DRUGS FOR HYPERTENSION

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DRUGS FOR HYPERTENSION

Post  counselor on Mon Oct 15, 2012 11:47 am

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DRUGS FOR HYPERTENSION




DRUGS FOR HYPERTENSION





The hypertension is a major risk factor for disorders of the heart, brain, eye, kidney. In fact, hypertension can cause:
• Hypertrophy of the left ventricle
• Heart failure
• Ischemia and myocardial infarction
• Stroke cerebral
• Hypertensive encephalopathy
• retinopathy
• Damage to the renal arteries


According to the guidelines, both U.S. and European, issued in 2003, we can classify hypertension in its severity as follows:

Systolic Diastolic

Normal pressure 120-129 80-84
The normal range 130-139 85-89

Grade 1 = mild hypertension 140-159 90-99

Grade 2 = moderate hypertension 160-179 100-109

Grade 3 = severe hypertension> 180> 110

Isolated systolic hypertension> 140 <90

Depending on the etiology distinguish:

SECONDARY HYPERTENSION

can be attributed due to well identified:
1) Drugs (oral contraceptives, cadmium, etc.).
2) Pheochromocytoma = chromaffin tissue tumor which liberates catecholamines.
3) Hypertension renal (glomerulonephritis, atheromatous renal artery occlusion, trauma or congenital defects, renin-angiotensin system).
4) Since mineralocorticoid (eg in Cushing's syndrome, Conn).
5) neurogenic hypertension by:
section of the buffer nerves, lesion of the nucleus of the solitary tract, increased intracranial pressure
artery occlusive disorders vertebrobasilar
6) Eclampsia of pregnancy.

Essential hypertension

We do not know what the causes. Is the most common type of hypertension 95% of cases.


Regulation of blood pressure
The control of blood pressure results from the interaction of:
• peripheral resistance (vascular tone first)
• cardiac output
• blood volume

Contribute to the control of vascular tone:
• adrenergic neurotransmission
• cholinergic neurotransmission
• dopaminergic neurotransmission
• the neurotrasmissine purinergic
• the system of arginine-vasopressin
• the system of cyclo-oxygenase and lipo-
• the renin-angiotensin
• channels for the Ca + + and K +
• nitric oxide produced by the endothelium
• the system of endothelin (ETA receptor on vascular muscle layer induces vasoconstriction after stimulation by ET-1, above)
• the system of cardiac natriuretic peptides which inhibit the release of angiotensin II, endothelin, vasopressin.
• The system of bradykinin (B2 receptor stimulation causes release of NO and vasodilation)

Vasomotor tone is controlled mainly by the core sub-retrofaciale the bulb.

This nucleus receives input from several brain areas and in particular from the nucleus of the solitary tract which controls the baroreceptor reflex and the area postrema, that is stimulated by angiotensin II in the blood.

Send efferent sympathetic neurons that control primarily preganglionic




DO NOT APPROACH TO DRUG hypertension

Weight loss
It can reduce the blood pressure by reducing the body weight especially in obese subjects.

Restricting the intake of Na +
You can have a drop of approximately 7 mmHg with an intake of 70-100 mEq per day, but only in about 50% of the subjects.

Reduction of alcohol intake
High amounts of alcohol produce increased pressure for liberation of norepinephrine.

Moderate physical activity
May reduce the pressure of about 10 mmHg.

Adequate intake of potassium
The K + may exert its effect on Na-K ATPase by reducing the Na + and thus the intracellular Ca + +.



PHARMACOLOGICAL APPROACH hypertension
The European Society of Hypertension recommend:
• initiating therapy with low doses of a single drug
• The emphasis is on the values ​​of pressure obtained after the use of the drug
• if the first drug in low doses does not work you can choose to increase the dose or change your medicine or somministrarne 2 together
• In the absence of results you can combine three drugs together.
• It 'important to assess the adverse drug reactions and therefore patient compliance
• The choice of drugs considered to start with the treatment are: diuretics, -blockers, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers.



