Pharmacology of Disopyramide

Pharmacology of Disopyramide

Indication	For the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, ventricular pre-excitation and cardiac dysrhythmias. It is a Class Ia antiarrhythmic drug.
Pharmacodynamics	Disopyramide is an antiarrhythmic drug indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia that are life-threatening. In man, Disopyramide at therapeutic plasma levels shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs.
Mechanism of action	Disopyramide is a Type 1A antiarrhythmic drug (ie, similar to procainamide and quinidine). It inhibits the fast sodium channels. In animal studies Disopyramide decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors.
Absorption	Nearly complete
Volume of distribution	Not Available
Protein binding	50%-65%
Metabolism	Hepatic
Route of elimination	In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite and 10% as the other metabolites.
Half life	6.7 hours (range 4-10 hours)
Clearance	Not Available
Toxicity	LD50=580 mg/kg in rats

Pharmacology of Ranolazine

Pharmacology of Ranolazine

Indication	For the treatment of chronic angina. It should be used in combination with amlodipine, beta-blockers or nitrates.
Pharmacodynamics	Ranolazine has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or blood pressure. It is the first new anti-anginal developed in over 20 years.
Mechanism of action	The mechanism of action of ranolazine is unknown. It does not increase the rate-pressure product, a measure of myocardial work, at maximal exercise. In vitro studies suggest that ranolazine is a P-gp inhibitor. Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia. Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia.
Absorption	Absorption is highly variable. After oral administration of ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of oral ranolazine relative to that from a solution is 76%.
Volume of distribution	Not Available
Protein binding	62%
Metabolism	Hepatic, metabolized mainly by CYP3A and to a lesser extent by CYP2D6. The pharmacologic activity of the metabolites has not been well characterized.
Route of elimination	Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces.
Half life	7 hours
Clearance	Not Available
Toxicity	In the event of overdose, the expected symptoms would be dizziness, nausea/vomiting, diplopia, paresthesia, and confusion. Syncope with prolonged loss of consciousness may develop.

Pharmacology of Milrinone

Pharmacology of Milrinone

Indication	Indicated for the treatment of congestive heart failure.
Pharmacodynamics	Milrinone, a synthetic dimethylxanthine derivative structurally related to theophylline and caffeine, is used in the treatment of peripheral vascular diseases and in the management of cerebrovascular insufficiency, sickle cell disease, and diabetic neuropathy.
Mechanism of action	Milrinone inhibits erythrocyte phosphodiesterase, resulting in an increase in erythrocyte cAMP activity. Subsequently, the erythrocyte membrane becomes more resistant to deformity. Along with erythrocyte activity, Milrinone also decreases blood viscosity by reducing plasma fibrinogen concentrations and increasing fibrinolytic activity.
Absorption	Milrinone is rapidly and almost completely absorbed after oral administration. Bioavailability is 92% (in healthy volunteers).
Volume of distribution	0.38 liters/kg [intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients] 0.45 liters/kg [intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients]
Protein binding	70 to 80%
Metabolism	There are five metabolites but the O-glucuronide represents the major pathway of biotransformation.
Route of elimination	The primary route of excretion of milrinone in man is via the urine.
Half life	2.3 hours
Clearance	0.13 L/kg/hr [congestive heart failure patients, following IV injections of 12.5 mcg/kg to 125 mcg/kg] 0.14 L/kg/hr [congestive heart failure patients, following infusions of 0.2 mcg/kg/min to 0.7 mcg/kg/min]
Toxicity	LD50 = 0.3 mg/L in rats

 

Pharmacology of Midodrine

Pharmacology of Midodrine

 

 

Indication	For the treatment of symptomatic orthostatic hypotension (OH).
Pharmacodynamics	Midodrine is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine formed by deglycination of midodrine. Desglymidodrine diffuses poorly across the blood-brain barrier, and is therefore not associated with effects on the central nervous system. Administration of midodrine results in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 to 30 mmHg at 1 hour after a 10-mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.
Mechanism of action	Midodrine forms an active metabolite, desglymidodrine, that is an alpha1-agonist, and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors.
Absorption	Rapidly absorbed following oral administration. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93% and is not affected by food.
Volume of distribution	Not Available
Protein binding	Not Available
Metabolism	Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues, and both compounds are metabolized in part by the liver.
Route of elimination	Not Available
Half life	The plasma levels of the prodrug peak after about half an hour, and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours.
Clearance	Renal cl=385 mL/minute
Toxicity	Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention. The single doses that would be associated with symptoms of overdosage or would be potentially life- threatening are unknown. The oral LD50 is approximately 30 to 50 mg/kg in rats, 675 mg/kg in mice, and 125 to 160 mg/kg in dogs. Desglymidodrine is dialyzable.
Affected organisms	Humans and other mammals

Pharmacology of Dofetilide

Pharmacology of Dofetilide

 

Indication	For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm
Pharmacodynamics	Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.
Mechanism of action	The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway).
Absorption	>90%
Volume of distribution	3 L/kg
Protein binding	60% -70%
Metabolism	Hepatic
Route of elimination	Not Available
Half life	10 hours
Clearance	Not Available
Toxicity	Not Available

Pharmacology of Phentermine

Pharmacology of Phentermine

Phentermine
Indication	For the treatment and management of obesity.
Pharmacodynamics	Phentermine is indicated in the management of exogenous obesity as a short term (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction. Phentermine hydrochloride is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.
Mechanism of action	Phentermine is an amphetamine that stimulates neurons to release or maintain high levels of a particular group of neurotransmitters known as catecholamines; these include dopamine and norepinephrine. High levels of these catecholamines tend to suppress hunger signals and appetite. The drug seems to inhibit reuptake of noradrenaline, dopamine, and seratonin through inhibition or reversal of the reuptake transporters. It may also inhibit MAO enzymes leaving more neurotransmitter available at the synapse.Phentermine (through catecholamine elevation) may also indirectly affect leptin levels in the brain. It is theorized that phentermine can raise levels of leptin which signal satiety. It is also theorized that increased levels of the catecholamines are partially responsible for halting another chemical messenger known as neuropeptide Y. This peptide initiates eating, decreases energy expenditure, and increases fat storage.
Absorption	Phentermine is rapidly absorbed after oral ingestion.
Volume of distribution	Not Available
Protein binding	Approximately 96.3%
Metabolism	Hepatic.
Route of elimination	Not Available
Half life	16 to 31 hours
Clearance	Not Available
Toxicity	LD50 is adult monkeys is 15 to 20 mg/kg. Symptoms of overdose include delirium, mania, self-injury, marked hypertension, tachycardia, arrhythmia, hyperpyrexia, convulsion, coma, and circulatory collapse.