Drugs Flashcards
psychotropics
drug capable of affecting the mind, emotions, and behavior
what is noradrenaline involved in
receptors all throughout brain so impact all brain systems arousal, wakefulness alertness in forebrain mood in amygdala/hippocampus pain in spinal cord
what is dopamine involved in
more restricted distribution
prominent in prefrontal cortex - decision, judgement, risk
nigrostriatal system (from substantia nigra to striatum) - motor control
mesolimbic/mesocortical system - behaviour, mood
tuberohypophyseal system - endocrine control
what is serotonin (5-HT) involved in
widespread distribution throughout brain
sleep, wakefulness, mood, feeding, sensory transmission, pain
Raphe nuclei - primary source of serotonergic fibres
monoamine uptake
NET - noradrenaline
SERT - serotonin
DAT - dopamine
transporters remove NT from synaptic cleft
drugs that cause monoamine uptake inhibition and some clinical uses
Cocaine - act on DAT
MDMA (ecstasy) - act on SERT, also on VMAT (transport into vesicles)
Amphetamine - target NET and VMAT and inhibit MAO
clinical uses - ADHD, narcolepsy (sleep), reduce apetite, PTSD, depression, weigth control
amphetamines
increase motor activity euphoria, excitement, insomnia, anorexia given to troops in war to be less sleepy and hungry (Benzedrine) can cause dependence high doses can cause psychosis
clinically: Adderall for ADHD
Ritalin for ADHD/narcolepsy
Methedrine for obesity
Cocaine (HCl form or free-base crack) effects
increased motor activity
euphoria, excitement, garrulousness (talkative), increased BP/HR
shorter lasting than amphetamines
strong dependence
Modafinil
increased wakefulness for narcolepsy
vigilance, improve cognitive performance (likely from wakefulness)
bind DAT and NET with low affinity, displaces cocaine for DAT
and other NT systems
low abuse potential because no ‘high’
cognitive enhancers (limitless) \+ study
caffeine, modafinil, methyphenidate, ampakines
hopes to reduce mental fatigue, increase motivation, attention, concentration, memory, normalise behaviour like sch./autism
chess study: takes longer on moves and thinks more if took enhancers but chance of winning decreased as game progressed, bad effect if there’s a time limit
Ampakines
+ study
cognitive enhancers
activate glutamate AMPA receptors
epileptic seizures if activate too much
Skinner box study: mice improve performance of pressing bar to get food, maintained high performance when stopped drug so new brain connections (limitless ending??)
promote release of BDNF so plasticity and growth
Depression monoamine theory
evidence: drugs like reserpine reduce monoamine (MA) levels and cause depression
but not clear how monoamine links to symptoms (take weeks to change)
drug classes:
monoamine oxidase inhibitors (phenelzine) prevent MA breakdown
monoamine uptake inhibitors (tricyclics, imipramine) target NET, SERT
selective monoamine uptake inhibitors (citalopram, fluoxetine=Prozac) target SERT (SSRI)
reboxatine target NET
duloxetine target NET and SERT (SNRI)
Schizophrenia (dopamine)
increased D2 receptor activity (+ve symptoms)
decreased D1 receptor activity (negative symptoms)
drug classes:
Chlorpromazine (1st generation, typical) - target D1, D2 and other
Clozaine/Risperidone (2nd, atypical) - more at D2 but also D1
side effects: motor, tardive dyskinesia (less with 2nd), gynecomastia (man breasts), weight gain, drowsy
Parkinson’s (less dopamine)
loss neurones in substantia nigra (less black substance)
suppression of voluntary movement, cognitive impairment
treatment:
Levodopa with carbidopa or benserazide
inhibit COMT so more levodopa in periphery to cross blood-brian barrier and converted to dopamine
target receptors to prevent dopamine metabolism too
deep-brain stimulation to cause DA release and trigger pathways
can cause schizo
local anaesthetics vs general anaesthetics
act locally to block nerve conduction
act in brain to cause loss of consciousness for operation/experiments - inhalation gases/IV infusion
structure of general anesthetics
variety of chemical structures with no specific one, nothing in common
(apart form opioids)
Stages of anaesthesia
how deep (need to know to get to right stage)
1) awake but drowsy, distorted perception, analgesia the end of stage
2) dangerous stage so need to move through it quickly, excitation, inhibitory neurones affected 1st, motor reflexes, unconscious, shouldn’t eat before, uncontrolled movement, lose temp control, irregular breathing, cardiac dysrhythmia
3) surgical anaesthesia, regular breathing, depressed cough/vomit reflex, pupils constrict then dilate, skeletal muscles relax, drop BP, loss corneal reflex
4) not good, deep, shallow breathing, fall BP, feeble pulse, wide pupils, no ventilation from depression of medulla oblongata so die
what is the best stage of anaesthesia?