DIURETICS

Thiazide Diuretics
They are among the most useful as antihypertensive diuretics, (perhaps because of their longer duration of action).
Are used thiazide diuretics such as chlorothiazide, hydrochlorothiazide or congeners such as chlorthalidone, chinetazone, metazolone).

ACTION diuretic
1) is secreted into the tubular lumen at the level of the proximal tubule.
2) They act on the distal tubule preventing the reabsorption of sodium per block co-transporter Na + / Cl-

Antihypertensive action
1) is observed for chronic administration of lower doses of the diuretic.
2) The plasma volume is only 5% below the normal value.
3) The cardiac output is normal.
4) The average pressure drop is lower because peripheral resistance.

The decrease in peripheral resistance appears to be due to the negative effect on the values ​​of intracellular calcium, perhaps mediated adverse effect on the financial statements of Na +.
Direct vasodilator effect may also occur.

The antihypertensive effect appears after 2-4 weeks.
If you do not see the effect is not advisable to increase the dosage (you would have more intense side effects).
Better associate with other antihypertensive diuretic.

PHARMACOKINETICS
Good oral absorption, except chlorothiazide that gives a bioavailability of 10%.
The effect usually lasts 12 hours for hydrochlorothiazide, and up to 72 hours for chlorthalidone.

TOXICITY '
Headache, dizziness, fatigue
Hyperuricemia
Hyperglycemia
Hypokalemia
Increase of LDL and VLDL.


Loop diuretics
Belong to this class furosemide, bumetanide, torsemide, ethacrynic acid.

Pharmacodynamics
1) They act on the ascending limb of the loop of Henle often blocking the symporter Na + / K + / 2Cl-.
These diuretics bind to the site for the Cl-symporter.

The diuretic effect is very pronounced because of the site of action by an intense absorption.
These diuretics cause:
a) strong elimination of Na + and Cl-.
b) increases the elimination of K
c) strong elimination of Ca + + and Mg + +
d) increases sharply the elimination of uric acid, but the chronic use reduces the elimination

The renal blood flow increases. Maybe prostaglandins are involved in renal effects, in fact, NSAIDs decrease reduces the diuretic effect.

PHARMACOKINETICS
- I am very bound to plasma proteins
- In addition to being ultrafiltrati, are also secreted by the proximal tubule.
-They have a short duration of action (from 30 min to 2 hours)

TOXICITY '
-These diuretics can cause:
a) hyponatremia, hypovolemia, and hypotension
b) hypokalemia and alkalosis
c) hypomagnesemia (arrhythmias) and hypocalcemia (tetanus)
d) ototoxicity (symporter block the ear).
d) hyperuricemia
e) increase of increazione of renin



Potassium-sparing diuretics
Belong to this class amiloride and triamterene, spironolactone but also, its metabolite canrenone, the potassium canrenoate.
Pharmacodynamics
Amiloride and triamterene block the channels for Na + ion located on the luminal membrane in the last portion of the distal tubule and collecting tubule
The depolarization of the cell stimulates the leakage of K + into the tubular lumen. Therefore, the blockade of Na + channel therefore hinders the leakage of K +.
Modesto is the increase of the excretion of Na + and Cl-
Decreases the excretion of K +, H +, Ca + + and Mg + +.
Decreases the excretion of uric acid

Spironolactone and derivatives competitively inhibit the binding of aldosterone to mineralocorticoid receptors.
Aldosterone causes retention of Na + and water and facilitates the elimination of K + and H +

Spironolactone causes then
Modest increase of the excretion of Na + and Cl-
Decrease in excretion of K +, H +, Ca + + and Mg + +.
Decrease in the excretion of uric acid

PHARMACOKINETICS
Amiloride has a duration of action of at least 24 hours. Spironolactone derivatives and take at least 48 hours.
Triamterene has only short-term (5 hours)

TOXICITY '
To amiloride
• Hyperkalemia
• Glucose intolerance

For spironolactone and canrenone
• Hyperkalemia
• Gynecomastia
• Hirsutism
• Menstrual irregularities

THERAPEUTIC USE
Short-acting diuretics such as loop diuretics are indicated in hypertensive emergencies.

