Dopaminergic Pharm

Question 1

Synthesis of DA

Answer 1

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

Question 2

Reserpine

Answer 2

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

Question 3

DA Catabolism

Answer 3

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

Question 4

DA systems

Answer 4

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

Question 5

Compare and contrast DA and NE

Answer 5

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

Question 6

Inhibits tyrosine hydroxylase in both DA and NE

Answer 6

Alpha-Me-tyrosine

Question 7

What releases NT in both DA and NE systems

Answer 7

D-amphetamine

Question 8

What inhibits reuptake in both DA and NE

Answer 8

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

Question 9

Desipramine

Answer 9

Inhibits reuptake in NE but not DA neurons

Question 10

What is the major mechanism for ending DA and NE action

Answer 10

Reuptake pumps

So inhibiting reuptake pumps will increase the NT’s action

Question 11

Parkinson’s pathology

Answer 11

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)

Question 12

Main therapeutic breakthrough for PD

Answer 12

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)

Question 13

schematic of PD functioning

Answer 13

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

Question 14

Increases DA concentration in nigrostriatal neurons

Answer 14

Levodopa

Question 15

DA receptor agonists

Answer 15

Pergolide, bromocriptine, ropinirole, pramipexole

Question 16

Enhances DA release

Answer 16

Amantidine

Question 17

Ach receptor antagonists

Answer 17

Certain centrally acting antimuscarinics like benztropine (can cross BBB)

Question 18

D2/D3 selective DA receptor agonists

Answer 18

Pramipexole

Ropinirole

Question 19

First COMT inhibitor

Answer 19

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

Then came entacapone one year later

Question 20

Levodopa + carbidopa

Answer 20

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

Question 21

Carbidopa

Answer 21

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

Question 22

MPTP

Answer 22

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

Question 23

MAOI

Answer 23

Seligiline

Rasagiline

Question 24

Most serious side effect of long-term levodopa

Answer 24

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

Question 25

Current therapeutic strategy for PD

Answer 25

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

Question 26

What DA systems are antipsychotics targeting?

Answer 26

Mesolimbic and mesocortical via D2 receptor antagonism | Side effects from the other two pathways

Question 27

Adverse effects of typical antipsychotics

Answer 27

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

Question 28

Difference between MAO and COMT

Answer 28

MAO is mitochondrial | COMT is cytoplasmic

Question 29

Antipsychotics used are derivative of the two basic chemical structures

Answer 29

``` Phenothiazines (chloropromazine) And butyrophenones (haloperidol) ```

Question 30

Arguments against the DA hypothesis of psychosis

Answer 30

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

Question 31

Typical antipsychotic drugs

Answer 31

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

Question 32

Extrampyramidal DA side effects of typical antipsychotics

Answer 32

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

Question 33

Endocrine DA side effects of typical antipsychotics

Answer 33

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

Question 34

Adverse peripheral effects of phenothiazines

Answer 34

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

Question 35

Some other uses of antipsychotics

Answer 35

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

Question 36

Atypical antipsychotics differ from typical antipsychotics in that

Answer 36

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 ?

Question 37

Examples of atypicals

Answer 37

``` Aripirazole Clozapine Olanzapine Risperidone Quetiapine ```

Question 38

Atypical antipsychotics advantage | Main disadvantage

Answer 38

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

Question 39

Clozapine unique AE

Answer 39

Agranulocytosis

Question 40

Both typicals and atypicals

Answer 40

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

Question 41

Clinical implications/strategy for antipsychotics

Answer 41

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

Question 42

Strongest genetic link to SZ to date is

Answer 42

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

Question 43

Aripiprazole Cariprazine

Answer 43

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