Neuropharmacology Flashcards
ACh
choline + acetyl CoA - choline acetyl transferase (CAT) -> ACh (synapse, neuromuscular junction or effector tissue) -> acetyl choline esterase AChE
Muscarinic receptors mAChR
g protein, parasympathetic (target tissues), CNS modulation (memory = Alzheimers)
M1, M3
gastric function and salivary + stomach secretion via Ca (+M5 activate Gaq (Ca)) (M3= vasodilation)
M2
reduce heart rate and neuronal excitability (+ M4 inhibit Gai/o, presynapse and post)
Nicotinic receptors nAChR
sympathetic (indirectly-ganglion) parasympathetic, sodium channels (memory, cognition = ADHD, schizophrenia)
Acetylcholinesterase AChE
-> choline and acetate
NE
neurotransmitter, selective for alpha - phenylalanine, tyrosine, dopamine -> NE -> monoamine oxidase (arousal, attention, memory)
Adrenaline
hormone, selective for beta - phenylalanine -> l dopa -> dopamine -> NA -> A, locus coerulus
NET
Noradrenaline transporter, DAT - dopamine = reuptake
a1 adrenoreceptor
Gq, Ca2+, vasoconstriction (skin and GI tract)
a2 adrenoreceptor
Gi, brain, reduce presynaptic neuron NA release (modulation) via ions?
B1 adrenoreceptor
Gs, Ca2+, cardiac output and renal, CNS
B2 adrenoreceptor
Gs , v K+=hyperpolarisation, bronchodilation, vasodilation (muscular), gluconeogenesis, GI motility, CNS
B3 adrenoreceptor
Gs, adipose tissue
Glutamate
glutamine via glutaminase, taken up by astrocytes (EAAT1/EAAT2 transporters), main excitatory neurotransmitter
Group 1 metabotropic glutamate receptor
post synaptic, GqmGlu1 and 5, long term depression too much = bad, not enough =decrease brain activity
Group 2 metabotropic glutamate receptor
presynaptic, GimGlu2, 3 - prevents release
Group 3 metabotropic glutamate receptor
presynaptic, GimGlu 4, 6, 7, 8
AMPA ion channel glutamate receptor
Na, most common, activated NMDA, increase with Na2+ (LTP)
Kainate ion channel glutamate receptor
Na, post (excitatory), pre (net inhibitory via GABA increasing), hippocampus (memory and learning)
NMDA ion channel glutamate receptor
Na+Ca, LTP, both glutamate and glycine, Mg blocks, depression and schizophrenia,
LTP
long term potentiation (learning), synaptic plasticity, strengthen connection =fire at low threshold stimulus (hippocampus, amygdala), associative/specific
Excitotoxicity
too much Ca kills neurons, epilepsy - ALS disease (EAAT2), ischemic stroke (no oxygen = no ATP = depolarisation, Glutamate = neuronal cell death)
NE a1 agonist
Phenylephrine = vasoconstriction, nasal decongestant, acute hypotension
NE a2 agonist
Clonidine- (reduce NA release) = hypertension (reduce sympathetic activity), anxiety, migraine and to produce sedation
NE B blocker
Propranolol = anxiety, migraines, CV disease
NE B2 agonist
Salbutamol = asthma (relief inhalers), cause bronchodilation (salmeterol long term)
NE B1 antagonist
Atenolol, metoprolol = cardiovascular disease, including tachycardia and arrhythmias, block symp
NET/DAT inhibitor
ADHD Methylphenidate (NET/DAT) and atomoxetine (NET) - inhibits reuptake
Amphetamine
ADHD facilitate release of NA and dopamine via binding to vesicle storage proteins and transporters
a2 agonists used in ADHD
Guanfacine and clonidine - lowers bp
MDMA
dopamine facilitated release
AMPA positive allosteric modulator
Ampakines -noontropics, reduce AMPA agonist side effects, stimulate LTP (Recetams)
red algae
Kainic acid, domoic = toxic - too much stimulation, neurons all fire together, confusion, memory loss
NMDA competitive antagonists
Ketamine - anaesthetic, amnesia, antidepressant (low dose)
PCP - schizophrenic symptoms, temp decrease memory and learning
NMDA - non competitive antagonist
Memantine - Alzheimer’s (neuroprotection from excitotoxicity)
GABA
glutamate via glutamic acid decarboxylase (GAD), GAT - recycling, GABA transaminase= breakdown, main inhibitory
GABAa +c
ionotropic, Cl+ transport, pentameric (binding a+B),
GABAb
GiPCR, post- inhibits adenylyl cyclase -> activates GIRK (K+ out of cell), pre-blocks Ca2+
GABAergic drugs
anxiety, depression, general anaesthesia, muscle spasms
Low expression of GABAa
impulse control, motivation, increase drug taking (low a2 subunit expression)
Drug similar to GABA
Gabapentin - doesn’t bind to GABAa, increase GAD, decrease VGCC and glutamate (NMDAr), pain + migraines - anti-epileptic
covalent (suicide) inhibitor for GABA transaminase
Vigobotrin (side effects = drowsiness, dizziness, fatigue) - anti-epileptic
positive allosteric modulator GABAa
Benzodiazepines (diazepam) - a&y, sedative, hard to quit, reduce anxiety
Z-drugs
(zopiclone) - sleeping, a&y, (side effects= driving, tolerance, hallucinations)
GABAb activator
Baclofen - muscle spasms (epilepsy)
Dopamine
L-tyrosine, L-DOPA->. Breadown via monoamine oxidase. Ventral tegmental area + substantia nigria ->stiatum + nuclear accumbens + motor cortex.