Drugs to long duration of action are able to lower the pressure of 10-15 mmHg, steadily reducing the volume and for the thiazide also peripheral resistance.
Thiazide diuretics are often used in conjunction with K + sparing to maintain appropriate serum potassium values. They can be used in combination with other antihypertensive

Diuretic agents are then used in therapy for edemigene syndromes associated with:
• heart disease (congestive heart failure)
• liver disease (cirrhosis) or
• kidney problems (nephrotic syndrome, glomerulonephritis, etc.)

Spirololattone and derivatives are drugs of choice in cases of primary or secondary hyperaldosteronism

Amiloride is useful in the treatment of cystic fibrosis.


Diuretics, carbonic anhydrase inhibitors
The prototype consists of the acetazolamide

Pharmacodynamics
The luminal membrane is equipped with a antiporter that transports Na + within the cell door and H + in the tubular lumen.

• The epithelial cells of the proximal convoluted tubule are rich in carbonic anhydrase. The inhibition of carbonic anhydrase cytoplasmic entails reduced availability of H + and therefore less reabsorption of sodium.
• It eliminates even more baking soda
• Increases the elimination of K + for increased availability of Na + in the distal nephron
• Poor effect of removal of Ca + + and Mg + +

Other effects
The carbonic anhydrase is also present in the eye where it is involved in the formation of aqueous humor.
The inhibition of carbonic anhydrase causes reduction of intraocular pressure

The carbonic anhydrase is present in the central nervous system and its inhibition causes drowsiness and antiepileptic effect.

In the erythrocytes anhydrase inhibition increases the levels of carbon dioxide in peripheral tissues

FARMACOCINETCA
The acetazolamide has half-life of 5-8 hours.

TOXICITY '
a) Bone marrow depression
b) Allergic reactions
c) drowsiness, and paresthesias
d) alkalinizing the urine causing ammonia, with the risk of encephalopathy
e) precipitation of calculations of calcium phosphate
f) metabolic acidosis



THERAPEUTIC USES
a) carbonic anhydrase inhibitors have little use in the treatment of edema and antihypertensive therapy
b) are useful in the treatment of glaucoma
f) can be useful in epilepsy, both small and great evil
g) appear to be useful for mountain sickness


Osmotic diuretics
Belong to this class mannitol, urea, glycerin and sorbitol.

Pharmacodynamics
• They are freely filtered by the glomerulus
• They are reabsorbed at the tubular little
Therefore:
• They extract water from the intracellular compartment and
• Increase the volume of urine
• Increase the elimination of all electrolytes

PHARMACOKINETICS
Mannitol is the most widely used drug. It is administered by intravenous infusion because it is excreted quickly (30-90 minutes)

TOXICITY '
a) In patients with heart failure or pulmonary congestion may cause pulmonary edema
b) are contraindicated in patients with intracranial bleeding.

THERAPEUTIC USES
• Acute renal failure due to acute tubular necrosis (from trauma, surgery)
• Acute attacks of glaucoma
• Cerebral edema




DRUGS OF renin-angiotensin system

THE renin-angiotensin system
Angiotensin II (Ang II) is considered one of the most important agents of control of cardiovascular homeostasis.
Its synthesis part dall'angiotensinogeno


Angiotensinogen
It 'sa  2 globulin. The human is 452 amino acids.
It 'synthesized mainly in the liver, in certain areas of the brain and kidney.
The levels of circulating angiotensinogen affect the formation of Ang II.
Oral contraceptives, glucocorticoids, thyroid hormones increase the synthesis of angiotensinogen.

Renin
It 'a glycoprotein of 340 amino acids
It 'summarized as prorenina (406 amino acids) and deposited in the juxta-glomerular cells on the walls of the afferent arterioles of the glomerulus
Renin converts angiotensinogen to Ang I.