plane 3 of stage 3
deep, shallow breathing, weak pulse, no response to surgery, dilated pupils, reduced muscle tone, absent/diminished reflexes
but difficult to measure because no movement
EEG and anaesthesia
can monitor depth
as deepens - amplitude of high frequency components fall and lower frequency amplitude increases
large amplitude slow frequency waves
changes are agent dependent
theories of general anaesthesia (GA)
lipid theory
protein theory
combination
Lipid theory of GA (mechanism, evidence, correlation, problems)
GA dissolve in membrane and change bilayer thickness/curvature/order of chains/elasticity so change protein properties
evidence: no defined structure, push GA out w/ pressure
Meyer-Overton correlation: more lipid soluble GA=more potent
problems: stereoisomers same solubility but 1 active 1 not
new compounds don’t fit correlation
more carbons more soluble but too long stops working (cut off effect)
non-immobilisers soluble but not anaesthetic
temp changes bilayer but not anaesthetic
Protein theory of GA (target proteins, evidence)
specific membrane proteins: GABAa receptor (inhibitory), 2 pore K channel (control resting pot.), NMDA receptor (excitatory)
evidence: mutate and look at potency
GABAa mutant - propofol not work, no change w/ alphaxalone
2PK mutant - halothane and isoflurance not work
NMDA mutant - xenon and isoflurane not work
identifying relevant anaesthetic protein targets
right place
work in same conc as used clinically
stereo selective effects - work in vivo and vitro
appropriate sensitivity and insensitivity to other compounds
ideal anaesthetic
rapid action and recovery
minimal irritant
miscible with air/O2 so no explosion
analgesic, muscle relaxant
anaesthetic potency
MAC (minimum alveolar concentration
alveolar partial pressure of inhaled anaesthetic which prevents movement to pain in 50% patients
what does a greater solubility of an inhaled agent in blood mean?
solubility in blood determined by bloog/gas co-efficient
greater solubility means reduced rate of rise of alveolar partial pressure so reduced rate rise of brain partial pressure and slower rate anaesthetic onset (slower activation if more soluble)
lower solubility means quicker to affect pass to and affect brain, because drug in alveoli need to fill arterial blood before go to brain
rate of equilibrium
brain (lean) has fast perfusion so rapid equilibrium
fat has less blood so slow perfusion and slow equilibrium
how does increased cardiac output affect anaesthetics?
