2 - Anti-Hypertensive Pharmacoloy- CNS, RAAS- acting drugs

What is the equation for blood pressure?

BP = CO × TPR

BP → Blood pressure

CO → Cardiac output

TPR → Total peripheral resistance

What are the main systems that regulate blood pressure?

SNS → sympathetic nervous system

RAAS → renin-angiotensin-aldosterone system

Local modulators

What is the baroreflex and what does it do?

Is the body's automatic response to changes in BP

It adjusts HR, cardiac output, and blood vessel constriction to help maintain normal BP

Sympathomimetic agents?

“Mimics” the endogenous ligand

Are agonists of α/β adrenergic receptors

Increases sympathetic activity

Sympatholytic agents?

Blocks or reduces α/β adrenergic receptors

Decreases sympathetic activity

What do adrenergic receptor subtypes have in common?

All α and β adrenergic receptors are linked to G-proteins

Cytosolic-localized GTPase enzymes that activate signaling pathways inside the cell

What G-protein is α1 coupled to, and what is its effect?

“squeeze”

Gq/11 → increases Ca²⁺

Contractibility, increases blood pressure

What G-protein is α2 coupled to, and what is its effect?

Inhibitory

Gi/o → decreases adenylyl cyclase

Decreased adenylyl cyclase in the heart, decreased cAMP and Ca²⁺ overall decreasing heart rate and contractility

What G-protein are β receptors coupled to, and what is their effect?

Stimulatory

Gs → increases adenylyl cyclase

Increased adenylyl cyclase, increased cAMP and Ca²⁺ → increased heart rate and contractility

How do β receptors differ in smooth muscle vs. cardiac muscle?

Smooth muscle → β2 activation relaxes blood vessels and lowers BP

Cardiac → β1 activation increases heart rate and contractility and raises BP

What is the effect of β receptor activation on NE release at the sympathetic nerve terminal?

It creates POSITIVE FEEDBACK, INCREASING NE RELEASE

NE is released → binds β receptor → signals the nerve terminal to release MORE NE

What is the effect of α2 receptor activation on NE release at the sympathetic nerve terminal?

It creates NEGATIVE FEEDBACK, DECREASING NE RELEASE

NE is released → binds α₂ receptor → signals the nerve terminal to release LESS NE

How does sympathetic activity increase cardiac output?

SNA releases NE, which activates β₁ receptors

Increasing heart rate and contractility and therefore increasing cardiac output and BP

How does sympathetic activity affect renin?

Sympathetic activity activates β₁ receptors in the kidneys

Increasing renin release and activating RAAS, which raises blood pressure.

How does β2 activation affect blood vessels?

β₂ activation increases cAMP

Causing vasodilation and decreased vascular resistance and BP

What controls vascular resistance and helps determine blood pressure?

Neural and local mechanisms control vascular resistance (TPR)

Which along with cardiac output (CO) determines blood pressure

What is the basic RAAS pathway?

β₁ stimulation causes renin release →

Renin converts angiotensinogen to Ang I →

ACE converts Ang I to Ang II →

Ang II activates AT1, causing vasoconstriction and aldosterone release →

Aldosterone increases sodium and water retention, raising BP →

What does Ang II do to increase BP?

Ang II activates AT₁ receptors

Causing vasoconstriction and aldosterone release, which increases BP

How does aldosterone increase BP?

Aldosterone increases sodium and water retention

Which increases blood volume and raises blood pressure

How does RAAS interact with the CNS/SNS?

Ang II increases sympathetic activity, which increases NE release and β₁ stimulation

Promoting more renin release and creating a cycle that raises BP

What happens when antihypertensive drugs inhibit SNA?

It decreases NE and epinephrine release

Reducing vascular resistance and lowering blood pressure

Examples of centrally acting sympatholytics?

Agonists of a2 and I1

1st gen → alpha-Methyldopa (prodrug), Clonidine, Guanfacine

2nd gen → Rilmenidine, Moxonidine

Difference between 1st and 2nd sympatholytics?

2nd gen have a getter affinity for I1 »»than a2

What receptors does centrally acting α₂ and I₁ agonists act on?

