Arterial Hypertension Management

7/29/2019 Arterial Hypertension Management

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Arterial hypertensionmanagement. Clinical

pharmacology of hypotensivedrugs.

Butranova O.I. PhD

2012


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Blood pressure levels


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Stratification of cardiovascular risk.


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The main tasks at treatment of

arterial hypertension:

1. Protection of organs - targets:

myocardium, in order to prevent hypertrophy

of the left ventricle of heart, coronary heart

disease, cardiac insufficiency, kidneys, in order to prevent renal

insufficiency,

brain, in order to prevent stroke.2. Improvement of life quality.

3. Reduction of death and sickness rate.


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Initiation of antihypertensive

therapy


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Combination of antihypertensive

drugs


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Possible

combinations of

antihypertensive

drugs


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Clinical pharmacology of diuretics

1) High Efficacy

Diuretics

(Inhibitors of

NA+-K+- 2Cl-Cotransport)

i) Sulphamoyl

Derivatives:

Furosemide,

Bumetanide.

ii) Phenoxyacetic Acid

Derivative: Ethacrynic

acid.

iii) Organomercurials:

Mersalyl.

2) Medium

Efficacy

Diuretics

(Inhibitors ofNa+-CI- Symport)

i) Benzothiadiazines

(Thiazides):

Chlorothiazide,

Hydrochlorothiazide,

Benzthiazide,

Hydroflumethiazide,

Clopamide.

ii) Thiazide Like

(Related

Heterocyclics):

Chlorthalidone,

Metolazone, Xipamide,Indapamide.

3) Weak or Adjunctive

Diuretics:

i) Carbonic Anhydrase Inhibitors:

Acetazolamide

ii) Potassium Sparing Duretics:

a) Aldos terone Antagonis t :

Spironolactone.

b) Direct ly Act ing (Inhib i tors of Renal

Epithelial NA+ Chann el):

Triamterene, Amiloride.

iii) Osmotic Diuretics:

Mannitol, Isosorbide, Glycerol.

iv) Xanthines:

Theophylline.


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Renal PhysiologyOverview

1/5 of plasma water passes into tubule through glomerulus

99% of water and 90+% of electrolytes recovered metabolically useful compounds are recovered

Sites of diuretic action

1. Proximal tubule high metabolic activity (secretion/resorption)Recovery of:

65% to 80% of sodium and water (Na/Cl co-transport, water follows)

99% of glucose, protein, amino acids recovered2. Descending limb - Loop of Henle

passive diffusion of urea, H2O, Na (thin wall)

source of counter-current multiplier

3. Ascending limb - Loop of Henlestrong active transport - Nanot permeable to H2O, urea

4. Distal tubule - diluting segmentas for ascending limb - loop

5. Distal tubule / Collecting tubulenot permeable to urea

active sodium resorption

sodium / potassium exchange

water permeability under ADH influence


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Thiazide diureticsChlorothiazide, Hydrochlorothiazide

Mechanism(s) of Action

1. Block facilitated Na/Cl co-transport in the early distal tubule. This is a relatively

minor Na absorption mechanism and the result is modest diuresis2. Potassium wasting effect

Blood volume reduction leads to increased production of aldosterone

Increased distal Na load secondary to diuretic effect

a + b = increase Na (to blood) for K (to urine) exchange which produces indirect K wasting

3. Increase in distal Ca re-absorption (direct effect)causes an increase in plasma calcium.

This is unimportant NORMALLY but makes thiazides VERY inappropriate choice forhypercalcemic patients.

4. Anti-diuretic effect in nephrogenic diabetes insipidus patients secondary to depletionof Na and Water.

Toxicity

Electrolyte imbalance (particularly hypokalemia)

Agranulocytosis

Allergic reactionsHyperuricemia

Thrombocytopenia

Pharmacokinetics

Onset in 2 hours

Peak in 4 hours

Duration 6 - 12 hours

Eliminated unchanged in the urine


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Loop (High Ceiling) DiureticsMechanism(s) of Action

1. Diuretic effect is produced by inhibition of active 1 Na+, 1 K+, 2 Cl- co-

transport (ascending limb - Loop of Henle). This produces potent diuresis asthis is a relatively important Na re-absorption site.

