BIT2010: pump in the E2-P transition state

BIT2010: Pharmaceutical Biotechnology

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Anchit Ghai

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Pharmacotherapy of Heart failure

Heart failure is the inability of the heart to pump out sufficient quantities of oxygenated blood to meet the demand of the body tissues. A person suffering from heart failure will have symptoms like confusion or memory impairment, cough with frothy sputum, swollen or tender abdomen with loss of appetite, increased urination at night, chronic lack of energy, difficulty in sleeping at night, respiratory problems like shortness of breath and swelling of lower limbs. Heart failure usually results from any structural or functional impairment of ventricular filling or ejection of blood.

The main aim of pharmacotherapy of heart failure is to restore cardiac performance and provide relief from congestion and symptoms of low cardiac output. Pharmacotherapy of heart failure also aims at reducing disease progression and increasing survival rates.

 

Various methods of pharmacotherapy of heart failure and their mode of action

 

Cardiac Glycosides:

Cardiac Glycosides are organic substances which decrease the contraction rate of the heart and increases its output force.

Mechanism

The basic mechanism of action of this class of compounds is that they act on the sodium-potassium ATPase pump present on the cardiac muscle cells and inhibit their activity. They stabilize the pump in the E2-P transition state hence preventing the pumping in of potassium ions and pumping out of sodium ions. The potassium ions and cardiac glycosides compete for binding to them pump, hence increasing intracellular sodium concentration. This raised intracellular sodium concentration ends up inhibiting the function of NCX which is also an ion exchanger which is present in the membrane. NCX is responsible for pumping out Ca and Na ions. Thus, there will be a build-up of both calcium and sodium ions. These unbalanced calcium levels and increased intracellular calcium levels end up increasing Ca ion uptake into the sarcoplasmic reticulum via the SERCA2 transporter. This greater ion uptake by sarcoplasmic reticulum facilitates a larger release of Ca ions upon stimulation, hence increasing the intensity and speed of contractions by the cell.

The cardiac output is increased by the heart rate is reduced as the refractory period of the AV node gets increased. The benefit is that the heart has to exert a lesser overall force to pump the same quantity of blood. Commonly used cardiac glycosides are digoxin and digitoxin.

Cardiac glycosides however, have shown toxicity which limits their use in pharmacotherapy of heart failure. Many cases of digoxin toxicity have been reported and some patients have also lost their lives due to digoxin related toxicity.

Structure

Structure of Digoxin which is a coomonly used cardiac glycoside

Cardiac Glycosides generally consist of a R group and sugar group along with a steroidal glycoside. The molecule has five fused rings which end up forming the steroid nucleus. The presence of functional groups such as aldehyde, methyl and hydroxyl groups further confer the biological activity to these molecules. The molecule’s kinetics and solubility greatly depend on the sugar groups attached at the sugar-end of the molecule.

ACE Inhibitors:

Angiotensin-converting-enzyme inhibitors are a class of drugs that induce lower blood pressure and reduced oxygen demand by the tissues of the heart by decreasing blood volume and relaxing blood vessels.

Mechanism

ACE inhibitors prevent Angiotensin-I (AI) from getting converted to Angiotensin-II (AII) by inhibiting the function of the angiotensin-converting enzyme. This enzyme is a vital component of the renin-angiotensin system. By blocking the conversion of AI to AII this class of drugs ends up increasing the venous capacity and reducing the arteriolar resistance. This further leads to a reduced cardiac index, reduced cardiac volume and lesser stroke volume and work. Reduced resistance in the blood vessels of the kidneys leads to the excretion of sodium in the urine which is known as natriuresis. Renin concentration on the blood goes up due to the negative feedback of the conversion of Angiotensin-I to Angiotensin-II. The level of Angiotensin-I increases and the levels of aldosterone and Angiotensin-II decrease. Under normal condition Angiotensin-II is responsible for vasoconstriction, ventricular hypertrophy and remodelling and release of vasopressin. The reduced level of Angiotensin-II leads to decreased blood pressure. This helps overcome heart failure. Commonly used ACE inhibitors are Ramipril, captopril, lisinopril, enalapril, trandolapril, zofenopril, perindopril, and benazepril.

ACE inhibitors can have a lot of adverse effects like Hyperkalemia, headache, hypotension, coughing, fatigue, nausea, dizziness, renal impairment and increase in inflammation-related pain. Thus, ACE inhibitors need to be prescribed with caution.

Chemical structures of some ACE Inhibitors

Inotropes:

Inotropes are compounds that modify the intensity or energy of muscular contractions. Inotropes may be positively or negatively inotropic. Positively inotropic compounds increase the force of muscular contractions while negatively inotropic compounds reduce the strength of muscular contractions.

A wide variety of drugs and molecules from different classes fall under this category based on their function. Examples of positively inotropic agents: Amiodarone, Calcium, Digoxin, Berberine, Calcium sensitizers, Angiotensin-II, Glucagon, Insulin and Catecholamines. Examples of negatively inotropic agents: Beta blockers, Non-dihydropyridine Calcium channel blockers, Quinidine and Flecainide.

