1. ST MARRY COLLEGE OF PHARMACY
(APPROVED BY AICTE ,AFFILIATED TO JNTU.
NEAR RFC, DESHMUKHY,POCHAMPALLI HYD.)
2. Introduction
Nomenclature
Indications
Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
Drug Interactions
Adverse Drug Reactions
Pharmacodynamics
Mechanism of Action
Efficacy
Pharmacogenomics
Special Population Study
3. Bromocriptine is a semisynthetic ergot
alkaloid derivative
It is a Sympatholytic, D2-Dopamine Receptor
Agonist, which activates post-synaptic
dopamine receptors
4. o Brand Names:
Parlodel® (Novartis) – Capsule, Tablet
Cycloset™ (VeroScience) - Quick-release
formulation
o Generic Name/International Non-Propriety Name
(INN):
Bromocriptine Mesylate
5. Parlodel®
5 mg Capsules – Brown
and White
2.5 mg Tablets – White
and Round
Cycloset™
0.8 mg tablets are
white and round,
imprinted with "C" on
one side and "9" on
the other
6. Formula: C32H40BrN5O5
Molecular Weight:
Average - 654.595
Monoisotopic - 653.221282062
Chemical Name/Systematic IUPAC Name is:
(5′α)-2-bromo-12′-hydroxy-5′-(2-methylpropyl)-
3′,6′,18-trioxo-2′-(propan-2-yl) ergotamine
8. Acromegaly (Parlodel®)
Bromocriptine alone or as adjunctive therapy with
pituitary irradiation or surgery, reduces serum Growth
Hormone by 50% or more in approximately ½ of patients
treated, although not usually to normal levels
Parkinson's Disease (Parlodel®)
Bromocriptine is indicated in the treatment of the signs
and symptoms of Parkinson's disease
As adjunctive treatment to levodopa (alone or with a
peripheral decarboxylase inhibitor - carbidopa)
9. Type 2 Diabetes (Cycloset™)
Approved by FDA in 2009
Cycloset is a quick-release oral formulation of
bromocriptine mesylate
Act as an adjunct to diet and exercise to improve glycemic
control in adults with Type 2 diabetes
Act on circadian neuronal activities within the
hypothalamus to reset abnormally elevated hypothalamic
drive for increased plasma glucose, triglyceride, and free
fatty acid levels in fasting and postprandial states in
patients with insulin-resistant
10.
11.
12. Bromocriptine tablets or capsules are taken orally
with water or food
Bioavailability
28 % (parlodel®)
65-95% (cycloset™)
Bromocriptine and its metabolites appear in the
blood as early as 10 minutes after oral
administration
14. 90-96% bound to serum albumin
Volume of Distribution = 61 liter
Human Serum Albumin Molecule
15. Extensive hepatic first-pass metabolism primarily by:
Hydrolysis of the amide bond to produce lysergic acid
and a peptide fragment
Hydroxylation (oxidation and conjugation)
(Metabolites are inactive and non-toxic)
Bromocriptine is extensively metabolized by the
cytochrome P450 system, specifically CYP3A4
16. 85% in feces (via biliary elimination)
Bromocriptine and its metabolites are excreted primarily
via the liver into the bile
6% in Urine
Only 6% is eliminated via the kidney
Half-life elimination (t½) :
2-8 hrs (initial phase) – Parent drug
8-20 hrs (terminal phase) - Metabolites
17. Tolerability to Bromocriptine may be reduced by
alcohol
The hypotensive effects of bromocriptine may be
additive with drugs used for hypertension
Bromocriptine is both a substrate and an inhibitor of
CYP3A4
Co-administering drugs which are strong inhibitors
and/or substrates of CYP3A4 can increase
bromocriptine plasma levels
20. Bromocriptine & D2 Dopamine Receptors
Bromocriptine stimulates centrally-located dopaminergic
receptors resulting in a number of pharmacologic effects
Various subtypes of Dopamine receptors are D1, D2, D3, D4,
and D5. They are divided into:
D1-like receptors (D1 and D5)
D2-like receptors (D2, D3, and D4)
Bromocriptine has potent agonist activity of D2 like
receptors
Bromocriptine is partial agonist or antagonist of D1 like
receptors
21. Bromocriptine – agonist drug binds to the post-
synaptic receptors and stimulates action potential
Postsynaptic D2 stimulation is primarily responsible
for the anti-parkinsonian effect of dopamine agonists
Presynaptic D2 stimulation causes neuroprotective
effects
Bromocriptine & D2 Dopamine Receptors
22. Bromocriptine also exhibits agonist activity on
Serotonin receptors (5-hydroxytryptamine, 5-HT
receptors)
Binding affinity on: 5-HT1D >> dopamine D3 >> 5-HT1A >>
5-HT2A >> 5-HT1B >> 5-HT2C receptors
It exhibits partial agonist activity at receptor 5-HT2B
It exhibits antagonist activity on α2A-adrenergic,
α2C, and α2B receptors
It inactivates 5-HT7 receptors
Bromocriptine & Serotonin 5-HT Receptors
23. The dopamine D2 receptor is a
7-transmembrane G-protein
coupled receptor associated
with Gi proteins
In lactotrophs, stimulation of
dopamine D2 receptor causes
inhibition of adenylyl cyclase,
which decreases intracellular
cAMP concentrations and
blocks IP3-dependent release
of Ca2+ 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
24.