2. Potassium wasting effectBlood volume reduction leads to increased production of aldosterone

Increased distal Na load secondary to diuretic effect

a + b = increase Na (to blood) for K (to urine) exchange which produces indirect Kwasting (same as thiazides but more likely)

3. Increased calcium clearance/decreased plasma calciumsecondary to passive decreases in loop Ca++ reabsorption.

This is linked to inhibition of Cl- reabsorption.

This is an important clinical effect in patients with ABNORMAL High Ca++

Pharmacokinetics (Furosemide)

Absorption - oral bioavailability = 60 - 70 %.

Bioavailability is reduced with renal failure and chronic severe congestive heartfailure (bowel edema?)

Protein binding = 90% or more

Elimination - half-life 1 - 2 hours. Half-life is prolonged with hepatic and renalfailure (especially the combination).


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Loop (High Ceiling) Diuretics

Toxicity

Relatively frequent

electrolyte imbalances

Relatively rare

allergic reactions

leukopenia or agranulocytosis

ototoxicitypancreatitis

thrombocytopenia

Drug Interactions

Effect of loop diuretic reduced by non-steroidal anti-inflammatory drugs

Potentiate hypotensive effects of"ACE" inhibitors

Potentiated ototoxicity or nephrotoxicity ofamphotericin B, aminoglycosides, many

othersPotentiate hypokalemia associated with amphotericin B, mineralocorticoids, some

synthetic penicillins, many others (that induce hypokalemia)

Decreased activity oforal anticoagulants, heparin, enzymes, insulin

Potentiateneuromuscular junction blockers (hypokalemia)

Distal (Potassium Sparing)


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Distal (Potassium Sparing)

DiureticsSpironolactone, triamterene

Mechanism of action

Inhibition of Na/K exchange at aldosterone dependent distal tubular site

Spironolactone - competes with aldosterone for regulatory site

Triamterene - decreases activity of pump directly

Either mechanism decreases potassium wasting

Either mechanism produces poor diuresis (when used alone)

relatively unimportant Na recovery site

Diurectic activity increased if:

sodium load (body) is high

aldosterone concentrations are high

sodium load (tubule) is high - secondary to diuresis

Other electrolytes unaffectedDrug interactions

interact with any other drugs affecting:sodium balancepotassium balancerenin-angiotensin-aldosterone see other references - interact with any other drugs affected by:electrolyte balance

Toxicity

spironolactone may produce adrenal and sex hormone effects with LONG-TERM useBoth drugs may produce electrolyte imbalance


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Carbonic anhydrase inhibitors

Acetazolamide, Dichlorphenamide, Methazolamide,

EthoxzolamideMechanism of Action

Carbonic anhydrase (CA) facilitates excretion of H+ andrecovery of bicarbonate by the proximal renal tubule andciliary epithelium of the eye. Sodium is recovered inexchange for H+.

Inhibitors block CA block sodium recovery. A very milddiuresis is produced (this is really a side effect of theiruse in glaucoma) because relatively unimportantmechanism for Na recovery and because proximal

tubule site means that other sodium recoverymechansims continue to process their normal fraction ofthe sodium load.

O ti di ti


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Osmotic diureticsGlucose (metabolizable), Mannitol, Urea, Glycerin (non-metabolizable), Iodine Radiocontrast Agents

(incidental)

Mechanism(s) of Action

1. Reduce tissue fluid (edema) by creating osmotic draw from tissue to blood stream

2. Reflex cardiovascular effect by osmotic retention of fluid within vascular space which increasesblood volume (contraindicated with Congestive heart failure)

3. Diuretic effect

Makes H2O reabsorption far more difficult for tubular segments insufficient Na & H2O capacityin distal segments

Increased intramedullary blood flow (washout)

Incomplete sodium recapture (asc. loop). this is indirect inhibition of Na reabsorption (Na stays intubule because water stays)

Net diuretic effect:

Tubularconcentration of sodium decreases

Total amount of sodium lost amount increases

GFR unchanged or slightly increased

Toxicity

Fluid and electrolyte imbalance

produces over-expansion of extracellular fluid and circulatory overload.Circulatory overload may be accompanied by dilutional hyponatremia.

