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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.htm7/29/2019 Arterial Hypertension Management
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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/Hypotension7/29/2019 Arterial Hypertension Management
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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.htm7/29/2019 Arterial Hypertension Management
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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/Captopril7/29/2019 Arterial Hypertension Management
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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_reaction7/29/2019 Arterial Hypertension Management
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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/Angioedema7/29/2019 Arterial Hypertension Management
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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.htm7/29/2019 Arterial Hypertension Management
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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
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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.htm7/29/2019 Arterial Hypertension Management
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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.
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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