delay induction because remove anaesthetic from area so conc/ can’t build up, prevent overdose
recovery from anaesthetic
rate of reduction of alveolar partial pressure determines rate of recovery (how quick breathe)
intravenous anaesthetics
Propofol
thiopental
etomidate
ketamine
propofol (MJ overdose)
GABAa receptor liver metabolised lipid soluble in fatty tissue pleasant antiemetic (stop vomit) apnoea (respiratory depression) and decrease BP
thiopental
dangerous barbiturate (CNS depressant) GABAaR lipid soluble cross blood-brain barrier rapidly distribute to other tissues live metabolised poor analgesic and muscle relaxant cardiorespiratory depression
etomidate
rapid recovery without hangover
ketamine
hallucinations not used apart from horses and battlefield child anaesthesia abuse/dependence treat depression irreversible effects in bladder
inhalation anaesthetics
depress respiration, increase artierial CO2, impair O2 exchange, decrease brain metabolic rate, even though increase cerebral blood flow
relax skeletal muscles
machine to breathe it in and out goes to scavenger not air
halothane, isoflurancce, NO, neuromuscular blacking drugs
halothane
potent, smooth induction, non-irritant, moderate muscle relaxation, hepototoxicity for surgeon
isoflurance
less potent than halothane, decrease BP, depress respiration, muscle relax, less hepatotoxicity
nitric oxide
maintain anaesthesia, analgesic, need with other anaesthetics, for labour pain
neuromuscular blocking drugs
muscle relax, lighter anaesthetic, relax vocal cords, respiration assistance
pain
unpleasant sensory and emotional experience to real or potential tissue damage and depends on distraction, previous exp., expectation, context etc.
pain pathways
peripheral nociceptive afferent neurones activated by stimuli
central mechanisms generate pain sensation
neuropathic pain
pain without tissue damage
peripheral pain pathways (fast and slow pain)
pass info from periphery
1) fast pain - A.delta fibres, myelinated, 1-5um diameter, fast conductance, mechanosensitive and temp sensitive
2) slow pain - C fibres, unmyelinated, 0.1-1.5um diameter, slow, mechanosensitive and temp sensitive and chemical stimuli
mutations so no pain
in Na channels in Ad or C fibres
what is slow pain pathway for?
to immobilise so don’t damage further
spinothalamic tract
carry pain to CNS
pain to afferent fibres (C/Adelta) which come in dorsal root ganglia to dorsal horn of spinal cord then crosses to other side and go up tract to thalamus to sensory cortex and then feel pain
Gate theory of pain
2 signals like pain and distraction can’t pass through ‘crossing’ at the same time so large peripheral fibres with distraction can stop pain going to brain
descending pathways
modulate pain signal
parallel pathways modulate affective dimensions of pain (emotional) and control autonomic activity
pathways include Raphe nuclei, reticular formation, pathway from cortex
PAG (periaqueductal gray) key in system, if activate can cause analgesia
opiate (opioid) analgesics
most potent painkillers
from opium poppy
opioid is opiates + synthetic substances
opioid effects
CNS: analgesia w/o unconsciousness, respiratory depression, nausea/vomit from activate chemotrigger zone in medulla
sensitivity to CO2: breathing centre in medulla, CO2 drives breathing, respiratory depression reduces CO2 sensitivity so stop breathing and die of overdose
other CNS effects: euphoria, dry mouth, drowsy, no cough reflex, pupils constrict
other effects: increase tone in GI tract (less store), less gut motility, constipation, delay emptying so slow drug absorption
histamine release so urticaria, bronchoconstriction, hypotension
how were opioid receptors discovered and explain
through binding studies
opiates labelled with radioisotopes so see receptors
what does the presence of opioid receptors suggest?