Hyperkalemia is possible

Extravasation

may cause edema and skin necrosis. (Be careful with mannitol).

Extravasation may also occur into central nervous system Be careful with cranial traumacases (hemorrhage leads to extravasation)

Pharmacokinetics

Onset= 1 - 3 hours (diuresis)= 15 - 30 minutes (cerebral edema)Duration= 3 - 6 hoursElimination is 80 - 90% renal


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ACE inhibitors ACE inhibitors produce vasodilation by inhibiting the formation of

angiotensin II. This vasoconstrictor is formed by the proteolyticaction of renin (released by the kidneys) acting on circulatingangiotensinogen to form angiotensin I. Angiotensin I is thenconverted to angiotensin II by angiotensin converting enzyme.

ACE also breaks down bradykinin (a vasodilator substance).

Therefore, ACE inhibitors, by blocking the breakdown of bradykinin,increase bradykinin levels, which can contribute to the vasodilatoraction of ACE inhibitors. The increase in bradykinin is also believedto be responsible for a troublesome side effect of ACE inhibitors,namely, a dry cough.

Angiotensin II constricts arteries and veins by binding toAT1receptors located on the smooth muscle, which are coupled to a Gq-protein and the the IP3 signal transduction pathway. Angiotensin IIalso facilitates the release of norepinephrine from sympatheticadrenergic nerves and inhibits norepinephrine reuptake by thesenerves. This effect of angiotensin II augments sympathetic activityon the heart and blood vessels.
http://www.cvpharmacology.com/vasodilator/ARB.htmhttp://www.cvpharmacology.com/vasodilator/ARB.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://www.cvpharmacology.com/vasodilator/ARB.htmhttp://www.cvpharmacology.com/vasodilator/ARB.htm


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Mechanisms for maintaining


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Fall in blood pressure (hypotension)

The release of a protein renin from cells in the kidney (thejuxtaglomerularapparatus).

Angiotensin I

Angiotensin II

Aldosteron

Mechanisms for maintaining

the blood pressure

cuts off all but the first 10amino

acidresidues ofangiotensinogen

angiotensin converting enzyme (ACE),

n ors ave e o ow ng
http://en.wikipedia.org/wiki/Hypotensionhttp://en.wikipedia.org/wiki/Reninhttp://en.wikipedia.org/wiki/Kidneyhttp://en.wikipedia.org/wiki/Juxtaglomerular_apparatushttp://en.wikipedia.org/wiki/Juxtaglomerular_apparatushttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Angiotensinogenhttp://en.wikipedia.org/wiki/Angiotensin_converting_enzymehttp://en.wikipedia.org/wiki/Angiotensin_converting_enzymehttp://en.wikipedia.org/wiki/Angiotensinogenhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Juxtaglomerular_apparatushttp://en.wikipedia.org/wiki/Juxtaglomerular_apparatushttp://en.wikipedia.org/wiki/Kidneyhttp://en.wikipedia.org/wiki/Reninhttp://en.wikipedia.org/wiki/Hypotension


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n ors ave e o ow ngactions:

Dilate arteries and veins by blocking angiotensin II formation andinhibiting bradykinin metabolism. This vasodilation reduces arterialpressure, preload and afterload on the heart.

Down regulate sympathetic adrenergic activity by blocking thefacilitating effects of angiotensin II on sympathetic nerve release andreuptake of norepinephrine.

Promote renal excretion of sodium and water (natriuretic and diureticeffects) by blocking the effects of angiotensin II in the kidney and byblocking angiotensin II stimulation ofaldosterone secretion. Thisreduces blood volume, venous pressure and arterial pressure.

Inhibit cardiac and vascular remodeling associated with chronichypertension, heart failure, and myocardial infarction

Cardiorenal Effects of ACE
http://cvphysiology.com/Cardiac%20Function/CF007.htmhttp://cvphysiology.com/Cardiac%20Function/CF008.htmhttp://www.cvpharmacology.com/diuretic/natriuretics.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://cvphysiology.com/Blood%20Pressure/BP025.htmhttp://www.cvpharmacology.com/clinical%20topics/hypertension.htmhttp://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/hypertension.htmhttp://cvphysiology.com/Blood%20Pressure/BP025.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://www.cvpharmacology.com/diuretic/natriuretics.htmhttp://cvphysiology.com/Cardiac%20Function/CF008.htmhttp://cvphysiology.com/Cardiac%20Function/CF007.htm