α₂ and I₁ receptors in the CNS

Second generation → high affinity for I1 » over A2

How do sympatholytics lower BP?

Decreases SNA

Reducing heart activity, renin release, and vascular resistance

How do Sympatholytics indirectly suppress RAAS?

They reduce NE stimulation of renal β₁ receptors

Decreasing renin release and RAAS activity, which lowers blood pressure.

How do centrally acting α₂ and I₁ agonists lower BP?

Sympatholytics

Reducing sympathetic activity and NE release, which lowers vascular resistance and BP.

Sympatholytic at central/presynaptic vs. vascular α₂ receptors?

The agonists activates both

Central/presynaptic α₂A → decreases vascular resistance → decreases BP

Vascular α₂A → increases vascular resistance → opposes the BP-lowering effect

Even though its opposing ….. the vascular effects do not negate the central / presynaptic effects

What are the therapeutic uses of centrally acting drugs?

Hypertension

Autonomic Failure → Extensive hypertension

What is the drug of choice for hypertension in pregnancy?

α-Methyldopa

Is clonidine a good choice for treating pheochromocytoma-induced hypertension?

No

Clonidine is used diagnostically, not as the primary treatment

If clonidine FAILS to suppress catecholamine levels, this supports a diagnosis of pheochromocytoma

How is ethanol a “double edged sword” to sympathetics?

It counteracts clonidine evoked hypotension → by activating CNS activity

It also enhances clonidine-evoked sedation

Ethanol is double-edged → less hypotension, more sedation

Side effects of sympatholytics?

Sedation!

Rebound phenomenon

What centrally acting agonist side effects are more evident with Alpha-Methyldopa?

Hemolytic anemia

Hepatitis

What is the rebound phenomenon with clonidine?

Sudden discontinuation of clonidine causes a surge in NE release
Activating α1 and β1 receptors and causing a rapid increase in BP

Clonidine → do NOT stop abruptly → risk of severe rebound hypertension!!

Adrenergic neuron blockers?

Peripherally acting → Guanethidine

Peripherally and Centrally acting → Reserpine

MOA of Guanethidine?

It gets taken up into the presynaptic nerve terminal by NET

Then enters presynaptic vesicles and displaces catecholamines/NE→ reducing their availability for release

I.e. → Displaces NE from presynaptic vesicle → decrease sympathetic activity

Side effects of peripherally acting adrenergic neuron blocker, Guanethidine?

Orthostatic Hypotension

Drug-drug interactions with peripherally acting adrenergic neuron blocker, Guanethidine?

Phenylephrine/cold medicines → α1 vasoconstriction → can oppose BP lowering

Cocaine and TCAs → inhibit NE uptake → interfere with guanethidine

Ethanol → enhances guanethidine-induced hypotension

How does tyramine reverse guanethidine-induced hypotension?

Tyramine displaces guanethidine and releases stored NE

Causing α1-mediated vasoconstriction that raises BP and reverses hypotension

MOA of Reserpine?

Blocks VMAT, a transporter, preventing NE from being stored in presynaptic vesicles

Causing NE depletion and decreasing sympathetic activity, decreasing BP

Side effects of peripherally and centrally acting adrenergic neuron blocker, Reserpine?

Sedation

Depresion

G.I Ulcerations

Sides effects are less evident with lower (0.05-0.1mg/d) vs prescribed (0.75-10mg/d) doses

Precautions and DDIs with Reserpine?

Migraine → avoid/use caution because reserpine can worsen or trigger migraines.

Cold medicines / vasoconstrictors → can oppose BP-lowering effects by causing vasoconstriction

Examples of alpha-blockers?

Selective A1 → Prazosin, Doxazosin

Non selective A1+A2 → Phentolamine

How does α1 blockade by phentolamine lower BP?

α1 blockade causes vasodilation

Why can phentolamine cause tachycardia?

α2 blockade increases NE release

Which stimulates β1 receptors and increases HR and contractility

How does prazosin / doxazosin lower BP?

They block α₁ receptors

Causing vasodilation and lowering vascular resistance and BP.

Why does prazosin / doxazosin cause less tachycardia than phentolamine?

