CLIN 514- Recent Trends In Therapeutics Course INSTRUCTOR: Professor Peivand Pirouzi

1. A Presentation By
Romeela Maryam
Olayinka A. Awofodu

2.  Introduction
• Nomenclature
• Indications
 Pharmacokinetics
• Absorption
• Distribution
• Metabolism
• Excretion
• Drug Interactions
 Adverse Drug Reactions
 Pharmacodynamics
• Mechanism of Action
• Efficacy
 Pharmacogenomics
 Special Population Study
 Question Session

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®  Cycloset™
5 mg Capsules – Brown 0.8 mg tablets are
and White white and round,
imprinted with "C" on
one side and "9" on
the other
2.5 mg Tablets – White
and Round

6.  Chemical Name/Systematic IUPAC Name is:
(5′α)-2-bromo-12′-hydroxy-5′-(2-methylpropyl)-
3′,6′,18-trioxo-2′-(propan-2-yl) ergotaman
Formula: C32H40BrN5O5
Molecular Weight:
Average - 654.595
Monoisotopic - 653.221282062

7.  Hyperprolactinemia-Associated Dysfunctions
(Parlodel®)
 It is indicated for the treatment of dysfunctions
associated with hyperprolactinemia:
• Amenorrhea
• Galactorrhea
• Infertility
• Hypogonadism

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

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

13. Peak plasma concentration:
parlodel® 1-3 hrs
(for within 1hr fasting)
cycloset™ 1.5-2 hrs
(High-fat meal)

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

18.  Nausea (49%)
 Hypotension (30%)
 Headache (19%)
 Dizziness (17%)
 Less than 10 percent:
 Abdominal cramps, Anorexia, Constipation, Dyspepsia,
Dysphagia, Epigastric pain, GI hemorrhage, Vomiting,
Drowsiness, Fatigue, Faintness, Hallucinations, Visual,
Insomnia, Lightheadedness, Nightmares, Paranoia, Psychosis,
Seizure, Vertigo, Arrhythmias, Bradycardia, Hypertension,
Mottled skin, Orthostasis, Vasospasm, Palpitations, Pericardial
effusions, Raynaud's syndrome exacerbation, Syncope,
Blepharospasm,……

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 & D2 Dopamine Receptors
 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

22. Bromocriptine & Serotonin 5-HT Receptors
 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

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

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

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

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

32. Adult ADHD
{Attention Deficit Hyperactivity Disorder}

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.

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