1. Antihypertensives Steven L. Bealer Rm 408C BPRB 7-7706
Recommended reading:
Katzung, 9th Ed.; Chap. 11 (pg )
Goodman and Gilman, 11th Ed.;
Chap. 30 Renin and angiotensin; pp
Chap. 33 Therapy for Hypertension; pp
Online;
Abbreviations:
ACE, angiotensin converting enzyme HDL, high density lipoprotein
ADH, antidiuretic hormone HT, hypertension
Ang II, angiotensin II LDL, low density lipoprotein
BP, blood pressure NE, norepinephrine
CHF, congestive heart failure SV, stroke volume
CO, cardiac output SymNS, sympathetic nervous system CNS, central nervous system TPR, total peripheral resistance
GFR, glomerular filtration rate VSM, vascular smooth muscle
_____________________________________________________________________

2. Objectives:
Know mechanisms of blood pressure regulation and cardiovascular pathophysiology which chronically increase blood pressure (Review).
Understand types and etiologies of major forms of clinical hypertension.
General treatment strategy for hypertension.
Know major classes of anti-hypertensive agents, their general sites and mechanisms of action.
Identify specific, widely used, antihypertensive agents, sites of action, mechanisms of action, indications and contraindications.
Understand strategies for hypertension management associated with other pathologies.

3. Hypertension: The Silent Killer
Heart Attack
Stroke
Kidney Failure
1. Maintenance of adequate perfusion pressure- critical
a. Too low- inadequate nutrients, oxygen, removal of metabolic products
b. Too high- organ damage, esp. heart, brain, kidney, eyes
A. BP one of most closely controlled physiological variables
a. multiple, redundant mechanisms- reflexes
1. To maintain blood pressure over the long term
2. Hypertension= pathology in one or more control mechanisms
A. altered set point for BP control (resetting to higher pressure)
1. defended by control mechanisms
2. Often necessitates multiple pharmacological therapies
4. Cause of morbidity/mortality
A. end organ damage
1. myocardial infarction
2. stroke
3. kidney failure
5. Therapy=
a. Life style
b. Pharmacological Therapy
6. Therapeutic GOAL- Reduce CO and/or TPR
CRITICAL POINT!
Hypertension- asymptomatic
Morbidity and mortality due to end organ damage

4. Determinants of Arterial Pressure
Blood
Volume
Mean Arterial
Pressure = X
Arteriolar
Diameter
Stroke
Volume
Heart
Rate
CRITICAL POINT!
Change any physical factors controlling CO and/or TPR and MAP can be altered.
Review-
1. Cardiac and vascular function contribute to arterial pressure.
2. BP can be altered by changing either CO or TPR
3. Both CO and TPR are influenced by several physical factors
4. CO primarily function of heart, TPR a function of vasculature
5. Changes in BP opposed by reflexes
a. Servo null control system- set point, sensor, processor, compensation
1. Arterial baroreflexes-short term (sec-min)
2. Renal pressure/natriuresis response- long term
b. Both major reflexes act as compensatory mechanism to maintain BP at a set level
c. Changes in pressure opposed by compensation in both CO/TPR
Contractility
Filling Pressure
Blood Volume
Venous Tone

5. Mechanisms Controlling CO and TPR
1. Neural
SymNS
PSNS
Artery
Vein
2. Hormonal
Renal
Ang II
Adrenal
Catecholamines
Aldosterone
Review-
Major Mechanisms of BP control-
a. Neural- control of autonomic nervous system (PSNS, SymNS)
b. Vasoactive hormones
1. Controlled by CNS
a. vasopressin;
b. adrenal catecholamines; (SymNS activation)
c. renal renin (SymNS activation)
2. Systemic control
a. renal renin release (renal perfusion pressure; Na+
c. Local Factors
1. endothelial agents- derived from endothelial cells in arterioles
2. arteriolar gas concentration- circulating 0o, CO2, H+
2. All interact to control blood pressure
3. Targets of antihypertensive therapy
3. Local Factors
CRITICAL POINTS!
1. These organ systems and mechanisms control physical factors of CO and TPR
2. Therefore, they are the targets of antihypertensive therapy.

