T3 - IE1 - Cardiology - Nauli - Hypertension II Sympatholytic Agents

Taking α2 receptor antagonist will result in _________

a. decreasing cAMP

b. increasing cAMP

c. decreasing intracellular calcium

d. increasing intracellular calcium

Increasing cAMP

α2 receptor antagonist results in increasing cAMP because α2 receptor works on Gαi, the pathway that inhibits production of cAMP. Inhibition of α2 receptor blocks Gαi resulting in the increase of cAMP.

Which tissues does α1A, α1B, and α1D agonism affect and what are the following effects?

Blood vessels -> vasoconstriction

Cardiac muscle -> (+) inotropic (i.e., increase contractility strength)

Urinary Smooth Muscle -> Contraction (urinary retention)

Intestinal smooth muscle -> Relaxation (regular absorption of water, which leads to solid stools, ANTAGONISM causes diarrhea due to lack of H2O absorption)

Skin -> Pale

Which tissues does α2A, α2B, a2C agonism affect and what are the following effects?

Nerve Terminal (α2A) -> Decrease NE release

Blood Vessels (α2B) -> Vasoconstriction

β islet cells -> Decrease insulin secretion

Which tissues does β1 agonism affect and what are the following effects?

Heart, cerebral cortex -> (+) chrono, ionotropic

Juxtaglomerular cells -> increase renin secretion

Which tissues does β2 agonism affect and what are the following effects?

Blood vessels -> vasodilation

Lung and cerebellum -> relaxation

β islet cells -> Increase insulin secretion

Which tissue does β3 agonism affect and what are the following effects?

Adipose tissue -> lipolysis

What is a sympatholytic agent?

A sympatholytic drug is a medication that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system

What type of Sympatholytic agents are used for hypertension?

- β adrenergic receptor antagonists

- α-1 adrenergic receptor antagonists

- Combined α1 and β-adrenergic receptor antagonists

- α2 adrenergic receptor agonists

What is the suffix for beta adrenergic receptor antagonists?

- "lol" (e.g Nadolol, esmolol, betaxolol)

Describe the three generations of Beta blockers

- First generation = Non selective

- Second generation = Selective

- Third generation = selective and non-selective

True or False? Beta blockers can be used to control volume by affecting the renin-angiotensin and aldosterone?

False

Beta blockers are used for cardiac control by affecting the heart rate (chronotropic) and heart contraction (inotropic) thus reducing cardiac output

True or False? Beta blockers are useful for patients who have hypertension as well as ischemic heart disease, congestive heart failure, or those who have had a myocardial infarction?

True

Beta blockers will help reduce cardiac overload thus helping those with heart conditions

Which types of patients tend to be less responsive to beta blockers?

- Elderly

- African Americans

Why must beta blockers be tapered down when discontinuing therapy?

Rebound hypertension can occur due to an upregulation of receptors during the use of β blockers

How long should tapering of beta blockers occur?

β blockers should be tapered down for at least 10 to 14 days prior to discontinuation

What are the contraindications when using beta blockers?

- Diabetes

- Asthma

- Peripheral arterial disease

What are the reasons for the contraindications of the β blockers in patients with diabetes, asthma, and peripheral arterial disease (PAD)?

Beta blockers inhibit insulin release in the β islet cells (β2 receptor)

Cause constrictions in the lungs (β2 receptor)

Change lipid profile of adipose tissue (β3 receptor)

FYI not exam related

Under physiological conditions, adrenaline will activate beta receptors thus inducing insulin release and cause relaxation in the lungs. Beta blockers will inhibit this action by adrenaline.

Which types of drugs can cause a decrease in the effects of beta blockers?

Non Steroidal Anti-Inflammatory Drugs (NSAIDS) e.g., Indomethacin

What hypertensive therapy would most likely result in reflex vasoconstriction in the sympathetic control portion?

Beta Blockers

Which of the following is used to treat hypertension?

a. α1 - antagonist

b. α2 - antagonist

c. β1 - agonist

d. β2 - antagonist

α1 - antagonist

α1 antagonists works by blocking the effects of vasoconstriction of the blood vessels and decreasing ionotropic activity of the cardiac muscle

Which of the following is not a contraindication of β-blocker in hypertension treatment?

a. asthma

b. hot flush

c. peripheral arterial disease

d. diabetes

hot flush

Hot flushes are not life threatening as compared to asthma, diabetes, or peripheral heart disease.