The secretion of renin is controlled by:
1) chemoreceptors
Epithelial cells located between the afferent and efferent glomerular arterioles are sensitive to the flow of NaCl through the macula densa (poor flow stimulates the release of renin). The effect is mediated by adenosine or prostaglandins
2) baroreceptors of the vessel walls kidney, but also extrarenal.
The increase of blood pressure inhibits the release of renin (reduced pressure increases the liberation).
3) The stimulation of adrenergic receptors  1 on the juxta-glomerular cells increases the release of renin
4) -adrenergic receptors inhibit the release of renin.
5) Feedback mechanisms:
a) short-term feedback mechanism (stimulation of AT1 receptors on juxtaglomerular cells)
b) long-term feedback mechanism (pressure increase by Ang II. Such a mechanism disables the 3 pathways activators).

Angiotensin Converting Enzyme (ACE)
E 'a protein of 1278 amino acids
It 'also known as kinase II or dipeptidyl carboxypeptidase
And 'present in plasma. Strong localization in the endothelium and vascular lung and in the brain.
Converts Ang I to Ang II, but also metabolizes bradykinin and substance P

• The Ang I is almost inactive;
• the Ang II is the most active;
• the Ang III is as powerful as the Ang II in aldosterone release, is 4-10 times less active as a vasoconstrictor and stimulate the adrenal medulla;
• the Ang (1-7) has vasodilator and natriuretic action. Counteracts the effects of Ang II.
• The Ang II controls the blood pressure homeostasis and volemic through the following effects:
• direct vasoconstrictor effect
• increased release of catecholamines via presynaptic receptors
• increased release of endothelin
• stimulated synthesis of aldosterone
• direct reduction of natriuresis and diuresis
• release of vasopressin
• stimulation of water intake and salt
• Effect of positive inotropic


RECEPTORS
1) AT1 (high affinity for losartan)
Mediate most of the actions of Ang II.
Are coupled to G proteins, stimulate various phospholipases (C, D and A2) and trigger the hydrolysis of fosfatidilinositidi membrane.
2) AT2 (high affinity for PD 123 177
Strong distribution in the fetus. In adults found in the adrenal gland, brain, heart and vascular endothelium.
Median liberation of NO and vasodilation.
3) AT3. Are localized on neurons where increased NO production and liberation of cyclic GMP.
4) AT4. Are located primarily in the brain, kidney and adrenal gland and heart. Inhibit the renal reabsorption of sodium and produce vasodilatation.
Angiotensin CONVERTING ENZYME (ACE) INHIBITORS

In 1960, Ferreira discovered that venom inhibits the kinase crotalidi, reducing the metabolism of bradykinin
Later it was discovered that inhibit the conversion of Ang I to Ang II.
In 1977 was synthesized captopril, the first ACE inhibitor peptide, paving the way for the development of many other inhibitors on the market today.

Pharmacodynamics
ACE inhibitors exert the following effects:
• abolish the conversion of Ang I to Ang II
• abolish the responses to Ang I to Ang II not
• Increase the production of Ang (1-7)
• Increase blood levels and effects of bradykinin
• Increase the synthesis of prostaglandins stimulated by bradykinin
• Reduce pre-and afterload
• Evoke reduction in plasma levels of aldosterone
• produce natriuresis and diuresis, although modest

PHARMACOKINETICS
• Captopril is administered 2-3 times a day because it has a half-life of about 2 hours.
• Enalapril is a prodrug, which generates the active enalaprilat; this has half-life of 30-35 hours.
• The lisinopril half-life of about 12.5 hours and has renal elimination.
• Other ACE inhibitors are the quinapril (which generates a metabolite, quinaprilat, strong ACE inhibitor), ramipril, the moexipril, the spirapril, the fosinopril etc.

