NAME: Muhammad Suleman Urf Usama

REG NO: BPH213087

DATE: 30-10-2023
SEC# 02
SUBJECT:Pharmacology and Therapeutics

Submitted to: Ma’am RUBINA SHOUKAT

DOPAMINE RECEPTOR AGONISTS

Pharmacology of Bromocriptine
Table of Contents
Introduction:........................................................................................................................................2
Dopaminergic Receptors:....................................................................................................................2
General Mechanism of Action:...........................................................................................................2
Indications:..........................................................................................................................................3
A.Dopamine Agonists to Relieve Symptoms of Parkinson’s disease:...........................................3
B. Dopamine Agonists to Treat Side Effects of Antipsychotic Agents:........................................3
C. Dopamine Agonists to Treat Hyperprolactinemia:..................................................................3
D. Dopamine Agonists to Treat Hypertensive Emergency:..........................................................3
E. Dopamine Agonists to Treat Type 2 Diabetes:..........................................................................4
Adverse Effects of Dopamine Agonists:.............................................................................................4
A. Gastrointestinal Effects:.............................................................................................................4
B. Cardiovascular Effects:..............................................................................................................4
C. Dyskinesias:.................................................................................................................................4
D. Mental Disturbances:.................................................................................................................4
E. Miscellaneous:.............................................................................................................................4
Contraindications:...............................................................................................................................4
Dopamine Agonists Drugs:.................................................................................................................5
Pharmacology of Bromocriptine........................................................................................................5
Introduction:........................................................................................................................................5
Brand Name:....................................................................................................................................5
Generic Name:.................................................................................................................................5
Chemical formula:...........................................................................................................................5
Indications:..........................................................................................................................................5
Pharmacodynamics:............................................................................................................................5
Mechanism of Action:.........................................................................................................................5
Pharmacokinetics:...............................................................................................................................6
Half life:................................................................................................................................................6
Therapeutic use:..................................................................................................................................6
Toxicity:...............................................................................................................................................6
Adverse effects:....................................................................................................................................6
Refrences:.............................................................................................................................................6
 DOPAMINE RECEPTOR
AGONISTS
Introduction:
Drugs acting directly on dopamine receptors may have a beneficial effect in addition to that
of levodopa. Unlike levodopa, they do not require enzymatic conversion to an active
metabolite, have no potentially toxic metabolites, and do not compete with other substances
for active transport into the blood and across the blood-brain barrier. Moreover, drugs
selectively affecting certain (but not all) dopamine receptors may have more limited adverse
effects than levodopa. A number of dopamine agonists have antiparkinsonism activity. The
older dopamine agonists (bromocriptine and pergolide) are ergot (ergoline) derivatives and
are rarely if ever used to treat parkinsonism. Their side effects are of more concern than
those of the newer agents (pramipexole and ropinirole).

Dopaminergic Receptors:
Dopamine receptors are expressed in the central nervous system, specifically in the
hippocampal dentate gyrus and subventricular zone. Dopamine receptors are also expressed
in the periphery, more prominently in the kidney and vasculature,
There are five types of dopamine receptors, which include D1, D2, D3, D4, and D5. Each
receptor has a different function and is found in different locations.
The function of each dopamine receptor:
 D1: memory, attention, impulse control, regulation of renal function, locomotion
 D2: locomotion, attention, sleep, memory, learning
 D3: cognition, impulse control, attention, sleep
 D4: cognition, memory, fear, impulse control, attention, sleep
 D5: decision making, cognition, attention, renin secretion

General Mechanism of Action:

