Pharm of Hypertension

Pharmacotherapy of
hypertension
Patrick Edsall, PharmD

patrickedsall@rossu.edu
Ross University, School of Medicine
1
Preamble
• Practice questions available on eCollege
• Recommended reading:
– Basic and Clinical Pharmacology, by Katzung and Trevor, Section III, 13th Edition
• Ch 11, Antihypertensive Agents:
http://accessmedicine.mhmedical.com/content.aspx?bookid=1193&sectionid=69104839
• CH 17, Vasoactive Peptides: http://accessmedicine.mhmedical.com/content.aspx?bookid=1193&sectionid=69106039
– Goodman & Gilman’s The Pharmacological Basis of Therapeutics, by Brunton,
Chabner & Knollman, 12th Edition
• Ch 26: Renin and Angiotensin: http://accessmedicine.mhmedical.com/content.aspx?bookid=374&sectionid=41266233
• CH 27: Treatment of Myocardial Ischemia and Hypertension:
http://accessmedicine.mhmedical.com/content.aspx?bookid=374&sectionid=41266234
2
Prior Lecture Context
• From Cellular Signaling
– Recall GPCR and ligand-gated signaling
• From Diuretics 1/2/3
– Recall pharmacology for diuretics
• From Intro to ANS Pharmacology
– Recall responses of effector organs for cholinergic and
adrenergic impulses, esp cardiovascular, renal and lungs
3
Learning Objectives
1. List the antihypertensive drug classes:
a. Diuretics
b. Sympatholytics
c. Vasodilators
d. Inhibitors and antagonists of the renin-angiotensin system
(RAS)
4
Learning Objectives
2. List the following drugs and assign them to the appropriate
antihypertensive class:
– hydrochlorothiazide, indapamide, furosemide, spironolactone,
clonidine, methyldopa, prazosin, propranolol, labetalol, esmolol,
hydralazine, nitroprusside, minoxidil, diazoxide, nifedipine,
nicardipine, verapamil, diltiazem, fenoldopam, aliskiren, captopril,
enalapril, enalaprilat, losartan
5
Learning Objectives
3. For each drug in the drug list:
a. Explain the molecular mechanism of action of each class or
subclass of antihypertensive drug
b. Describe the hemodynamic and non-vascular actions of
antihypertensive drugs
c. Describe the routes of administration and the elimination
processes of antihypertensive drugs
d. Describe the main adverse effects and contraindications of
antihypertensive drugs
6
Learning Objectives
4. Outline the strategies for the clinical use of antihypertensive
drugs in hypertension and other cardiovascular disorders
7
Hypertension Agents LO #2
Drug Classes and Drugs to consider

Inhibitors and antagonists
Diuretics Sympatholytics Vasodilators of the renin-angiotensin
system
(hydrochlorothiazide*) (clonidine*) hydralazine aliskiren

(indapamide*) (methyldopa*) minoxidil captopril
(furosemide*) (prazosin*) nitroprusside enalapril - enalaprilat
(spironolactone*) (propranolol*) diazoxide losartan
(labetalol*) fenoldopam
(esmolol*) (nifedipine**)
(nicardipine**)
(verapamil**)
(diltiazem**)
Drugs in brackets either have been*, or will be**, mentioned elsewhere

8
8
Context
Hypertension
• Why are we concerned?
– Damage: vessels in heart, kidney, brain
– Associated:
• renal failure, coronary disease, HF
• stroke, dementia
• Decreased BP
decreased morbidity
decreased mortality
• Unfortunately, only 1/3 of diagnosed patients control BP

appropriately…
• First line: reduction of sodium intake (lifestyle) 9
9
Pharmacological targets LO #3
Review
BP = CO X PVR
• BP: Blood Pressure

• CO: Cardiac Output
• PVR: Peripheral Vascular
Resistance
FIGURE 11-1
10
Numbers 1-4 reflect the targets for pharmacology for hypertension

- There is ~instantaneous response / control exerted at
- PVR: Arterioles
- PVR: Postcapillary venules
- CO: Heart
- There is control exerted over a greater amount of time exerted at
- Renal control of volume
Under normal circumstances (postural changes, etc), influence exerted as part of a

feedback-control loop:
- Baroreceptors sense pressure, provide information to sympathetic NS
- RAS senses hemodynamics, responds
- What happens when you stand from lying down? Where is the blood pooling:
- Remember: Aldosterone impacts blood pressure by acting on the distal tubules and
collecting ducts of the nephron
- Increases reabsorption of ions and water to cause the conservation of sodium
- Secretion of potassium
 increase in blood pressure and blood volume
10
Homeostatic mechanisms regulating blood
pressure – nervous control
• The baroreceptor reflex
– Sensitivity range: 60-180 mmHg
– Activation time: few seconds
– Level of (theoretic) correction: ~ 90%
• The chemoreceptor reflex

• The response to brain ischemia

– Sensitivity range: < 40 mmHg
– Level of (theoretic) correction: ~ 90% 11
11
Homeostatic mechanisms regulating blood
pressure – humoral control
• The renin-angiotensin system
– Sensitivity range: < 100 mmHg
– Activation time: few minutes
• The renal regulation of salt and water excretion

– Sensitivity range: any blood pressure value
– Activation time: hours or days
• The aldosterone system

– Activation time: hours or days
– Level of (theoretic) correction: ~ 75% 12
Humoral response is slower than the response under nervous control
12
LO #1,2
Classifying antihypertensive drugs

• Diuretics
– Thiazides and congeners
– Loop diuretics
– Potassium-sparing diuretics
• Sympatholytics
– Centrally acting antiadrenergic agents
– α adrenergic blockers
– β adrenergic blockers
– α / β adrenergic blockers
13
Many of these agents you have seen previously. I will fill in any pharmacology you have not
seen, and try to give a reasonable picture of their use in the control of hypertension
13
LO #1
Classifying antihypertensive drugs

