pharmacology Flashcards
4 ways you can inactivate NA once released from pre synaptic terminal
- neuronal uptake (major)
- metabolism by the pre synaptic terminal by monoamine oxidase
- extraneuronal uptake
- post synaptic metabolism by monoamine oxidase and COMT
action of cocaine at synapses
prevents neuronal reuptake of NA at the pre-synaptic terminal –> and therefore there is increased activation of the receptors –> increased response when nerves being activated
action of amphetamine/ephedrine at synapses
indirectly acting sympathomimetics –> displace NA from the vesicles even with no activation by an AP –> non-exocytotic release of NA and activation of response
pathway for making NA
tyrosine –> L-DOPA –> dopamine –> NA –> adrenaline
pathways that dopamine is involved in…
- movement
- behaviour
- dependence
- pituitary function –> prolactin secretion
how does cocaine become addictive
linked to its dopaminergic action
which NT does cocaine act on
- blocks dopamine, NA, and serotonin uptake
- blocks Na channels
which areas of the brain are involved in the extrapyradmidal motor system
corpus striatum
substantia nigra
globis pallidum
Subthalamic nucleus
thalamus
motor cortex
which NTs are involved in the extrapyramidal motor system
dopamine
glutamate
GABA
what causes parkinson’s disease (in general - NTs)
degeneration of dopaminergic pathways
treatment for parkinson’s disease
L-DOPA (precusor for dopamine that can piggy back on an amino acid carrier) and peripheral dopamine decarboxylase inhibitor (so that the L-DOPA is only used in the CNS and not wasted in the PNS)
what causes Huntington’s disease (in general - NTs)
GABA deficiency
treatment for huntington’s
GABA agonist
dopamine antagonists
how can a NT be both excitatory and inhibitory at different places
depends on which receptors are present
what is the difference between local and general anaesthetic
local - regionalised inhibition of pain/sensory pathways with no loss of consciousness
general - depresses cortical processing of pain/sensory signal with a loss of consciousness
what is analgesia
stops sensitization of the sensory nerve endings by prostaglandins
how do local anaesthetic agents work?
they reversibly block conduction of nerve impulses at the axonal membrane
what are the 3 broad types of local anaesthetics?
aminoesters (procaine)
aminoamides (lignocaine)
benzocaine
difference in duration and metabolism between aminoesters and aminoamides
aminoesters - shorter acting, and are hydrolysed by esterases
aminoamides - longer acting and are metabolised through hepatic metabolism
what is the proportion of the blockade of sensory and motor functions in a nerve with local anaesthetics
when sensory 100% blocked, motor only ~25% blocked
where do local anaesthetics bind to
the transmembrane domain (IC) of the Na channel
What are the two mechanisms of the local anaesthetics getting to the I/C transmembrane domain of the Na channel
1) hydrophobic (benzocaine)
2) hydrophillic (aminoesters and aminoamides)
what is the hydrophobic mechanism of local anaesthetics blocking the Na channel
crosses the lipid membrane (no matter whether the channel is activated or not) as it is mostly in the non-ionized form. It then binds to and blocks the channel, preventing Na influx and therefore preventing threshold and AP
what is the hydrophilic mechanism of local anaesthetics blocking the Na channel
crosses through the membrane predominantly in the uncharged form. Once IC it promotes the formation of the charged from. The charged form binds to the Na channel only when the Na channel is open (needs activated channels) –> prevents Na influx and therefore prevents threshold and AP
which mechanism of the way local anaesthetics work is faster
the hydrophobic way - eg. benzocaine
do local anaesthetics change the resting membrane potential of the axon?
no
which nerves are the most sensitive to local anaesthetics? Motor, sensory or Autonomic?
