NILOL

Indications

• Hypertension
• Arrhythmias
• Angina pectoris
• Post-myocardial infarction

Dosage

Children: Child 12–17 years: 25–50 mg once daily. For children aged 1 month–11 years, 0.5–2 mg/kg once daily, given in 2 divided doses.

Adults: Usual starting dose for hypertension is 25-50 mg once daily, which can be adjusted based on response. Maximum daily dose is 100 mg.

Mechanism of action

Atenolol selectively blocks beta-1 adrenergic receptors in the heart, leading to decreased heart rate, myocardial contractility, and conduction velocity, thus reducing cardiac workload and oxygen consumption.

Pharmacodynamics

Atenolol lowers blood pressure and heart rate through its action on the heart, reducing the effects of catecholamines. It also decreases renin release from the kidneys, contributing to its antihypertensive effect.

Pharmacokinetics

Atenolol is well absorbed after oral administration, with a bioavailability of approximately 50%. It is primarily eliminated via the kidneys, and its half-life is about 6-9 hours. Dose adjustment may be necessary in renal impairment.

Adverse effects

• Gastrointestinal disorders
• Anxiety
• Decreased appetite
• Altered mood
• Postural hypotension
• Impaired concentration
• Drowsiness
• Hyperhidrosis
• Skin reactions
• Thrombocytopenia
• Arrhythmias
• Constipation
• Hypersensitivity
• Lupus-like syndrome
• Dry mouth
• Dyspepsia
• Flushing
• Oedema
• Pallor
• Pulmonary oedema
• Seizures
• Speech disorder
• Taste altered
• Abnormal thinking
• Urinary retention
• Cardiac arrest
• Extravasation necrosis
• Angioedema
• Coronary vasospasm
• Hyperkalaemia
• Metabolic acidosis

Interactions

• Propafenone (increases risk of cardiovascular adverse effects)

Precautions

• Care must be taken to ensure the correct drug is prescribed and dispensed.
• Use caution in renal impairment.
• Breastfeeding is advised to be avoided.

Pregnancy

Manufacturer advises caution.

Breast-feeding

Manufacturer advises avoidance.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Atenolol 25 mg tablets
• Atenolol 50 mg tablets
• Atenolol 100 mg tablets

Indications

• Hypertension
• Angina pectoris (prophylaxis)

Dosage

Children: Not licensed for use in children.

Adults: Initially 5 mg three times a day, which may be adjusted according to response, with a typical maintenance dose of 10-20 mg three times a day. For modified-release formulations, the initial dose is often 20 mg twice daily.

Mechanism of action

Nifedipine blocks voltage-gated L-type calcium channels in vascular smooth muscle and myocardial cells. This action prevents calcium ions from entering the cells during depolarization, reducing peripheral arterial resistance and dilating coronary arteries. This results in lowered blood pressure and increased oxygen delivery to the heart, alleviating angina symptoms. The mechanism by which nifedipine inhibits calcium influx is not completely understood, but it is believed to involve interference with ion-control gating mechanisms of the calcium channels.

Pharmacodynamics

Nifedipine is an inhibitor of L-type voltage-gated calcium channels, which reduces blood pressure and increases oxygen supply to the heart. The immediate-release formulations require dosing three times daily due to their shorter duration of action. The typical daily dose ranges from 10 to 120 mg, with careful monitoring for excessive hypotension and potential angina exacerbation.

Pharmacokinetics

Nifedipine is rapidly absorbed following oral administration, with peak plasma concentrations typically occurring within 30 minutes to 2 hours for immediate-release forms. Its bioavailability is affected by first-pass metabolism, and it is extensively metabolized in the liver. The half-life of nifedipine varies, but it generally ranges from 2 to 5 hours. The drug is primarily excreted as metabolites in the urine, with only a small fraction excreted unchanged.