USES TERPEUTICI
Are considered drugs of choice for
1) Hypertension
Fall peripheral resistance, but poor sympathetic activation and tachycardia. Diuretics increase the response. No answer hypertension primary hyperaldosteronism).
2) heart failure. In severe heart failure are associated with diuretics and cardiac glycosides

They are also used for
3) ischemic heart disease. ACE inhibitors, as well as reducing the preload and afterload, prevent endothelial damage and reduce the formation of atherosclerotic plaque. Also reduce left ventricular hypertrophy
4) Prevention of damage post-infarct
4) diabetic nephropathy. Rallentatano the progression of renal failure from diabetes and hypertension

TOXICITY '
1) Strong first dose hypotension in patients with high reninemia
2) Cough iatrogenic in 5-20% of patients
3) Hyperkalemia
4) fetal damage (the second and third trimester of pregnancy
5) Rush skin
6) angioneurotic edema (1-2%)
AT1 RECEPTOR ANTAGONIST

In the 70's only been developed the first peptide antagonists for the receptors of Ang II, as the saralasina.
At the end of the 80 we have the first nonpeptidici antagonist (S-8307 and S-8308)
In 1995, losartan, AT1 receptor antagonist, is approved for clinical use.
Other members of this class of drugs are irbesartan, valsartan, candesartan etc.

Pharmacodynamics
Stabilize-pressor effects of Ang II
-Perhaps the Ang II AT1 receptors finding employment, could stimulate more AT2 receptors that mediate vasodilation.
-Reduces the peripheral stimulation of the sympathetic
-They block the central effects (release of vasopressin stimulation of water intake and salt)
-They block the renal effects of Ang II
-Increased renal excretion of uric acid
-Reduces left ventricular hypertrophy

PHARMACOKINETICS
-Good oral absorption
-They have 24-hour duration of action. Losartan has half-life of 2 hours, but it is converted to EXP 3174, a non-competitive antagonist with half-life of 6-9 hours which is 10-40 times more potent than losartan.


TOXICITY '
• produce excessive hypotension in subjects with high renin levels or who are taking high doses of diuretics
• Possible hyperkalemia
• Headache, dizziness and gastrointestinal pain
• Potential fetopatico the second and third trimester of pregnancy.

They have the advantage over ACE inhibitors cause less frequently iatrogenic cough and angioedema.


THERAPEUTIC USES
• High blood pressure
• Heart failure
• Cardiac Hypertrophy
• Ischemic heart disease in post-infarction
• delay the progression of deterioration of renal function in diabetic subjects


INHIBITORS OF VASOPEPTIDASI

Are being studied various compounds that inhibit both ACE, the endopeptidase that degrades atrial natriuretic peptides.
These are compounds of potential interest for hypertension, heart failure and ischemic heart disease.

Receptor agonists
 2-adrenergic

In addition to clonidine, are part of this group of drugs the guanfacine, the guanabenz, rilmenidine and the a-methyldopa.

Clonidine

Pharmacodynamics
• Its action is mainly due to stimulation of receptors  2 adrenergic receptors in the CNS.
• The main site of action is the medulla oblongata. In fact:
1) also intracisternal administration of the drug antihypertensive action.
2) The central administration of an  2 antagonist suppresses the effect.

• The stimulation of receptors  2 central reduces the discharge of the sympathetic nervous system in the suburbs.
• In the clonidine may also act by stimulating presynaptic receptors  2-in suburbs and thus reducing the release of norepinephrine
• The antihypertensive effect may partly depend on binding of clonidine to I1 imidazoline receptors. Rilmenidine and moxonidine still bind most of clonidine to these receptors

After administration of clonidine is observed:
• Reduction of heart rate
• Reduction of stroke volume
• Decreased peripheral resistance, especially in the upright position.
• Reduction in the release of renin
• Effect diuretic to reduce the release of vasopressin and increased renal prostaglandin
• For high doses is observed, however, the initial vasoconstriction by stimulation of postsynaptic receptors  2

In addition to the cardiovascular effects of clonidine has:
• analgesic effect
• reduces the signs of opioid withdrawal and alcohol
• reduces the intraocular pressure