• Vasodilators
– Nitric oxide releasers
– K+ channel openers
– Ca2+ channel blockers
– D1-dopamine receptor agonists
• Inhibitors and antagonists of the renin-angiotensin system (RAS)
– Renin inhibitors
– Angiotensin converting enzyme (ACE) inhibitors
– Angiotensin receptor antagonists
14
14
LO #2,3
Diuretics (Decrease Na+, Volume)

• Therapeutic goal: reduction of vascular Na+
• Mechanism of action: Diuretics 1/2/3 lectures
• Effect
– Initial: ↓BP via ↓volume and ↓CO (PVR may ↑)
– 6-8 weeks: CO and volume normalize: ↓PVR
– Na+ contributes to PVR via ↑ vessel stiffness and neural reactivity
(mech unclear)
• ↑ Na+ leads to altered Na+-Ca2+ exchange, resulting in ↑ intracellular
Ca2+ (theory)
• ↓ Na+ input / diuresis reverses vessel stiffness

15
Additional proposed mechanisms:

Induction of renal prostaglandin biosynthesis
Opening of K+ channels → hyperpolarization → reduced probability of L-type Ca2+
channels opening → decreased Ca2+ entry and reduced vasoconstriction
15
LO #4
Diuretics
• Thiazides and thiazide-like drugs are first choice
antihypertensive agents
– Appropriate for mild-moderate hypertension with normal renal and
cardiac function
– Antihypertensive doses are lower than those required for diuresis
• Loop diuretics are preferable to thiazides only in some well

recognized clinical situations
– Malignant hypertension**, concomitant chronic kidney disease, etc
16
** The term "malignant hypertension" entered the medical lexicon in 1928 because, at that
time, patients with this condition had a prognosis that was similar to patients with many
cancers. However, antihypertensive therapies that can quickly and safely lower blood
pressure have improved outcomes and, therefore, the term is now used only by billing and
coding personnel. (Hypertensive emergency)
16
LO #4
Diuretics
• Potassium-sparing diuretics
– Can be used in combination with thiazides to counteract hypokalemia
– Spironolactone is used in the treatment of hypertension due to
hyperaldosteronism
• Diuretics can enhance the hypotensive effects of many

antihypertensive agents
• Adverse effects: (see Diuretics lectures), remember potassium!
17
17
LO #3
Diuretics
• Hemodynamic actions of thiazides
– Heart rate: normal
– Cardiac output: decreased (early), normal (late)
– Peripheral vascular resistance: unaffected (early), decreased (late)
– Postural hypotension: negligible
– Renal blood flow: decreased (early) normal (late)
– Efficacy of antihypertensive effect: moderate
18
18

system

(nicardipine**)
(verapamil**)
(diltiazem**)

19
19
Autonomic and hormonal control of cardiovascular
function
Review
BP = CO X PVR
• BP: Blood Pressure

• CO: Cardiac Output
• PVR: Peripheral Vascular
Resistance
FIGURE 6–7
20
This diagram helps illustrate the relationships between Autonomic and Hormonal control
of BP
- This section is about sympathetic control
- Note the major points of intervention for the SNS
20
Baroreceptor reflex arc
Vessel stretch inhibits sympathetic outflow
FIGURE 11-2
21
Baroreflexes are responsible for rapid, moment-to-moment adjustments in blood

pressure, such as in transition from a reclining to an upright posture.
• Central sympathetic neurons arising from the vasomotor area of the medulla are
tonically active.
• (1) Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about
by the internal pressure (arterial blood pressure).
• (2), (3) and (4) Baroreceptor activation inhibits central sympathetic discharge.
Conversely, reduction in stretch results in a reduction in baroreceptor activity.
• Thus, in the case of a transition to upright posture, baroreceptors sense the reduction in
arterial pressure that results from pooling of blood in the veins below the level of the
heart as reduced wall stretch, and sympathetic discharge is disinhibited.
• (5) The reflex increase in sympathetic outflow acts through nerve endings to increase
peripheral vascular resistance (constriction of arterioles) and cardiac output (direct
stimulation of the heart and constriction of capacitance vessels, which increases venous
return to the heart), thereby restoring normal blood pressure.
• The same baroreflex acts in response to any event that lowers arterial pressure,
including a primary reduction in peripheral vascular resistance (eg, caused by a
vasodilating agent) or a reduction in intravascular volume (eg, due to hemorrhage or to
loss of salt and water via the kidney).
21
LO #1
Sympatholytics
(↓PVR, ↑Venous Pooling, Inhibit cardiac function)
• Hypertension is initiated and sustained in part by sympathetic
activation
• Used in moderate to severe hypertension
• Adverse effects associated with sub-classes
• Eg. β-blockers have common adverse effects
• Use of these agents will likely engage a compensatory mechanism

which is not under sympathetic control
• Renal retention of Na+ leads to ↑ volume
 Use with a diuretic
22
22
LO #3
Sympatholytics
Centrally acting sympatholytic agents
• Mechanisms of action
• Clonidine:
– Activation of α2 in brain stem: activating an inhibitory neuron, resulting in
reduced sympathetic outflow from the CNS, producing a decrease in peripheral
resistance, renal vascular resistance, heart rate, and blood pressure. “↑
sensitivity to baroreceptors”
– Activates imidazoline receptor, final pathway for sympathetic outflow
• Methyldopa:
– False neurotransmitter, works like NE in periphery
– Therapeutic value is as clonidine in the brainstem
23
Vasomotor centers remain sensitive to baroreceptor input, these agents turn down the
response
- Not posturally dependent
- Clonidine:
- Activation of alpha 2 adrenoceptors in the lower brainstem region reduces
sympathetic outflow (main mechanism)
- At high doses, can see activation of peripheral alpha 2 adrenoceptors (not used
therapeutically)
- At imidazoline receptor:
- Non-adrenergic binding site located in rostral ventrolateral medulla,
which is the final common pathway for sympathetic outflow
- With reduced outflow, reduced HR (lower CO)
- With reduced outflow, reduced PVR
- With reduced outflow, relaxed capacitance
- With reduced outflow, reduced renal vascular resistance (maintain renal flow)
- Methyldopa:
- L-Dopa analog converted to alpha-methylnorepi – works as NE in periphery
- Therapeutic value is as clonidine centrally
23
LO #3
Sympatholytics
• Adverse effects
• CNS: drowsiness, depression, headache, asthenia, xerostomia, sleep
disorders, mental clouding
• Cardio: bradycardia (caution in HF, arrhythmia)
• Heme: possible positive Coomb’s test
• Other: sexual dysfunction, skin (clonidine patch)
• Caution, Contraindication
• Severe rebound hypertension in abrupt discontinuance
• Contraindication in clinical depression
• Caution with concomitant MAO inhibitors
24
• Hypertensive crisis may result from abrupt discontinuance

