Beta Blockers and Adrenoceptors

• Beta blockers block beta adrenergic receptors, reducing heart workload by lowering heart rate and contractility.
• Propranolol, discovered by Sir James Black, is a top drug for cardiovascular diseases like arrhythmia, heart attack, heart failure, angina, and hypertension.
• Atenolol, propranolol, carvedilol, bisoprolol, and metoprolol are better drugs that were developed.
• Adrenaline (epinephrine) is released from the adrenal glands.
• Noradrenaline (norepinephrine) is released by sympathetic neurons.
• Beta adrenoceptors couple to Gs protein, increasing cAMP to mediate signaling.

Receptor Effects

• β1 receptor = Gs ↑ (cAMP & PKA)
• β2 receptor = Gs ↑ (cAMP & PKA)
• B3 receptor = Gs ↑ (cAMP & PKA)
• a1 receptor = Gq↑ (PLC-DAG & IP3)
• a2 receptor = Gi (PLC-DAG & IP3)

Beta 1 Adrenoceptors

• Increase probability of HCN channel.
• Increase intracellular calcium entry from L-type calcium channel.
• Increase heart rate (positive chronotropy).
• Increase heart contraction (positive inotropy).
• Beta 1 adrenoceptor activation on the SA node pacemaker (HCN channel)

Positive Inotropic Effect

• B1 adrenoceptor activation on the L-type calcium channel
• Phosphorylation of channel increases Ca2+ entry, Ca2+ release, and force, increasing inotropic effect.
• Phosphorylation of phospholamban activates Ca2+ reuptake for faster relaxation and more calcium availability for next contraction.

Heart Rate Management

• Stopping the activation of the B1 receptor will lower heart rate.
• A drug that blocks the activation of the B1 receptor (antagonist) is needed, such as a beta blocker (Bisoprolol).
• Bisoprolol is favored over propranolol (also a beta blocker) for treating high heart rate because it selectively targets beta 1 adrenergic receptors, whereas propranolol is non-selective.

Beta 1 Receptor in Hypertension

• Beta 1 blocker (Bisoprolol) can be used.
• Alpha 1 blocker (Prazosin) can be used.

Beta Blockers in Angina

• Angina involves reduced blood flow to the heart muscle.
• Angina causes temporary squeezing/crushing chest pain.
• Angina affects ~2 million people in the UK.
• Atherosclerosis is the main cause and is usually clinically silent (no symptoms).

Angina Types and Management

• Two types of angina: "stable angina" and "unstable angina".
• Stable angina: pain follows excitement or exercise; most common form.
• Increasing cardiac O2 demand not met by restricted blood supply.
• Ischemic areas develop, causing pain.
• Beta blockers reduce O2 demand.
• Decreasing activation of the cardiac B1 adrenoceptor has a negative inotropic and chronotropic effect on the heart.
• Reduced oxygen demand allows sufficient blood flow.
• Beta blockers reduce the demand so that heart muscle does not require additional oxygen, which relieves the symptoms of angina.

Atherosclerosis

• Atherosclerosis contributes to angina.
• Atherosclerosis (build-up of cholesterol-rich plaques) causes stenosis (narrowing) of arteries.
• Plaques generally form in the coronary arteries, within 6 cm of the aorta.
• Plaque also occurs in renal and carotid arteries, and in the aorta.

Beta Blockers and Blood Flow

• Local regulation of blood flow triggers vasodilation to increase oxygen supply.
• Beta blockers relieve angina symptoms by restoring blood flow supply (False).

Propranolol and Side Effects

• Many therapeutic uses of propranolol (non-selective antagonist) and also side effects associated with its use, for example:
• Bronchoconstriction caused by block of pulmonary B2 receptors; risk for asthma sufferers.
• Fatigue due to reduced blood flow to skeletal muscle because of reduced cardiac output (B1 receptor block) and reduced vasodilation in arteries to muscle (B2 receptor block) (no physical activity / exercise).
• Coldness/numbness in fingers and toes due to reduced blood flow (B2 receptor block); risk for Raynaud's sufferers.
• Constriction of bladder by block of B3 receptors: exacerbates overactive bladder.
• Block of B2 and B3 receptors can be a problem, so attempts to create B1 receptor-selective compounds.
• The development of selective agonist and antagonist is crucial in producing more targeted therapy which will aid in reducing side effects of drug.
• The development of propranolol laid the foundation for the discovery of selective beta receptor drugs.

James Black and Drug Design

• The development of selective beta receptor drugs, which led to the creation of propranolol.
• In the 1950s James Black was working as the Head of Department of Physiology at Glasgow Veterinary College.
• A chemist colleague of James Black's suggested that a phenyl group would be roughly the same size and shape as 2 x Cl.
• Drugs like Propranolol, Atenolol, Metoprolol and Bisoprolol are widely used in the clinic.
• Remember, a drug is able to mediate its action because of its structure.
• A slight change in a structure can change the pharmacology of a drug from agonism to antagonism and vice-versa.