Peripheral arterial disease occurs when there is too much fat in the arteries (β3 due to the antagonism of lipolysis - i.e., liposynthesis)

_____________ is an antihypertensive agent that reduces cardiac output selectively.

a. Hydrochlorothiazide

b. ACE inhibitors

c. Third generation β1-blocker

d. β1-selective blocker

β1-selective blocker.

Hydrochlorothiazide works on cardiac output however it is not selective. ACE inhibitors works on peripheral resistance. Third generation β1 is incorrect because third generations are non-selective AND selective.

Τherefore, β1-selective blocker is correct (also it says in the name it is "SELECTIVE")

The only factor that does not require an extra precaution with a beta-blocker is ___________.

a. drug interaction with indomethacin

b. drug interaction with thiazide diuretic

c. elderly African American patient

d. insulin-dependent patient

Drug interaction with thiazide diuretic.

β blockers can be used in combination with diuretics. The other answer choices are either contraindications or is a population that has less effective use of beta blockers

α1, α2, β1, β2, β3 are all ________________ receptors

- adrenergic

Adrenergic receptors are part of the G-protein coupled receptors

Cardiac Overload

Myocardial Infarction

Ischemic Heart Disease

Congestive Heart Failure (CHF)

α1 selective antagonists suffix

-osin

exception with indoramin and urapidil

α1 selective antagonists

alfuzosin

bunazosin

doxazosin

prazosin

tamulosin

terazosin

urapidil

indoramin

α1 blockers reduce ______________ ________ and increase _______ _________, this causes sympathetically mediated reflex increase in HEART RATE and PLASMA RENIN activity in the short term

- arteriolar resistance

- venous capacitance

In long-term therapy of α1 blockers, _______ persists from the short-term effect, but _______ _____ and _____ _________ activity return to normal

- vasodilation

- cardiac output

- plasma renin

Thus, leading to an increase to Cardiac Output.

In long-term therapeutic of α1 blockers, retention of _____ and ________ occurs in many patients during continued administration, and this attenuates the postural hypotension

- water

- salt

Thus, long-term use of α1 antagonists may cause congestive heart failure unless given in combination with a diuretic.

α1 antagonists are only used as a first line agent in patients with...

BPH (benign prostatic hyperplasia)

Due to possibility of congestive heart failure when body retains water and salt to counteract the effects of α1 blocking.

α1 and β adrenergic receptor antagonists drugs

- labetalol (NORMODYNE)

- carvedilol (COREG)

What receptors are affected by Labetalol?

- α1 is blocked causing vasodilation and reducing inotropic activity, leading to reduction of cardiac output

- β1 is blocked thus decreasing (+) chrono, inotropic activity and reducing cardiac output

- β2 is partially activated causing vasodilation

Remember that Labetalol is non-selective for both alpha and beta receptors.

Which drugs are used as an α and β combination hypertensive drug?

- Labetolol (Mixture of four stereoisomers)

- Carvedilol (third generation beta blocker, but with α1 receptor antagonist activity)

Which of the following hypertensive therapy would most likely result in reflex cardiac chronotropy for a short-term therapy?

a. thiazide diuretics

b. loop diuretics

c. α1 antagonists

d. β1 selective blockers

α1 antagonists

α1 blockers (antagonists) results in reflex cardiac chronotherapy for short-term therapy

Carvedilol is used for what types of treatment?

- Hypertension

- Heart failure

What receptors does the drug Carvedilol (Coreg) affect?

- α1 (non selective antagonist, 10%)

- β1 (Non selective antagonist, 90%)

- The ratio of alpha 1 to beta receptor antagonist potency or carvedilol is 1:10

Labetalol is _____-____________

- NON-SELECTIVE

Name the two MAJOR side effects associated with α1 adrenergic receptor antagonists hypertensive drugs

- Orthostatic Hypotension (during first dose)

- Water and Salt Retention (during chronic use)

The ratio of α1 to β receptor antagonist potency for carvedilol is...