Mechanism

Positively inotropic agents either increase the intracellular calcium concentration by increasing calcium influx into the cell or by stimulating calcium release from sarcoplasmic reticulum, or they increase the sensitivity of calcium receptors thus causing an increase in myocardial contractility. Negatively inotropic agents reduce cardiac load and decrease myocardial contractility. Generally, positively inotropic agents are used to treat congestive heart failure.

Low blood pressure, irregular heartbeat, Dizziness or light-headedness, Headaches, Diarrhoea, Fatigue and Erectile dysfunction are some of the adverse effects of inotropes.

Mechanism of action of some Inotropes

 

Angiotensin-II Receptor Blockers (ARBs):

ARBs are a class of drugs that halt the action of Angiotensin-II by blocking the binding between Angiotensin-II and Angiotensin-II receptors. This leads to reduced blood pressure as the blood vessels get dilated. This reduced blood pressure helps to ease heart failure as it now becomes easier for the heart to pump this blood. Commonly used ARBs are Irbesartan, candesartan, Losartan, Olmesartan, Telmisartan, valsartan, and azilsartan.

Mechanism

Angiotensin-II is a peptide hormone that increases blood pressure and promotes vasoconstriction especially by causing the muscles around the blood vessels to contract. The vasoconstriction also further causes hypertension. By blocking the binding of Angiotensin-II with its receptor, the activity of Angiotensin-II is stopped, and dilation of blood vessels occur which reduces blood pressure. Lower blood pressure reduces the workload of the heart.

ARBs have several side effects. Some of them are: rash, fatigue, orthostatic hypotension, abnormal taste sensation, headache, diarrhoea, drowsiness, dizziness, hyperkalemia, cough, indigestion, and upper respiratory tract infection. Sometimes serious side effects like kidney failure, liver failure, allergic reactions, decrease in white blood cells, decrease in blood platelets or swelling of tissues may be observed.

Structure

Structures of some common ARBs

ARB drugs mainly have tetrazole group and may possess one or two imidazole groups. Most ARBs have a basic common structure with slight modifications. Losartan possess a chloride group. Irbesartan possesses a cyclopenthyl group instead of a chloride group. Olmesartan has a hydroxyl as well as a ?-carboxyl group in the imidazol ring.

 

Beta Blockers:

Beta blockers (?-blockers) are compounds that help in managing abnormal heart rhythms and also help in protecting the patient from a second heart attack or myocardial infarction after the first heart attack. Beta receptors are stimulated by epinephrine and are present on the cells of many body tissues and organs like kidneys, arteries, airducts, heart muscles and smooth muscles. Beta receptors are responsible for stress responses.

Some commonly used Beta Blockers are:

Ø  Propranolol

Ø  Labetalol

Ø  Bucindolol

Ø  Carvedilol

Ø  Carteolol

Ø  Sotalol

Ø  Pindolol

Ø  Atenolol

Ø  Timolol

Ø  Nadolol

Ø  Betaxolol

Ø  Metoprolol

 

Mechanism

These drugs interfere with the binding between the Beta receptors and epinephrine or other stress hormones. This interference ends up lowering the stress response initiated by the stress hormones. Beta blockers are structurally and functionally competitive antagonists that block the binding of catecholamines, epinephrine and norepinephrine with adrenergic beta receptors present on the sympathetic nervous system by blocking to the receptors themselves. These receptors mediate fear and flight-or-fight response. Beta blockers help combat heart failure by reducing the heart rate and by modulating the renin-angiotensin system in favour of reducing the oxygen demand of the heart. It reduces the secretion of renin which further lowers extracellular volume and increases the oxygen carrying capacity of the blood. Catecholamines cause an increase in oxygen demand, increase in inflammatory mediator and cardiac remodelling which end up worsening heart failure. By blocking the Beta receptors which receive signal from catecholamines, these drugs are able to lower the deleterious effects of substances such as catecholamines and help to improve ejection fraction. The competitive binding of beta blockers is dependent on hydrogen bonds between the compound and the receptor.

Use of Beta blockers may lead to occurrence of adverse symptoms like bronchospasm, nausea, dyspnoea, diarrhoea, exacerbation of Raynaud’s syndrome, bradycardia, heart block, hypotension, fatigue, hair loss, dizziness, insomnia, hallucinations, sexual dysfunction, nightmares, erectile dysfunction and abnormal lipid and glucose metabolism.

Structure

Structures of some common Beta Blockers

?-ethanolamine and aromatic rings are two essential components of every Beta blocker. Two types of aromatic rings can be found in Beta blockers, either benzoheterocyclic or heterocyclic rings. The side chains are variable.

 

Aldosterone Antagonists:

Aldosterone antagonists are drugs that bind to and block the action of mineralocorticoid receptors to which aldosterone binds. This group of drugs is primarily prescribed as adjunctive drugs rather than stand-alone therapeutics.

Commonly used Aldosterone Antagonists:

Ø  Spironolactone (First to be used and most commonly used)

Ø  Eplerenone

Mechanism

These drugs dampen the biological response of Aldosterone by blocking the mineralocorticoid receptors. Since activity of Aldosterone is blocked, re-absorption of sodium is inhibited in the collecting duct part of the nephrons of the kidneys. This disrupts the sodium and potassium exchange and ends up promoting water excretion and urine formation. This added diuretic effect helps to reduce cardiac workload and oedema.

 

General criteria for prescribing Aldosterone antagonists

 

Structure of Spironolactone

          

 

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