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Cardiorenal Effects of ACE

Inhibitors

Vasodilation (arterial & venous)

- reduce arterial & venous pressure

- reduce ventricular afterload & preload

Decrease blood volume

- natriuretic

- diuretic

Depress sympathetic activity

Inihibit cardiac and vascular hypertrophy

Therapeutic Use of


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Therapeutic Use of

ACE Inhibitors

Hypertension

Heart failure

Post-myocardial infarction

ACE inhibitors can be divided into


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ACE inhibitors can be divided into

three groups based on their

molecular structure Sulfhydryl-containing agentsCaptopril (trade name Capoten), the first ACE inhibitor

Zofenopril

Dicarboxylate-containing agentsThis is the largest group, including:

Enalapril (Vasotec/Renitec)

Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace)

Quinapril (Accupril)

Perindopril (Coversyl/Aceon)

Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril)

Benazepril (Lotensin)

Imidapril (Tanatril)Zofenopril (Zofecard)

Trandolapril (Mavik/Odrik/Gopten)

Phosphonate-containing agentsFosinopril (Fositen/Monopril) is the only member of this group
http://en.wikipedia.org/wiki/Captoprilhttp://en.wikipedia.org/wiki/Zofenoprilhttp://en.wikipedia.org/wiki/Enalaprilhttp://en.wikipedia.org/wiki/Ramiprilhttp://en.wikipedia.org/wiki/Quinaprilhttp://en.wikipedia.org/wiki/Perindoprilhttp://en.wikipedia.org/wiki/Lisinoprilhttp://en.wikipedia.org/wiki/Benazeprilhttp://en.wikipedia.org/wiki/Imidaprilhttp://en.wikipedia.org/wiki/Zofenoprilhttp://en.wikipedia.org/wiki/Trandolaprilhttp://en.wikipedia.org/wiki/Fosinoprilhttp://en.wikipedia.org/wiki/Fosinoprilhttp://en.wikipedia.org/wiki/Trandolaprilhttp://en.wikipedia.org/wiki/Trandolaprilhttp://en.wikipedia.org/wiki/Zofenoprilhttp://en.wikipedia.org/wiki/Zofenoprilhttp://en.wikipedia.org/wiki/Imidaprilhttp://en.wikipedia.org/wiki/Imidaprilhttp://en.wikipedia.org/wiki/Benazeprilhttp://en.wikipedia.org/wiki/Benazeprilhttp://en.wikipedia.org/wiki/Lisinoprilhttp://en.wikipedia.org/wiki/Lisinoprilhttp://en.wikipedia.org/wiki/Perindoprilhttp://en.wikipedia.org/wiki/Perindoprilhttp://en.wikipedia.org/wiki/Quinaprilhttp://en.wikipedia.org/wiki/Quinaprilhttp://en.wikipedia.org/wiki/Ramiprilhttp://en.wikipedia.org/wiki/Ramiprilhttp://en.wikipedia.org/wiki/Enalaprilhttp://en.wikipedia.org/wiki/Zofenoprilhttp://en.wikipedia.org/wiki/Zofenoprilhttp://en.wikipedia.org/wiki/Captopril


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Adverse drug reactions include

hypotension,cough,

hyperkalemia,

headache,

dizziness,

fatigue,nausea,

renal impairment.

A persistent dry cough is a relatively common adverse effectbelieved to be associated with the increases in bradykinin levelsproduced by ACE inhibitors, although the role of bradykinin in

producing these symptoms remains disputed by some authors.Patients who experience this cough are often switched toangiotensin II receptor antagonists.
http://en.wikipedia.org/wiki/Adverse_drug_reactionhttp://en.wikipedia.org/wiki/Hypotensionhttp://en.wikipedia.org/wiki/Coughhttp://en.wikipedia.org/wiki/Hyperkalemiahttp://en.wikipedia.org/wiki/Headachehttp://en.wikipedia.org/wiki/Vertigo_(medical)http://en.wikipedia.org/wiki/Fatigue_(physical)http://en.wikipedia.org/wiki/Nauseahttp://en.wikipedia.org/wiki/Bradykininhttp://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonisthttp://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonisthttp://en.wikipedia.org/wiki/Bradykininhttp://en.wikipedia.org/wiki/Nauseahttp://en.wikipedia.org/wiki/Fatigue_(physical)http://en.wikipedia.org/wiki/Vertigo_(medical)http://en.wikipedia.org/wiki/Headachehttp://en.wikipedia.org/wiki/Hyperkalemiahttp://en.wikipedia.org/wiki/Coughhttp://en.wikipedia.org/wiki/Hypotensionhttp://en.wikipedia.org/wiki/Adverse_drug_reaction


