatening!
Postictal period
- lasts 5-30 minutes after a seizure and is characterized by drowsiness, confusion, depression/anxiety, and sometimes psychosis (includes hallucinations and delusions)
Types of seizures characterized by:
location in brain they initiate and how widely they propagate
Focal seizures
- may be simple (retain consciousness)
- complex (loss)
- jerking may start in specific muscle group then spread to surrounding muscle groups (Jacksonian March)
- automatisms
- may become generalized overtime
Automatisms
unusual activities that are not consciously created, like smacking the lips
Generalized seizures
- tonic-clonic: sustained contractions of muscles throughout the body followed by periods of alternating muscle contraction and relaxation (previously: grand mal)
- myoclonic: brief (~1s) shock like contraction of muscles that may be localized or generalized
**all involves loss of consciousness
Non-convulsive seizures
- absence and atonic seizures
Absence seizures
abrupt onset of impaired consciousness
- can be subtle with only a slight turn of the head or staring
- loss of consciousness but person does not fall over
- may return to normal right after seizure ends
- there may be period of postictal disorientation (previously petit mal)
Atonic seizures
characterized by sudden loss of muscle strength
- consciousness maintained usually though person may fall down
Benzodiazepines vs Barbiturates (on GABA receptor)
- benzodiazepine = no effect on GABA receptor without GABA
- barbiturates = can act as GABA agonists at higher conctns
Benzodiazepines vs Barbiturates (effect)
- Benzodiazepines = increase frequency at which the GABA receptor opens ; increases potency of GABA
- Barbiturates increase duration at which GABA receptor is open ; increases efficacy of GABA
Risks for Benzodiazepine and Barbiturates
- overdose for both is possible
- riskier for barbiturates bc of direct gating at GABA receptor
- symptoms: sluggishness, incoordination, faulty judgment, and death
- additive risk when taken with CNS depressants like alcohol and opioids
Vigabatrin
- anti-seizure
- inhibit GABA-T
Tiagabine
- anti-seizure
- inhibit GAT-1
Carbamazepine
- anti-seizure
- block voltage-gated Na channels in neuronal membranes
- cause conformational change of inactivation gate
- rate dependent = block increases with increased frequency of neuronal discharge = prolongation of inactivated state of Na channel and refractory period of neuron
Gabapentin
- GABA covalently bound to a lipophilic cyclohexane ring
- crosses BBB
- little activity at GABA receptor (developed to be a centrally active GABA agonist) but inhibits voltage-gated Ca channels
- binds to alpha-2-delta subunit of Ca channel (not a direct block; disrupts regulatory function)
- blocking Ca influx reduces neurotransmitter (glutamatergic) release
Pharmacokinetic considerations of seizure drugs
- used for long time to prevent recurrence so consider pharmacokinetic profile to avoid toxicity and drug interactions
- despite wide variety, most exhibit similar pharmacokinetic properties = well-absorbed, good bioavailability, and cross BBB, low extraction rxns (long-acting)
T or F. Anti-seizure drugs can accumulate in fat tissues
T, lipophilic!
Can take these drugs once every few days, etc. better pharmacokinetic profiles than other lectures
Anti-seizure meds
Cannabinoids
class of chemical compounds that act at the cannabinoid receptors
Cannabis contains hundreds of phytocannabinoids:
particularly delta-9 tetrahydrocannbinol (THC) and cannabidiol (CBD)
Cannabis contains hundreds of non-cannabinoid constituents
including terpenoids which give plant characteristic smell
- anti-inflammatory, anti-bacterial and anti-anxiety effects??