25. Additionally, receptor activation blocks
phosphorylation of p42/p44 MAPK and decreases
MAPK/ERK kinase phosphorylation. Inhibition of MAPK
appears to be mediated by c-Raf and B-Raf-
dependent inhibition of MAPK/ERK kinase. Dopamine-
stimulated growth hormone release from the
pituitary gland is mediated by a decrease in
intracellular calcium influx through voltage-gated
calcium channels rather than via adenylyl cyclase
inhibition
Stimulation of dopamine D2 receptors in the
nigrostriatal pathway leads to improvements in
coordinated muscle activity in those with movement
disorders e.g Parkinson’s disease
26.
27. In treatment of Type 2 diabetes, Bromocriptine is
unique in that it does not have a specific receptor that
mediates its action on glucose and lipid metabolism.
Rather, its effects are mediated via resetting of
dopaminergic and sympathetic tone within the CNS.
Quick-release formulation of bromocriptine (Cycloset)
is thought to act on circadian neuronal activities within
the hypothalamus to reset abnormally elevated
hypothalamic drive for increased plasma glucose,
triglyceride, and free fatty acid levels in fasting and
postprandial states in patients with insulin-resistant
28.
29.
30. The cytochrome P450 (CYP) family of liver enzymes
is responsible for the metabolism of bromocriptine
DNA variations in genes that code for these enzymes
will affect the metabolism of bromocriptine
31. Certain foods can also mimic the effects of genetic
variations
One of the most common examples is grapefruit
juice, which is an inhibitor of CYP3A4
In people regularly drinking grapefruit juice,
bromocryptine will not be metabolized at the same
rate as in most people
33. ADHD
Attention-deficit/hyperactivity disorder (ADHD)is a common
neurobehavioral disorder that has been related to the brain’s chemistry
and anatomy
ADHD is a persistent pattern of inattention and/or
hyperactivity/impulsivity that occurs more frequently and more
severely than is typically seen in people at comparable levels of
development
Why ADHD?
1- Research shows that ADHD subjects have lower levels of dopamine
2- Adults ADHD shows a reduced response to the drug
methylphenidate which increases brain dopamine levels than those
without ADHD
3- Based on the therapeutic action of dopaminergic agents in treating
attention deficit hyperactivity disorder (ADHD), ADHD symptoms may
be related to a reduction in central dopaminergic activity
4- Bromocriptine - Dopamine Receptor Agonist may reduce ADHD
symptoms by increasing levels of dopamine?
34. AISRS
The AISRS total score consists of 18 items from the original
Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS)
which were derived based on Diagnostic and Statistical Manual-
4 (DSM-IV) criteria for ADHD. The ADHD-RS include 9 items that
address symptoms of inattention and 9 items that address
symptoms of impulsivity and hyperactivity. Each item is rated
from 0 to 3. The AISRS total score can range from 0 to 54. A
higher score corresponds to a worse severity of ADHD.
The AISRS inattentive subscale score consists of 9 items from
the original ADHD-RS which address inattention. Each item is
rated from 0 to 3. The AISRS inattentive subscale score can
range from 0 to 27. A higher score corresponds to a worse
severity of ADHD inattentiveness.
35.
36.
37. Drug Name: Parlodel®
Formulation: Capsule
Route of Administration: Oral
Dose : 5mg
Dosing Interval: Once a day
38. BACKGROUND: A Study to Test the Safety and Efficacy
of Bromocriptine in Patients With ADHD
TITLE: A Phase II Randomized, Double-Blind, Placebo-
Controlled, Clinical Trial to Study the Safety and
Efficacy of Bromocriptine for Adult Patients With
Attention Deficit Hyperactivity Disorder (ADHD)
SUMMARY: The purpose of this study is to investigate
the safety and efficacy of Bromocriptine for Attention
Deficit Hyperactivity Disorder (ADHD) when compared
to standard treatment- methylphenidate.