sensory (smallest)
methods of administration of general anaesthetics
inhalation
intravenous
respiratory side effects of general anaesthetics
- impaired ventilation
- depression of respiratory centre
- obstruction of airways
- retention of secretions
cardiovascualr side effects of GA
- decreased vasomotor centre function
- depress contractility
- peripheral vasodilation
- cardiac arrythmias
- inadequate response to fall in BPor CO
2 theories of how GA works
1) Lipid theory - accumulation of GA in the lipid space causes expansion –> squashes the proteins –> cant work very well
2) inhibition of excitatory receptors or enhancement of inhibitory receptors
what is thought to cause epilepsy
too little inhibitory input to motor nerve or too much excitatory input to motor nerve
treatment of epilepsy
- benzodiazepines (enhance inhibitory (GABA) receptor activity)
- phenytoin (limits excitatory nerve activation
others
what are benzodiazepines used for
epilepsy
anxiety
sleep disorders - insomnia
premedication
acute alcohol withdrawal
which drugs can be used to treat anxiety
benzodiazepines
non-benzodiazepines (B-adrenoceptor antagonists, Buspirone, zopiclone, zolpidem)
barbiturates
why are barbituates bad?
- very toxic
- low therapeutic index
- induction of liver enzymes
- abrupt withdrawal can cause death
- highly addictive
why are benzodiazepines better than barbituates
less depression of respiratory and cardiovascular centres less dependence considered safe in overdose only increase the frequency of Cl ion channel opening not increase the duration of the opening
how do benzodiazepines work
they act on the GABA A receptor by binding to the allosteric site modulating: increasing the affinity of the R for GABA –> increased Cl- influx into the cell
(increasing the number of times the channel opens)
what are the effects of allosteric modulators
- ceiling effect of inhibitors –> increased therapeutic window
- positive modulation of endogenous agonist rather than continuous effect of exogenous agonist
- great receptor subtype selectivity possible
what are the unwanted side effects of benzodiazepines
drowsiness
confusion
impaired coordination
tolerance - increased dose needed over time
dependence
what does benzodiazepines interact with
alcohol, antihistamines and barbituates
what is potency
the relative position of the dose-effect curve along the dose axis
how do barbituates work
bind the orthostatic site of the GABA A receptor causing increased Cl- ion influx
what is drug efficacy
the ability of a drug to do the right thing
what is pharmacological efficacy
the strength of the receptor activation
what is clinical efficacy
the strength of the beneficial effect
what are 2 non benzodiazepines that act as hypnotics
zolpidem and zopiclone
what is a non benzodiazepine that acts as an anxiolytic
buspirone
explain the NTs in the extrapyramidal motor system
- inhibitory dopamine released from substantia nigra to corpus striatum
- corpus striatum release stimulatory ACh onto GABA neuron which stimulates substantia nigra
what causes Parkinson’s disease
degeneration of the dopaminergic neurons of the substantia nigra to corpus striatum leading to reduced dopamine levels
what are the motor symptoms of Parkinson’s disease
tremor
rigidity of limbs
bradykinesia
impairment of postural reflexes
facial muscles impassive and no blinking
monotonous, hypophonic speech
parkinson’s gait (shuffling and fasiculations)
decreased manual dextretiy
what are some of the non-motor signs of Parkinson’s disease
olfactory deficiencies
bowel and bladder problems
cognitive deficiencies
depression
raised anxiety levels
sleep disturbances
fatigue
pain
sexual dysfuncion
what are the “first signs” of Parkinson’s disease
loss of smell and bowel and bladder problems
how much of the dopaminergic neurons need to be degenerated for you to show symptoms of Parkinson’s disease
~80%
what are ways in which we can replace the dopamine in the substantia nigra
- increase dopamine synthesis
- increase dopamine release
- give dopamine receptor agonists
- reduce dopamine metabolism
why do we give cholinergic antagonists with dopamine replacement