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Contraindications and precautions

The ACE inhibitors are contraindicated inpatients with:

Previous angioedema associated with ACE inhibitor therapy

Renal artery stenosis (bilateral, or unilateral with a solitary functioningkidney)

Hypersensitivity to ACE inhibitors

ACE inhibitors should be used with cautionin patients with:

Impaired renal function

Aortic valve stenosis or cardiac outflow obstruction

Hypovolemia ordehydration

Hemodialysis with high-flux polyacrylonitrile membranes

ACE inhibitors areADECpregnancy category D
http://en.wikipedia.org/wiki/Angioedemahttp://en.wikipedia.org/wiki/Renal_artery_stenosishttp://en.wikipedia.org/wiki/Aortic_valve_stenosishttp://en.wikipedia.org/wiki/Hypovolemiahttp://en.wikipedia.org/wiki/Dehydrationhttp://en.wikipedia.org/wiki/Hemodialysishttp://en.wikipedia.org/wiki/Australian_Drug_Evaluation_Committeehttp://en.wikipedia.org/wiki/Pregnancy_categoryhttp://en.wikipedia.org/wiki/Pregnancy_categoryhttp://en.wikipedia.org/wiki/Australian_Drug_Evaluation_Committeehttp://en.wikipedia.org/wiki/Hemodialysishttp://en.wikipedia.org/wiki/Hemodialysishttp://en.wikipedia.org/wiki/Dehydrationhttp://en.wikipedia.org/wiki/Hypovolemiahttp://en.wikipedia.org/wiki/Hypovolemiahttp://en.wikipedia.org/wiki/Aortic_valve_stenosishttp://en.wikipedia.org/wiki/Aortic_valve_stenosishttp://en.wikipedia.org/wiki/Renal_artery_stenosishttp://en.wikipedia.org/wiki/Renal_artery_stenosishttp://en.wikipedia.org/wiki/Angioedema


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Angiotensin Receptor Blockers

(ARBs) Similar effects to angiotensin converting enzyme (ACE) inhibitors Used for the same indications (hypertension, heart failure, post-

myocardial infarction).

Their mechanism of action, however, is very different from ACEinhibitors:

ARBs are receptor antagonists that block type 1 angiotensin II (AT1)receptors on bloods vessels and other tissues such as the heart.

These receptors are coupled to the Gq-protein and IP3 signaltransduction pathway that stimulates vascular smooth musclecontraction.

Because ARBs do not inhibit ACE, they do not cause an increase inbradykinin, which contributes to the vasodilation produced by ACEinhibitors and also some of the side effects of ACE inhibitors (coughand angioedema).

Distribution of angiotensin
http://www.cvpharmacology.com/vasodilator/ACE.htmhttp://www.cvpharmacology.com/clinical%20topics/hypertension.htmhttp://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://cvphysiology.com/Blood%20Pressure/BP026.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/hypertension.htmhttp://www.cvpharmacology.com/vasodilator/ACE.htm


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Distribution of angiotensinreceptors in the body

AT1 receptors are mainly found in the heart,adrenal glands, brain, liver and kidneys. Theirmain role is to regulate blood pressure as wellas fluid and electrolyte balance.

AT2 receptors are highly expressed in thedeveloping fetus but they decline rapidly afterbirth. In the adult, AT2 receptors are present

only at low levels and are mostly found in theheart, adrenal glands, uterus, ovaries, kidneysand brain.