• Why Xerostomia?
• Salivary glands use parasympathetic activation for the watery secretions,
sympathetic for the viscous secretions (via alpha 2 and beta 2)
• Best answer I have seen: clonidine acts on the presynaptic alpha2-
receptor to decrease NE release and hence decrease secretions from the
salivary gland, resulting in xerostomia
24
LO #3
Sympatholytics
• Hemodynamic actions
– Heart rate and cardiac output: unchanged or slightly decreased
– Venous tone: slightly decreased
– Peripheral vascular resistance: decreased
– Postural hypotension: slight or negligible
– Renal blood flow: unchanged
• Therapeutic uses in hypertension

– Clonidine and methyldopa (usually given together with a diuretic) are second
choice antihypertensive agents
– Methyldopa is often preferred for the treatment of hypertension in pregnancy
(long experience has shown that it is not harmful to the fetus) (*BetaB and
CCBs are also used in Pregnancy*)
25
25
LO #3
From - Dr Babbini’s Introduction to ANS pharmacology lecture 26
- Quick review
- ALL are metabotropic
- ALPHA-1 ~ increases activity
- ALPHA-2 ~ decreases activity
- BETA ~ increases activity
- Beta-1: heart
- Beta-2 : lungs
26
LO #3
Sympatholytics
α1 adrenergic blockers
• Mechanism of action:
• Prazosin: selective inhibitor of α1 at arterioles and venules
• Adverse effects:
• Postural hypotension, especially after the first dose (tolerance)
• Dizziness, palpitations, lassitude, nasal stuffiness
• Sexual dysfunction, incl. priapism, delayed ejaculation
• Use in hypertension:
• Limited, can be used as second agent
• JNC 8 recommends against use for hypertension
• Can be useful for patients with benign prostatic hyperplasia
27
27
LO #3
Sympatholytics
α1 adrenergic blockers
– Heart rate: unchanged or slightly increased
– Cardiac output: unchanged or slightly increased
– Venous tone: decreased
– Postural hypotension: prominent
– Renal blood flow: unchanged
– Duration of the antihypertensive effect: variable, 10-24 h
• Why unchanged heart rate? (α1 selectivity)

• NE will be released in response to pressure drop, but will exert negative
feedback on PRESYNAPTIC alpha-2 receptors, self-limiting more NE release
(see note below) 28
• In addition, it is thought that prazosin will have some CNS effect whereby it may blunt
the baroreceptor reflex
• Salt and water will be retained, so use a diuretic concomitantly
28
LO #3
Sympatholytics
β adrenergic blockers
Proposed mechanisms of action
(decreasing order of importance)
1. Decrease in cardiac output

• Blockade of cardiac β1 adrenoceptors
2. Inhibition of renin release
• Blockade of β1 adrenoceptors of juxtaglomerular cells
3. Inhibition of norepinephrine release from presynaptic adrenergic
terminals
• Blockade of presynaptic β adrenoceptors
4. Reduction of central adrenergic tone
• Blockade of hypothalamic and bulbar β adrenoceptors
29
• The agents block beta receptors

• Some agents have additional activities
• Propranolol was first agent – less used for hypertension
• Used for stage fright
29
LO #3
Sympatholytics
β and α/β adrenergic blockers
Hemodynamic actions in hypertension
Propranolol Labetalol
(and other β blockers) (and other α/β blockers)
Heart rate: Decreased Unchanged
Cardiac output: Decreased Unchanged or decreased
Venous tone: Unchanged Decreased
Peripheral vascular resistance: Increased (early) Decreased
Decreased (late)*
Postural hypotension: Negligible Evident
Renal blood flow: Decreased (early) Unchanged
Normal (late)
Efficacy of antihypertensive effect: Good High
All B-blockers increase vasodilation, see Goodman & Gilman for discussion 30
Labetalol
- Blocks alpha1-, beta1-, and beta2-adrenergic receptor sites; elevated renins
are reduced. The ratios of alpha- to beta-blockade differ depending on the route of
administration: 1:3 (oral) and 1:7 (IV).
- Labetalol has 4 isomers: 2 are inactive, 1 is a potent alpha blocker, 1 is a
potent beta blocker
- MOA: at alpha  decreased systemic vascular resistance (no change in
HR/CO)
- IV for hypertensive emergency
Propranolol
- Competitively blocks response to beta1- and beta2-adrenergic stimulation
which results in decreases in heart rate, myocardial contractility, blood pressure,
and myocardial oxygen demand.
- Remember that Beta-blockers REDUCE PVR ultimately: multiple
mechanisms proposed; minimally, note the inhibition of renin release at
juxtaglomerulal tissue (see G&G for other mechanisms)
30
LO #3, 4
Sympatholytics
• Adverse effects
– Blocking β1: can become bradycardic
– Blocking β2: concern in asthma, peripheral vascular insufficiency
and diabetes
• Choice of agent –
– Pure β blockade can result in unwanted effects
• Esmolol is β1 selective: significant reduction of impact on airway
compared to propranolol (non-selective)
– Adding α blockade can help moderate reflex response to lowered
CO
31
- DM is not caused by beta-blockade, but should invoke caution. Normally,

catecholamines promote glycogenolysis in response to hypoglycemia, and non-
selective Beta blockers (hitting B2) can delay recovery from hypoglycemia in
insulin-dependent DM (infrequent in Type 2, non-insulin-dependent DM). Worth
noting is that beta-blockade can also blunt the patient’s awareness of
hypoglycemia (tremor / tachy / nervousness), with potentially dire
consequences. Use with caution in patients with frequent hypoglycemic events.
31
LO #4
Sympatholytics
• Use:
– Not first line hypertension agent, can be used with vasodilators to
block reflex
– HF and Post-MI: improved morbidity and mortality
– Labetalol: hypertensive emergency
– β-Blockade places ceiling on HR, even when exercising
32
32

system

(nicardipine**)
(verapamil**)
(diltiazem**)