All dopamine receptors couple to G proteins. The D1 and D5 receptors couple to the Gs family of G
proteins, and therefore an agonist binding to these receptors activate adenylyl cyclase and thus
stimulates cAMP synthesis. The D2, D3, and D4 receptors couple to the Gi/o family of G proteins,
and agonists inhibit adenylyl cyclase and thus cAMP synthesis. Increased intracellular cAMP
activates protein kinase A, which phosphorylates many downstream protein targets, including 32-kDa
dopamine and cAMP-regulated phosphoprotein (DARPP-32), ionotropic glutamate receptor, and
GABA receptors. Because the DARPP-32 inhibits protein phosphatase 1, this phosphoprotein
regulates the phosphorylation state and thus activity of various protein kinase A target proteins and
neuronal activity.
Dopamine receptors act not only as monomers but also as homodimers, heterodimers or
heteromers.D1-D2 receptor dimers, as well as D5 receptors, are coupled to the Gq family of G
proteins that activate phospholipase C and increase intracellular calcium concentrations. Also,
dopamine receptors may act via G protein-independent mechanisms, such as direct interactions of
dopamine receptors with ion channels and cAMP-independent regulation of protein kinase B (Akt),
inhibiting glycogen synthase kinase 3 activity. The latter signaling pathway has been suggested as an
intracellular signaling mechanism for the development of schizophrenia, bipolar disorders, and other
behavioral changes involved in dopamine receptor activity.

Indications:
A.Dopamine Agonists to Relieve Symptoms of Parkinson’s disease:
Various dopamine agonists can increase dopamine activity in the brain. The majority of dopamine
agonists used in Parkinson disease are D2 dopamine receptor agonists. Ergot derivatives, older
dopamine agonists, interact not only with dopamine D1 and D2 receptors but many other
neurotransmitter receptors such as serotonin
and adrenergic receptors. Newer dopamine
agonists, which are non-ergot agents, have a
high affinity to dopamine D2 and D3 receptors.
Amantadine is not a dopamine agonist. It may
inhibit the reuptake of dopamine and increase
the synthesis and release of dopamine.
Amantadine may inhibit D2 dopamine
receptors and N-methyl-D-aspartate (NMDA)-
type glutamate receptors.

B. Dopamine Agonists to Treat Side

Effects of Antipsychotic Agents:
Extrapyramidal symptoms similar to those in Parkinson disease are common in the patients treated
with antipsychotic agents, especially first-generation drugs. The blockade of the D2 dopamine
receptors in the nigrostriatal pathway is the suggested mechanism responsible for the extrapyramidal
side effects. Administration of dopamine agonists or levodopa to treat antipsychotic-induced
Parkinson syndrome may antagonize antipsychotic treatment and exacerbate psychotic symptoms.
Atypical, second-generation antipsychotic agents exhibit lower affinity for D2 dopamine receptors
and have activity at serotonin receptors, which is thought to reduce extrapyramidal side effects.

C. Dopamine Agonists to Treat Hyperprolactinemia:

Dopamine gets released from the hypothalamus. It binds to dopamine D2 receptors and inhibits the
synthesis and secretion of prolactin from the anterior
pituitary gland. Antipsychotic agents, which have
dopamine antagonist properties that block dopamine
binding to its receptors. By eliminating the inhibitory
effects of dopamine on prolactin secretion,
hyperprolactinemia is a very common adverse effect of
many antipsychotics.

D. Dopamine Agonists to Treat Hypertensive Emergency:

The D1 receptors are present on the smooth muscle of the renal, mesenteric, and coronary arteries and
peripheral blood vessels in the skeletal muscle. Dopamine action on these receptors produces
decreased blood pressure by reducing peripheral vascular resistance due to vasodilation. Dopamine
agonists used to treat hypertensive emergencies do not show an affinity for D2 receptors.
E. Dopamine Agonists to Treat Type 2 Diabetes:
The FDA has approved bromocriptine for the
treatment of type 2 diabetes. Bromocriptine is
an agonist to the D2 receptor and an antagonist
to the D1 receptor. Because insulin release gets
inhibited by stimulation of the D2 receptor and
inhibition of the D1 receptor, the
molecular/cellular mechanism of action of
bromocriptine in insulin release and improved
glycemic control in type 2 diabetes is still
unclear. It is, however, suggested that
bromocriptine may improve glycemic control
by normalizing hypothalamic circadian
activities.

Adverse Effects of Dopamine Agonists:

A. Gastrointestinal Effects:
Anorexia and nausea and vomiting may occur when a dopamine agonist is introduced and can be
minimized by taking the medication with meals.Constipation, dyspepsia, and symptoms of reflux
esophagitis may also occur. Bleeding from peptic ulceration has been reported.

B. Cardiovascular Effects:
Postural hypotension may occur, particularly at the initiation of therapy. Painless digital vasospasm is
a dose-related complication of long-term treatment with the ergot derivatives (bromocriptine or
pergolide). When cardiac arrhythmias occur, they are an indication for discontinuing treatment.
Peripheral edema is sometimes problematic. Cardiac valvulopathy may occur with pergolide.

