Exam 2- Lecture 1: Calcium Channel Blockers, Beta-Blockers, & Alpha-Blockers

What are beta-blockers indicated in the management of?

• Hypertension

• Arrhythmias

• Heart failure

• Migraine prophylaxis

• Anxiety

What do beta-blockers oppose the function of?

Sympathetic nervous system

• Act as antagonists of the “flight-or-flight” response (ex. increased HR)

What is the impact of beta-adrenergic signaling?

High context dependent

• In heart beta1 & beta2 adrenergic receptors increase HR acting excitatory

• But in same receptors on small vessels in brain act in an inhibitory manner causing vasodilation

Where do action potentials start in?

Pacemaker cells of heart driven through influx of cations into the cell

• Causes increase in membrane potential

What does the increase in membrane potential eventually surpass?

Threshold potential of cells generating an electrical impulse that is shared to non-pacemaker cells through gap junctions

What does the shared action potentials w/ non-pacemaker cells ultimately cause?

Contraction of cardiomyocytes & a heartbeat

What are beta-adrenergic receptors found on both pacemaker & non-pacemaker cells of the heart both activated by?

Epinephrine &/or norepinephrine released by neurons of sympathetic nervous system

What will bind to the beta receptor?

G-protein

• Swaps out GDP for GTP & becomes activated

What does the activated G-protein activate?

Adenylyl cyclase

What does adenylyl cyclase convert?

ATP to cAMP

What does cAMP activate?

Protein kinase A (PKA)

What does the activated PKA phosphorylate?

L-type calcium channels, increasing amount of calcium inside cell & allows increased conduction velocity in pacemaker cells or increased contractility in non-pacemaker cells

What is the MoA for beta-blockers?

Inhibits activation of beta-receptors leading to decreased conductance (rate) & decreased contractility (strength)

What do beta-blockers have other mechanisms in?

Other tissues in a contextual manner, but same mechanism of how the work at a cellular level applies but will change physiological response

What are non-selective (1st generation) beta-blockers (beta1-beta2)?

• Timolol

• Propranolol

• Sotalol

What are selective (2nd generation) beta-blockers (beta1)?

• Atenolol

• Esmolol

• Metoprolol

• Acebutolol

• Bisoprolol

What are non-selective (3rd generation) beta-blockers (beta1, beta2, alpha1)?

• Carvedilol

• Labetalol

What are the side effects of beta-blockers?

• Heart block

• Hypotension

• Bronchospasm

• Diarrhea

• Hypertriglyceridemia

• Fatigue

• Insomnia

What are alpha-blockers indicated in the management of?

• Hypertension

• Urinary retention

• Benign prostate

• Hyperplasia

• Kidney stones (when in ureter)

• Pheachromacytoma (adrenal tumor; increases epi/NE)

• Drug induced hypertensive crisis

What do alpha-blockers oppose the function of (similar to beta-blockers)?

Sympathetic nervous system

• Act as antagonists of “fight-or-flight” response (ex. increase vasoconstriction)

What are alpha-receptors present throughout?

Body, but differ in subtype expressed

Where are alpha1-receptors found near?

Exclusively in peripheral vascular smooth muscle cells & are primarily excitatory in nature

Where are alpha2-receptors found in?

Central nervous system on pre-synaptic nerve terminals to provide negative feedback, decreasing the release of epi/NE, functioning in an inhibitory manner

What does calcium move across smooth muscle cell membranes through?

L-type calcium channels

What does calcium activate?

Calmodulin

What does calmodulin activate?

CAM kinase

What does CAM kinase phosphorylate?

MLCK

What does MLCK phosphorylate?

Myosin heads & induces contraction of smooth muscle cells

What binds to alpha-receptors?

Epi/NE

• Causes conformational change in receptors allowing for docking of a stimulatory G-protein

What does the G-protein exchange?

GDP for GTP

• G-protein becomes activated

What does the activated G-protein subsequently activate?

Phospholipase C (PLC)

What does PLC cleave?

Membrane bound PIP2 into DAG & IP3

What does DAG activate?

Protein kinase C (PKC)

• Enhancing myosin head phosphorylation & smooth muscle cells contraction

What does IP3 bind to?

Its IP3 receptor (IP3R) on sarcoplasmic reticulum

• Causes release of calcium into cytosol

What does released calcium further enhance?

Typical calcium signaling in smooth muscle cells, causing contraction

What is the MoA of alpha-blockers?

Inhibit activation of alpha-receptors leading to decreased contractility to smooth muscle cells

What are examples of selective alpha1 receptor blockers?

• Terazosin

• Prazosin

• Tamsulosin

• Doxazosin

What are examples of nonselective alpha1 & alpha2 receptor blockers?

• Phenoxybenzamine (allosteric modulator, does not bind active site)

• Phentolamine (binds active site, competitive)

What are side effects of alpha-blockers?

• Hypotension

• Flushing

• Edema

• Reflex tachycardia

• Altered urinary frequency

What are critical molecular entities in maintenance of BP, typically in situations where body is experiencing bouts of hypotension?

Angiotensin converting enzyme (ACE) & angiotensin II (ATII)

What are ACE & ATII both indicated in?

• Hypotension

• Coronary artery disease

• Heart failure

Where is ACE produced most prominently?

Endothelial cells in lungs

What is ATII the enzymatic product of?

Conversion of ATI by ACE

What is ATII an incredibly potent?

Vasoconstrictor & important activator of other interacting pathways to control BP including anti-diuretic hormone & aldosterone

What is the molecular pharmacology in RAAS?

Decreased BP is sensed by juxtaglomerular cells of kidney

• Causes them to release renin

What does the liver constitutively produces?

Precursor molecule called angiotensinogen (inactive substrate precursor)

What does renin cleave?

Specific amino acid from angiotensinogen to produce angiotensin I (ATI)

What does ATI move through?

Circulatory system where it will encounter ACE in pulmonary vasculature & be enzymatically converted to ATII

Where does ATII (receptors) act?

Multiple sites

• Vascular smooth muscle: AT-II causes constriction & leads to increased BP

• Posterior pituitary: AT-II causes release of anti-diuretic hormone (ADH), which acts on kidneys to increase water reabsorption

• Zone glomerulosa: AT-II causes ZG cells to release aldosterone leading to increased sodium & therefore water reabsorption, leading to increased blood volume & therefore BP

What is the MoA of ACE inhibitors?

Prevent conversion of ATI to ATII leading to decreased sodium & therefore water reabsorption & vasodilation, all leading to decreased BP & blood volume

What is the MoA of ATII receptor blockers?

Inhibit binding of ATII to ATII receptor preventing same interactions that are downstream of conversion of AT-I to AT-II

What are examples of an ACE inhibitors?

• Benzapril

• Captopril

• Enalapril

• Lisinopril

What are examples of ARBs?

• Candesartan

• Losartan

• Valsartan

What are side effects of ACE inhibitors & ARBs?

• Hypokalemia

• Hypotension

• Angioedema

• Dry cough (ACEi)