R i i t i th
http://en.wikipedia.org/wiki/Adrenal_glandshttp://en.wikipedia.org/wiki/Fetushttp://en.wikipedia.org/wiki/Fetushttp://en.wikipedia.org/wiki/Adrenal_glands


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Renin angiotensin pathway

ARBs have the following actions


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ARBs have the following actions,which are very similar to ACE

inhibitors: Dilate arteries and veins and thereby reduce arterial

pressure and preload and afterload on the heart.

Down regulate sympathetic adrenergic activity byblocking the effects of angiotensin II on sympatheticnerve release and reuptake of norepinephrine.

Promote renal excretion of sodium and water (natriureticand diuretic effects) by blocking the effects ofangiotensin II in the kidney and by blocking angiotensinII stimulation ofaldosterone secretion.

Inhibit cardiac and vascular remodeling associated withchronic hypertension, heart failure, and myocardialinfarction.
http://cvphysiology.com/Cardiac%20Function/CF007.htmhttp://cvphysiology.com/Cardiac%20Function/CF008.htmhttp://www.cvpharmacology.com/diuretic/natriuretics.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://www.cvpharmacology.com/clinical%20topics/hypertension.htmhttp://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://www.cvpharmacology.com/clinical%20topics/myocardial%20infarction.htmhttp://www.cvpharmacology.com/clinical%20topics/heart%20failure.htmhttp://www.cvpharmacology.com/clinical%20topics/hypertension.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://www.cvpharmacology.com/diuretic/diuretics.htmhttp://www.cvpharmacology.com/diuretic/natriuretics.htmhttp://cvphysiology.com/Cardiac%20Function/CF008.htmhttp://cvphysiology.com/Cardiac%20Function/CF007.htm


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ARBs include the following drugs:

candesartan

eprosartan

irbesartan

losartan

olmesartan

telmisartan

valsartan


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Table 1: Comparison of ARBpharmacokinetics

DrugBiological

half-life [h]

Protein

binding

[%]

Bioavailability

[%]

Renal/hepatic

clearance [%]Food effect

Daily

dosage

[mg]

Losartan 2 98.7 33 10/90 Minimal 50-100

EXP 3174 6-9 99.8 - 50/50 - -

Candesartan 9 >99 15 60/40 No 4-32

Valsartan 6 95 25 30/70

40-50%

decreased

by

80-320

Irbesartan 11-15 90-95 70 1/99 No 150-300Telmisartan 24 >99 42-58 1/99 No 40-80

Eprosartan 5 98 13 30/70 No 400-800

Olmesartan 14-16 >99 29 40/60 No 10-40

ARBs Side Effects and


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ARBs Side Effects andContraindications

As a drug class, ARBs have a relatively low incidence of side effectsand are well-tolerated. Because they do not increase bradykininlevels like ACE inhibitors, the dry cough and angioedema that areassociated with ACE inhibitors are not a problem. ARBs arecontraindicated in pregnancy. Patients with bilateral renal arterystenosis may experience renal failure if ARBs are administered. The

reason is that the elevated circulating and intrarenal angiotensin II inthis condition constricts the efferent arteriole more than the afferentarteriole within the kidney, which helps to maintain glomerularcapillary pressure and filtration. Removing this constriction byblocking angiotensin II receptors on the efferent arteriole can causean abrupt fall in glomerular filtration rate. This is not generally aproblem with unilateral renal artery stenosis because the unaffected

kidney can usually maintain sufficient filtration after AT1 receptorsare blocked; however, with bilateral renal artery stenosis it isespecially important to ensure that renal function is notcompromised.


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Beta-Adrenoceptor Antagonists

(Beta-Blockers) Beta-blockers bind to beta-adrenoceptors and thereby block the binding of

norepinephrine and epinephrine to these receptors.

Therefore, beta-blockers are sympatholytic drugs. Some beta-blockers,when they bind to the beta-adrenoceptor, partially activate the receptorwhile preventing norepinephrine from binding to the receptor. Thesepartialagonists therefore provide some "background" of sympathetic activity whilepreventing normal and enhanced sympathetic activity.

These particular beta-blockers (partial agonists)are said to possess intrinsic sympathomimeticactivity (ISA).

Some beta-blockers also possess what is

referred to as membrane stabilizing activity(MSA).