THC Absorption
- aka bioavailability
- fraction of drug that reaches effectors (plasma, CNS)
- smoking = rapid and efficient delivery from lungs to brain
- bioavailability of smoked THC is 25%, reaching peak plasma conctn in 6-10 mins
- vs. ingested = 6%; 2-6 hours
THC Distribution
- highly lipophilic
- tissues with less blood flow accumulate THC more slowly and release it over a longer period of time (ex: adipose tissue)
- THC stored in fat in chronic users can be released into blood for days
THC Metabolism
- liver by cytochrome P450 2C9 enzyme producing the metabolites 11-OH-THC and THC-COOH
THC Excretion
- within 5 days, 80-90% of THC dose is excreted as metabolites mostly
- 65% feces
- 25% urine
- can detect in urine (2-5 days for low dose THC)
- weeks in chronic daily cannabis smokers bc lipophilic)
Cannabinoid receptors
Gi
CB1 and CB2
CB receptors lead to decrease in …
cyclic adenosine monophosphate (cAMP) accumulation which inhibits influx of Ca in firing neuron and inhibits neurotransmitter release
- decrease synaptic transmission = inhibit neurotransmitter release
T or F, THC is a full agonist at CB1
F! partial agonist!
Among the most abundant GPCRs
CB1
- found on glial cells (non-neuronal cells of brain)
- also found in peripheral organs (heart, liver fat, stomach, testes) and peripheral nerves
CB2 receptor distribution
mostly on immune cells
Potential therapeutic effects of THC
attenuation of nausea, increased appetite, decreased intraocular pressure, chronic pain relief
Adverse effects of Cannabis
- acute effects: panic attacks, severe anxiety, psychosis, paranoia, convulsions, hyperemesis ; rare but associated with high THC doses
- prenatal effects: neurodevelopment of fetus affected; dose-relationship not identified
- lung cancer: especially smoked cannabis
- driving: increases motor vehicle accident; THC impairs perception, psychomotor performance, cognitive functions, and affective functions; also decreased rxn time
COMT
enzyme important in degrading monoamine neurotransmitters particularly noradrenaline and dopamine
Tolerance
decreased response to the effects of the drug, necessitating ever larger doses to achieve the same effect
Psychological dependence
compulsive drug-seeking behaviour in which the individual uses the drug receptively for personal satisfaction, often in the face of known risks to health
Physiological dependence
revealed when withdrawal of the drug produces symptoms and signs that are frequently opposite of those sought by the user
Substance use disorder
inability to control the use of legal or illegal substances despite negative consequences
- diagnosed by 11 diagnostic crieteria
A manufactured compound whose properties imitate those of the active constituents of cannabis
Synthetic cannabinoids
- act in a similar way as THC but different structure
Why synthetic cannabinoids?
- increased specificity
- decreased off target effects
- easier dosing
- better controlled studies
Nabilone
partial agonist at CB1; synthetic analog of THC
Dronabinol
partial agonist at CB1; (-) trans isomer of delta 9-THC, approved for nausea and vomiting in patients who undergo chemotherapy and anorexia in AIDS wasting syndrome
Nabixmols
- sativex
- botanical drug (cannabis extract)
- 1:1 mixture THC and cannabinol
- sublingual spray
- Canada; for pain relief (MS or cancer)
- less psychotropic effects than smoked cannabinoids
Rimonabant
- inverse agonist at CB1 receptor
- obesity treatment but withdrawn due to serious adverse effects of depression and suicide ideation
Endocannabinoid synthesis
- similar types of molecules to arachidonic acid
- made from phospholipid bilayer of cell membrane
Endocannabinoid signalling
- AEA & 2-AG = retrograde neurotransmitters
- not stored in vesicles; synthesized on demands when and where they are needed!!