to try and restore the dopaminergic/cholinergic balance in the striatum
why do we give L-DOPA and not straight dopamine to Parkinson’s patients
because dopamine doesnt cross the BBB causes you to vomit violently
what is in levodopa
amino acid isomer of L-DOPA and a peripheral dopamine decarboxylase inhibitor
why do we give a peripheral dopamine decarboxylase inhibitor with L-DOPA administration
to prevent dopamine conversion in the periphery, so the majority can get into the brain
what does peripheral conversion of L-DOPA cause
nausea, vomiting, orthostatic hypotension, cardiac dysrhythmias, pupil dilation (avoid giving to patients with glaucoma)
why is their a debate on when to start treatment of Parkinson’s with Levodopa
- requires some functional dopaminergic neurnos (so cant start too late)
- effectiveness declines with time (cant start too early)
what are the central side effects of levodopa
visual and auditory hallucinations
abnormal motor movements
mood changes
depression and anxiety
what are the drug interactions of levodopa
vitamin B6
MAO inhibitors
inhalational anaesthetic
anticonvulsants and neuroleptics
other than Levodopa, what are the other drugs available for Parkinsons patients
- dopamine agonists (may be preferred in younger patients)
- DDC inhibitor (in gut and periphery)
- MAO(B) inhibitor (reduce metabolism of dopamine)
- COMT inhibitor (reduction metabolism of L-DOPA)
- Amantadine (anti-viral - enhances release of dopamine)
which treatment option for Parkinson’s may delay disease progression? and how?
MAO(B) inhibitors - may reduce formation of free radicals that degenerate the dopaminergic neurons
What is drug dependence
state where drug use becomes compulsive taking precedance over other needs
what is drug abuse
use of illicit substances characterised by recurrent and clinically significant adverse consequences
why do people become dependent on drugs
- rewarding effect (positive reinforcement, craving)
- habituation or adaptation (rely on drug to feel well desire to avoid negative symptoms)
Which part of the brain is involved in “dependence”?
nucleus accumbens and ventral pallidum
what are the key NTs involved in modulating dopaminergic transmission
ACh
Serotonin
NA
GABA, glutamate
opoids
what causes you to die with an overdose of amphetamine
peripheral consequences - hyperthermia, tachycardia, increased BP, vascular collapse
what causes the suppression of appetite when taking amphetamines
linked to its effect on serotonin
what is the action of MDMA
releases dopamine and serotonin
how does LSD work
it is an agonist of 5HT2 receptors
- activates autoreceptors on 5-HT neurons in raphe
action of caffeine
adenosine antagonist
phsophodiesterase inhibitor
how does ethanol cause depression of the CNS
- inhibits Ca channel opening
- enhances GABA action
- inhibits glutamate receptors
why do you get marked tolerance of ethanol
heavy drinking causes the activation of liver enzymes and therefore it is eliminated quicker
what is the effect of cannibis
inhibits adenylate cyclase –> therefore inhibition of transmission
what are the first, second and third generation drugs for treating depression
1st - tricyclic antidepressants and MAO inhibitors
2nd - SSRIs and SSNRI
3rd - novel monoaminergic drugs, and non-monoaminergic drugs
what is the pharmacological action of tricyclic antidepressants
- inhibit neuronal uptake of NA and serotonin
- antagonise alpha adrenoceptors, muscurinic receptors, histamine receptors and serotonin receptors
- membrane stabilising activity at high concentrations
why are tricyclic antidepressants considered “not as good” as newer antidepressants
- poor selectivity
- narrow therapeutic window
- longish half lives (gradual accumulation)
what is the pharmacological action of MAO inhibitors
increase the levels of serotonin, NA and DA
which antidepressant has a “cheese reaction”
irreversible MAO inhibitor
what are the advantages of SSRIs
- selective for serotonin uptake
- few adrenergic, histaminergic and cholinergic actions
- high therapeutic index
what are the 2 precautions when prescribing SSRIs
- can cause suicidal tendencies in young adolescents
- can cause serotonin syndrome if combined with MAOIs and TCAs