33
33
LO #3
Vasodilators (Relax vascular smooth muscle)

Application Site of Action Mechanism of action
hydralazine Outpatient arterioles unknown
Hypertension
minoxidil Outpatient arterioles K+ channel opening
Hypertension
diazoxide Hypertensive arterioles K+ channel opening
Emergency
nitroprusside Hypertensive arterioles production of nitric oxide
Emergency and veins
fenoldopam Hypertensive arterioles D1-receptor activation
Emergency
dihydropyridine CCB Both arterioles Calcium Channel Blocker
non-dihydropyridine CCB Both arterioles and Calcium Channel Blocker
myocardium
34
“Relax” is a bit of a misnomer – more accurately: “decrease likelihood of contraction”
34
LO #3
Vasodilators
(Relax vascular smooth muscle)
• For hypertension:
– Relaxation of smooth muscle of arterioles leads to reduced
PVR (nitroprusside also relaxes veins)
– Compensation: baroreceptors  sympathetic NS

(and RAS and Aldosterone eventually)
 Use with other agents to maintain BP reduction
35
35
LO #3
Vasodilators - Hydralazine
– Relaxes arteriolar smooth muscle, exact mechanism uncertain,
evidence suggests:
• Inhibition of IP3 induced release of calcium from the sarcoplasmic reticulum
• Stimulation of NO release from vascular endothelium
• Opening high conductance K+ channel
• Therapeutic uses
– Hypertension (second choice drug)
– Heart Failure, especially in African American populations (along
with isosorbide dinitrate)
36
36
LO #3
– Heart rate: increased
– Cardiac output: increased
– Venous tone: unchanged
– Renal blood flow: increased
This will induce reflex responses
37
37
LO #3
• Adverse effects
– As an of extension of pharmacological effects:
• CNS: asthenia, headache, nausea, dizziness
• Cardio: palpitations, sweating and flushing, reflex tachycardia
• Cardio: myocardial ischemia, angina (in risk patients)
– Other:
• Lupus-like syndrome:
– arthralgia, skin rash, fever, serum sickness, hemolytic anemia
– reverses on discontinuation
• Contraindications and precautions
– Coronary artery disease
– Cerebrovascular disease
38
38
LO #3,4
Vasodilators - Minoxidil
– Opens K+ channels on smooth arteriolar muscle leading
to hyperpolarization and relaxation
 more difficult for Ca2+ channels to open
• Therapeutic uses:
– Useful in severe and drug-resistant hypertension
• Strong reflex sympathetic stimulation
• Must be used with loop diuretic and β blocker
39
39
LO #3
– Heart rate: much increased
– Cardiac output: much increased
– Efficacy of antihypertensive effect:high
– Duration of the effect: 24-48 hours
40
40
LO #3
– Na+ and water retention are prominent
– Increased HR, CO and myocardial O2 consumption

• Baroreceptor mediated activation
• Dangerous in Left ventricular hypertrophy and diastolic dysfunction  can lead
to heart failure
– Without appropriate regimen, tachyphylaxis, palpitations, angina,

edema
– Headache, sweating, hypertrichosis are common

41
Minoxidil is a potent stimulator of Renin production, although this is not seen to be the
cause of sodium/water retention.
Best used for men with refractory hypertension and renal insufficiency
Used topically for baldness (Rogaine)
41
LO #3,4
Vasodilators - Diazoxide
– Opens K+ channels on smooth arteriolar muscle leading to
hyperpolarization and relaxation
• Pharmacokinetics
– Like a thiazide-type diuretic, but no diuresis
– IV use for hypertensive emergency
– Insulinoma (used for hypoglycemia)
• Inhibits insulin release, possibly secondary to opening of K+ channels
on β cells of pancreas
42
Chemistry - The drug is a benzothiadiazine derivative

- Like thiazide diuretics, but it does not cause diuresis, apparently because it lacks a
sulphonamide group
42
LO #3
• Adverse effects
– Salt and water retention (same mechanism as minoxidil)
– Extreme hypotension may result
– Physiological reflex can cause/worsen:
• Angina, ischemia, heart failure in patients with ischemic heart disease
– Hyperglycemia is common (see proposed mechanism above)
– Hypertrichosis
• Contraindication and precautions

– Compensatory hypertension (i.e. stenosis of aorta)
– Impaired cerebral circulation
– Coronary disease
– Heart failure
– Sulfa drug hypersensitivity
• A sulfur atom is present in the diazoxide molecule
– Diabetes mellitus
43
43
LO #3
– Heart rate and cardiac output: increased
– Postural hypotension: absent
– Efficacy of antihypertensive effect: high
44
44
LO #3
Vasodilators - Nitroprusside
– Releases NO, which activates
the guanylyl cyclase – cyclic
GMP – PKG pathway
• Pharmacological effect:
– Dilates arterial and venous vessels, lowering PVR and
decreasing venous return
45
- NO activates guanylyl cyclase in vascular smooth muscle  increases intracellular