- act on CB receptors which are on PRESYNAPTIC membranes
Endocannabinoid metabolism
- AEA and 2AG are rapidly cleared from the synapse and inactivated by fatty-acid amide hydrolase (FAAH) monoacylclycerol lipase (MAGL)
- suppression of these enzymes prolongs activity of endocannabinoids
Opium
dried latex obtained from the poppy
Opiates
any drug derived from opium
Opioid
any drug that binds to an opioid receptor
- includes opiates, synthetic opioid agonists (fentanyl, heroin, oxycontin)
Narcotic
- Greek; “narco” = to make numb
- originally referred to any drug with sleep-inducing properties
- now usually used by law enforcement to refer to illegal use of opioids for non-medicinal purposes
Opioid receptors
- Gi
- leads to neuronal inactivation and reduced transmitter release
Ligand specificity of opioid receptors
- extracell loops = controls which ligand binds = form pocket that confers cell activity of ligand binding
- intracell tail = which G proteins bind, how well, intracell signalling processes
least homology = extracell and intracell = happens in important regions = specificty
Effects of mu opioid agonists
- analgesia
- reward
- antitussive
- respiratory depression
- constipation
- morphine, codeine, heroine
Effects of mu opioid antagonists
- aversive
- prevent reward
- block overdose
- naloxone
Naloxone
treatment for opioid addiction and overdose; antagonist is intensely unpleasant (counters positive mood) ; effective in acute overdose
Effects of delta opioid agonists
- not rewarding
- no analgesia (except chronic pain, migraine)
- some seizure-inducing (not commercially available, under investigation)
Effects of delta opioid antagonists
no obvious effects
Effects of kappa opioid agonists
- aversive
- hallucinogenic
- anxiogenic (causes/increases anxiety)
- Salvia (isolate form a plant; some ppl steep for tea; ppl use this recreationally)
Effects of kappa opioid antagonists
- potential antidepressant/anxiolytic
Full mu opioid agonists include
morphine, methadone, fentanyl, and heroin
T or F. Codeine is a full agonist at the mu opioid receptor
F, partial!
This mu opioid agonist has a mild to moderate analgesic efficacy but a SAFER therapeutic index
Codeine; less likely to overdose
T or F. Codeine is more potent than morphine
T!
Buprenorphine
- partial agonist at mu
- antagonist at delta and kappa
- common treatment for pain and opioid addiction - opioid agonist therapy
opioid agonist therapy
Buprenorphine
Beta-arrestins
family of intracellular proteins important for regulating signal transduction at GPCRs
These proteins arrests G protein signalling that leads to tolerance following chronic opioid use
Beta arrestin ; also activates its own intracellular signalling pathways that contribute to some of the drug effects
Receptor selectivity
selectivity for different receptor subtypes
Functional selectivity
selectivity for different signalling pathways coupled to the same receptor
Mu opioid receptor G-protein signalling pathway
drives analgesia
Mu opioid beta arrestin signalling pathway
drives respiratory depression
“tickling” the receptor
possibility of designing ligands that activate one pathway over the other to maintain analgesia without the respiratory depression (safer opioid?)
beta-arrestin vs GPCR
T or F. Most mu opioids are well absorbed when taken orally
T! But morphine undergo extensive first-pass metabolism
& codeine avoids first pass so more effective orally!
Morphine metabolized by …
phase II glucuronidation and morphine-6-glucuronide (M6G)
Most important glucuronidation enzyme
UGT2B7 (morphine)
morphine-6-glucuronide
an active metabolite
- can prolong morphine effects
Addition of large polar bodies that makes them more likely to be excreted (it inactivates them)
Glucuronidation
Codeine is metbaolized into morphine by …
CYP2D6; codeine is a prodrug!
Slow vs fast metabolizers of CYP2D6
Slow CYP2D6 = Poor metabolizers = lower responses to codeine ; will require much higher doses to get same effect
Fast metabolizers of CYP2D6 = more analgesic but also susceptible to side effects
These are excreted mainly in the urine (includes M3G and M6G)
polar metabolites; small amounts of unchanged drug also in urine
Three types of endogenous opioid peptides
beta endorphins
enkephalins
dynorphins
- widely distributed neurotransmitters that mediate pain, reward, learning and memory, and cognition
All opioid peptides share common AA sequence of:
Tyrosine, Glycine, Phenylalanine
Tyr-Gly-Gly-Phe
**various extensions are added during post-translational modification yielding opioid peptides from 5 to 31 AAs in length
Beta endorphins
unbiased! GPCR and beta arrestin signalling
Serine proteases
degrades endogenous opioids
by blocking the enzyme that degrades or metabolizes the neurotransmitters = increased levels of compound ; promoting effects of beta endorphins
Beta endorphins = mu opioid primarily and delta –> activation of mu = pain -> analgesia also euphoria
T or F. Delta agonists are not effective in treating acute pain
T! If consistently in pain = delta receptors move to membrane so more delta on nociceptors so available to bind to agonists
Opioid receptors are localized in the brainstem
rostroventral medulla
Opioid receptors in rostroventral medulla
they increase diffuse noxious inhibitory control
Dopamine neurons are located primarily in the …
ventral tegmental area (VTA)
Mu opioid receptors in the VTA are located on …
inhibitory GABAergic interneurons
- so opioids inhibit inhibition (disinhibition) leading to dopamine release
inhibitory GABAergic interneurons
- so opioids inhibit inhibition (disinhibition) leading to dopamine release
1) decreasing nociception at the level of the nociceptor, in the spinal cord, and in the brain stem
2) decreasing the emotional and cognitive aspects of pain (make the pain bother you less)
Most opioid agonists used for pain are
mu agonists
These opioid agonists are being developed for chronic migraines
delta agonists (seizures side effects)
TRV250
delta opioid receptor biased agonist currently under development by Trevena
Why are delta agonists not as effective at treating acute pain?
