Tuesday 31 May 2011

Sildenafil


Sildenafil Basic Facts:
  • Type 5 phosphodiesterase (PDE5) inhibitor (competitive binding agent).
  • Prevents breakdown of cyclic GMP.
  • The molecular structure of sildenafil is similar to that of cyclic GMP.
  • Used predominantly in treatment of male erectile dysfunction
  • Prolongs penile corporeal smooth muscle relaxation.
  • Sildenaphil is only effective when cyclic GMP is present in penile smooth muscle.
Sildenafil Clinical Uses:
  • Altitude sickness
  • Male erectile dysfunction
  • Pulmonary artery hypertension
Sildenafil Adverse Reactions:
  • Dyspepsia
  • Facial flushing
  • Headache
  • Nasal congestion
  • Priapism
  • Visual disturbance of blue/green colour discrimination
Sildenafil Drug Interactions:
  • Alpha-blockers - hypotension
  • Cimetidine - increases sildenafil concentrations.
  • Erythromycin - increases sildenafil concentrations.
  • Nitric oxide donors - ie amyl nitrite (Popper)
  • Organic nitrates
  • Protease inhibitors - increases sildenafil concentrations.
Sildenafil Contraindications:
  • Conditions predisposing to priapism.
  • Hypotension
  • Nitrate use
  • Recent cerebrovascular accident
  • Recent myocardial infarction
  • Retinitis pigmentosa
  • Severe hepatic dysfunction
  • Severe renal impairment
Sildenafil Pharmacokinetics:
  • Absorption reduced if taken with a high fat meal - delays maximum plasma concentration by 1 hour, maximum concentration reduced by 1/3rd.
  • Metabolized by liver enzymes.
  • Excreted by both the liver & kidneys.
Tags: Altitude Sickness - cGMP - Cyclic GMP - Erectile Dysfunction - Phosphodiesterase - Pulmonary Hypertension - Sildenafil - Sildenaphil
Posted by Medicalchemy
Medicalchemy Group: History of Medicine - Images - Mnemonics - Syndromes - Acute Medicine - Anaesthesiology - Anatomy - Anthropology - Biochemistry - Cardiology - Dentistry - Dermatology - Drug ADR - Drugs - Embryology -
Emergency Medicine - Endocrinology - Epidemiology - Family Medicine - Forensic Medicine - Gastroenterology - Genes - Genetics - Geriatrics - Gynecology - Haematology - Health Informatics - Hepatology - Immunology - Infection - Intensive Care - Medical Dictionary - Medical Education - Medical Statistics - Metabolic Medicine - Microbiology - Nephrology - Neuroanatomy - Neuroscience - Nuclear Medicine - Nutrition - Obstetrics - Occupational Health - Oncology - Ophthalmology - Orthopaedics - Otolaryngology - Paediatrics - Palliative Care - Parasitology - Pathology - Pharmacology - Physiology - Proteomics - Psychiatry - Public Health - Radiology - Respiratory - Rehabilitation - Rheumatology - Sports Medicine - Surgery - Toxicology - Tropical Medicine - Urology - Vascular - Virology.

Saturday 30 October 2010

Prucalopride (Brand Name Resolor)


Prucalopride Basic Facts:
  • Brand name Resolor - developed by Movetis.
  • New drug for treatment of constipation.
  • Acts as a selective, high affinity 5-HT4 receptor agonist.
  • Targets the impaired motility associated with chronic constipation - leading to a normalisation of bowel movements.
  • Indicated for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.
  • Median time to the first spontaneous bowel movement is 2 1/2 hours.
Actions:
  • First in class dihydrobenzofurancarboxamide.
  • Selective, high affinity serotonin (5-HT4) receptor agonist.
  • Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation.
  • The 5-HT4 receptor stimulation induces colonic mass movements.
  • Prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors - differentiating it from tegaserod & cisapride.
Pharmacokinetics:
  • Prucalopride is rapidly absorbed & extensively distributed.
  • Elimination is mainly unchanged in the urine.
  • The renal excretion of unchanged prucalopride involves both passive filtration & also active secretion.
  • Plasma clearance averages 317 ml/min.
  • Terminal half-life is 24–30 hours.
  • Steady-state drug concentrations are reached within 3–4 days.
Dosing:
  • 2 mg once daily.
  • Exceeding the daily dose of 2 mg is not expected to increase efficacy.
Drug Interactions:
  • Low interaction potential.
  • Therapeutic concentrations of prucalopride do not affect the CYP-mediated metabolism of drugs.
Side Effects:
  • Most common are headache & gastrointestinal symptoms.
  • GI symptoms - Abdominal pain, diarrhoea, nausea - about 20% patients.
  • These effects occur mostly at the start of therapy and tend to disappear within a few days.
  • Prucalopride has no significant effect on QT interval.
Tags: 5-HT4 receptor antagonist - Constipation - Prucalopride - Resolor - Serotonin
Posted by Medicalchemy
Medicalchemy Group: History of Medicine - Images - Mnemonics - Syndromes - Acute Medicine - Anaesthesiology - Anatomy - Anthropology - Biochemistry - Cardiology - Dentistry - Dermatology - Drug ADR - Drugs - Embryology -
Emergency Medicine - Endocrinology - Epidemiology - Family Medicine - Forensic Medicine - Gastroenterology - Genes - Genetics - Geriatrics - Gynecology - Haematology - Health Informatics - Hepatology - Immunology - Infection - Intensive Care - Medical Dictionary - Medical Education - Medical Statistics - Metabolic Medicine - Microbiology - Nephrology - Neuroanatomy - Neuroscience - Nuclear Medicine - Nutrition - Obstetrics - Occupational Health - Oncology - Ophthalmology - Orthopaedics - Otolaryngology - Paediatrics - Palliative Care - Parasitology - Pathology - Pharmacology - Physiology - Proteomics - Psychiatry - Public Health - Radiology - Respiratory - Rehabilitation - Rheumatology - Sports Medicine - Surgery - Toxicology - Tropical Medicine - Urology - Vascular - Virology.