PHARMACOKINETICS
Excellent oral absorption
Penetrates well into the CNS
Metabolic elimination of 50%, 50% urinary
TOXICITY '
• Sedation and drowsiness, male impotence
• For overdose depression, circulatory and breathing
• Dry mouth
• Water retention (in the absence of diuretics)
• Insomnia, anxiety, depression
• Rush skin
After abrupt discontinuation can be observed hypertensive crisis

THERAPEUTIC USE
• Using very limited as an antihypertensive
• E 'used in withdrawal symptoms from opiates and alcohol
• Glaucoma
• Hot flushes in menopause


-methyldopa

Pharmacodynamics
It acts on the central nervous after conversion to -metilnoradrenalina which is a potent agonist  2 adrenergic receptor.

The administration of the drug induces
• Reduction in peripheral vascular resistance
• Little effect on cardiac output and heart rate
• Reduced renin activity (moderate relevance)
• Reduction of plasma NA
• Possible orthostatic hypotension, but less severe than with peripherally acting drugs

PHARMACOKINETICS
Oral absorption is incomplete (25%)
Elimination is for 2/3 renal, 1/3 metabolic
With evening dosing reduces the risk of orthostatic hypotension.

TOXICITY '
• Sedation, headache, dizziness
• Postural hypotension
• hyperprolactinemia, gynecomastia, male impotence
• More rarely: haemostatic anemia, thrombocytopenia and leucopenia. Sometimes hepatitis

THERAPEUTIC USE
It is most certainly use during pregnancy because it seems to have no teratogenic effect
Its use is limited by side effects.

Guanabenz and guanfacine
Have lower risk of rebound hypertension stopping treatment

Rilmenidine and moxonidine
Have much lower sedative effect to clonidine




RECEPTOR ANTAGONIST
 1 ADRENERGIC


RECEPTOR ANTAGONIST
 ADRENERGIC

See Chapter on adrenergic drugs

Vasodilators

Hydralazine

Pharmacodynamics
1) The 'effect of idrolazina is largely unknown
2) It seems to interfere with the flow of the transmembrane Ca + +.

Induces vasodilation of arterioles, little veins. Orthostatic hypotension is infrequent.
Vasodilatation has been accompanied by reflex sympathetic activation with:
a) increased frequency and cardiac output
b) increased plasma renin activity
c) fluid retention that reduce the antihypertensive effect. For these reasons, hydralazine should not be used alone, but in association with -blockers or diuretics.

PHARMACOKINETICS
Good intestinal absorption, but strong I pass metabolism (acetylation).
Is eliminated metabolically in the liver, but extrahepatic
The 'effect lasts up to 12 hours.




TOXICITY '
• Headache, tachycardia, hypotension
• Cardiac ischemia due to increased heart rate or "coronary steal"
• immunological reactions including lupus

THERAPEUTIC USE
• The reflex tachycardia limits its effect.
• It can be used alone, but together with -blockers, when these are insufficient, and diuretics.

Minoxidil and diazoxide

Pharmacodynamics
Activate the channel for the ATP-sensitive K. Thus increase the permeability of the cell membrane to K + leaking from the cell (cell hyperpolarization).


These drugs induce:
1) Vasodilation mostly arteriolar.
2) The antihypertensive effect is accompanied by strong sympathetic activation that produces:
-Tachycardia and increase in cardiac output
-Increased plasma levels of NO and renin

PHARMACOKINETICS
Very good gastrointestinal absorption for the minoxidil; diazoxide which is used only intravenously
Minoxidil as such is not active. It becomes after conversion to minoxidil sulfate.
The elimination is mostly for metabolic glucuroconjugation.

TOXICITY '
1) Water retention due to reduction in renal perfusion pressure
2) reflex tachycardia
3) Hypertrichosis for the minoxidil
4) Risk of ischemia in patients with coronary artery disease.

THERAPEUTIC USE
Are not indicated as monotherapy, but with  blockers and diuretics in hypertensive patients who do not respond to other treatments.