bc expressed very low in pain pathways in a normal individual not in pain… BUT conditions of chronic pain like migraines = up-regulation of expression of delta receptors on pain pathways
Why have kappa agonists that penetrate brain not been developed for pain?
due to dysphoria/hallucinogenic effects (SALVIA)
These kappa agonists do not cross the BBB
peripherally restricted kappa agonists
These drugs bind kappa receptors in the skin and inhibit pain transmission while avoiding CNS adverse events
peripherally restricted kappa agonists
CR845
- peripherally restricted kappa agonists
- potent analgesic
- anti-inflammatory
- anti-itch
- little CNS effects
- under development by Cara Therapeutics
Tolerance
decreased response to the effects of the drug, necessitating even larger doses to achieve the same effect
Desensitization to opioid agonists
- following agonist binding and G-protein signalling, beta arrestin is recruited to shut off signalling
- receptor+agonist is pulled off the membrane and recycled in an endosome (degraded or recycled back to membrane)
- repeated opioid use leads to less receptors on the membrane = reduced agonist effect (tolerance)
This develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal
physical dependence
Brain disease driven by dysfunction in reward, motivation, memory circuitry
Addiction
Addiction characterized by: (5)
- inability to abstain consistently
- behavioural control impairment
- drug craving
- diminished recognition of significant problems with ones behaviours and interpersonal relationships
- dysfunctional emotional response
Agonist replacement therapy
comprehensive treatment approach including maintenance of an opioid agonist and cognitive behavioural therapy
This blunts the symptoms of opioid withdrawal
Agonist replacement therapy
T or F. Replacement agonists have longer half-lives, so avoid the repeated high/crash cycle
T
Advantages to agonist replacement therapy
- reduced drug cravings
- better participation in addiction treatment (behaviour therapy) since withdrawal symptoms aren’t a distraction
- improved socials functioning
- reduction in infectious disease/death associated with illicit drug use
Methadone
- long-term acting full agonist at mu opioid receptor
- first replacement therapy approved for opioid use disorder
- disadvantage = full agonist so overdose still possible
Partial agonist at mu opioid receptor and an antagonist at kappa and delta opioid receptor
Buprenorphine
- safer agonist profile
- antagonist activity at kappa may improve mood
- marketed as suboxone (buprenorphine+nalaxone)
T or F. Buprenorphine risk of abuse is much higher than methadone
F! much lower (partial agonist at mu)
A psychoactive agent that causes changes in perception
hallucinogen
Associated with substantial changes in thoughts, emotions, and consciousness
Hallucinogens
Criteria for a drug to be classified as a hallucinogen: (5)
- in proportion to other effects, changes in thought, perception, and mood should be predominate
- intellectual or memory impairment should be minimal
- stupor, narcosis, or excessive stimulation should be an integral effect
- ANS side effects should be minimal
- addictive craving should be absent
Hallucinogenic effects of LSD is mediated by
5HT-2a
- mice knockout did not show head bobs to LSD
High affinity partial agonist at 5HT-2a receptors
LSD
Why don’t all 5HT-2a agonists cause hallucinations?
biased agonism
- LSD activates phospholipase A2 instead of phospholipase C (like serotonin does)
- leads to regulation of different genes
Is pretreated with this it blocks hallucinogenic effects of LSD
- Ketanserin
- 5HT-2a antagonist
LSD effects
- dilated pupils, increased heart rate and BP
- sensory perception distortion
- sometimes feeling of enlightenment
- adverse psychiatrics effects such as anxiety, paranoia, and delusions are possible
- hallucinogen persisting perception disorder (HPPD)
HPPD
- hallucinogen persisting perception disorder
- distressing visual hallucinations that appear following drug use
- rare!