must be natural endogenous opioids in body
endogenous opioid peptides
enkephalins, endorphins (endogenous morphine)
in areas associated with nociception (pain) e.g. PAG, rostral ventral medulla, substantia gelantosa
beta endorphin in hypothalamus, send projections to PAG and noradrenergic nuclei in brain stem
role in pain perception, reward, stress, autonomic control
multiple opiate receptors
there are multiple ligands to 1 receptor, under different circumstances 1 is more effective
opioid receptor subtypes (names, distribution, functions)
u mu
d delta
k kappa
with diff ligands and distributions
MOP (u) widely in CNS and periphery, cortex, thalamus, PAG, substantia gelatinosa (SG)
KOP (k) hypothalamus, PAG, SG
DOP (d) pontine nuclei, amygdala, cortex
functions: analgesia, k no respiratory depression and dysphoria, only u euphoria, d no pupil constrict and no sedation
ligands: enkephalins for M/D, morphine for M
opioid receptor mechanisms
G-protein coupled so inhibit adenylate cyclase, reduce NT release, activate K and inhibit Ca channels
opioids stored as large propeptides cleaved at presynaptic terminal
directly inhibit pain by reducing transmission to spinal cord
OR
increase descending inhibition so enhance descending pathway and block GABA release
tolerance
increased dose required for same effect, occurs in a few days (no effect on constipation and pupils)
agonist and receptor internalised, beta arrestin binds, receptor removed and destroyed so less effect because less receptors
dependence
physical - reset homeostatic mechanisms from repeated use and adaptation, withdrawal if abrupt termination
psychological - craving
psychological outlasts physical
pharmacokinetics
morphine analogues not absorbed well orally so injection for pain
2ndary metabolism - conjugated with glucoronide
hepatic metabolism - to gut with bile and retaken up
most excreted in urine
types of opioid drugs
morphine
fentanyl - acute pain and anaesthetic, very potent, rapid onset, short, used to stop heroin/cocaine use
codeine - less potent, methyl ester of morphine, weaker, less side effects, combine with paracetamol and over the counter because below therapeutic dose
pethidine - short, less potent, child birth, respiratory depression, dry mouth, blurry, less constipate than morphine
methadone - chronic pain, no euphoria, less sedation, slow recovery, useful for withdrawal and addicts
opioid antagonists
nalorphine, naloxone, naltrexone
most are competitive except nalorphine
treat overdose, treat respiratory depression in babies
partial opioid agonist
buprenorphine (Temgesic) at MOP
sublingual/injection/intrathecal
similar to morphine but less respiratory depression
for chronic pain/dependence
history of cannabinoids
lecture 11
main part of cannabinoids
THC
THC (tetrahydrocannabinol) central effects
impaired STM and motor coordination, sense of time, mood, cognition, catalepsy (trance), hypothermia, analgesia, antiemetic, increase apetite
experiment: pilots decrement in performance even 24hrs later - applies to cars
THC peripheral effects
tachycardia, vasodilation, IOP falls (intraocular pressure in eye), bronchodilator
THC pharmacokinetics
rapid onset from smoking
oral takes longer but lasts longer (4-8 hrs instead of 30mins to 2hrs)
conjugation and enterohepatic circulation prolongs duration
highly lipophilic so accumulate slowly in fat and can detect weeks after
cannabinoids mode of action
CB1 receptor: main, ligand binding of THC, GPCR (binding decreased by non-hydrolysable GTP analogue)
wide distribution in brain lots in cerebral cortex because decisions
inhibit Ca channels, activate K channels so inhibit PKA less cAMP inhibit transmission
CB2 (also GPCR) on immune cells, inhibit adenylyl cyclase
endogenous ligands for CB1/CB2 receptors
anandamide (1st found)
2-AG (2nd found)
various others
where does anandamide and 2-AG come from?
