bromocriptine for prof pievand
TRANSCRIPT
BROMOCRIPTINE
A Presentation By
Romeela Maryam
Olayinka A. Awofodu
Introduction• Nomenclature• Indications
Pharmacokinetics• Absorption• Distribution• Metabolism• Excretion• Drug Interactions
Adverse Drug Reactions Pharmacodynamics
• Mechanism of Action• Efficacy
Pharmacogenomics Special Population Study Question Session
INTRODUCTION
Bromocriptine is a semisynthetic ergot alkaloid derivative
It is a Sympatholytic, D2-Dopamine Receptor Agonist, which activates post-synaptic dopamine receptors
Nomenclature
o Brand Names: Parlodel® (Novartis) – Capsule, Tablet Cycloset™ (VeroScience) - Quick-release
formulation
o Generic Name/International Non-Propriety Name (INN):Bromocriptine Mesylate
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
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) ergotaman
Chemical Information
Indications Hyperprolactinemia-Associated
Dysfunctions (Parlodel®)
It is indicated for the treatment of dysfunctions associated with hyperprolactinemia:
• Amenorrhea • Galactorrhea• Infertility • Hypogonadism
Indication 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)
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
Indication
Indication
PHARMACOKINETICS
Absorption
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
Peak plasma concentration:
parlodel® 1-3 hrs (for within 1hr fasting)
cycloset™ 1.5-2 hrs
(High-fat meal)
Absorption
Distribution
90-96% bound to serum albumin Volume of Distribution = 61 liter
Human Serum Albumin Molecule
Metabolism 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
Excretion
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
Drug Interactions
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
ADVERSE DRUG REACTIONS
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,……
PHARMACODYNAMICS
PHARMACODYNAMICS
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
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
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
Mechanism Of Action 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
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
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
PHARMACOGENOMICS
PHARMACOGENOMICS
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
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
SPECIAL POPULATION STUDY
Adult ADHD{Attention Deficit Hyperactivity
Disorder}
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?
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.
NEW INDICATION Drug Name: Parlodel® Formulation: Capsule Route of Administration: Oral Dose : 5mg Dosing Interval: Once a day
Hypothetical CLINICAL STUDY 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.
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
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 ]
RECRUITMENTENROLLMENT: n= 99ELIGIBILITY
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
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
Proposed start-up date: February 2013 Proposed completion date: February
2015 STUDY SPONSOR: Novartis INVESTIGATOR: Dr. Adam Brahman
REFERENCESo DRUG BANK Open Data Drug & Target Database http://
www.drugbank.ca/drugs/DB01200o Bromocriptine- Cycloset®, Parlodel® http://reference.medscape.com
/drug/parlodel-bromocriptine-343124o 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/pharma.shtmlo 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/Bromocriptine%20monograph.doc
o http://psychiatryresidents.find-forum.net/t418-normalization-of-risperidone-induced-hyperprolactinemia-with-the-addition-of-aripiprazole
QUESTIONS SESSION
THANK YOU