This effect is similar to the membrane stabilizing activity ofsodium-channels blockers that represent Class I antiarrhythmics.
http://www.cvpharmacology.com/norepinephrine.htmhttp://www.cvpharmacology.com/antiarrhy/sodium-blockers.htmhttp://www.cvpharmacology.com/antiarrhy/sodium-blockers.htmhttp://www.cvpharmacology.com/antiarrhy/Vaughan-Williams.htmhttp://www.cvpharmacology.com/antiarrhy/Vaughan-Williams.htmhttp://www.cvpharmacology.com/antiarrhy/sodium-blockers.htmhttp://www.cvpharmacology.com/antiarrhy/sodium-blockers.htmhttp://www.cvpharmacology.com/antiarrhy/sodium-blockers.htmhttp://www.cvpharmacology.com/norepinephrine.htm


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Generations of beta-blockers

The first generation of beta-blockers werenon-selective, meaning that they blocked bothbeta-1 (1) and beta-1 (2) adrenoceptors.

Second generation beta-blockers aremore cardioselective in that they are relativelyselective for 1 adrenoceptors. Note that thisrelative selectivity can be lost at higher drugdoses. Finally, the third generation beta-blockers

are drugs that also possess vasodilator actionsthrough blockade of vascularalpha-adrenoceptors.
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Functioning of beta-adrenoreceptor


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Beta2-receptor in the vessel

B t Bl k


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Beta-Blockers

Cardiac Effects

Decrease contractility(negative intropy)

Decrease relaxation rate

(negative lusitropy)Decrease heart reat

(negative chronotropy)

Decrease conduction velocity(negative dromotropy)

Vascu lar Effects

Smooth muscle contraction(mild vasoconstriction)

B t bl k d H t i
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Beta-blockers and Hypertension Beta-blockers decrease arterial blood pressure by

reducing cardiac output.

Many forms of hypertension are associated with anincrease in blood volume and cardiac output.

Acute treatment with a beta-blocker is not very effectivein reducing arterial pressure because of a compensatoryincrease in systemic vascular resistance. This may occur

because of baroreceptor reflexes working in conjunctionwith the removal of 2 vasodilatory influences thatnormally offset, to a small degree, alpha-adrenergicmediated vascular tone.

Chronic treatment with beta-blockers lowers arterial

pressure more than acute treatment possibly because ofreduced renin release and effects of beta-blockade oncentral and peripheral nervous systems.

Hypertension in some patients is caused by emotionalstress, which causes enhanced sympathetic activity.Beta-blockers can be very effective in these patients

Theraputic Use of
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Theraputic Use ofBeta-Blockers

Hypertension

Angina

Myocardial infarction

Arrhythmias

Heart failure

Clinical Uses

Class/Drug HTN Angina Arrhy MI CHF Comments


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Abbreviations: HTN, hypertension; Arrhy, arrhythmias; MI, myocardial

infarction; CHF, congestive heart failure; ISA, intrinsic

sympathomimetic activity.

Class/Drug HTN Angina Arrhy MI CHF Comments

Non-selective

1/2

carteolol X ISA; long acting; also used for glaucoma

carvedilol X X -blocking activity

labetalol X X ISA; -blocking activitynadolol X X X X long acting

penbutolol X X ISA

pindolol X X ISA; MSA

propranolol X X X X MSA; prototypical beta-blocker

sotalol X several other significant mechanisms

timolol X X X X primarily used for glaucoma

1-selective

acebutolol X X X ISA

atenolol X X X X

betaxolol X X X MSA

bisoprolol X X X

esmolol X X ultra short acting; intra or postoperative HTN

metoprolol X X X X X MSA

nebivolol Xrelatively selective in most patients; vasodilating

(NO release)

Side Effects and


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Side Effects andContraindications

Cardiovascular side effectsbradycardia,reduced exercise capacity,

heart failure,hypotension,

atrioventicular (AV) nodal conductionblock.

Beta-blo ckers are therefo re

contraindicated in patients w i th s inus

bradycardia and part ial AVblock

Side Effects and Contraindications


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Side Effects and Contraindications

Other side effects

Bronchoconstriction can occur, especially when non-selective beta-blockers areadministered to asthmatic patients.

Therefore, non-selective beta-blockers are contraindicated inpatients with asthma or chronic obstructive pulmonary disease.

