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BMB > Dopaminergic Pharm > Flashcards

Dopaminergic Pharm Flashcards

1
Q

Synthesis of DA

A

Tyrosine–> DOPA–> DA–>NE
Minority of locations stop the synthesis at DA- substantial nigra

Tyrosine hydroxylase is the first enzyme and the rate limiting step

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2
Q

Reserpine

A

Depletes monamine transmitters (DA, NE, 5-HT) from aminergic neurons by inhibiting active uptake from cytoplasm into vesicles, making them vulnerable to MAOs.

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3
Q

DA Catabolism

A

HVA is a major DA metabolite- levels can be a measure of a DA system activity; lower HVA concentration indicates lower DA activity. DA metabolites are distinct from NE metabolites

Via MAO and COMT breakdown

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4
Q

DA systems

A

Nigrostriatal- from SN cell bodies to striatum terminals. 80% of brain DA is here. Degenerates in PD
Mesolimbic and mesocortical- from midbrain area (VTA) to nucleus accumbens and frontal cortex. Therapeutic targets for antipsychotics.
Hypothalamic- from arcuate nucleus to median eminence. Involved in regulation of hormone release from pituitary (AKA tuberoinfundibular)
Others- various interneurons

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5
Q

Compare and contrast DA and NE

A

Similar biosynthesis, vesicular uptake
Different reuptake pumps that end action
Very different postsynaptic receptors

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6
Q

Inhibits tyrosine hydroxylase in both DA and NE

A

Alpha-Me-tyrosine

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7
Q

What releases NT in both DA and NE systems

A

D-amphetamine

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8
Q

What inhibits reuptake in both DA and NE

A

Cocaine- in both the CNS and periphery
CNS- NAcc: Psychotropic
Periphery- in cardiovascular system. Can cause death in acute overdose, increase HR, vasoconstriction, and BP

Now medically sometimes used as a local anesthetic and vasoconstrictor

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9
Q

Desipramine

A

Inhibits reuptake in NE but not DA neurons

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10
Q

What is the major mechanism for ending DA and NE action

A

Reuptake pumps

So inhibiting reuptake pumps will increase the NT’s action

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11
Q

Parkinson’s pathology

A

Substantial loss of pigmented neurons in SN pars compacta by naked eye and substantial degeneration of the nigrostriatal tract by staining
Lewy bodies of assembled alpha-synuclein seen in degenerating neurons (protein misfolding like)

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12
Q

Main therapeutic breakthrough for PD

A

L-DOPA (levadopa) is therapeutic for motor symptoms and replenishes depleted striatal DA.
L-DOPA crosses the BBB 10x faster than DA, because its transport is facilitated by a carrier (DOPA is an amino acid)

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13
Q

schematic of PD functioning

A

DA neurons originating in the substantial nigra normally inhibit the GABAnergic output from the striatum, while cholinergic interneurons there exert and excitatory effect. So, without DA neuron inhibition, there is only excitation from Ach interneurons that allow the GABAnergic striatal neurons to fire

So the goal is to enhance DA function or decrease Ach function

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14
Q

Increases DA concentration in nigrostriatal neurons

A

Levodopa

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15
Q

DA receptor agonists

A

Pergolide, bromocriptine, ropinirole, pramipexole

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16
Q

Enhances DA release

A

Amantidine

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17
Q

Ach receptor antagonists

A

Certain centrally acting antimuscarinics like benztropine (can cross BBB)

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18
Q

D2/D3 selective DA receptor agonists

A

Pramipexole

Ropinirole

19
Q

First COMT inhibitor

A

Tolcapone
Similarity to carbidopa, blocks peripheral metabolism of levodopa to enhance delivery of levodopa to CNS

Then came entacapone one year later

20
Q

Levodopa + carbidopa

A

Sinemet (brand name) or atamet

Carbidopa cannot cross BBB- stops the breakdown there; DA in periphery gets side effects
L-DOPA crosses and goes to DA, which cannot cross BBB- get DA in CNS therapeutic

21
Q

Carbidopa

A

A peripherally acting inhibitor of DOPA decarboxylase
Helps lower the dose of L-DOPA given, since it allows for a greater concentration delivered to CNS- dose to the brain is still the same, so get less side effects in periphery

22
Q

MPTP

A

A neurotoxin in batches of meperidine that lesions the nigrostriatal DA neurons and produces clinical symptoms of PD
Gets broken down to MPP+, cannot cross BBB to get out, symptoms improved by L-dopa, selectively toxic to nigrostriatal DA neurons

23
Q

MAOI

A

Seligiline

Rasagiline

24
Q

Most serious side effect of long-term levodopa

A

Dyskinesias
As time goes on, L-DOPA loses efficacy and its therapeutic window narrows, due to ongoing loss of nigra DA neurons.
On-off nature of disease/treatment worsens
Combated by using continuous infusion of Sinimet as a gel into jejunum

25
Q

Current therapeutic strategy for PD

A

Postpone use of L-dopa + carbidopa until necessary and limit dosage of levodopa as much as possible
Start with very low dose and then titrate up to efficacy, use other drugs instead or in addition to, timing doses (L-dopa has a short half life), drug holidays

26
Q

What DA systems are antipsychotics targeting?