production of cGMP
- cGMP activates protein kinase G
- PKG activates phosphatases which inactivate myosin light chains
- Although used for hypertensive crisis, it is worth noting that many hypertension patients
appear to have impaired NO production
- Note both the NO and CN- moeities
45
LO #3,4
• Pharmacokinetics:
– Administered intravenously (commonly infused)
– Rapidly metabolized by red blood cells to NO and CN-; cyanide is
metabolized to thiocyanate
– Pharmacological effect lasts 1-10 minutes
– Hypertensive emergency
– Management of acute dissecting aortic aneurysm
– Severe heart failure (reduced afterload)
46
• In patients with normal left ventricular function (LVF), venous pooling is the
predominant effect on CO (CO falls)
• In patients with impaired LVF and diastolic ventricular distension, the reduction in
arterial impedance is the predominant effect, leading to a rise in CO
46
LO #3
• Adverse Effects:
– Cyanide accumulation (CN-)
• Metabolic acidosis, arrhythmias, cardiovascular collapse
• Death can occur
• Concomitant administration of sodium thiosulphate or
hydroxocobalamin(B12) can prevent cyanide accumulation without change
in the hypotensive efficacy
– Normal CN- metabolism  Thiocyanate
• Renal elimination – may be slow or impaired
• Excess can lead to weakness, disorientation, psychosis, muscle spasm,
convulsions
– Excessive hypotension / rebound hypertension
47
Cyanide poisoning can be treated with high doses hydroxocobalamin (vitamin B12)
47
LO #3
• Contraindications:
– Treatment of compensatory hypertension
– To produce controlled hypotension during surgery in patients

with known inadequate cerebral circulation or in moribund
patients requiring emergency surgery
– High output heart failure associated with reduced systemic

vascular resistance (eg, septic shock)
48
• Student should review these with an eye for describing why they are contraindications
• Compensatory HTN: why is compensation occurring? Underlying cause? (aortic
coarctation, arteriovenous shunting)
• During surgery with inadequate cerebral circulation: why not?
• HF with reduced SVR: what would happen?
48
LO #3
– Heart rate: increased
– Cardiac output: decreased (in non-HF)
– Venous tone: much decreased
– Peripheral vascular resistance: much decreased
– Postural hypotension: prominent
– Renal blood flow: small decrease
– Efficacy of antihypertensive effect: high
– Duration of the antihypertensive effect: 5-6 min
49
49
LO #3
Vasodilators - Fenoldopam
– Agonist at peripheral D1 receptors results in dilation of
peripheral arterioles and natriuresis
– Significant vasodilation of renal afferent and efferent arterioles
– Activation of D1-like receptors on the proximal tubules inhibits

tubular sodium reabsorption by inhibiting Na/H-exchanger and
Na/K-adenosine triphosphatase activity
50
- 6 times as potent as dopamine in producing renal vasodilatation; has minimal adrenergic

effects
- Under high Na+ conditions, Dopamine (at D1-like receptors), acts to limit the resorption
of Na through activity on Na-H and Na-K-ATP channels
- Hypo-K is 2/2 increased diuresis
- MOA hint (fenol-DOPAM) DOPAM = dopamine, agonist
50
LO #3,4
– Administered intravenously (infused)
– Pharmacological effect lasts ~ 1 hour
– Does not cross blood-brain barrier
• Therapeutic use:
– Hypertensive emergency
– Post-operative hypertension
51
51
LO #3
– Reflex tachycardia, headache, flushing
– Increased intraocular pressure
• Contraindications / concerns:
– Glaucoma
– Hypokalemia: monitor!
– Angina/obstructive coronary disease
• Tachycardia: increase O2 requirements
52
- Hypokalemia: Serum potassium concentrations <3 mEq/L were observed within 6 hours
of fenoldopam initiation; monitor potassium concentrations appropriately
52
LO #3
Vasodilators
Calcium Channel Blockers (CCBs)
• In-depth coverage in Angina lecture (soon!)
– Inhibits Ca2+ influx at vascular smooth muscle and myocardium
– Dihydropyridines (nifedipine and nicardipine)
• Smooth muscle relaxed, limited cardiac muscle effect
– Non-dihydropyridines (verapamil and diltiazem)

• Effect on cardiac muscle dominates, minor smooth muscle relaxation effect
53
53
LO #3,4
Vasodilators - CCBs
• Therapeutic use:
– Can be used as a first-line agent (more effective in AA population)
– Hypertensive emergency (nicardipine)
– Heart rate: increased (dihydropyridines); unchanged or decreased (verapamil,
diltiazem)
– Cardiac output: increased (dihydropyridines); unchanged (verapamil, diltiazem)
– Renal blood flow: unchanged or increased
54
- Long term epidemiological studies reported an increased risk of mortality when short-
acting nifedipine is used in hypertension. Slow-release formulations apparently do not
increase this risk. While there is still debate about causation, it seems that the sudden
decrease in blood pressure causes a pronounced reflex tachycardia which can precipitate
a myocardial infarction in patients at risk.
54

system

(nicardipine**)
(verapamil**)
(diltiazem**)

55
55
Renin and Angiotensin
• Renin-Angiotensin System (RAS)
participates significantly in the
pathophysiology of hypertension
• Angiotensin II
– Increases BP through a number of
rapid and slow processes
– Renin is rate-limiting step to
Angiotensin II production
56
56
• Renin is released by Granular

Juxtaglomerular Cells in wall of
the Afferent arteriole
Exocytosis into renal artery
• Note location of Macula Densa
57
57
Three major pathways controlling renin release
1. The macula densa pathway
– Decreased delivery of Na+ and Cl- to the distal tubule stimulates
renin release
2. The intrarenal baroreceptor pathway
– Decreased stretch of a stretch receptor on the afferent arteriole
stimulates renin release
3. The β-adrenoceptor pathway
– Activation of β1 adrenoceptors on juxtaglomerular cells stimulates
renin release
58
Pathway #1: Flux of NaCl across Macula Densa:

- Increased NaCl = inhibit renin
- Decreased NaCl = increase renin
• This is actually more focused on [Cl-] ions as the Na-2Cl-K co-transporter is saturated
with Na at this point
Pathway #2: BR within nephron

- Increase BP = decrease renin
- Decrease BP = increase renin
Pathway #3: NE release from postganglionic sympathetic nerves onto B1 receptors on

juxtaglomerular cells
58
(+) Tubular
Delivery of
NaCl to MD
(-)
Figure 26.2A (Goodman and Gilman).