Hypoglycemia can occur with beta-blockade because 2-adrenoceptors normally stimulate hepatic glycogen breakdown(glycogenolysis) and pancreatic release of glucagon, which worktogether to increase plasma glucose.

Therefore, blocking 2-adrenoceptors lowers plasma glucose.1-blockers have fewer metabolic side effects in diabeticpatients; however, the tachycardia which serves as a warningsign for insulin-induced hypoglycemia may be masked.

Therefore beta-blockers are to be used cautiously in diabetics.


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Calcium-Channel Blockers (CCBs)

Currently approved CCBs bind to L-type calcium channels locatedon the vascular smooth muscle, cardiac myocytes, and cardiacnodal tissue (sinoatrial and atrioventricular nodes).

These channels are responsible for regulating the influx of calciuminto muscle cells, which in turn stimulates smooth musclecontraction and cardiac myocyte contraction.

In cardiac nodal tissue, L-type calcium channels play an importantrole in pacemaker currents and in phase 0 of the action potentials.

Therefore, by blocking calcium entry into the cell, CCBs causevascular smooth muscle relaxation (vasodilation), decreasedmyocardial force generation (negative inotropy), decreased heart

rate (negative chronotropy), and decreased conduction velocitywithin the heart (negative dromotropy), particularly at theatrioventricular node
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Calcium-Channel Blockers

Cardiac effects

Decrease contractility(negative inotropy)

Decrease heart rate(negative chronotropy)

Decrease conduction velocity(negative dromotropy)

Vascular effectsSmooth muscle relaxation

(vasodilation)

Th ti U f


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Therapeutic Use of

Calcium-Channel Blockers

Hypertension

(systemic & pulmonary)

Angina

Arrhythmias

Different Classes of Calcium


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Different Classes of Calcium-

Channel Blockers There are three classes of CCBs. They differ not only in

their basic chemical structure, but also in their relativeselectivity toward cardiac versus vascular L-type calciumchannels. The most smooth muscle selective class ofCCBs are the dihydropyridines. Because of their highvascular selectivity, these drugs are primarily used toreduce systemic vascular resistance and arterialpressure, and therefore are primarily used to treathypertension. They are not, however, generally used to

treat angina because their powerful systemic vasodilatorand pressure lowering effects can lead to reflex cardiacstimulation (tachycardia and increased inotropy), whichcan dramatically increase myocardial oxygen demand.

Dihydropyridines include the


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Dihydropyridines include the

following specific drugs:

amlodipine

felodipine

isradipine

nicardipine

nifedipine

nimodipine

nitrendipine


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Phenylalkylamine class

Verapamil, is relatively selective for the

myocardium, and is less effective as a

systemic vasodilator drug. This drug has a

very important role in treating angina (byreducing myocardial oxygen demand and

reversing coronary vasospasm) and

arrhythmias


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Benzothiazepine class

Diltiazem is intermediate between

verapamil and dihydropyridines in its

selectivity for vascular calcium channels.

By having both cardiac depressant andvasodilator actions, diltiazem is able to

reduce arterial pressure without producing

the same degree of reflex cardiacstimulation caused by dihydropyridines.

Side Effects and


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Contraindications

Dihydropyridine CCBs can cause flushing, headache, excessivehypotension, edema and reflex tachycardia. The activation ofsympathetic reflexes and lack of direct cardiac effects makedihydropyridines a less desirable choice for angina. Long-actingdihydropyridines have been shown to be safer anti-hypertensivedrugs, in part, because of reduced reflex responses. The cardiac

selective, non-dihydropyridine CCBs can cause excessivebradycardia, impaired electrical conduction (e.g., atrioventricularnodal block), and depressed contractility. Therefore, patients havingpreexistent bradycardia, conduction defects, or heart failure causedby systolic dysfunction should not be given CCBs, especially thecardiac selective, non-dihydropyridines. CCBs, especially non-dihydropyridines, should not be administered to patients being

treated with a beta-blocker because beta-blockers also depresscardiac electrical and mechanical activity and therefore the additionof a CCB augments the effects of beta-blockade.


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Resistant hypertension


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Resistant hypertension

List of hypertensive emergencies


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List of hypertensive emergencies

Documents

Arterial Hypertension Management