Drug design | construction of drug molecule

Drug design

Drug design is the approach of finding drugs by design, based on their biological targets. Typically a drug target is a key molecule involved in a particular metabolic or signalling pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a microbial pathogen.
Some approaches attempt to stop the functioning of the pathway in the diseased state by causing a key molecule to stop functioning.
Drugs may be designed that bind to the active region and inhibit this key molecule.
However these drugs would also have to be designed in such a way as not to affect any other important molecules that may be similar in appearance to the key molecules. Sequence homologies are often used to identify such risks.
Other approaches may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state.
The structure of the drug molecule that can specifically interact with the biomolecules can be modeled using computational tools.
These tools can allow a drug molecule to be constructed within the biomolecule using knowledge of its structure and the nature of its active site.
Construction of the drug molecule can be made inside out or outside in depending on whether the core or the R-groups are chosen first. However many of these approaches are plagued by the practical problems of chemical synthesis.Newer approaches have also suggested the use of drug molecules that are large and proteinaceous in nature rather than as small molecules.
There have also been suggestions to make these using mRNA. Gene silencing may also have therapeutical applications.

Read More

Rational drug design | method of drug design

Rational drug designing

Unlike the historical method of drug discovery, by trial-and-error testing of chemical substances on animals, and matching the apparent effects to treatments, rational drug design begins with a knowledge of specific chemical responses in the body or target organism, and tailoring combinations of these to fit a treatment profile.
Due to the complexity of the drug design process two terms of interest are still serendipity and bounded rationality.
Those challenges are caused by the large chemical space describing potential new drugs without side-effects.
A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as x-ray crystallography and NMR spectroscopy.
This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide which was approved in 1995.
Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.

The activity of a drug at its binding site is one part of the design. Another to take into account is the molecule's druglikeness, which summarizes the necessary physical properties for effective absorption. One way of estimating druglikeness is Lipinski's Rule of Five.

Read More

Beta blocker | Clinical use

Beta blocker

Beta blockers (sometimes written as β-blockers) are a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias and cardioprotection after myocardial infarction.
Whilst once first-line treatment for hypertension, their role was downgraded in June 2006 in the United Kingdom to fourth-line as they do not perform as well as other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers especially in combination with thiazide-type diuretics carry an unacceptable risk of provoking type 2 diabetes.

Propranolol was the first clinically useful beta adrenergic receptor antagonist. Invented by Sir James W. Black it revolutionized the medical management of angina pectoris and is considered to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.


Pharmacology

Beta blockers block the action of endogenous catecholamines (epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular), on β-adrenergic receptors, part of the sympathetic nervous system which mediates the "fight or flight" response.

There are three known types of beta receptor, designated β1, β2 and β3. β1-Adrenergic receptors are located mainly in the heart and in the kidneys. β2-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3-receptors are located in fat cells.


β-Receptor antagonism
Stimulation of β1 receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β1 receptors on the kidney causes renin release. Stimulation of β2 receptors induces smooth muscle relaxation (resulting in vasodilation and bronchodilation amongst other actions), induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of β3 receptors induces lipolysis.

Beta blockers inhibit these normal epinephrine-mediated sympathetic actions, but have minimal effect on resting subjects. That is, they reduce the effect of excitement/physical exertion on heart rate and force of contraction, dilation of blood vessels and opening of bronchi, and also reduce tremor and breakdown of glycogen.

It is therefore expected that non-selective beta blockers have an antihypertensive effect. The
antihypertensive mechanism appears to involve: reduction in cardiac output (due to negative chronotropic and inotropic effects), reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity.

Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade – resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.

Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention.


Intrinsic sympathomimetic activity
Some beta blockers (e.g. oxprenolol and pindolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.

Agents with ISA are not used post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.

α1-Receptor antagonism
Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.


Other effects
Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbance caused by some agents.Beta blockers protect against social anxiety: "Improvement of physical symptoms has been demonstrated with beta-blockers such as propranolol; however, these effects are limited to the social anxiety experienced in performance situations."Beta blockers can impair the relaxation of bronchial muscle (mediated by beta-2) and so should be avoided by asthmatics.