not stored in vesicles but made on demand when calcium increases and 2 calcium sensitive enzymes cleave them from membrane phospholipids
EMT (endocannabinoid membrane transporter) releases ligands from pre/post synaptic neurones so can go post to pre (retrograde)
enzymes that break down CB endogenous ligands
FAAH (fatty acid amide hydrolase) breaks down anandamide
(knockout in mice means reduced pain and more sensitive to exogenous ligand because can’t break it down)
MAGL (monoacylglycerol lipase) breaks down 2-AG
FABP5
transporter of cannabinoids
deletion stops eCB-mediated control of synaptic transmission in dorsal raphe nucleus
retrograde signalling of cannabinoids
depolarise post-synaptic will inhibit pre-synaptic (DSI)
and same for excitation (DSE)
so post affecting pre
depolarise means Ca open so make cannabinoids and come out EMT and bind receptors so inhibit transmitter release into cell
cannabinoids and glial cells
release NT like ATP activates microglia in immune response
synthetic cannabinoids
JWH - very potent, leaked to black market as ‘spice’
synthetic chemical are dried and shredded so smoked or liquids to vaporise
more severe adverse effects like peripheral effects
turn into zombies
hard to know what’s in drug you buy
medical uses of cannabinoids
none so need license to work
some derivatives on market like CBD oil
antiemetic effects for chemotherapy (Nabilone for unresponsive to conventional antiemetics)
desirable side effects - sedation, drowsy, euphoria
undesirable - dizzy, dysphoria, depression, hallucinations, paranoia, hypotension
analgesia - CB1 in pain processing areas so agonist cause analgesia
appetite - VTA reward, desire to eat, hard to study
MS - reduce pain, not cost effective
anti-cancer - inhibit growth, weak evidence
CBD (cannabidiol)
no THC so no psychoactive effects
lacks evidence
for pain, depression, anxiety, acne, cardiac health, antipsychotic, for abuse, anti-diabetic, for extreme epilepsy
anandamide uptake inhibitor, activate TRPV1 receptor and GOR55 R and 5-HTIA, modify adenosine uptake
marijuana
hallucinations, paranoia, depression, anxiety, long term effects, gateway drug
why are drugs addictive?
rewards from dopamine/serotonin release
drug affects VTA nuclei, release dopamine so reward/motivation
drugs block uptake of 5-HT from Raphe nuclei so increase wellbeing
incentive salience - cognitive process for desire because reward, hi-jacked by drugs
top-down control
normal brain motivated through pathway: orbital frontal cortex make decision, regulated in prefrontal cortex in central gyrus, memory
drugs override self regulation and strong memory for reward so overcome natural pathways
addiction study in animals
sweet liquid vs drugs and measure preference with pusing lever no. of times
heroine push lever a lot more compared to nicotine
innate tolerance
genetic sensitivity, after 1st dose
acquire tolerance
pharmacokinetic, changes in metabolism and absorption as take more
e.g. reduce systemic conc. with enzyme that breaks drug down
OR change in receptor/systems reduce response
cross tolerance
less response if taking another because work through same mechanism
e.g. cocaine and amphetamines
treatment criteria for addiction
quick and easy access help mental health stay in treatment behavioural therapy medication monitoring test for diseases
pharmacological approaches to treating addiction
withdrawal symptoms - substitute drug (methadone for heroin addicts)
long term substitution - methadone/buprenorphine/legal heroin
block response to drug - Naltrexone blocks opioid
aversive therapy - Disulfiram
reduced continued drug use - treat underlying e.g. mental health
Disulfiram
antabuse
unpleasant effect to ethanol because blocks breakdown
not used often
take daily orally but why would you if you want alcohol
small amounts in mouthwashes can trigger reaction
some antibiotics block pathway so can’t drink alcohol
cocaine mode of action
blocks uptake transporters for dopamine and 5-HT
NAc (nucleus accumbens) released dopamine
everything rewired over time
changes AMPAR levels, impaired cystine-glutamate exchange, change intrinsic membrane excitability of MSN (medium spiny neurones) so more spines
cocaine withdrawal and treatment
crash 1-4 days after binge
withdrawal 1-10 weeks after
extinction - still low mood and episodic cravings