6. Summary-Types and Etiology of Hypertension
1. White coat hypertension
office or environmental
2. Secondary hypertension- due to specific organ pathology
1. renal artery stenosis
2. pheochromocytoma
3. aortic coarctation
4. adrenal tumor
1. White Coat hypertension
Due to stress associated with office/hospital visit
Need 3-6 independent measures of high blood pressure for diagnosis
2. Secondary Hypertension- Common causes
Increased blood pressure secondary to a known pathology
1. renal artery stenosis- systemic pressure increases to maintain renal
perfusion pressure
2. pheochormocytoma- tumor in chromafin cells of adrenal gland
hypersecretion of adrenal catecholamines
3. aortic coarctation- increased upper body pressure to maintain lower
body perfusion
4. adrenal tumor- hypersecretion of aldosterone
3. Essential (Primary) Hypertension
Chronically increased blood pressure with no known cause
Clinically- 95% of human hypertension
3. Essential Hypertension
No known cause.
CRITICAL POINT!
Pharmacological Therapy used primarily for essential hypertension.

7. General Treatment Strategy of Hypertension
Summary
General Treatment Strategy of Hypertension
1. Diagnosis independent measurements.
2. Determination of primary vs. secondary hypertension.
3. If secondary, treat underlying pathology.
4. If primary, initiate lifestyle changes
smoking cessation
weight loss
diet
stress reduction
less alcohol
etc.
1. General Strategies for treatment of Hypertension
a. Hypertension easily detected, easily treated
b. Secondary HT-treat primary pathology
c. Essential HT- non-drug therapy
1. Weight reduction
2. salt restriction-dec.. BP in 50% moderate HT
3. withdrawal of drugs (e.g. steroids, oral contraceptives
4. tobacco
5. alcohol
6. stress reduction
2. Pharmacological Treatment Essential Hypertension
a. Goal- reduce BP by decreasing CO and/or TPR
b. Strategy- alter cardiac and/or VSM function
1. Reduce vascular volume
2. altering SymNS transmission
3. Altering cardiac and/or vascular smooth muscle function
5. Pharmacological treatment.
CRITICAL POINTS!
Goal- normalize pressure- decrease CO and/or TPR
Strategy- alter volume, cardiac and/or VSM function

8. Pharmacological Treatment
Classes of Antihypertensive Agents
1. Diuretics
2. Peripheral a-1 Adrenergic Antagonists
3. Central Sympatholytics (a-2 agonists)
4. b-Adrenergic Antagonists
5. Anti-angiotensin II Drugs
6. Ca++ Channel Blockers
Antihypertensive Agents- 7 classes
1. Sites and mechanisms of action different
a. All decrease CO and/or TPR
2. Often used in combination
a. to oppose compensatory reflex responses
1. Baroreflex activation of compensatory systems
b. to increase effectiveness of treatment
1. Due to diminished effectiveness at high dose of single agent
2. Due to onset of adverse side effects at high doses
c. due to compelling conditions
1. Coexistent conditions which make multiple agents more effective
7. Vasodilators
CRITICAL POINTS!
Each designed for specific control system
Often used in combination

9. 1. Diuretics 1. Thiazides hydrochlorothiazide (HydroDIURIL, Esidrix);
chlorthalidone (Hygroton)
2. Loop diuretics
furosemide (Lasix); bumetadine (Burmex);
ethacrynic acid (Edecrin)
3. K+ Sparing
amiloride (Midamor); spironolactone (Aldactone);
triamterene (Dyrenium)
4. Osmotic
mannitol (Osmitrol); urea (Ureaphil)
DIURETIC AGENTS
1. Diuretics commonly used for hypertension
a. vary in natriuretic efficacy, renal site of action, hypotensive efficacy
2. Generally 1st pharmacological therapy
a. unless contraindicated
b. Diuretic as or more effective than
1. Ca++ channel blockers or ACE inhibitors (Dec., 2002, JAMA)
2. Alpha-adrenergic antagonists (Sept, 2003, Hypertension)
1st line treatment for hypertension
5. Other
Combination - HCTH + triamterene (Dyazide)
acetazolamide (Diamox)

