2. - CNS neurotransmitter controlling emotion, movement,
reward mechanism, and metabolic precursor of
norepinephrine and epinephrine
( C9H11NO3)
- is a nonessential amino acid the body makes from
another amino acid called phenylalanine. It is a building
block for several important brain chemicals called
neurotransmitters, including epinephrine, norepinephrine,
and dopamine. Neurotransmitters help nerve cells
communicate and influence mood. Tyrosine also helps
produce melanin, the pigment responsible for hair and
skin color. It helps in the function of organs responsible
for making and regulating hormones, including the
adrenal, thyroid, and pituitary glands. It is involved in the
structure of almost every protein in the body.
3.
4. 1. NIGROSTRIAT PATHWAY
- involve in the production of movements
(tremors and muscle rigidity)
2. MESOCORTICAL PATHWAY
- motivation and emotional response
3. MESOLIMBIC PATHWAY
- pleasure and reward behaviour
- heavily implicated in addiction
4. TUBEROHYPOPHYSEAL PATHWAY
- regulation of prolactin
5. - it is a progressive neurodegenerative
illness characterized by tremor, muscular
rigidity, bradykinesia and postural imbalance.
6.
7. LEVODOPA is a metabolic precursor of
dopamine. Dopamine itself does not cross the
blood-brain barrier, but its immediate
precursor, Levodopa, is actively transported
into the CNS and is converted to dopamine in
the brain. Large doses of levodopa are
required, because much of the drug is
decarboxylated to dopamine in periphery,
resulting nausea, vomiting, cardiac
arrhythmias and hypotension.
8. • CARBIDOPA diminishes the metabolism of
levodopa in the GI tract and peripheral
tissues; thus, increases the availability of
levodopa to the CNS.
• Addition of carbidopa lowers the dose of
levodopa needed by FOUR-TO-FIVE FOLD,
and decreases the side effects.
9. 1. Levodopa, USP (S)-2-amino-3-(3,4-
dihydroxyphenyl) propanoic acid
- white/almost white crystalline powder
- slightly soluble in water, acidic and basic
solution
- insoluble in alcohol, chloroform, and
ether
- pKa=9.9 and 11.8
10. 2. Carbidopa, USP (S)-3-(3,4-
dihydroxyphenyl)-2-hydrazyl-2
- white crystalline powder
- slightly soluble in water
- pKa = 7.8
- metabolized into a-methyl-3-methoxy-4-
hydroxyphenylpropionic acid and a-methyl-3,4-
dihydroxyphenylpropionic acid.
11. - Are utilized to prolong the plasma half-life of
levodopa or block the striatal metabolism of
DA.
Selegiline an irreversible MAO-B inhibitor
potentiates levodopa by blocking its
metabolism by MAO and improve the “wearing-
off” effect of levodopa.
Rasagiline is five times more potent than
selegiline.
12. 1. Selegiline Hydrochloride, USP. (R)-N-methyl-N-(1-
phenylpropan-2-yl)prop-2-yn-1-amine hydrochloride
(ELDEPRYL)
- off-white powder, soluble in water and
methanol
-pKa = 7.4
2. Rosagilline Mesylate, (R)-N-(pro-2-ynyl)-2,3-dihydro-1H-
inden-1-amine methanesulfonate (AZILECT)
- white to off-white powder, soluble in water or
ethanol and slightly soluble in isopropanol
13. a. Pergolide- binds at D2-type and 5-HT2B
receptor and is withdrawn in the market because
it induce valvular heart disease by acting 5-HT2B
receptor
b. Carbegoline- binds at D2-like receptors, 5-
HT2A and 5-HT2B receptors. In US, tx for
hyperprolactinemia and tx for PD in other
countries.
c. Bromocriptine- agonist at D2-like receptors,
14. 1. Bromocriptine Mesylate, USP (6aR,9R)-5-bromo-
N-((2R,5S,10aS,10bS0-10b-hydroxy-5-isobutyl-2-
isopropyl-3,6-dioxooctahydro-2H-
oxazolo[3,2a]pyrrolo[2,1c]pyrazin-2-yl)-7-methyl-
4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-
carboxamide methanesulfonate (PARLODEL)
- white solid, soluble in ethanol and water
- pKA = 6.6 and 15, half-life 0.3 hours
2. Carbigoline, (6aR,9R,10aR)-7-allyl-N-(3-
(dimethylamino)propyl)-N-(ethylcarbomoyl)-4,6,6a,
7,8,9,10a-octahydroindolo[4,3-fg]quinoline-9-
carboxamide (DOSTINEX)
- white powder, soluble in alcohol, chloroform,
and N,N-dimethylformamide, insoluble in water
15. a. Pramipexole- D2 and D3 agonist but no
appreciable affinity for D1, D5, 5-HT2A, and 5-
HT2B
b. Ropinirole- low affinity to 5-HT2A, 5-HT2B, and
D1-like receptors.
Preparations:
1. Apomorphine Hydrochlorite, USP (6aR)-6-methyl-
5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolone-
10,11-diol hydrochloride (APOKYN)
-white or off-white powder or crystal soluble in
hot water
- pKa = 8.92
16. 2. Pramipexole Dihydrochloride, (S)-2-amino-6-
propylamino-dihydrochloride (MIRAPEX)
- white to off-white powder soluble in water,
slightly soluble in methanol and
ethanol, and insoluble in
dichloromethane
-tx signs and symptoms of idiopathic PD and
restless leg syndrome (RLS), alone or
with combination with levodopa.