- can persist for months, years after a bad trip and harm a person (heavily distressing)
- can be deadly ; don’t know true mechanism driving the perception differences but maybe involves changes in serotonin signalling and visual cortex changes
LSD Tolerance
- single dose can lead to profound tolerance that lasts for several days
- accompanied by down-regulation of 5-HT2 but not other 5-HT receptors
- cross-tolerance of LSD w/ other hallucinogens acting at serotonin receptors (psilocybin and DMT)
Analogue to serotonin
psilocybin
What happens when psilocybin mushrooms are ingested?
- euphoria
- visual and mental hallucinations
- changes in perception
- distorted sense of time
- spiritual experiences
- adverse: nausea and panic attacks
One of the few hallucinogenic drugs that are self-administered in animals (addiction liability)
Phencyclidine
Exception to rule – addictive and drug of abuse through its activity at the dopamine transporter (hallucinogens)
Phencyclidine
Analgesia of nitrous oxide might be due to
release of dynorphin and activation of kappa opioid receptor
Atropine and scopolamine
- tropane alkaloids from Datura plant
- competitive antagonists at the muscarinic cholinergic receptors
Leading cause of disability worldwide, particularly in those under 50
Migraine
Visual disturbances consisting of flashing lights or zigzag lines moving across the field of vision
Aura
T or F. Migraines affect more men than women
F! More women than men
- increase incidence in women due to hormones?? (after puberty)
Familial hemiplegic migraine
- includes weakness of half of the body
- autosomal dominant inheritance
- mutations associated with FHM (P/Q-type Ca channel, Na+/K+ ATPase, Na+ channel subunit)
- mutations lower threshold for cotrical spreading depression
Largest cranial nerve
Trigeminal nerve
Peripheral processes of the trigeminal system is divided into three branches
Ophthalmic, maxillary, and mandibular
3 purposes of trigeminal system
- sense pain and temp in head region
- innervates dura matter
- controls cerebral blood vessels (trigeminovascular system)
Serotonin and Migraine
Vessels have serotonin receptors and release of serotonin = vasoconstriction particularly the 5HT-1D receptors on vessels
Calcitonin gene-related peptide (CGRP)
- trigeminal peripheral afferents
- released from afferents in response to pain => vasodilation
- CGRP elevated in those with migraine
Potent vasodilators that are tuned to pain detection (primarily in nociceptors)
CGRP; elevated levels in those with migraines
Prophylactic vs Abortive strategies for migraines
- Prophylactic: give drug before someone has migraine chronically to reduce likelihood (taken daily)
- Abortive: taken once an attack occurs (to avoid severity or to avoid when feel coming on)
Propanolol for migraines
- beta blockers
- antagonist at beta adrenergic receptors
- works by decreasing BP to have less pressure on cerebral blood vessels = reduce trigger of migraines within cerebral vasculature
Anticonvulsants for migraines
- gabapentin
- works by inhibiting Ca channels which can reduce neuronal activity that can promote seizures
- may also inhibit cortical spreading depression in migraine
- shown to be effective at blocking pain transmission - first line therapies or chronic pain treatments
Antidepressant for migraines
- increasing levels of serotonin in synapse
- works to normalize serotonin levels to normal levels to remove risk factor that could be contributing to development of migraine
Medication overuse headache
severe cases of migraines; emergency room -> give opioids; can be effective short-term but risk of med overuse headache - constant use of opioid drug = make headaches worse!