10. Diuretics (cont) 1. Site of Action Renal Nephron
2. Mechanism of Action
Urinary Na+ excretion
Urinary water excretion
Extracellular Fluid
and/or Plasma Volume
1. Site of Action
a. renal nephron
b. diuretic agents work at different segments of nephron
2. Mechanism of Action
a. all diuretics decrease sodium reabsorption
b. act on renal systems, transporters, hormones, ion channels
c. Where Na+ goes, Water will surely follow
3. Effect on cardiovascular system
a. acute decrease in plasma volume
b. chronically, decrease in TPR, CO returns to normal
mechanism unknown
c. often used to compensate for Na+ retaining reflex induced by other
antihypertensive agents.
3. Effect on Cardiovascular System
Acute decrease in CO
Chronic decrease in TPR, normal CO
Mechanism(s) unknown

11. Diuretics (cont) 4. Adverse Reactions dizziness,
electrolyte imbalance/depletion,
hypokalemia,
hyperlipidemia,
hyperglycemia (Thiazides)
gout
5. Contraindications
hypersensitivity,
compromised kidney function
cardiac glycosides (K+ effects)
hypovolemia,
hyponatremia
4. Adverse Reactions
a. most secondary to decreased volume or altered electrolyte status
1. many renal mechanisms of Na+ reabsorption tied to transport of other
electrolytes i.e. K+ Ca++, Mg++.
b. hyperlipidemia and increased low density lipoprotein- unknown mechanism
c. hyperglycemia, K+ depletion inhibits insulin secretion
5. Contraindications
a. exaggerated response leading to adverse reactions- hypersensitivity
b. compromised kidney function- insufficient delivery to site of action
1. agents act on lumen, decreased kidney function decreases access of
agent to renal tubule, due to decreased GFR and/or renal blood flow
c. cardiac glycoside sensitivity changes with K+
1. Decreased Plasma K+ increases sensitivity to cardiac glycosides
(Digitalis)
d. exacerbates existing low volume or salt conditions

12. Diuretics (cont) 6. Therapeutic Considerations
Thiazides (most common diuretics for HTN)
Generally start with lower potency diuretics
Generally used to treat mild to moderate HTN
Use with lower dietary Na+ intake,
and K+ supplement or high K+ food
K+ Sparing (combination with other agent)
Loop diuretics (severe HTN, or with CHF)
Osmotic (HTN emergencies)
Maximum antihypertensive effect reached
before maximum diuresis- 2nd agent indicated
6. Therapeutic Considerations
a.. Thiazides- Modest diuretic (distal conv. tubule)
a. usually first therapy, mild to moderate hypertension
b. Dec. BP mmHg, wks for max effect
c. co-administered with K+ sparing if hypokalemia present
d. most effective with low sodium diet
e. Generally effective on their own, often used in combination
f. most commonly prescribed antihypertensive in US
b.. Loop diuretics- rapid, profound diuresis (loop of Henle)
a. More severe hypertension, or HT with CHF
c. K+ sparing diuretics (distal convoluted tubule, collecting duct)
a. Patients with hypokalemia
b. only modest increase in Na+ excretion
c. used in combination when K+ conservation is indicated
d. Osmotic diuretics- very effective diuretics (throughout tubular lumen)
a. usually iv only
b. hypertension emergencies
e. Max antihypertensive efficiency- more volume loss does not lower pressure farther, second class indicated

13. Peripheral a-1 Adrenergic Antagonists
Drugs: prazosin (Minipres); terazosin (Hytrin)
1. Site of Action- peripheral arterioles, smooth muscle
Peripheral -adrenergic Antagonists
1. Site of Action -- Peripheral Arterioles (resistance vessels)
a. surrounded by smooth muscle
b. heavily innervated by post-synaptic SymNS nerves
c. neurotransmitter = norepinephrine
d. neuromuscular junction is major site of SymNS control of
arteriolar diameter, which directly effects TPR
CRITICAL POINT!
Major mechanism/site of SymNS control of blood pressure.

14. Peripheral a-1 Adrenergic Antagonists, cont.
2. Mechanism of Action
Competitive antagonist at a-1 receptors on vascular
smooth muscle.
2. Mechanism of action
Competitive Antagonist of norepinephrine (a-1 receptor subtype)
a. post-synaptic membrane
1. a-1 receptors are post-junctional
a. respond to neurally released norepinephrine
2. a-2 receptors are extrajunctional
a. respond to circulating catecholamines
b. binds to a-1 adrenergic receptors
c. . post-junctional receptor
d. prevents effects of neurally released norepinephrine
predominant mechanism of SymNS control of VSM constriction
3. Effects of a-1 receptor blockade
a. arteriolar dilation- removal of tone- allow relaxation of VSM
b. decreased TPR
c. little or no direct effects on CO
3. Effects on Cardiovascular System
Vasodilation, reduces peripheral resistance
CRITICAL POINT!
Blocking -receptors on vascular smooth muscle allows
muscle relaxation, dilation of vessel, and reduced resistance.