Liraglutide (Brand Name Victoza)


General Liraglutide Facts:
  • Liraglutide (NN2211).
  • Marketed under the brand name Victoza.
  • Developed by Novo Nordisk for the treatment of type 2 diabetes.
  • Approved by the European Medicines Agency (EMEA) on July 3, 2009.
  • Approved by the U.S. Food and Drug Administration (FDA) on January 25, 2010.
Chemistry:
  • Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist.
  • It has 97% amino acid sequence homology to endogenous human GLP-1(7-37).
Actions & Pharmacodynamics:
  • Long-acting glucagon-like peptide-1 (GLP-1) analog.
  • GLP-1(7-37) represents <20%>
  • Liraglutide improves control of blood glucose.[4]
  • It reduces meal-related hyperglycemia (for 12 hours after administration).
  • It increases insulin secretion, delays gastric emptying, & suppresses prandial glucagon secretion.
  • It lowers blood triglyceride levels.
  • Liraglutide like GLP-1(7-37), activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein (Gs) in pancreatic beta cells.
  • Liraglutide thus increases beta cell intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations.
  • The insulin secretion reduces as blood glucose concentrations fall & approach euglycemic levels.
  • Glucagon secretion is also decreased by liraglutide in a glucose-dependent manner.
  • The mechanism of blood glucose lowering also involves a delay in gastric emptying.
  • As liraglutide acts in a glucose-dependent manner, it shows negligible risk of hypoglycemia.
  • Liraglutide also decreases appetite & maintains body weight.[3]
Pharmacokinetics:
  • GLP-1(7-37) has a half-life of 1.5–2 minutes due to degradation by dipeptidyl peptidase IV (DPP-IV) & neutral endopeptidases (NEP).
  • Liraglutide is stable against metabolic degradation by the above described peptidases giving a much longer plasma half-life of 13 hours following subcutaneous administration.
ADRs (Side Effects):
  • Liraglutide has only mild & transient side effects, mainly gastrointestinal.
  • Possible cancer risk (see below).
ADRs - Cancer:
  • Review by the FDA advisory panel (April 2, 2009) regarding the significance of malignant C-cell carcinoma & thyroid C-cell focal hyperplasia in rats & mice.
  • Victoza has a Black Box Warning, "Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk".[1]
  • The FDA have noted that serum calcitonin was slightly increased in liraglutide patients but still within normal ranges.
  • Ongoing monitoring for 15 years in a cancer registry has been instituted.[2]
Dosing:
  • The Victoza pen comes in doses of 0.6 mg, 1.2 mg, & 1.8 mg.
  • Given once a day, at any time, independent of meals.
  • Best to be injected around the same time of day, once the most convenient time of day has been found.
  • Subcutaneous injection in abdomen, thigh or upper arm.
  • Recommended starting dose is 0.6 mg once daily.
  • After at least one week, the dose should be increased to a maintenance dose of 1.2 mg.
  • Some patients may benefit from an increase in dose from 1.2 mg to 1.8 mg, based on clinical response after at least one week on 1.2 mg dosing.
Dosing - Combination Therapies:
  • Metformin - No dose adjustment.
  • Metformin + thiazolidinedione - No dose adjustment.
  • Sulphonylurea - Sulphonylurea dose adjustment may be needed to reduce risk of hypoglycaemia.
  • Metformin + sulphonylurea - Sulphonylurea dose adjustment may be needed to reduce risk of hypoglycaemia.
References:
1] - Victoza Package Insert Date of Issue: January 2010 Version: 1
2] - N Engl J Med, 362:774
3] - Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes. Diabetes Care. Oct 2008
4] - http://diabetes.webmd.com/news/20080924/new-diabetes-drug-liraglutide-works (Sept 2008)

Tags: Cancer - Diabetes Mellitus - EMEA - GLP-1 - GLP-1(7-37) - Glucagon-like peptide-1 - Hypoglycaemia - Insulin - Liraglutide - Metformin - Novo Nordisk - Peptidase - Sulphonylurea - Victoza
Posted by Medicalchemy
Medicalchemy Group: History of Medicine - Images - Mnemonics - Syndromes - Acute Medicine - Anaesthesiology - Anatomy - Anthropology - Biochemistry - Cardiology - Dentistry - Dermatology - Drug ADR - Drugs - Embryology -
Emergency Medicine - Endocrinology - Epidemiology - Family Medicine - Forensic Medicine - Gastroenterology - Genes - Genetics - Geriatrics - Gynecology - Haematology - Health Informatics - Hepatology - Immunology - Infection - Intensive Care - Medical Dictionary - Medical Education - Medical Statistics - Metabolic Medicine - Microbiology - Nephrology - Neuroanatomy - Neuroscience - Nuclear Medicine - Nutrition - Obstetrics - Occupational Health - Oncology - Ophthalmology - Orthopaedics - Otolaryngology - Paediatrics - Palliative Care - Parasitology - Pathology - Pharmacology - Physiology - Proteomics - Psychiatry - Public Health - Radiology - Respiratory - Rehabilitation - Rheumatology - Sports Medicine - Surgery - Toxicology - Tropical Medicine - Urology - Vascular - Virology.