Schematic portrayal of the three major physiological pathways regulating renin release.
59
Points to consider
- Note the three pathways to release RENIN
- Note the points of action on the system that are pharmacological interventions
- Note the Short and Long term feedback loops, and how they are modulated
SHORT loop negative feedback

Increased renin  increased AngII  activation of AT1 receptors on juxtaglomerular cells
 inhibit renin release
LONG loop negative feedback

Increased renin  increased AngII  activation of AT1 receptors  increased arterial BP
 (1) High pressure barorecep: activated  sympathetic reduction  reduced renin
 (2) Increased preglomerular pressure: reduced renin
 (3) Reduced NaCl reabs @ prox tubule  increased NaCl concentration at distal tubule
(seen at Macula densa)  reduced renin
59
• Angiotensin II formation
– Angiotensin converting enzyme (ACE) is a dipeptidyl carboxypeptidase that
hydrolyzes angiotensin I to angiotensin II
– The enzyme is located on the luminal surface of vascular endothelial cells
– The conversion takes places mainly in the lung, due to its large vascular bed, but
also in several other tissues (e.g. heart)
• Angiotensin receptors
– Four subtypes of angiotensin receptors: AT1 through AT4
– Most of the known actions of angiotensin II are mediated by the activation of AT1
receptors
– AT1 receptor is G-protein coupled
– Activation leads to a phospholipase C mediated generation of IP3/DAG
 Release of intracellular Ca2+
60
60
Actions of Angiotensin II
• Cardiovascular system
– Direct and generalized vasoconstriction
• Activation of angiotensin AT1 receptors leads to Ca2+ channel opening through
a stimulation of the IP3 system
– Increased myocardial contractility
• Due to increased Ca2+ entry during the plateau phase of the action potential
61
61
• Adrenal cortex and medulla
– Stimulation of the zona glomerulosa
• Leads to an increased synthesis and secretion of aldosterone
– Release of catecholamines from adrenal medulla
• Cell growth
– The increased production of growth factors leads to stimulation
of growth and division of vascular and cardiac muscle cells
• Results in vascular and cardiac hypertrophy
62
62
• Urinary system
– Vasoconstriction of glomerular afferent and efferent arterioles
• Efferent arterioles are more sensitive to angiotensin than afferent arterioles
– Contraction of mesangial cells
• Decreases the capillary surface area available for secretion
• The final effect upon GFR depends upon the physiological state
• Normally GFR is slightly reduced
• During renal artery hypotension GFR is increased
– Increased Na+/H+ exchange in the proximal tubule
– Increased Na+ reabsorption and K+ secretion in distal nephron
• Due to aldosterone release
– Inhibition of renin secretion (feed-back effect)
63
63
• Peripheral nervous system
– Stimulation of NE release from sympathetic nerve
terminals
– Decreased NE reuptake
– Sensitization of the effector cells to NE
• Central nervous system
– Increased central sympathetic outflow
– Stimulation of thirst (dipsogenic effect)
– Increased secretion of vasopressin and ACTH
64
64
Figure 26.6 (from Goodman and Gilman). Summary of the three major effects of AngII and the
mechanisms that mediate them. Key to figure: NE, norepinephrine. 65
65
Therapeutic options
Figure 26.8 (from Goodman and Gilman). Inhibitors of the RAS. ACE-I, angiotensin-
converting enzyme inhibitor; ARB, angiotensin receptor blocker; DRI, direct renin inhibitor 66
66
LO #3
Angiotensin converting enzyme inhibitors

• Drugs “…prils”
– Captopril (oral) and enalaprilat (IV) are active drugs
– Enalapril (oral) is cleaved to enalaprilat in the liver
• Mechanism of action
– Inhibit the angiotensin converting enzyme (ACE) that hydrolyzes angiotensin I to
angiotensin II
– ACE also inactivates bradykinin; inhibition yields higher plasma levels of bradykinin
– Agents are oral (except enalaprilat), prodrugs are activated in liver
– Half-lives are variable
• captopril, enalapril ~2 hours
• enalaprilat ~36 hours
67
These are the “ACE” drugs
67
LO #3
ACE inhibitors
• Pharmacodynamics:
– Inhibition of renin-angiotensin system (RAS)
– Increased levels of bradykinin (potent vasodilator)
– Antihypertensive effect is principally from actions on RAS
– No sympathetic reflex  Useful in ischemic heart disease
– Note the effect these agents will have on the short-loop negative feedback:
• ACE inhibitors (and ARBs and DRIs) lead to

an INCREASE in systemic renin
• This may attenuate their overall effect
68
Bradykinin:
- A potent vasodilator, works in part by stimulating release of NO and prostacyclin
- Effect of ACE agents is largely on RAS, but also from stimulation on the kallikrein-kinin
(bradykinin) system
- No reflex? Basically, hypotension doesn’t occur, so no reflex. High enough dose? Yes,
you’d get reflex.
68
LO #4
ACE inhibitors
• Therapeutic use
– Hypertension
– Hypertensive emergency (enalaprilat)
– Also role in CHF, Diabetes, Chronic Kidney Disease
69
Use in hypertension
- Thiazide diuretics can increase substantially the antihypertensive effect
- Myocardial infarction: Overall mortality is reduced when treatment is begun during peri-
infarction period
- Chronic congestive heart failure: decrease the progression of heart failure, the incidence
of sudden death and myocardial infarction, and they improve the quality of life
- Diabetic glomerulopathy, hypertensive nephroangiosclerosis: decrease the progression
of the disease by preventing the angiotensin II induced vasoconstriction on the efferent
glomerular arteriole
69
LO #3
ACE inhibitors
• Adverse effects
– Hypotension and postural hypotension
• especially if hypovolemic
– Angioedema
– Hyperkalemia (multifactorial)
• Up to 10% within 1 year
• Risk for arrhythmia
– Dry and disturbing cough
• Likely related to Bradykinin
– Alteration or loss of taste (dysgeusia)
– Headache, dizziness, fainting
70
Angioedema risk is 4.5 times higher in African American populations
70
LO #3
ACE inhibitors
– Bilateral renal artery stenosis (or stenosis of the renal artery
of a solitary kidney)
– Severe stenosis of abdominal aorta
– Advanced renal insufficiency – agents eliminated renally
– Previous history of angioedema
– Coronary artery disease
– Hypovolemic states
– Hyperkalemic states
– Pregnancy, women in fertile age
• Category D
• Fetal hypotension, renal failure, malformation, fetal death
71
- Patients with bilateral renal artery stenosis (or stenosis of a single remaining renal artery)
usually have sufficient blood flow to maintain renal function. These patients will have a
higher tone in the constriction of their efferent arteries to maintain this
glomerular perfusion. If these patients are given an ACE inhibitor, tone is removed due to
relaxation of the efferent artery, and perfusion is lost. This can lead to significant renal
damage.
71
LO #3
ACE inhibitors
– Heart rate: unchanged
– Cardiac output: unchanged
– Venous tone: decreased
– Postural hypotension: slight
– Renal blood flow: unchanged or increased
– Efficacy of antihypertensive effect: good
72
72
LO #3
Angiotensin II receptor antagonists