15. Peripheral a-1 Adrenergic Antagonists, cont.
4. Adverse effects
nausea; drowsiness; postural hypotenstion;
1st dose syncope
5. Contraindications
Hypersensitivity
6. Therapeutic Considerations
no reflex tachycardia; small 1st dose;
does not impair exercise tolerance
useful with diabetes, asthma, and/or
hypercholesterolemia
use in mild to moderate hypertension
often used with diuretic,  antagonist
4. Adverse effects
a. 1st dose precipitous fall in BP
b. due in part to no or minimum reflex tachycardia (a2-adrenergic
autoinhibition of norepinephrine release in the heart).
5. Contraindications
a. No compelling contraindications
b. Hypersensitivity
6. Therapeutic Considerations
a. no reflex tachycardia- does not impair exercise tolerance
b. can use with diabetes, asthma, hypercholesterolemia
1. does not alter plasma glucose or mask hypoglycemic tachycardia
2. does not inhibit airway b-adrenergic receptors
3. alters plasma lipids favorably (decreased LDL, mechanism unknown)
c. combinations-
1. Diuretic to counteract sodium retention
2. b antagonist- can lower dose, additive
7. Other sympatholytic agents- not -antagonists
1. Guanethidine (Ismelin)-replaces norepinephrine in nerve terminal
2. Reserpine (Sandril, Serpasil)- depletes norepinephrine in terminal

16. Central Sympatholytics (a-2 Agonists)
Drugs: clonidine (Catapres), methyldopa (Aldomet)
1. Site of Action
CNS medullary
cardiovascular centers
clonidine; direct a-2 agonist
methyldopa: “false neurotrans.”
2. Mechanism of Action
CNS a-2 adrenergic stimulation
Peripheral sympathoinhibition
1. Site of Action CNS
a. medullary cardiovascular centers
1. clonidine- direct agonist
2. methyldopa- converted to methylnorepinephrine
a. acts like norepinephrine
2. Mechanism of action
a. a-2 agonist activates CENTRAL a-2 receptors
b. hypotensive action due to CNS action
3. Effects on Cardiovascular System
a. CNS inhibition SymNS outflow
b. decreased vasoconstriction
c. decreased TPR
Decreased norepinephrine release
3. Effects on Cardiovascular System
Decreased NE-->vasodilation--> Decreased TPR
CRITICAL POINT!
Stimulation of a-2 receptors in the medulla decreases peripheral
sympathetic activity, reduces tone, vasodilation and decreases TPR.

17. Central Sympatholytics (a-2 Agonists); cont.
4. Adverse Effects
dry mouth; sedation; impotence;
5. Contraindications
6. Therapeutic Considerations
generally not 1st line drugs;
methyldopa drug of choice for pregnancy
4. Adverse Effects- due to CNS actions
a. dry mouth
b. sedation
c. impotence
5. Contraindications
a. no strong contraindications
6. Therapeutic Considerations
a. Often used in conjunctions with diuretic
b. Sudden discontinuation can lead to rebound SymNS and increase BP
c. Methlydopa common drug in pregnancy
d. NOT 1st line drug
e. low dose predominant central hypotension
high dose, begin to stimulate systemic vasoconstrictor -2 receptors
prolonged use--salt/water retention, add diuretic
Rebound increase in blood pressure

18. b Adrenergic Antagonists
Drugs: propranolol (Inderal); metoprolol (Lopressor)
atenolol (Tenormin); nadolol (Corgard);
pindolol (Visken)
1. Sites of Action
b-1
b-1
1. Site of Action- b receptors
a. Heart
b. Kidney
2. Mechanism of action
a. Competitive antagonists b-receptors
2. Mechanism of Action
competitive antagonist at b- adrenergic receptors