39. STUDY TYPE: Interventional
STUDY DESIGN:
Allocation: randomized
End-point classification: Safety and Efficacy Study
Masking: double-blind( subject and investigator)
Primary Purpose: Treatment
STUDY ARM
Experimental: Bromocriptine
Active Comparator: Methylphenidate
Placebo
40. PRIMARY OUTCOME MEASURES:
Mean Change From Baseline in the Adult Attention
Deficit Hyperactivity Disorder Investigator Symptom
Rating Scale (AISRS)
Total Score After 4 Weeks of Treatment [Time Frame:
after 4 weeks of treatment ] [ Designated as safety
issue: No]
SECONDARY OUTCOME MEASURE:
Mean Change From Baseline in the AISRS Inattentive
Subscale Score After 4 Weeks of Treatment [ Time
Frame: after 4 weeks of treatment ] [ Designated as
safety issue: No ]
41. RECRUITMENT
ENROLLMENT: n= 99
ELIGIBILITY
Ages Eligible for Study: 18 Years to 55 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
CRITERIA
Inclusion Criteria:
Patient is between 18 and 55 years of age (inclusive)
Patient is an adult with a current DSM-IV diagnosis of
ADHD of inattentive or combined subtype, as
assessed via a structured interview using the ACDS
and AISRS
Females of child-bearing potential must use
acceptable methods of birth control during the study
and for 1 month post-therapy
42. Exclusion Criteria
Patient has a history of a neurological disorder resulting in
ongoing impairment
Patient has a lifetime history of a psychotic disorder, bipolar
disorder, or post-traumatic stress disorder
Patient has evidence of ongoing depression
Patient is sensitive or allergic to methylphenidate
Patient has glaucoma
Patient has a previous history of narrowing or blockage of the
GI tract
Patient has a history of a sleep disorder (e.g., insomnia, sleep
apnea, nightmares, or night terrors) within 6 months prior to
screening
Patient has a history of a cardiovascular disorder within 6
months prior to screening
Patient has moderate or severe persistent asthma
Patient has a history of substance abuse or dependence not in
sustained full remission for at least one year according to
DSM-IV
Patient has taken part in a research study within the past 30
days of signing informed consent
43. Proposed start-up date: February 2013
Proposed completion date: February 2015
STUDY SPONSOR: Novartis
INVESTIGATOR: Dr. Adam Brahman
44. o DRUG BANK Open Data Drug & Target Database
http://www.drugbank.ca/drugs/DB01200
o Bromocriptine- Cycloset®, Parlodel®
http://reference.medscape.com/drug/parlodel-bromocriptine-343124
o Bromocriptine in type 2 diabetes mellitus
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152192/
o Human Genome Project Information
http://www.ornl.gov/sci/techresources/Human_Genome/medicine/phar
ma.shtml
o American Medical Association – Pharmacogenomics http://www.ama-
assn.org/ama/pub/physician-resources/medical-science/genetics-
molecular-medicine/current-topics/pharmacogenomics.page
o Bromocriptine Adverse Reactions from Clinical Trials
http://www.druglib.com/druginfo/parlodel/side-effects_adverse-
reactions/
o http://www.pbm.va.gov/Clinical%20Guidance/Drug%20Monographs/Brom
ocriptine%20monograph.doc
o http://psychiatryresidents.find-forum.net/t418-normalization-of-
risperidone-induced-hyperprolactinemia-with-the-addition-of-aripiprazole
Editor's Notes
ergoline alkaloids found in ergot fungi
A sympatholytic (or sympathoplegic) drug is a medication which inhibits the postganglionic functioning of the sympathetic nervous system (SNS
It is indicated in patients with prolactin-secreting adenomas (tumors)
Surgery, radiotherapy,somatostatin analogues and dopamine agonists act at the level of the pituitary adenoma
Levodopa is a medicine that the brain converts to dopamine
Carbidopa is a medicine (called a decarboxylase inhibitor) that, when taken with levodopa, helps prevent the levodopa from converting to dopamine outside the brain
Hydrolysis of the amide bond to produce lysergic acid and a peptide fragment
After single oral doses, the mean elimination half-life from plasma varies from 2 to 8 hours for the parent drug and 8 to 20 hours for the metabolites
such as azole antimycotics, HIV protease inhibitors . The concomitant use of erythromycin, other macrolide antibiotics or octreotide has been shown to increase bromocriptine plasma levels. The bioavailability of bromocriptine increased by approximately 40% when it was administered together with octreotide
People who carry variations in CYP 3A4 genes often do not metabolize bromocriptine at the same rate or extent as in most people. This can influence response in many ways; Less active or inactive forms of CYP 3A4 enzymes that are unable to break down and efficiently eliminate bromocriptine from the body can cause drug overdose in patients