C. Dyskinesias:
Abnormal movements similar to those introduced by levodopa may occur and are reversed by
reducing the total dose of dopaminergic drugs being taken.

D. Mental Disturbances:
Confusion, hallucinations, delusions, and other psychiatric reactions are potential complications of
dopaminergic treatment and are more common and severe with dopamine receptor agonists.

E. Miscellaneous:
Headache, nasal congestion, increased arousal, pulmonary infiltrates, pleural and retroperitoneal
fibrosis, and erythromelalgia are other reported adverse effects of the ergot-derived dopamine
agonists. Cardiac valvulopathies have occurred with pergolide. Erythromelalgia consists of red,
tender, painful, swollen feet and, occasionally, hands, at times associated with arthralgia; symptoms
and signs clear within a few days of withdrawal of the causal drug. In rare instances, an uncontrollable
tendency to fall asleep at inappropriate times has occurred, particularly in patients receiving
pramipexole or ropinirole; this requires discontinuation of the medication.

Contraindications:
Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent
myocardial infarction, or with active peptic ulceration.
The ergot-derived agonists are best avoided in patients with peripheral vascular disease.
Dopamine Agonists Drugs:
 Bromocriptine
 Pergolide
 Pramipexole
 Ropinirole
 Rotigotine

Pharmacology of Bromocriptine
Introduction:
Bromocriptine mesylate is a semisynthetic ergot alkaloid derivative with potent dopaminergic
activity.Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to
hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome.

Brand Name: Cycloset,Parlodel

Generic Name: Bromocriptine
Chemical formula: C32H40BrN5O5

Indications:
For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders
and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct
therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy
in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor
complications. Bromocriptine has also been used off-label to treat restless legs syndrome and
neuroleptic malignant syndrome.

Pharmacodynamics:
Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of
pharmacologic effects. This semisynthetic ergot derivative exhibits potent agonist activity on
dopamine D2-receptors. It also exhibits agonist activity on 5-hydroxytryptamine (5-HT) 1D, dopamine
D3, 5-HT1A, 5-HT2A, 5-HT1B, and 5-HT2C receptors, antagonist activity on α2A-adrenergic, α2C, α2B, and
dopamine D1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D4 and 5-
HT7 receptors. The tuberoinfundibular pathway of the brain originates in the hypothalamus and
terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary
from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits
prolactin secretion making bromocriptine an effective agent for treating disorders associated with
hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at
5-HT1B and 5-HT2B receptors.

Mechanism of Action:
The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with
Gi proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase,
which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca 2+ from
intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition
of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl
cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases
MAPK/ERK kinase phosphorylation.

Pharmacokinetics:
 Aborption: Bromocriptine and its metabolites appear in the blood as early as 10 minutes
following oral administration and peak plasma concentration are reached within 1-1.5 hours.
Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect
achieved after 8 hours.
 Metabolism: Completely metabolized by the liver, primarily by hydrolysis of the amide
bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic.
Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces
via biliary secretion.
 Excretion: Parent drug and metabolites are almost completely excreted via the liver, and
only 6% eliminated via the kidney.

Half life: 2-8 hours

Therapeutic use:
This drug has been widely used to treat Parkinson’s disease in the past but is now rarely used for this
purpose, having been superseded by the newer dopamine agonists. The usual daily dose of
bromocriptine for parkinsonism varies between 7.5 and 30 mg. To minimize adverse effects, the dose
is built up slowly over 2 or 3 months depending on response or the development of adverse reactions.

Toxicity:
Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common
adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps,
nasal congestion, diarrhea, and hypotension.

Adverse effects:
 Blurred vision.
 chest pain or discomfort.
 difficulty in speaking.
 dizziness or lightheadedness, especially when getting up suddenly from a lying
or sitting position.
 double vision.
 feeling, seeing, or hearing things that are not there.
 feeling of constant movement of self or surroundings.

Refrences:
Katzung, B.G., Masters, S.B. and Trevor, A.J., Eds. (2012) Basic and Clinical
Pharmacology. 12th Edition, McGraw-Hill Medical, New York.