19. b Adrenergic Antagonists, cont.
3. Effects on Cardiovascular System
a. Cardiac--  HR,  SV  CO
b. Renal--  Renin   Angiotensin II   TPR
4. Adverse Effects
impotence; bradycardia;
fatigue; exercise intolerance;
3. Effects on Cardiovascular System
a.. Heart; decreases contractility; decreases CO
antagonizes catecholamine tachycardia
b. Kidney; decreases renin release, Ang II, TPR
4. Adverse effects
a. chronic fatigue- cardiac effect
b. low exercise tolerance- cardiac effect
c. bradycardia
d. possible increased airways resistance- b-2 receptor block
5. Contraindications
a. asthma; pulmonary disease- decreased pulmonary function b-2 receptor block
b. diabetes- can mask hypoglycemic tachycardia,
alters carbohydrate metabolism, increases recovery time from hypoglycemia
c. low heart rate
5. Contraindications
asthma; diabetes; bradycardia;
hypersensitivity

20. b-Adrenergic Antagonists, cont.
6. Therapeutic Considerations
Selectivity
nadolol (Corgard) non selective, but 20 hr 1/2 life
metoprol (Lopresor) b-1 selective, 3-4 hr 1/2 life
Risky in pulmonary disease even selective b-1,
Available as mixed a/b blocker available-labetalol
(Trandate, Normodyne)
Use post myocardial infarction- protective
Use with diuretic- prevent reflex tachycardia
6. Therapeutic Considerations
a. b- selectivity 1 or 2
b. asthma- b-1 selective
c. often used with diuretic to prevent reflex tachycardia
d. nadolol (Corgard)- non-selective, but 1/2 life= hrs
e. metoprol (Lopresor)-selective b-1, but shorter 1/2 life 3-4 hr.
f. use post myocardial infarction, cardioprotective
g. Mixed a/b blocker available (labetalol)(Trandate, Normodyne)
decreases TPR (), prevents reflex tachycardia ()

21.   Anti-Angiotensin II Drugs Angiotensin II Formation Ang II
2. Ang II Receptor Antagonists
losartan (Cozaar);
candesartan (Atacand);
valsartan (Diovan)
Angiotensin II Formation
Angiotensin Converting Enzyme-
Inhibitors
enalopril (Vasotec);
quinapril (Accupril);
fosinopril (Monopril);
moexipril (Univasc);
lisinopril (Zestril, Prinivil);
benazepril (Lotensin);
captopril (Capoten)
Angiotensin II formation
A. Renin cleaves Ang I from angiotensinogen
B. Angiotenin I is inactive decapeptide
C. Angiotensin Converting Enzyme cleaves 2 amino acids-
resulting in the biologically active Angiotensin II
D. Cardiovascular/fluid volume effects mediated by AT1 receptor stimulation
2. Anti-angiotensin II Drugs/ Classes and Mechanism of Action
A. ACE inhibitors- mechanism of action
1. Reduce or eliminate activity of angiotensin II converting enzyme
2. Decrease formation of ang II
B. Angiotensin II AT1 receptor blockers- mechanism of action
1. Competitive antagonist at AT1 receptor
2. Prevents binding of angiotensin II
Angiotensinogen
Ang I
ACE
Lung
VSM
Brain
Kidney
Adr Gland
Ang I 
AT1
Ang II
ACE
AT2 
Ang II
Renin

22.         Anti-Angiotensin II Drugs, cont
3. Effect on Cardiovascular System  
Volume
Aldosterone
Vasopressin 
Angiotensin II
HR/SV
Angiotensin II
Norepinephrine
3. Effects on Cardiovascular System
a. Renal
1. Maintenance of normal GFR
2. Reduces plasma vasopressin and aldosterone
Decreased CO
b. Cardiac
1. Decreased Ang II and Norepinephrine effects
Decreased SymNS influence; Decreased CO
c. Vascular
1. Decreased Ang II
Decreased TPR- due to Ang II
Decreased TPR- due to SymNS activation from CNS
Decreased TPR- due to Ang II/ NE terminal interaction
Vasoconstriction 
SymNS  
SymNS CO 
TPR  CO