- someone with headaches greater than 15days/month
- regular overuse >3mos
- headache has developed or markedly worsened during medication overuse
First specific anti-migraine agents
ergot alkaloid (like LSD) - no longer first line therapy
Treatment strategies under development for migraines
- small molecule CGRP antagonists
- monoclonal antibodies to CGRP/CGRP receptors
Pathway to drug development
- preclinical
(approved for human testing) - safety
- efficacy
- larger population = confirm findings (rare side effects more detectable with more ppl)
- FDA revirew to confirm safety and effectiveness
- drug approved
Rimegepant (Nurtek)
- one of few remaining small molecule CGRP receptor antagonists that remains in clinical development
- effective migraine treatment
- less effect on liver aminotransferase levels (safer for longterm use)
- FDA approved
Peptidoglycan structure
- alternating glycan strands: GlcNAc and MurNAc
- cross-linked by peptides
- indiv strands polymerized by enzyme glycosyltransferase in to pg chain
- transpeptidase cross link the strands (penicillin binding protein)
therapeutic index
ratio of minimum concentration likely to produce an adverse effect to the minimum concentration needed to produce a desired effect
ability to penetrate
delivery of antibiotics to site of infection is most difficult challenge of antibiotic delivery
Acremonium
Fungus that provided cephalosporins
Penicillium notatum
fungus for Penicillin
Beta lactams
- unusual 4 member rings of penicillins and cephalosporins
- inhibit cell wall synthesis by inhibiting DD-transpeptidase (responsible for cross-linking)
- bacteriocidal
- also called PBP
- originally only effective on gram + (still work better on them though)
Beta-lactamases
- made by many gram negs that hydrolyze beta-lactam ring
- Staph
Beta-lactamase inhibitors
- Calvulanic acid
- potent inhibitors of beta-lactamases used in combinations to protect hydrolyzable penicillins from inactivation
- given together with beta-lactams for protection
Vancomycin
- NOT a beta-lactam (no 4 ring)
- also inhibits peptidoglycan cross-linking
- Actinobacteria
Bacteria use this to synthesize nucleic acids that make up their DNA
folic acid
A nutrient obtained from the environment that is the precursor for folate in bacteria
PABA (metabolic pathway that is unique to bacteria)
These resemble PABA and dihydrofolic acid respectively, and interfere with PABA metabolic pathways
Sulfonamides and trimethoprim
Usually given together to block sequential steps in synthesis of folic acid
Sulfonamides and trimethoprim
This adds AA to growing AA chain
transpeptidase (tRNA)
Chloramphenicol and Macrolides
bind to 50S subunit and block transpeptidation
Tetracyclines
bind to 30S subunit to prevent binding of incoming tRNA
Aminoglycosides
bind 30S ribosomal subunit
- blocks initiation of complex
- cause misreading of the code on mRNA template
- inhibit translocation
Aminoglycosides block protein synthesis at multiple levels
- Two ribosomal subunits have to come together before RNA can be translated into protein so aminoglycosides blocks this
- Wrong amino acid added to growing change or none at all (nonsense sequence)
- Block translocation; after protein is made, need to be released to cell so it can float around intracell space; process of releasing = translocation = aminoglycosides block the release/translocation of mature peptide/protein form ribosome
T or F. Eukaryotes can synthesize folic acid from PABA
F! they can’t; only prokaryotes can
Bacterial resistance
- drug inactivation or modification (beta lactamases)
- alteration of binding site (MRSA alteration of PBP)
- alteration of metabolic pathways (sulfonamide resistant bacteria begin to use pre-formed folic acid)
- reduced drug accumulation (efflux pumps)
Stevens-Johnson syndrome and toxic epidermal necrolysis
rare conditions in which the skin becomes detached from the underlying tissue and sloughs off the body
**Lower dermis detached from epidermis(upper layer of skin)
Not known why antibiotics cause these effects = autoimmune rxn maybe ?
Anticholinergic medication can ________ _______
impair vision
= falls!
High risk medications for seniors
- proton pump inhibitors
- benzodiazepines
- natural opium alkaloids
Potentially inappropriate medication
Beers Criteria
T or F. Women tend to use more meds and also more PIMs
T
Excessive use of medication
polypharmacy
Changes in organ system when aging
5h decade; 40s
T or F. Less CO when aging
T! more sensitive to CV meds in terms of vasodilation = dizziness!
For medications oxidatively metabolized, _______ dose
reduce
Drug dose adjustments in older adults is mostly due to
renal function
Paradox of exposure for older adults
the more exposed to meds = the more sensitive