• Drugs “…sartans”
– Losartan
– As a group - “ARBs”
– Competitive antagonism at angiotensin II receptors (these drugs
selectively block AT1 receptors)
– All agents are oral
– Losartan half-lives ~2 hours
73
These are the “ARB” drugs
73
LO #3,4
– Potently and selectively inhibit Angiotensin II
• Reduce contraction of vascular smooth muscle
• Inhibit slow and rapid pressor responses
• Inhibit aldosterone secretion
• Inhibit release of adrenal catecholamines
• Inhibit growth-promotion
• CNS effects (thirst, vasopressin)
– No effect on bradykinin
• Therapeutic use
– Hypertension
– Also role in CHF, Diabetes, Chronic Kidney Disease
74
Efficacy is equivalent to ACE agents -
74
LO #3

• Adverse effects
– Hypotension and postural hypotension
– Angioedema (less than ACEs)
– Hyperkalemia (multifactorial)
• Risk for arrhythmia
– Dry and disturbing cough (less than ACEs)
75
75
LO #3

– Bilateral renal artery stenosis (or stenosis of the
renal artery of a solitary kidney)
– Severe stenosis of abdominal aorta
– Hyperkalemic states
– Pregnancy, women in fertile age
• Category D
• Fetal hypotension, renal failure, malformation, death
76
76
LO #3
Direct Renin Inhibitor - aliskiren

– Competitive inhibition of renin; reduces circulating
angiotensin I, II and aldosterone
– Low oral bioavailability (~2.5%)
– Long half-life (25-40 hours)
– Produces dose-dependent decrease in BP
– Plasma renin increases up to 16-34 fold due to loss of short-
loop feedback
– Decreases aldosterone levels
77
Aliskiren is the only agent on the market – relatively new
77
LO #3

• Therapeutic use: mild-moderate hypertension
– Effective in severe hypertension in studies too
– GI: diarrhea, dyspepsia
– Headache, dizziness, fatigue
– Cough, angioedema (less than ACE inhibitor/ARB)
– Rare: severe hypotension
78
78
LO #3

• Contraindications
– Pregnancy Category D (RAS inhibition)
– Diabetes patients taking an ACE inhibitor or ARB.
• Caution
– Renal impairment: increased incidence of renal impairment,
hypotension, and hyperkalemia
79
79
Hypertensive emergency
• Very High blood pressure and organ damage
• Who?
– Poorly controlled hypertension
– Discontinuance of BP med (clonidine, e.g.)
• Brain / Heart / Kidneys at risk
• Treat:
– Monitor BP, fluids
– Pharmacology: do not “fix” too rapidly
80
Definition: Hypertensive emergency –

Blood pressure with either systolic pressure greater than 180 mmHg or diastolic pressure
greater than 120mmHg WITH end organ damage (eg, retinopathy, etc)
From UpToDate 2016:

Optimal therapy, including the choice of agent and the blood pressure goal, varies
according to the specific hypertensive emergency. It is generally unwise to lower the blood
pressure too quickly or too much, as ischemic damage can occur in vascular beds that have
grown accustomed to the higher level of blood pressure (ie, autoregulation). For most
hypertensive emergencies, mean arterial pressure should be reduced by about 10 to 20
percent in the first hour and then gradually during the next 23 hours so that the final
pressure is reduced by approximately 25 percent compared with baseline.
80
Drugs for hypertensive emergencies
Hypertensive emergency can be defined as a clinical situation in which the elevated blood pressure is
immediately life-threatening and requires the blood pressure to be lowered to a safe level within a matter of
minutes to one hour.
Drug Onset Avoid or use cautiously in patients with:

Nitroprusside * Seconds High intracranial pressure, renal failure, toxic amblyopia
Nitroglycerin * 1-5 min High intracranial pressure, constrictive pericarditis
Diazoxide * 1-5 min Angina, intracranial hemorrhage, severe stenosis of aorta
Labetalol ** 1-5 min Asthma, bradycardia, AV block, decompensated heart failure
Esmolol * 1-2 min Asthma, bradycardia, AV block, decompensated heart failure
Fenoldopam * 1-5 min Glaucoma
Nicardipine ** 2-20 min High intracranial pressure, angina, decompensated heart failure
Enalaprilat 15 min Renal failure, hyperkalemia, pregnancy
* IV infusion; ** IV bolus (may be followed by IV infusion) 81
81
Choice of the antihypertensive drug in patients with concomitant diseases
Antihypertensive drug
Concomitant disease Diuretics β blockers Ca2+ channel ACEi / ARB
blockers
Insulin-dependent
C C I
diabetes
Gout A
Hyperlipidemias C C
Angina I I
Heart Failure I C A I
Post MI I I
Bradyarrhythmia A A
Tachyarrhythmia I I
Renal Insufficiency I* A** A
Bilateral renal artery
A
stenosis
Key to drug choice: I = indicated, C = use with caution, A = avoid
* Loop diuretics;
** Potassium sparing diuretics. 82
82
Choice of the antihypertensive drug in patients with concomitant diseases (cont)
Antihypertensive drug
Concomitant disease Diuretics β blockers Ca2+ channel ACEi / ARB
blockers
Peripheral vascular
C
disease
Severe stenosis of aorta C C A
Bronchospastic diseases A I C
Pregnancy C C C A
Key to drug choice: I = indicated, C = use with caution, A = avoid
* Loop diuretics;
** Potassium sparing diuretics.
83
83
This is JNC7 (2003)
84
84
This is JNC8 (2014)
- KEY: start with lifestyle modifications
85
85
86
86
87
87
Summary of hemodynamic effects of antihypertensive drugs (1)
Parameters Diuretics Central β blockers αβ blockers
sympatholytics
Heart rate Unchanged Slight decrease Decreased Unchanged
Cardiac output Decrease (early) Slight decrease Decreased Unchanged