23. Anti-Angiotensin II Drugs, cont
4. Adverse Effects
hyperkalemia
angiogenic edema (ACE inhib); cough (ACE inhib);
rash; itching;
5. Contraindications
pregnancy; hypersensitivity; bilateral renal stenosis
6. Therapeutic Considerations:
use with diabetes or renal insufficiency;
adjunctive therapy in heart failure;
often used with diuretic;
Enalapril, iv for hypertensive emergency
4. Adverse Effects
a. hyperkaelemia
b. altered gustatory sensation
c. angioedema- sudden edema skin/ mucous membranes; etiology unknown
d. cough- increase bradykinin / prostaglandins
5. Contraindications
a. pregnancy- injury or death to fetus
b. bilateral renal stenosis- renal function depends on renin- angII system
6. Therapeutic Considerations
a. use with diabetes or renal insufficiency
1. Ang II contributes to decreased renal function
b. use in heart failure
1. Ang II contributes to ventricular remodeling
c. usually used with diuretic, additive with thiazide
1. Decreases sodium retention by reducing aldosterone
d. used where diuretic or b-blocker contraindicated or ineffective

24. Ca++ Channel Blockers
Drugs: verapamil (Calan); nifedipine (Procardia);
diltiazem (Cardizem); amlodipine (Norvasc)
1. Site of Action-
Vascular smooth muscle
2. Mechanism of Action-
Blocks Ca++ channel
decreases/prevents contraction
1. Site of Action
a. Ca++ channels on vascular and cardiac muscle
2. Mechanism of Action
a. inhibition of Ca++ influx into muscle tissue
b. dilates coronary and vascular smooth muscle
3. Effects on Cardiovascular System
a. decreased TPR; predominant hypotensive effect K+
Ca++
3. Effect on Cardiovascular system
Vascular relaxation
Decreased TPR
Na+

25. Ca++ Channel Blockers, cont.
4. Adverse Effects
nifedipine --Increase SymNS activity;
headache; dizziness; peripheral edema
5. Contraindications
Congestive heart failure; pregnancy and lactation;
Post-myocardial infarction
6. Therapeutic Considerations
verapamil- mainly cardiac; interactions w/ cardiac
glycosides
nifedipine- mainly arterioles
diltiazem-both cardiac and arterioles
at high doses, AV node block may occur;
nifedipine may increase heart rate (reflex)
4. Adverse Effects
a. most associated with excessive vasodilation
1. mild to moderate edema
2. flushing
3. tachycardia- Nifedipine- due to reflex SymNS activation
aggravates angina
4. bradycardia- Diltiazem, verapamil,
5. Contraindications
a. congestive heart failure for all- negative inotropic effect
b. pregnancy and lactation- injury to fetus, neonate???
c. myocardial infarction- cardiac effects
6. Therapeutic Considerations
a. wide efficacy profile including African Americans and elderly
b. differential effects on cardiac and arterioles
c. long acting appear safe

26. Vasodilators
Drugs: hydralazine (Apresoline); minoxidil (Loniten);
nitroprusside (Nipride); diazoxide (Hyperstat I.V.);
fenoldopam (Corlopam)
1. Site of Action- vascular smooth muscle
2. Mechanism of action
nitroprusside NO
fenoldopam DA
1. Site of Action
2. Mechanism of Action- Systemic vascular vasodilation
a. hydralazine- alters intracellular calcium, increases nitric oxide
in arterioles
b. minoxidil- opens K+ channels on arteriolar membranes, stabilizes membrane
c. nitroprusside- induces nitric oxide from endothelial cells (arterioles and veins)
d. diazoxide- opens K+ channels, stabilizes membrane (arterioles)
e. fenoldopam- activates dopamine(D1) receptors on VSM (arterioles)
1. Low doses dopamine stimulates primarily dopamine receptors-
Vasodilation
2. Higher doses- stimulates B1 receptors- positive inotropic effect
Increases CO
Also releases NE from vascular nerve terminals-- vasoconstriction    K+
minoxidil
diazoxide
Na+
Ca++
Ca++
hydralazine