1:10

Carvedilol PREVENTS reflex with the α1 receptor antagonism of peripheral resistance (10%) due to its main effect on cardiac output (90%)

Carvedilol is used for treatment of _______ and ________ ______ _______

- hypertension

- symptomatic heart failure

α2 adrenergic receptor agonist MOA

activates Gαi which inhibits cAMP and causes activation of α2

How does α2 adrenergic receptor agonist lower blood pressure?

α2A activation to prevent further release of norepinephrine

The immediate effect of α2 adrenergic receptor agonist causes...

blood pressure spike.

At higher doses, it will cause a great spike in blood pressure so avoid sudden bolus, we need to inject slowly.

Clonidine (CATAPRES) is not a drug of choice for monotherapy of hypertension because of its __________

a. CNS side effect of the heart

b. contact dermatitis

c. low efficacy to treat pheochromocytoma

d. rebound hypertension effect

CNS side effect of the heart.

It may cause arrhythmia by interacting with the Sino-atrial node (sinus arrest)

An antihypertensive agent that has the least CNS side effects is ____________

a. methyldopa (ALDOMET)

b. metyrosine (DESMER)

c. guanadrel (HYLOREL)

d. reserpine (HARMONYL)

guanadrel

Guanadrel is a peripherally acting inhibitor so it has the least effects on the CNS.

Which of the following statement is correct about labetalol (NORMODYNE)?

a. It has partial agonist selectivity for α1 receptor

b. It has partial agonist selectivity for α2 receptor

c. It has selective activity for β1 receptor

d. It has inhibitor activity for α1-receptor

It has inhibitor activity for α1-receptor

A. is not correct because labetalol is NON-SELECTIVE in its activity

Methyldopa is a ______________

- pro-drug

Methyldopa is converted to α-methyldopamine and converted to α-methylNE (α-methylnorepinephrine)

Methyldopa MOA

methylDOPA is converted to α-methyldopa by aromatic L-amino acid decarboxylase.

α-methyldopa is converted to α-methylNE by dopamine β-oxidase

α-methylNE activates α2A in the nerve terminal of CNS which causes decrease in NE

α-methylNE activates ______ in the nerve terminal of CNS

- α2A

However, it does not metabolize by MAO. So there is buildup which may lead to "pseudo tolerance". This is the downside of Methyldopa.

The α-methylnorepinephrine will __________.

a. activate α2A adrenergic receptor in nerve terminal

b. activate α2B adrenergic receptor in blood vessel

c. inhibit α1A adrenergic receptor in blood vessel

d. inhibit α1B adrenergic receptor in nerve terminal

Activate α2A adrenergic receptor in nerve terminal.

α-methylNE is a byproduct of Methyldopa (pro-drug)

Methyldopa (ALDOMET) has an advantage of treating patients with...

pregnancy, when they have pre-eclampsia (pregnancy-induced HTN).

Main advantage of using methyldopa over other medications.

Guanadrel (Hylorel) MOA

"False Neurotransmitter"

Guanadrel (Hylorel) will accumulate, store, and release like NE or other NT.

Guanadrel is stored in the nerve terminal of PNS

Guanadrel INHIBITS ____ in the blood vessel

- α2B

Guanadrel functions in the peripheral nervous system.

Carvedilol is a ___ __________ (third generation), but with ____ receptor ANTAGONIST activity

- β blocker

- α1

The ratio of α1 to β receptor antagonist potency for carvedilol is 1:10

What is the Mechanism of Action for α2a agonist hypertensive drugs?

- The mechanism of action for a2 adrenergic receptor agonists is that they stimulate the

α2A adrenergic receptors in the brainstem, resulting in a reduction in sympathetic outflow

from the CNS

Why are α2a agonists not commonly used?

- CNS side effects on the heart

What is the mechanism of action for Guanadrel (Hylorel)?

- Inhibits the function of peripheral prostganglionic adrenergic neurons by acting as a "false neurotransmitter"

- Guanadrel is stored in the body and when NE is released, Guanadrel will compete with NE to reach the receptor

What are the side effects associated with Methyldopa?

