Dopaminergic Pharm Flashcards
Synthesis of DA
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
Reserpine
Depletes monamine transmitters (DA, NE, 5-HT) from aminergic neurons by inhibiting active uptake from cytoplasm into vesicles, making them vulnerable to MAOs.
DA Catabolism
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
DA systems
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
Compare and contrast DA and NE
Similar biosynthesis, vesicular uptake
Different reuptake pumps that end action
Very different postsynaptic receptors
Inhibits tyrosine hydroxylase in both DA and NE
Alpha-Me-tyrosine
What releases NT in both DA and NE systems
D-amphetamine
What inhibits reuptake in both DA and NE
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
Desipramine
Inhibits reuptake in NE but not DA neurons
What is the major mechanism for ending DA and NE action
Reuptake pumps
So inhibiting reuptake pumps will increase the NT’s action
Parkinson’s pathology
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)
Main therapeutic breakthrough for PD
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)
schematic of PD functioning
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
Increases DA concentration in nigrostriatal neurons
Levodopa
DA receptor agonists
Pergolide, bromocriptine, ropinirole, pramipexole
Enhances DA release
Amantidine
Ach receptor antagonists
Certain centrally acting antimuscarinics like benztropine (can cross BBB)
D2/D3 selective DA receptor agonists
Pramipexole
Ropinirole
First COMT inhibitor
Tolcapone
Similarity to carbidopa, blocks peripheral metabolism of levodopa to enhance delivery of levodopa to CNS
Then came entacapone one year later
Levodopa + carbidopa
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
Carbidopa
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
MPTP
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
MAOI
Seligiline
Rasagiline
Most serious side effect of long-term levodopa
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
Current therapeutic strategy for PD
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
What DA systems are antipsychotics targeting?
Mesolimbic and mesocortical via D2 receptor antagonism
Side effects from the other two pathways
Adverse effects of typical antipsychotics
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
Difference between MAO and COMT
MAO is mitochondrial
COMT is cytoplasmic
Antipsychotics used are derivative of the two basic chemical structures
Phenothiazines (chloropromazine) And butyrophenones (haloperidol)
Arguments against the DA hypothesis of psychosis
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
Typical antipsychotic drugs
Chlorpromazine
Fluphenazine
Haloperidol
DA receptor antagonists- D2 is best, but this receptor also mediates side effects
Extrampyramidal DA side effects of typical antipsychotics
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
Endocrine DA side effects of typical antipsychotics
Increased prolactin- increased lactation, gynecomastia, etc
Decreased gonadotropins- inhibits ovulation, menses
Decreased corticosteroids- decreased adrenal corticosteroid secretion
Adverse peripheral effects of phenothiazines
Anti cholinergic activity- dry mouth, blurred vision, constipation
Alpha-adrenergic blockade- orthostatic hypotension, inhibition of ejaculation
Endocrine- appetite increase, weight gain
Some other uses of antipsychotics
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
Atypical antipsychotics differ from typical antipsychotics in that
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 ?
Examples of atypicals
Aripirazole Clozapine Olanzapine Risperidone Quetiapine
Atypical antipsychotics advantage
Main disadvantage
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
Clozapine unique AE
Agranulocytosis
Both typicals and atypicals
Have similar efficacy
All are lipid soluble, large Vd, well-absorbed orally, cross BBB, long half life- once/day dose
Clinical implications/strategy for antipsychotics
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
Strongest genetic link to SZ to date is
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
Aripiprazole
Cariprazine
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