27. Vasodilators, Cont 3. Effect on cardiovascular system
vasodilation, decrease TPR
4. Adverse Effects
reflex tachycardia
Increase SymNS activity (hydralazine, minoxidil,diazoxide)
lupus (hydralazine)
hypertrichosis (minoxidil)
cyanide toxicity (nitroprusside)
5. Contraindications
3. Effects on Cardiovascular System
a. vasodilation resulting in decreased TPR
4. Adverse effects
a. reflex tachycardia
b. nausea, vomiting
c. possible fluid retention
d. hypertrichosis (excessive hair growth)- minoxidil
e. cyanide poisoning (nitroprusside)
f. lupus (hydralazine)
5. Contraindications
6. Therapeutic Considerations
a. used for resistant hypertension or hypertensive emergencies
b. nitroprusside- emergency, malignant hypertension, iv only
c. hydralazine, may cause lupus but safe for pregnancy
d. diazoxide, emergency hypertension, iv.
6. Therapeutic Considerations
nitroprusside- iv only
hydralazine- safe for pregnancy
diazoxide- emergency use for severe hypertension

28. Sites and Mechanisms of Action
Summary
Sites and Mechanisms of Action
3. -2 agonists
Receptor antag.
2. a-antag.
5. ang II antag.
7. Vasodilators
6. Ca++ antag.
4. b-blockers
1. Diuretics
4. b-blockers
Other- 5. ACE inhibitors
Lung, VSM, Kidney, CNS
1. Sites of action
a. each class acts by specific mechanism, some at multiple sites
2. Antihypertensives work on all systems and all levels of regulation
a. Neural (SymNS)
1. Brain
2. Vascular Smooth Muscle
3. Kidney
b. Hormonal
1. Blocks circulating catecholamines
2. Blocks Ang II system
c. Local
1. Alters mechanism of smooth muscle contraction
2. releases vasodilatory factors
3. All alter CO and/or TPR
CRITICAL POINTS!
1. Can alter CO/TPR at number of sites and/or mechanisms.
2. Antihypertensives mechanistically specific, and alter blood
pressure through physiologically diverse effects on CO/TPR.
3. All organ systems and/or effector mechanisms are p’col targets.

29. some common co-existing conditions
Hypertension treatment with
some common co-existing conditions
Heart Failure
ACE inhibitors
Diuretics
Myocardial Infarction
b-blockers
ACE inhibitors
Diabetes
ACE Inhibitors
AVOID- b-blockers
1. Heart Failure
ACE inhibitors- decreases pressure, blocks direct effects of AngII on heart
Inhibits remodeling
Decrease Pre- and Afterload
Diuretics- decrease volume associates with heart failure
2. Myocardial infarction
-antagonist- cardioprotective; dec SymNS dominance
ACE-inhibitor- prevents AngII stimilatory effects on SymNS
inhibits remodelling
3. Diabetes
ACE-inhibitors- increase renal function in diabetic renal neuropathy
improves intrarenal hemodynamics, dec. glomerular pressure
AVOID  blockers- mask signs of hypoglyciemia (tachycardia)
4. Isolated systolic hypertension (Elderly)
Diuretic preferred- decrease preload
dihydropyridine Ca++ antagonist- decrease afterload
Isolated systolic hypertension (Older persons)
Diuretics preferred
calcium channel antagonist

30. Treatment Strategy with Some Common co-existing Conditions, cont
Renal Insufficiency
ACE Inhibitors
Angina
b-blocker
Calcium channel antagonists
Asthma
Ca++ channel blockers
AVOID- b-blockers
5. Renal Insufficiency
ACE-inhibitors- can improve renal function;
6. Angina
-antagonist- negative inotropic and chronotropic effect, decrease oxygen demand
Ca++ antagonist- decreases afterload, decreases ischemia (dialtion)
and O2 demand
7. Asthma
Ca++ channel blocker- inhibits contraction of airway smooth muscle
AVOID -antagonist- b-2 stimulation increases airway diameter
8. Elderly
Diuretic preferred-
long acting dihydropyridine Ca++ antagonist-

31. Summary Important Points
Hypertensive Agents
Each class of antihypertensive agent:
1. has as specific mechanism of action,
2. acts at one or more major organ systems,
3. on a major physiological regulator of blood pressure,
4. reduces CO and/or TPR to lower blood pressure,
5. has specific indications, contraindications, and
therapeutic advantages and disadvantages associated
with the mechanism of action.

32. Baroreflexes CO X SVR= MAP MAP= set point Reflexes defend set point
Arterial Baroreflexes
Pressure/Natriuresis
Change in MAP opposed by reflex response to maintain set pressure.
Hypertension- pressure resets to higher level-defended by reflex systems.
CRITICAL POINT!
**Multiple therapies often needed to block reflex compensation.
CO X SVR=
MAP