Normal (late)
Venous tone Unchanged Slight decrease Unchanged Decreased
Postural Negligible Slight Negligible Prominent

hypotension
Total peripheral Unaffected Decreased Increase (early) Decreased
resistance (early), Decrease (late)
Decreased (late)
Renal blood Decrease (early) Unchanged Decrease (early) Unchanged
flow Normal (late) Normal (late)
Antihypertensiv Low Moderate Good High
e efficacy
Drugs Thiazides Clonidine Propranolol Labatelol
Loops Methyldopa 88
88
Summary of hemodynamic effects of antihypertensive drugs (2)
Parameters α1 blockers Vasodilators Ca2+ ACE
PO IV Channel inhibitors
blockers
Heart rate Unchanged or Increased Increased Increased(N) Unchanged
slightly increased Decreased(V)
Cardiac output Unchanged or Increased Decreased(N) Increased(N) Unchanged

slightly increased Increased(D) Unchanged(V)
Venous tone Decreased Unchanged Unchanged Unchanged Decreased
Postural Prominent Negligible Prominent(N) Negligible Slight

hypotension Absent(D)
Total peripheral Decreased Decreased Decreased Decreased Decreased

resistance
Renal blood flow Unchanged Increased Decreased(N) Unchanged Unchanged or

increased
Antihypertensive Moderate Moderate (M) High Moderate Good

efficacy High (M)
Drugs Prazosin Hydralazine(H) Nitroprusside(N) Nifedipine(N) Captopril

Minoxidil(M) Diazoxide(D) Verapamil(V) Enalapril
89
89

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Pharm of Hypertension

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Pharmacotherapy of

Patrick Edsall, PharmD

Drug Classes and Drugs to consider

(hydrochlorothiazide*) (clonidine*) hydralazine aliskiren

Drugs in brackets either have been*, or will be**, mentioned elsewhere

• Unfortunately, only 1/3 of diagnosed patients control BP

• BP: Blood Pressure

Numbers 1-4 reflect the targets for pharmacology for hypertension

Under normal circumstances (postural changes, etc), influence exerted as part of a

• The chemoreceptor reflex

• The response to brain ischemia

• The renal regulation of salt and water excretion

• The aldosterone system

Humoral response is slower than the response under nervous control

Classifying antihypertensive drugs

Classifying antihypertensive drugs

Diuretics (Decrease Na+, Volume)

• ↓ Na+ input / diuresis reverses vessel stiffness

Additional proposed mechanisms:

• Loop diuretics are preferable to thiazides only in some well

• Diuretics can enhance the hypotensive effects of many

• Adverse effects: (see Diuretics lectures), remember potassium!

Drug Classes and Drugs to consider

(hydrochlorothiazide*) (clonidine*) hydralazine aliskiren

Drugs in brackets either have been*, or will be**, mentioned elsewhere

• BP: Blood Pressure

Baroreflexes are responsible for rapid, moment-to-moment adjustments in blood

• Use of these agents will likely engage a compensatory mechanism

• Hypertensive crisis may result from abrupt discontinuance

• Therapeutic uses in hypertension

From - Dr Babbini’s Introduction to ANS pharmacology lecture 26

• Why unchanged heart rate? (α1 selectivity)

1. Decrease in cardiac output

• The agents block beta receptors

- DM is not caused by beta-blockade, but should invoke caution. Normally,

Drug Classes and Drugs to consider

(hydrochlorothiazide*) (clonidine*) hydralazine aliskiren

Drugs in brackets either have been*, or will be**, mentioned elsewhere

Vasodilators (Relax vascular smooth muscle)

“Relax” is a bit of a misnomer – more accurately: “decrease likelihood of contraction”

– Compensation: baroreceptors  sympathetic NS

 Use with other agents to maintain BP reduction

This will induce reflex responses

– Increased HR, CO and myocardial O2 consumption

– Without appropriate regimen, tachyphylaxis, palpitations, angina,

– Headache, sweating, hypertrichosis are common

Used topically for baldness (Rogaine)

Chemistry - The drug is a benzothiadiazine derivative

• Contraindication and precautions

- NO activates guanylyl cyclase in vascular smooth muscle  increases intracellular

- Note both the NO and CN- moeities

– To produce controlled hypotension during surgery in patients

– High output heart failure associated with reduced systemic

– Significant vasodilation of renal afferent and efferent arterioles

– Activation of D1-like receptors on the proximal tubules inhibits

- 6 times as potent as dopamine in producing renal vasodilatation; has minimal adrenergic

- MOA hint (fenol-DOPAM) DOPAM = dopamine, agonist

– Non-dihydropyridines (verapamil and diltiazem)

Drug Classes and Drugs to consider

(hydrochlorothiazide*) (clonidine*) hydralazine aliskiren

Drugs in brackets either have been*, or will be**, mentioned elsewhere

• Renin is released by Granular

• Note location of Macula Densa

Pathway #1: Flux of NaCl across Macula Densa:

(hydrochlorothiazide) (clonidine) hydralazine aliskiren

(hydrochlorothiazide) (clonidine) hydralazine aliskiren

(hydrochlorothiazide) (clonidine) hydralazine aliskiren

(hydrochlorothiazide) (clonidine) hydralazine aliskiren