- Sedation

- Depression

- Dry mouth

- Parkinsonian

- Hyperprolactinemia (increase prolactin)

- Gynecomastia (breast enlargement)

- Galactorrhea (milk production)

To minimize these side effects, a single dose at bedtime is recommended, however some patients require more than one dose

Methyldopa can be used with pregnancy, True or False?

True, Methyldopa is not CI for pregnant patients, this is one of the advantages of this drug

When do we generally use alpha 2 agonists?

When patients are not responding to combination of other types of antihypertensive drugs

Which of the following is correct for metyrosine (DEMSER)?

a. It causes psychosedation

b. It is a pro-drug

c. it acts a false neurotransmitter

d. it inhibits neuro-vesicular transporter

It causes psychosedation

This is similar side effect to Reserpine (Harmonyl)

Metyrosine (DEMSER) MOA

α-methyl-L-tyrosine and tyrosine hydroxylase

Reserpine (HARMONYL) are contraindicated in patients with....

a history of depression

Reserpine (HARMONYL) MOA

Sympathectomy

Functions on the pre-synaptic neuron to prevent the release of norepinephrine from release in the synapse i.e., inhibition of catecholamine transporter

Which of the following statement is correct about labetalol (NORMODYNE)?

a. It has partial agonist selectivity for α1-receptor.

b. It has partial agonist selectivity for α2-receptor.

c. It has selective activity for β1-receptor.

d. It has inhibitory activity for α1-receptor.

It has inhibitory activity for alpha 1 receptor

Which of the following statement is correct about carvedilol (COREG)?

a. It is used in emergency hypertension.

b. It has partial agonist selectivity for α2-receptor.

c. It has selective activity for β1-receptor.

d. It has inhibitory activity for α1-receptor.

It has inhibitory activity for alpha 1 receptor

lonidine (CATAPRESS) is not a drug of choice for monotherapy of hypertension because of its __________.

a. CNS side effect on the heart

b. contact dermatitis

c. low efficacy to treat pheochromocytoma

d. rebound hypertension effect

CNS side effect on the heart

The following anti-hypertensive agents are contraindicated in pregnancy, except __________.

a. aliskiren (TEKTURNA)

b. captopril (CAPOTEN)

c. losartan (COZAAR)

d. methyldopa (ALDOMET)

methyldopa (Aldomet)

Guanadrel (HYLOREL) will __________.

a. activate α1A adrenergic receptor in blood vessel

b. activate α1B adrenergic receptor in nerve terminal

c. inhibit α2A adrenergic receptor in nerve terminal

d. inhibit α2B adrenergic receptor in blood vessel

inhibit α2B adrenergic receptor in blood vessel

Long-term use of α1 antagonists may cause ________ ________ __________ unless given in combination with a diuretic.

- congestive heart failure

Due to salt and water retention, a counter effect of cardiac output, the body of the patient will overload and become congested causing congestive heart failure.

Due to partial agonism of β1 in labetalol, it is considered...

a blocking effect or slight increase of cardiac output versus A LARGE INCREASE of cardiac output of normal β1 agonism. This is easier understood for β1 as being an antagonist of this receptor instead.

Labetalol is a partial agonist (i.e., easier to understand as an antagonist due to decreased effects vs. regular agonism) of β1 and a partial agonist of ______

- β2

However, partial agonism of β2 leads to vasodilation of the blood vessels (this is partial activation).

In β1 agonism, it still slows down normal chrono, inotropic activity in full agonism.

Labetalol inhibits α1 as a partial agonist as well but its considered antagonism by reducing the effects of full agonism with partial.

Labetalol has the disadvantages that are inherent in _____-________ ______________ products: the extent of α receptor antagonism compared to β receptor antagonism is somewhat _________ and varies from patient to patient

- fixed-dose combination

- unpredictable

Labetalol has the disadvantages that are inherent in fixed-dose combination products: the extent of α receptor ______________ compared to β receptor __________ is somewhat unpredictable and varies from patient to patient

- antagonism

- antagonism (technically partial agonism of both receptors)

Labetalol is given INTRAVENOUSLY to reduce blood pressure rapidly for...

hypertensive emergencies

Due to Carvedilol's non-selective ___________ effects on _____ (~10%) and _____ (~90%) receptors

- blocking

- α1

- β1

It prevents reflex on the peripheral resistance.