D1
GsPCRs (post)
D2
GiPCRs (post and pre)
reward pathway
VTA -> Nucleus accumbens (regulated by hippocampus), schizophrenia=overstimulation (+ve -increase consciousness-salience, prefrontal cortex, -ve - not social)
Parkinsons
Substantia vigria -> striatum (low level of dopamine via pe cell death, tremor, bradykinesia)
Hypoglutamate hypothesis
glutamate in VTA stimulates dopamine neurotransmission to PFC and nucleus accumbus (ketamine and PCP help schizophrenia symptoms)
Parkinsons precursor
L-dopa +carbidopa (DOPA decarboxylase inhibitor), dopamine produces and used when needed (high dose = dyskinesia, muscle contraction, hallucinations, change therapeutic index)
Parkinsons treatment
increase dopamine in corpus striatum
dopamine receptor agonist examples
Bromocriptine (oral) + apomorphine (subcutaneous) - (hallucinations, vomiting, disruption of reward pathway-gambling, impulsive) - Parkinson’s
MAOb inhibitor
Selegiline - decrease breakdown dopamine + NA, depression, in combination with L-dopa
D2 antagonist schizophrenia
Haloperidol - typical antipsychotics, non selective= a1-hypotension+dizziness, H1-sedation, weight gain, mAChR-reduce parasympathetic. (Parkinson’s symptoms, lack of pleasure anhedonia)
D1 and D2 inhibitor schizophrenia
Clozapine - also serotonin receptors, increase dopamine-negative symptoms, less side effects
Seretonin
5-HT made from tryptophan, broken down by MAOa, SERT uptake, 10% brain=mood, sleep, reality perception, daydreaming (default mode network), 90% GI tract
Serotonin receptors
7 subtypes Gi, Gq, Na+ and Gs.
Depression
moamine theory=decrease in monoamine neurotransmission->less post synaptic activation (lack of serotonin doesn’t cause depression+placebo effect)
SSRI
selective seretonin reuptake inhibitors, selectively increase serotonin, first-line, low side effects (dry mouth, insomnia, nausea)
Tricyclic antidepressants SNRIs
NAT +SERT inhibitors, side effects- a1, H1, mAChR, overdose danger
Monoamine oxidase inhibitor effects
first created, irreversible or reversible, narrow therapeutic index, don’t metablise marmite, cheese, beer -> increase NE (last line)
Seretonin syndrome
MOAIs with SSRIs, TCAs or MDMA=synergetic toxicity-> delirium
Anxiety
psychological + physiological, increase heart rate, tremor, independent of external events (GAD, panic, phobia, PTSD, OCD)
SSRI example
Fluoxetine (used in depression and anxiety at lower dose)
Tricyclic antidepressant examples
Amitriptyline and nortriptyline
MAO inhibitor examples
Moclobemide - MAOa (NA+S), Selegeline - MAOb (NA+D), Phenelzine - non selective inhibitors
Ketamine in depression
treatment resistant depression, disinhibits GABAergic interneurons, blocks GABA release -> dopamine in hippocampus/VTA
Anxiety drugs
Propranolol and clonidine/guanfacine - NE modulators, prop reduce heart rate, clon decrease NE.
Benzodiazepines