Sodium Nitroprusside

Pharmacodynamics
Acts as a vasodilator releasing nitric oxide and thus stimulating guanylate cyclase in smooth muscle cells.

PHARMACOKINETICS
After intravenous administration has immediate action (30 seconds) and rapid disappearance (3 minutes)

TOXICITY '
Can cause headache and palpitations
In subjects with hepatic impairment should (lack of sulfhydryl groups) can cause lactic acidosis Cyanide, originating from nitroprusside.

THERAPEUTIC USE
For intravenous infusion is the drug of choice for hypertensive emergencies.




Channel blockers Ca + +

ADJUSTING THE FOOTBALL MOBILE PHONE
1) The cell concentration of calcium is 7.10 M.
And extracellular is 10000 times higher.
2) The Ca + + enters cells through channels activated by depolarization of the membrane (voltage-gated channels).
3) It can also enter through channels activated by receptors for neurotransmitters and hormones.
4) The calcium entered the cell and causes the release of calcium from the sarcoplasmic reticulum.
5) After excitation, the high concentration of Ca + + is lowered by the intracellular sequestration in the endoplasmic reticulum, mitochondria or for distribution on the inner surface of the cell membrane.
6) is also lowered by extrusion from the cell by the Ca-ATPase and the exchanger Na: Ca


CHEMICAL STRUCTURE OF DRUG CLASS
Were studied various classes of compounds:
Fenilalchilamine (verapamil)
Benzodiazepines (diltiazem)
Dihydropyridines (nifedipine, nimodipine ...)

Pharmacodynamics
The Ca + + channel blockers are effective on voltage-gated channels. These channels are divided into: Channels L (Long lasting) channels N, T channels depending on the conductance and voltage sensitivity.

Only the channels L are sensitive to channel blockers Ca + +. In particular the Calcium channel blockers interact with the subunit -1c of the channel L.

E 'above the channel in the inactivated state that is tied, thus delaying the return to the idle state and then to the activated again.
Verapamil and diltiazem are tied in part to the open channel.

The calcium channel blockers evoke the following effects:
• Relaxation of arterial smooth muscle. It follows decreased blood pressure for reduction in peripheral vascular resistance. Effect on arteries, veins scarce.

• Cardiac Effects:
-In the SA node and the AV depolarization depends largely on the flow of Ca + +, for which these drugs reduce excitation of the SA node and AV conduction.
-In the myocyte Ca + + binds to the troponin removing the inhibitory control on the interaction myosin-actin. These drugs have negative inotropic effect.

Dihydropyridines
The dihydropyridines have more marked effects on vascular tissue than on the heart. It follows that is observed with slight tachycardia dihydropyridines, for reflex sympathetic activation.

Verapamil and Diltiazem
Compared to dihydropyridines, have more marked effects on the SA node and on what AV, as well as on myocardial contractility, both in vitro and in clinical studies.

PHARMACOKINETICS
They are all well absorbed orally.
Are largely metabolized by CYP3A4.
The half-lives of the various compounds are very different.

TOXICITY '
1) Headache, flushing.
2) Possible peripheral edema, but not due to water retention
3) Constipation by verapamil.
4) In the elderly, the antihypertensive effect and heart rate-may be too intense for reduced metabolism.

THERAPEUTIC USE
1. Hypertension
Are effective antihypertensive drugs. The generation of the dihydropyridine (nifedipine and nicardipine) have short half-life (2 and 8 hours). The dididropiridine third generation (lacidipine, lercanidipine and amlodipine) have long half-life and effect constant over time.
2.Angina pectoris
Are useful both nell'angina by effort, that nell'angina vasospastic, because
Dilate the coronary
Decreased afterload
Decreased heart rate (verapamil and diltiazem)
Nell'angina stress the dihydropyridines are associated with -blockers to prevent tachycardia.
3. Supraventricular arrhythmias
Their main property is to slow the rate of atrio-ventricular conduction. They are useful for atrial flutter and atrial fibrillation.
Were not observed positive effects of these drugs after myocardial infarction, for which guidelines do not provide for the use.
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