3. Ropinirole Hydrochloride, 4-(2-(dipropylamino)
ethyl)indolin-2-one hydrochloride (REQUIP)
- white to pale greenish yellow powder, very
soluble to water
- t1/2= 3 hrs , tx RLS
18. • Catechol O-methyltransferase (COMT)
inhibitors allow a larger amount of levodopa to
reach the brain, which raises dopamine levels
there. They help provide a more stable,
constant supply of levodopa, which makes its
beneficial effects last longer.
• COMT inhibitors are always taken in
combination with levodopa. They do not have
any effect on Parkinson's disease symptoms by
themselves.
Entacaptone
- - does not penetrate BBB
- - only inhibits peripheral COMT
- - less motor fluctuations in combine with carbidopa
- - lack of toxicity
22. Schizophrenia is a mental disorder caused by
some inherent dysfunction of the brain
characterized by delusions, abnormal behaviour,
hallucinations and thought disorders (positive
symptoms), as well as loss of normal emotions,
abilities, and motivation (negative symptoms).
24. PHENOTHIAZINE
- (1876) by Badische Anilin und Soda Fabrik
(BASF) chemist, H. Caro and A Bernstein (1883)
High-Potency
Typical
Antipsychotics
- More EPS
- Less histaminic
(sedation),
alpha
adrenergic
(orthostasis),
and
anticholinergic
(dry mouth)
effect
Low-Potency Typical
Antipsychotics
- Less EPS but
more H1, a1, and
muscarinic side
effects
27. 1. Chlorpromazine Hydrochloride, USP 2-
chloro-10-[3-
(dimethylamino)propyl]phenothiazine
(THORAZINE)
- White to slightly creamy white, odourless, bitter
tasting, crystalline powder
- pKa= 9.43
- Minor substrate of CYP1A2 and 3A4, major
CYP2D6
- Strong inhibitor of CYPD2D6 weak CYP2E1
- Strong anticholinergic, sedative and potent
antiemetic
- EPS is low
28. 2. Thioridazine Hydrochloride, USP 10-[2-(1-
methyl-2-piperidyl)ethyl]-2-
(methylthio)phenothiazine (MELLARIL)
- White to slightly yellow, crystalline or micronized
powder, odourless, insoluble in H2O and
dehydrated alcohol.
- pKa= 9.66
- Low EPS and less antiemetic activity
- Tx of schizophrenic patients who fail to respond
adequately to treatment with other antipsychotic
drugs
3. Perphenizine, USP 2-[4-[3-(2-chloro-10H-
phenothiazin-10-yl)propyl]piperazin-1-yl]ethanol
29. 4. Trifluoperazine Hydrochloride 10-[3-(4-Methyl-
1piperazin)propyl-[2-(trifluoromethyl)phenothiazin
dihydrochloride (STELAZINE)
- Tx and management of schizophrenia and short
term tx of nonpsychotic anxiety
5. Thiothixine, USP N,N-
dimethyl-9-[3-(4-methyl-1-
piperazinyl)propylidene]thioxa
nthene-2-sulfonamide
(NAVANE)
-Major substrate of CYP1A2,
CYP1A2 inducers
-Management of withdrawn,
apathetic schizophrenic
30. Haloperidol
- Janssen Laboratories (1958)
- Blocks dopamine receptors in the brain with little
adrenergic or muscarinic activity
- Available as slow-release depot form
- 100-fold as potent as Chlorpromazine but have
increased ability to induce parkinson-like and other
extrapyramidal effects
31. 1. Haloperidol, USP 4-[4-(p-chlorophenyl)-4-
hydroxypiperidinol]-4-flourobutyrophenone
(HALDOL)
- Odorless white to yellow crystalline powder
- Rapidly absorbed with high bioavailability
- Excreted slowly in urine and feces
- Long term tx of psychosis and specially useful to
patients who are noncompliant with their drug
treatment
32.
33. 2. Haloperidol Decanoate 4-[4-4-chlorophenyl)-4-
hydroxypiperidinol]-4-fluorobutyrophenone
decanoate (HALDOL DECANOATE)
- Prodrug of haloperidol
- Metabolized in liver and peak plasma
concentration of 3-9 days
- Tx of long term maintenance in schizophrenia,
psychoses especially paranoid, and other mental
and behavioral problems
34. 4. Pimozine, USP 1-[1-[4,4-
bis(p-fluorophenyl)butyl]-4-
piperidyl]-2-
benzimidazolinone (ORAP)
- white to creamy white
solid pKa=9.42
- Critical drug for Gilles de
la Tourette disorder who
cannot tolerate
haloperidol
3. Droperidol, USP 1-1-[3-(p-fluorobenzoyl)propyl]-1-
2[3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone
(INAPSINE)
- With inhalation anesthetics, produce peripheral
vasodilation and hypotension
35. ∞ATYPICAL ANTIPSYCHOTIC AGENTS∞
- a.k.a Second-Generations, includes
Clozapine, Olanzapine, Quetiapine,
Risperidone, Aripiprazole, Ziprasidone
- First line treatment of schizoprenia
- Provides greater reduction o positive and
negative schizoprenia and improve cognitive
function
36. 1. Clozapine 8-chloro-11-(4-
methyl-1-piperazinyl)5H-
dibenzol[b,e][1,4]diazepine
(CLOZARIL)
- Yellow crystalline powder,
slightly soluble in water
- N-oxidation and N-
demethylation, major
metabolite
- T1/2=8hrs
- Only use for refractory cases
of schizophrenia
- Caution: patients with history
of seizures because of high
risk of mortality to elders with
dementia-related psychosis