Contra-indications

• Cardiogenic shock
• Aortic stenosis
• Severe maternal hypotension
• Fatal fetal hypoxia in pregnancy

Adverse effects

• Constipation
• Malaise
• Oedema
• Allergic reactions
• Angioedema
• Hypotension
• Reflex tachycardia

Interactions

• Grapefruit juice (severe increase in exposure)
• Rifampicin (severe decrease in exposure)
• Enzalutamide (moderate decrease in exposure)
• Dronedarone (moderate increase in exposure)
• Antifungal azoles (moderate increase in exposure)
• Miconazole (moderate increase in exposure)
• Cobicistat (moderate increase in exposure)
• Crizotinib (moderate increase in exposure)
• Dabrafenib (moderate decrease in exposure)
• Idelalisib (moderate increase in exposure)

Precautions

• Monitor blood pressure and heart rate regularly
• Use with caution in patients with significant left ventricular dysfunction
• Avoid excessive decrease in blood pressure
• Consider initial low doses in patients with renal impairment

Pregnancy

May inhibit labour; not to be used in multiple pregnancies unless no other acceptable alternative.

Breast-feeding

Manufacturer advises to avoid; present in breast milk.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Immediate-release capsules
• Modified-release formulations
• Oral suspension
• Solution for infusion

Mechanism of action

Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G_s coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA). In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca²⁺ ATPase to increase reuptake of calcium into the SR. It also phophorylates troponin I to reduce affinity of the protein for calcium. Both of these events lead to a reduction in contraction which, when coupled with the initial increase in contraction, allows for faster cycling and consequently higher heart rate with increased contractility. L-type calcium channels are also a major contributor to cardiac depolarization and their activation can increase frequency of action potentials and possibly the incidence of ectopic potentials. Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G_q coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction. By inhibiting myocardial beta 1-adrenergic receptors, atenolol produces negative chronotropic and inotropic activity. The negative chronotropic action of atenolol on the sinoatrial node results in a decrease in the rate of sinoatrial node discharge and an increase in recovery time, thereby decreasing resting and exercise stimulated heart rate and reflex orthostatic tachycardia by about 25-35%. High doses of the drug may produce sinus arrest, especially in patients with sinoatrial node disease (eg, sick sinus syndrome). Atenolol also slows conduction in the atrioventricular nose. Although stroke index may be increased moderately by about 10%, atenolol usually reduces cardiac output by about 20% probably secondary to its effect on heart rate. The decrease in myocardial contractability and heart rate, as well as the reduction in blood pressure, produced by atenolol generally lead to a reduction in myocardial oxygen consumption which accounts for the effectiveness of the drug in chronic stable angina pectoris; however, atenolol can increase oxygen requirements by increasing left ventricular fiber length and end-diastolic pressure, particularly in patients with cardiac failure. Atenolol suppresses plasma renin activity and suppresses the renin aldosterone angiotensin system. The toxic actions of beta-blockers appear to be related to properties such as membrane depressant activity and possibly due to actions on beta-adrenoceptors distinct from those in the cardiovascular system.

Pharmacodynamics

Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control.

Mechanism of action

Nifedipine blocks voltage gated L-type calcium channels in vascular smooth muscle and myocardial cells. This blockage prevents the entry of calcium ions into cells during depolarization, reducing peripheral arterial vascular resistance and dilating coronary arteries. These actions reduce blood pressure and increase the supply of oxygen to the heart, alleviating angina. The principal physiologic action of nifedipine is to inhibit the transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations. Calcium plays important roles in the excitation-contraction coupling processes of the heart and vascular smooth muscle cells and in the electrical discharge of the specialized conduction cells of the heart. The membranes of these cells contain numerous channels that carry a slow inward current and that are selective for calcium. Activation of these slow calcium channels contributes to the plateau phase (phase 2) of the action potential of cardiac and vascular smooth muscle cells. The exact mechanism whereby nifedipine inhibits calcium ion influx across the slow calcium channels is not known, but the drug is thought to inhibit ion-control gating mechanisms of the channel, deform the slow channel, and/or interfere with release of calcium from the sarcoplasmic reticulum. By inhibiting calcium influx, nifedipine inhibits the contractile processes of cardiac and vascular smooth muscle, thereby dilating the main coronary and systemic arteries. Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.

Pharmacodynamics

Nifedipine is an inhibitor of L-type voltage gated calcium channels that reduces blood pressure and increases oxygen supply to the heart. Immediate release nifedipine's duration of action requires dosing 3 times daily. Nifedipine dosing is generally 10-120mg daily. Patients should be counselled regarding the risk of excessive hypotension, angina, and myocardial infarction.