Carvedilol's main MOA to reduce blood pressure is through β1 antagonism, which reduces (+) chronotropic, inotropic activity of the heart and cerebral cortex but the 10% from α1 blockage allows it to vasodilate the blood vessels to prevent reflex.

Carvedilol's main MOA to reduce blood pressure is through ___ __________, but the 10% from α1 blockage allows it to vasodilate the blood vessels to prevent _________.

- β1 antagonism (i.e., reduces CO via reduction of (+) chronotropic, inotropic activity of the heart and cerebral cortex)

- reflex (from peripheral resistance)

α2 adrenergic receptor agonists drugs

clonidine (CATAPRES)

guanabenz (WYTENSIN)

guanfacine (TENEX)

α2 adrenergic receptor agonists MOA

Gαi -> inhibits cAMP production .> increase in α2 agonism

How does α2 adrenergic receptor agonists lower blood pressure?

α2A activation prevents further release of NE

However, when α2A adrenergic receptor agonists are used it causes a spike of blood pressure at first due to α2B agonism.

What happens when a higher dose of α2 adrenergic receptor agonists is given?

There is a blood pressure spike due to α2B agonism of blood vessels causing vasoconstriction. A higher dose will cause a greater spike.

If we do injection, it is recommended that it is very slowly.

Pheochromocytoma

Adrenal gland tumor that causes the overproduction and excess release of catecholamines such as NE

α2 adrenergic receptor agonists may be used in patients with...

pheochromocytoma prior to surgery to inhibit the action of excess NE

α2 adrenergic receptor agonists causes a reflex in...

Cardiac output due to effects of peripheral resistance (i.e., NE release which inhibits vasoconstriction)

Thus, it is effective to use in combination with a β blocker to prevent reflex

α2 adrenergic receptor agonists is often combined with...

β blocker to prevent reflex

α2 adrenergic receptor agonists major adverse effects

1. postural hypotension (common)

2. symptomatic bradycardia and sinus arrest( can cause arrhythmia, very bad side effect thus withdrawn from market)

3. promote CHF (very bad side effect thus withdrawn from market)

4. CNS related side effects (sedation, xerostomia, erectile dysfunction, sleep disturbances, depression)

5. contact dermatitis (only found in clonidine patch)

Methyldopa is a _________ _________ ____________

- centrally activating activator

Methyldopa works on the CNS

Guanadrel is a __________ ___________ ___________

- peripherally acting inhibitor

Drugs such as reserpine and metyrosine are both ______________ and ____________ acting _____________

- peripheral

- central

- inhibitors

Metyrosine

Demser (tyrosine hydroxylase inhibitor)

Reserpine

HARMONYL

Methyldopa has ______________ reflex

- minimal

Pseudo-tolerance effect (in methyldopa, guanadrel, reserpine and metyrosine) is due to ______ and _______ ___________

- salt

- water retention

Which can lead to angioedema and CHF

Guanadrel will __________, ________ and ________ like norepinephrine

- accumulate

- store

- release

Acts like NE in the nerve terminal of the peripheral nervous system and INHIBIT α2B in the blood vessel, which prevents vasoconstriction and cause vasodilation. Potential minor reflex in CO increase (short-term)

Guanadrel is contraindicated in patients with...

pheochromocytoma

Guanadrel can only work when PNS is firing, in order for Guanadrel to be effective we need more Guanadrel than NE. Guanadrel will be out competed by NE level.

Guanadrel ____________ α2B in the blood vessel

- INHIBITS

It does this by competing with NE in terms of storage and release, which prevents NE to act on α2B to cause vasoconstriction thus, increase in vasodilation.

Metyrosine is used as an adjuvant to _____________ and other ___ _____________ __________ agents

- phenoxybenzamine (non-selective α1 blocker)

- α adrenergic blocking

Reserpine (HARMONYL) and Metyrosine (DEMSER) Adverse Effects

CNS (psychotic depression, suicidal risk)

PNS (orthostatic hypotension)