They selectively block α₁ receptors

While phentolamine also blocks α₂ receptors, negative feedback… which increases NE release and causes more reflex tachycardia

Side effects of alpha receptor blockers?

Orthostatic hypotension

Sexual dysfunction

Exaggerated tachycardia → non-selective

What side effects of alpha receptor blockers is more evident with selective blockers?

First dose effect phenomenon → can cause a sudden, exaggerated drop in BP

Increase risk of developing CHF

What is a selective β1-blocker?

Atenolol → mainly blocks β1 receptors in the heart

What is a nonselective β-blocker?

Propranolol → blocks both β1 and β2 receptors

Which β-blocker is β1-selective and also generates NO?

Nebivolol → β1-selective and promotes NO generation → vasodilation

Which β-blocker is a partial agonist due to intrinsic sympathomimetic activity (ISA)?

Pindolol

It has (+) ISA → meaning it partially activates β receptors while also blocking them

What is the role of β-blockers in hypertension treatment?

NOT first-line for hypertension → because they have a greater risk of developing diabetes compared with other antihypertensives

They are mainly used when there is a compelling indication → such as heart failure or post-MI

How do β-blockers lower BP?

They block β₁ receptors → reducing heart rate, contractility, and renin release

What is a unique effect of nebivolol?

Is β₁-selective and increases NO, causing vasodilation

Adverse effects of Beta blockers?

Adverse lipid profile → in non ISA

Hyperglycemia

Excessive bradycardia

Hyperkalemia!!!

Fatigue

Contraindications with Beta Blockers?

Asthma or diabetes

Peripheral arterial disease (PAD) traditionally → but was recently challenged because nebivolol and metoprolol did not worsen PAD in studies

What is the rebound phenomenon with β-blockers, and how can it be avoided?

Abruptly stopping a β-blocker can cause rebound tachycardia, hypertension, and other cardiac effects

Avoid it by gradually tapering the dose

Why should β-blockers not be used alone in pheochromocytoma?

Pheochromocytoma releases excess NE, which strongly stimulates α1 receptors and causes vasoconstriction

Blocking β receptors first leaves the α1 vasoconstriction unopposed → which can dangerously increase BP!!!

Why can β-blockers be a concern during exercise?

Can limit the normal increase in heart rate and cardiac output during exercise

Which can reduce exercise tolerance

What happens during a hyper-adrenergic state (“adrenaline rush”)?

Increased NE and epinephrine stimulate adrenergic receptors

This can occur with exercise, pheochromocytoma, hypoglycemia, or cocaine overdose

What can happen during an adrenaline rush from β2 activation?

Muscle fasciculations → involuntary twitches

Hypokalemia

Why can β-blockers cause hyperkalemia?

β2 normally moves K⁺ into cells → blocking β2 reduces this effect, increasing blood K⁺

What can happen if a β-blocker is given during a hyper-adrenergic state?

Paradoxical hypertension can occur!!!

Because β2 blockade removes β2-mediated vasodilation → leaving α1-mediated vasoconstriction unopposed

Drug-drug interactions of Beta Blockers?

Potassium-sparing diuretics → increased risk of hyperkalemia

NSAIDs

Precautions with beta blockers?

New onset diabetes → particularly in older more obese patients and in those with existing metabolic syndrome

Mixed α- and β-blockers?

Labetalol and Carvedilol

Block α1, β1, and β2 receptors

Advantages of mixed α- and β-blockers?

α1 blockade prevents vasoconstriction and β1 blockade prevents reflex tachycardia

Making them useful in hyper-adrenergic states!!!

Which peripherally acting vasodilators primarily target the arteries?

Hydralazine

Minoxidil

CCB

Fenoldopam

Aprocitentan / Tryvio

Diazoxide

Which peripherally acting vasodilators target both arteries and veins?

Nitrates → direct vasodilator

MOA of increases NO, causing arterial vasodilation and lowering BP.and side effects?

Increases NO, causing arterial vasodilation

Side effects → Lupus like syndrome!

What is the MOA of minoxidil and diazoxide?

Open K⁺ channels, causing hyperpolarization, less Ca²⁺ entry, and vasodilation

What is Minoxidil a prodrug of?

