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Flashcards in Drug Actions in Synaptic Transmission Deck (20):

Describe the 5 steps involved in neurotransmission. Include the sites where each step takes place.

1. neurotransmitter synthesis occurs in the neuron; requires specific precursor molecules to enter across the plasma membrane and rate limiting enzymes
2. vesicular storage occurs at the cell body to protect from cytosolic enzymes
3. synaptic release occurs at the pre-synaptic plasma membrane via interaction of SNAREs on vesicle and plasma membranes and influx of calcium causing depolarization
4. binding to receptor on the pre- or post-synaptic membranes
5. termination of action occurs via reuptake (pre-, post- or glial depending on where reuptake receptor is located), diffusion out of synaptic cleft, or metabolic degradation/transformation. Mechanism of termination depends on the drug.


Describe drug targets/actions during NT synthesis.

1. inhibition of enzymes involved
2. precursor availability (ex: low tryptophan, high AA diet of AA that use the same transporter => reduced serotonin production)
3. increase precursor availability to increase neurotransmission


Distinguish between noradrenergic and peptidergic neurotransmission with regard to the 5 steps. How do differences between the 2 processes influence strategies for their pharmacological manipulation?

1. NT synthesis: mRNA => rough ER => pre-propeptide => cleavage by peptidases => active neuropeptide
2. vesicular storage into large, dense core vesicles; packaging occurs in ER; hard to target
3. release requires longer duration of calcium influx b/c dense core vesicles are farther away from synapse; typically are co-released with other NTs when nerve terminal is active; still affected by membrane ion altering drugs
4. binding is complex and not well-known; difficult to cross BBB; non-peptide agonists/antagonists have been developed
5. termination is mainly by peptidase-mediated degradation; however, peptidases are not specific targets.

1. harder to target vesicles
2. similarly affected by calcium influx drugs b/c of co-release
3. difficult to get peptide drugs across BBB so must use non-peptide; binding to receptors is not well-known
4. hard to target peptidase-mediated termination b/c peptidases are not specific and can cause many side effects


Describe the effects of metyrosine on adrenergic neurotransmission.

MECHANISM - competitive inhibition of tyrosine hydroxylase (prevents tyrosine => DOPA; reduction of NT)


Describe the effects of reserpine on adrenergic neurotransmission.

MECHANISM - inhibits VMAT uptake of MAOs (inhibits vesicular transport => reduction of NT)


Describe the effects of bretylium on adrenergic neurotransmission.

INDICATION - ventricular arrhythmia
MECHANISM - inhibits action potential and calcium-dependent vesicular fusion (in NT and NPs; reduction of NT)


Describe the effects of cocaine on adrenergic neurotransmission.

INDICATION - analgesia in surgery
MECHANISM - blocks MAO reuptake receptor (increased NT in synapse)


Describe the effects of tricyclic antidepressants on adrenergic neurotransmission.

INDICATION - depression
MECHANISM - blocks MAO reuptake receptor (increased NT in synapse)


Describe the effects of monoamine oxidase inhibitors (MAOIs) on adrenergic neurotransmission.

INDICATION - depression
MECHANISM - blocks MAO-mediated degradation of NT in cytoplasm after reuptake => increased NT


Describe the effects of SSRIs on adrenergic neurotransmission.

INDICATION - depression
MECHANISM - selectively blocks serotonin reuptake receptors; increased NT


Describe the effects of amphetamines (or ephedrine) on adrenergic neurotransmission.

INDICATION - narcolepsy; ADHD
MECHANISM - reverse MAO reuptake transporters => increased NT


Describe the effects of naloxone/naltrexone on adrenergic neurotransmission.

INDICATION - opioid overdose or addiction
MECHANISM - non-peptide opioid receptor antagonist; decreases NT action


Describe the effects of ACE inhibitors (lisinopril) on adrenergic neurotransmission.

MECHANISM - inhibits peptide cleavage of angiotensin I to angiotensin II


Describe the effects of phenylephrine on adrenergic neurotransmission.

INDICATION - hypOtension during surgery
MECHANISM - direct agonist of adrenergic receptors; resistant to COMT degradation in synapse; increases NT


Describe the effects of L-DOPA on adrenergic neurotransmission.

INDICATION - parkinson's
MECHANISM - precursor loading for DOPA decarboxylase conversion of L-DOPA to dopamine; increased NT


Describe the effects of carbidopa on adrenergic neurotransmission.

INDICATION - parkinson's
MECHANISM - blocks DOPA decarboxylase; reduced dopamine; only acts in PNS to blocks systemic effects of L-DOPA administration; conserves beneficial effects in CNS


Describe the effects of Tyramine on adrenergic neurotransmission.

INDICATION - ingested in diet; not therapeutic
MECHANISM - when ingested while on MAOIs, avoids first pass metabolism => increased in blood => competes for NE reuptake receptor => blocks NE reuptake => increased NE in synapse


Describe drug targets/actions during vesicular storage.

inhibition of vesicular transport causes degradation of NT in cytosol => NT depletion


Describe drug targets/actions during release.

1. toxins to degrade SNAREs prevents vesicular fusion in the specific cell type that takes it up
=> botulinum toxin degrades SNAREs in cholinergic neurons => loss of AcH release => muscle paralysis; used to treat muscle spasms
=> tetanus toxin degrades SNAREs in motor neurons => increases muscle tone => lockjaw

2. drugs can stimulate NT release in a calcium-independent manner
=> amphetamine enters via synaptic reuptake transporters and reverses direction of NT transport => releases NT without Ca influx and no voltage change


Describe drug targets/actions during binding to receptors.

1. direct binding offers most selective drug action
2. indirect binding to pre-synaptic receptors can alter calcium influx