Clinical use
Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below.

Indications for beta blockers include:
Hypertension
Angina
Mitral valve prolapse
Cardiac arrhythmia
Congestive heart failure
Myocardial infarction
Glaucoma
Migraine prophylaxis
Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
Essential tremor
Phaeochromocytoma, in conjunction with α-blocker


Beta blockers have also been used in the following conditions:
Hypertrophic obstructive cardiomyopathy
Acute dissecting aortic aneurysm
Marfan syndrome (chronic treatment with propranolol slows progression of aortic dilation and its complications)
Prevention of variceal bleeding in portal hypertension
Possible mitigation of hyperhidrosis
Congestive heart failure
Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition, studies in the late 1990s showed their positive effects on morbidity and mortality in congestive heart failure. Bisoprolol, carvedilol and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure.
The beta blockers are a benefit due to the reduction of the heart rate which will lower the myocardial energy expenditure. This is turns prolongs the diastolic filling and lengthens coronary perfusion.Beta blockers have also been a benefit to improving the ejection fraction of the heart despite an initial reduction in it.
Trials have shown that Beta blockers reduce the absolute risk of death by 4.5% over a 13 month period. As well as reducing the risk of mortality, the number of hospital visits and hospitalizations were also reduced in the trials.

Anxiety and performance enhancement
Some people, particularly musicians, use beta blockers to avoid stage fright and tremor during public performance and auditions. The physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand. Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration.

Since they lower heart rate and reduce tremor, beta blockers have been used by some Olympic marksmen to enhance performance, though beta blockers are banned by the International Olympic Committee (IOC). Although they have no recognisable benefit to most sports, it is acknowledged that they are beneficial to sports such as archery and shooting.


Adverse effects
Adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, clinical depression, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.
Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares, depression) are more common in agents with greater lipid solubility, which are able to cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less common in agents with greater aqueous solubility (listed below).
Adverse effects associated with β2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β1-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses.
A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a patient's risk of developing diabetes whilst ACE inhibitors and Angiotensin II receptor antagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.[12] Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta-blockers as first-line treatment of hypertension due to the risk of diabetes.
Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha adrenergic system stimulation unopposed.The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics like furosemide and alpha blockers like phentolamine.


Examples of beta blockers

Dichloroisoprenaline, the first beta blocker.

Non-selective agents
Alprenolol
Carteolol
Levobunolol
Mepindolol
Metipranolol
Nadolol
Oxprenolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol

β1-Selective agents
Acebutolol
Atenolol
Betaxolol
Bisoprolol[16]
Esmolol
Metoprolol
Nebivolol

Mixed α1/β-adrenergic antagonists
Carvedilol
Celiprolol
Labetalol

β2-Selective agents
Butaxamine (weak α-adrenergic agonist activity)


Side Effects / Health Consequences
Low Blood Pressure
Slow Heart Rate
Impaired Circulation
Loss of Sleep
Heart Failure
Asthma
Depression
Sexual Dysfunction
Nausea
Headaches
Dizziness
Muscle Cramps

Comparative information


Pharmacological differences

Agents with intrinsic sympathomimetic action (ISA)
Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol

Agents with greater aqueous solubility
Atenolol, celiprolol, nadolol, sotalol

Agents with membrane stabilising activity
Acebutolol, betaxolol, pindolol, propranolol

Agents with antioxidant effect
Carvedilol
Nebivolol

Indication differences

Agents specifically indicated for cardiac arrhythmia
Esmolol, sotalol

Agents specifically indicated for congestive heart failure
Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol

Agents specifically indicated for glaucoma
Betaxolol, carteolol, levobunolol, metipranolol, timolol

Agents specifically indicated for myocardial infarction
Atenolol, metoprolol, propranolol

Agents specifically indicated for migraine prophylaxis
Timolol, propranolol

Propranolol is the only agent indicated for control of tremor, portal hypertension and esophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma.

Read More