Minoxidil N-O Sulfate

Side effects of Minoxidil and Diazoxide?

Water retention

Hair growth

Increased cardiac output

What adjunctive therapy is added to hydralazine, minoxidil, or diazoxide, and why?

Diuretic → reduces fluid retention

β-blocker → reduces increased cardiac output

What is the role of Ca²⁺ in vascular smooth muscle?

Ca²⁺ promotes smooth muscle contraction

How do CCBs affect cardiac muscle?

CCBs block L-type Ca²⁺ channels → causing decreased contractility (negative inotropy) → therefore decreased O₂ demand → decreased CO

Which CCBs also slow SA/AV node activity?

Verapamil and diltiazem

Block Ca²⁺ channels in the SA and AV nodes → causing slower conduction and HR and decreased contractility/CO

What are the 3 major families of calcium channel blockers and their prototypes?

Dihydropyridines (DHPs) → nifedipine, amlodipine, nicardipine, felodipine — act mainly on vascular L-type Ca²⁺ channels

Phenylalkylamine → verapamil → non-selective block of cardiac and vascular Ca channels

Benzothiazepine → diltiazem → non-selective block of cardiac and vascular Ca channels

MOA of Calcium Channel blockers?

Block voltage-gated L-type Ca²⁺ channels → reducing Ca²⁺ entry into cells → decrease contraction → decreased CO

Advantages of calcium channel blockers?

Well tolerated in diabetes and asthma

Effective in low-renin hypertension

No reflex tachycardia → EXCEPT NIFEDIPINE!!!!!

What are important precautions with CCBs?

Verapamil → increases serum digoxin levels and toxicity, and with quinidine → can cause substantial hypotension

Nifedipine → avoid in ischemic heart disease

MOA of sodium nitroprusside?

Releases NO → causing arterial and venous vasodilation

What is sodium nitroprusside used for?

Drug of choice → for hypertensive emergencies

Given by titrated IV infusion with direct BP monitoring

Precautions with sodium nitroprusside?

Monitor thiocyanate levels → due to risk of cyanide/thiocyanate toxicity → especially with kidney failure

MOA of aprocitentan / Tryvio ?

Blocks endothelin A and B receptors → reducing the vasoconstricting effects of ET-1

What is aprocitentan / Tryvio used for?

Treatment-resistant hypertension

Was approved in March 2024

Is the first new therapeutic target for systemic hypertension in over 30 years

What is neprilysin?

An enzyme involved in breaking down natriuretic peptides and other vasoactive substances → including Ang II

What is the overall result of Ang II acting at AT1 receptors?

Rapid pressor response → meaning a rapid increase in blood pressure

How does Ang II cause the rapid pressor response?

Ang II activates AT1 receptors

Causing vasoconstriction and increased sympathetic/NE activity

Which rapidly raises BP

How does Ang II cause the slow pressor response?

Ang II activates AT1 receptors

Causing Na⁺/water retention, aldosterone release, and renal vasoconstriction

Which increases blood volume and sustains higher BP

How does Ang II cause cardiovascular remodeling?

Ang II activates AT1 receptors

Increasing cardiac afterload and vascular wall tension

Leading to cardiac and vascular hypertrophy and remodeling over time

What drugs inhibit the renin-angiotensin system at the renin step?

β-blockers inhibit renin release

While aliskiren directly inhibits renin activity!

Why does Ang II increase with an ARB?

ARB blocks AT₁ → less AT₁ signaling → increased renin → increased Ang I → increased Ang II

What is the important combination-therapy warning for aliskiren?

Do NOT combine aliskiren with an ACE inhibitor or ARB in patients with diabetes

It can cause renal failure!!!!

Side effects of ACE inhibitors?

Cough → iron supplement dampens this

Hyperkalemia → also applies to BBs, ARBs, DRIs

Rash

Angioneurotic edema

Precautions of ACE inhibitors?

Fetal harm → exposure during the first trimester should be avoided

Acute renal failure → in presence of renal artery stenosis

What is the significance of centrally active ACE inhibitors?

They cross the BBB and may reduce dementia risk

Captopril, Fosinopril, Ramipril, Lisinopril, Perindopril, Trandolapril, Trandolapril