A

Mesolimbic and mesocortical via D2 receptor antagonism

Side effects from the other two pathways

27
Q

Adverse effects of typical antipsychotics

A

Motor, EPS- DA in nigrostriatal
Endocrine- in hypothalamic via D2
Muscarinic Ach receptors, 5-HT receptors, a1-adrenergic receptors, H1-histamine receptors, etc. use to lack of specificity for DA receptors

28
Q

Difference between MAO and COMT

A

MAO is mitochondrial

COMT is cytoplasmic

29
Q

Antipsychotics used are derivative of the two basic chemical structures

A 
Phenothiazines (chloropromazine)
And butyrophenones (haloperidol)
30
Q

Arguments against the DA hypothesis of psychosis

A

Therapeutic lag of antipsychotics- drugs reach their molecular targets within hours, but therapeutic effects appear only weeks later (possibly from altering post-synaptic receptor density)
Antipsychotic drugs affect other CNS targets, some with higher affinity than DA receptors
Atypical antipsychotics have lower activity at DA receptors than typical, but are still effective

31
Q

Typical antipsychotic drugs

A

Chlorpromazine
Fluphenazine
Haloperidol

DA receptor antagonists- D2 is best, but this receptor also mediates side effects

32
Q

Extrampyramidal DA side effects of typical antipsychotics

A

Acute dystonia- spasms of muscles of face, tongue, neck and back
Akathisia- motor restlessness
Parkinsonism- rigidity, tremor, shuffling gait
Tardive dyskinesia (late)- oral-facial involuntary movements, choreiform movements of extremities
Neuroleptic malignant syndrome- “haldol hypertheymia”, life threatening, hyperthermia, autonomic instability, muscle rigidity

33
Q

Endocrine DA side effects of typical antipsychotics

A

Increased prolactin- increased lactation, gynecomastia, etc
Decreased gonadotropins- inhibits ovulation, menses
Decreased corticosteroids- decreased adrenal corticosteroid secretion

34
Q

Adverse peripheral effects of phenothiazines

A

Anti cholinergic activity- dry mouth, blurred vision, constipation
Alpha-adrenergic blockade- orthostatic hypotension, inhibition of ejaculation
Endocrine- appetite increase, weight gain

35
Q

Some other uses of antipsychotics

A

Anti-emesis
Hyperkinetic movement disorders- huntington’s, Tourette’s
Alcoholic hallucinosis
Substance induced psychosis
Extreme agitation
Intractable hiccup
Huntington’s chorea- degeneration of striatal GABA neurons

Little therapeutic lag time for treating these

36
Q

Atypical antipsychotics differ from typical antipsychotics in that

A

Chemical structure
Much less EPS side effects at D2**
Few other DA side effects
Effective in some patients who fail to respond to typicals. May be better than typicals for negative symptoms.
Less potent at D2 than typicals- must be working at other targets like 5-HT, D4, A1, cholinergic ?

37
Q

Examples of atypicals

A 
Aripirazole
Clozapine
Olanzapine
Risperidone
Quetiapine
38
Q

Atypical antipsychotics advantage

Main disadvantage

A

Much wider therapeutic window than typicals

Metabolic abnormalities, notably higher death risk in pediatric and elderly patients. Diabetic risk is 2x and 3x in children

39
Q

Clozapine unique AE

A

Agranulocytosis

40
Q

Both typicals and atypicals

A

Have similar efficacy

All are lipid soluble, large Vd, well-absorbed orally, cross BBB, long half life- once/day dose

41
Q

Clinical implications/strategy for antipsychotics

A

Start with an atypical, wait for therapeutic lag, watch out for metabolic problems, be alert to poor compliance.
The right drug and dose is determined empirically over time for each individual

42
Q

Strongest genetic link to SZ to date is

A

Complement component C4A in MHC- may be involved in synaptic elimination during brain development
SZ end up having too many connections because of lack of pruning during critical periods of development

43
Q

Aripiprazole

Cariprazine

A

A partial agonist at D2 receptors- “a just right D2 activation”

New atypical that is a partial agonist at 5-HT1a, D2 and D3 and an inverse agonist at 5-HT2a, 5-HT2b, and H1 receptors

BMB (10 decks)

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