no treatment apart from contingency management (CM) which is rewards for not taking drug
CBT prevent relapse and avoid situation when likely to take drug
opioid addiction, mechanism, withdrawal, treatment
rush (45s) - intense pleasure
nod (15-20min) - sleepy, detached
high (hrs) - well being
straight (up to 8hrs) - no high no withdrawal (then withdraw)
activate receptors on GABA neurones in VTA so not inhibited and release more dopamine
chronic: reduce cAMP but slowly recover (increases adenylyl cyclase so more cAMP) and decrease dopamine receptors so tolerance
withdraw: more adenyl cyclase than normal so lots cAMP and hyperactivity within 8hrs
methadone alleviate withdrawal symptoms
methadone
long 1/2 life
take for 4 weeks as impatient and 12 weeks in community
lose tolerance and may overdose if miss days
likely taking heroine if missed more than 5 days
buprenorphine
less sedating than methadone
given on alternative days
2 forms: alone (subutex) or combination with opioid receptor antagonist naloxone (suboxone)
naloxone has no effect if taken orally but block it if injected
naltrexone
opioid receptor antagonist no tolerance, precipitates withdrawal only used in overdose because instant withdrawal insufficient evidence of effectiveness prevents relapse when no longer on drug
nicotine
carcinogens in smoke
lots of deaths (41% lung cancer)
nicotinic Rs in neuromuscular junction/brain
areas in reward (hippocampus, VTA, amygdala, NAc, PFc)
changes synapses after long use
treat with nicotine replacements - poorly absorbed orally, transdermal patches, E-cigarettes
Varenidine (partial nicotine agonist)
Bupropion (nicotine antagonist)
ethanol
4-5% population are alcoholics
affect many NT synapses
treatment with Acamprosate calcium SR tablets and counselling to stop relapse
weak NMDAR antagonist reduce cravings
Disulfiram
alleviate withdrawal with various drugs
how do all addictive drugs work?
VTA reward pathway
ego dissolution
melt away as a person
at one with everything
dream like but clear consciousness
3 major psychedelic agents
Lysergics (like LSD) target 5-HT2 receptor agonists, depression, addiction
Empathogen like MDMA (ecstasy) monoamine uptake inhibitor which affects serotonin
Dissociatives (like Ketamine=special K, phencyclidine-angel dust) target NMDARs
special k linked to depression
psychoactive monoamines
amphetamine
tryptamine
dopamine/serotonin/norepinephrine
psychedelics - mescaline, psilocin, psilocybin, LSD
serotonin folded into LSD structure
LSD
synthesised
interacts with 5-HT2 receptor (mutated lid means bind less)
structure keeps LSD in place in receptor
diff networks recruited depending on task and LSD disrupts networks
more brain regions talking to each other with higher intensity
can treat depression, anxiety, alcohol abuse
reduce anxiety in patients with terminal illness
ego inflation
alcohol and cocaine cause you to be more talkative, more about you, more aware of ourselves, not ego dissolution where you seize to be who you are
psilocybin
alleviates symptoms of depression
study in cancer patients
quick onset and long lasting
long study better (may be spontaneously get better)
MDMA
for PTSD
less rumination (dwelling)
reduced communication of hippocampus + prefrontal cortex so reduce traumatic memory
amygdala better communication so contextualise fear
study makes solitary octopus more sociable
forest plot
all studies summed up
dissociative psychedelics and schizophrenia
ketamine/PCP
glutamate theory of sch. is reduced activation of NMDAR (reduced NR1 subunit)
symptoms of psychedelics similar to sch.
Abs to NMDAR caused psychosis so could be from autoimmune disease
ketamine anaesthetic
intravenous horse tranquiliser
awake but detached
bronchodilator, anti-inflammatory
ketamine antidepressant
IV infusion
improve mood and decrease suicide
short lived high
disrupt areas in rumination (dwelling)
mechanism of ketamine antidepressant
NMDAR antagonist
targets NMDAR on inhibitory interneurones so reduce activity and fewer AP
less GABA so less inhibition of glutamatergic neurones
more glutamate
release BDNF
new synapses, synaptic strength, networks rearranged so stop depression
Esketamine nasal spray for treatment-resistant depression
correctly using psychedelics in psychiatry
pure drugs
correct dose
correct mindset
correct setting
