Classification of Ca-channel blockers

Group 1st II generation III

generation generation

Dihydropyridi Nifedipine Nifedipine Amlodipine Max effect on

nes SR vascular SMC
Felodipine
Nimodipine

Benzothiazep Diltiazem Diltiazem SR - Intermediate

ines position

Phenylalkyla Verapamil Verapamil - They have a greater

mines SR effect on the
myocardium than on
peripheral vessels
 Ca++ CHANNEL BLOCKERS (CCB,
calcium antagonists)
• BCCs are drugs that disrupt transmembrane transfer of
Ca ++ in voltage-dependent calcium channels
• There are two main types of Ca2+ channels
– 1. L- type ( slow ) - with slow inactivation and high conductivity
– 2. T- type - with rapid inactivation and low conductivity
• Ca2+ channel blockers act on L- type channels in
conductive tissues ( SA and AV ), cardiomyocytes, GM
vessels and other organs
 Blockers
slow calcium channels
Mechanism of action of Ca antagonists
Potentially dependent
slow L- type Ca channels 1. Blockade of voltage-gated Ca channels
in typical cardiomyocytes leads to a decrease
in the release of Ca from the sarcoplasmic
reticulum and a decrease in the force of
Sa contraction
(-) inotropic effect
Actin reduction
Myosin 2. Blockade of Ca-channels of the sinus
node leads to inhibition of the pacemaker
activity of atypical cardiomyocytes
(-) chronotropic effect
antiarrhythmic effect

3. Blockade of the Ca-channels of the AV

node leads to inhibition of conduction
(-) dromotropic effect
 Mechanism of action of Ca
antagonists
4. Blockade of potential-dependent
Ca-channels in vascular smooth muscle
cells
↓
decreased tone of peripheral vessels
(resistance arteries)
↓
hypotensive effect
decrease in OPSS and preload

5. Metabolically neutral (do not have a negative effect on lipid

and carbohydrate metabolism)
Localization of the action of BCC on calcium channels of
membranes
 Pharmacokinetic features of
Ca-channel blockers

T1/2 Frequency of Peculiarities Max effect

reception
I Nifedipine 3-6 hours 3 times a day The presence of a peak
Diltiazem therapeutic concentration,
Verapamil which increases the risk of
side effects

II Nifedipine SR 12-24 h 1-2 times a Smooth increase in After 2-4

Diltiazem SR day therapeutic concentration, weeks of
Verapamil SR lower risk of side effects, therapy
more convenient
administration

III Amlodipine 24 h 1 rub/day Long-term action of the drug After 4-8

(single dose), smooth weeks of
increase in effect therapy
 Features of pharmacodynamics
of Ca-channel blockers

Group
Diltiazem Verapamil
Nifedipine

1. Peripheral arteriolar tone, BP ↓↓↓ ↓↓ ↓↓

2. Heart rate ↑↑↑ ↓↓ ↓↓↓

3. Dilation of coronary arteries +++ ++ ++

4. Treatment of angina pectoris Vasospastic Voltages Voltages

5. Possibility of development of
± ++ ++
AV block
Ca++ CHANNEL BLOCKERS
• Indications
– All stages of hypertension
• Long acting DGP
• verapamil , diltiazem (in combination with hypertension, arrhythmia and
angina pectoris )
– Hypertensive crisis :
• nifedipine ( sublingual ),
• nicardipine i/v
– Angina pectoris :
• verapamil , diltiazem , nifedipine ( short acting )
– Arrhythmia :
• verapamil , diltiazem
Indications for the use of Ca antagonists
1. Arterial hypertension
2. IHD (angina pectoris) – if there are contraindications for β -
blockers, verapamil, diltiazem are prescribed
3. Vasospastic angina - dihydropyridine derivatives
4. Heart rhythm disorders (atrial) – for verapamil
5. AG against the background of metabolic disorders (DM,
dyslipidemia)
6. Combination of hypertension and broncho-obstructive diseases
Absolute contraindications
Verapamil, Diltiazem Nifedipin Group
- pronounced bradycardia at rest - severe aortic stenosis
- sick sinus syndrome - obstructive form of hypertrophic
- AV block II and III degrees cardiomyopathy
- cardiogenic shock - cardiogenic shock
- WPW syndrome - arterial hypotension
- Arterial hypotension (BP < 100 mmHg )
Ca++ CHANNEL BLOCKERS

• CCBs are particularly effective in cases of increased

stiffness of large vessels, one of the causes of high
blood pressure in the elderly.
• The action of BCC can be enhanced by magnesium
preparations
• There are no metabolic effects typical of diuretics and beta-
blockers.
 Side effects
For dihydropyridine derivatives (Nifedipine group), mainly for first generation
drugs:
- tachycardia, feeling of a rush of blood to the face, redness of the face and neck;
- peripheral edema (the appearance of pastosity on the ankles, shins (tibial
edema), sometimes on the back of the hands).
- for short-acting nifedipine - deterioration of the condition of patients with coronary
heart disease when the drug is abruptly discontinued
For verapamil, diltiazem :
- bradycardia, especially in patients with SSS;
- inhibition of AV conduction up to AV block;
- inhibition of myocardial contractile function, worsening of CHF
For all:
Arterial hypotension, especially in the elderly; dyspepsia;
from the gastrointestinal tract - constipation, dry mouth, etc.
 Features of the use of calcium
antagonists
 Practitioners should remember that the clinical application of calcium
antagonists is to a certain extent influenced by their pharmacokinetic
properties. Thus, nifedipine does not accumulate in the body, so its
effect (both primary and secondary) does not become stronger when
used regularly in the same dosage. Verapamil, on the contrary,
accumulates in the body when used regularly, which can lead to an
increase in both its therapeutic effect and the appearance of side
effects. Diltiazem can also accumulate in the body, but to a lesser
extent than verapamil. It should also be borne in mind the possibility of
pharmacokinetic interaction of calcium antagonists with some other
drugs. The greatest clinical significance, apparently, is the ability of
verapamil to increase the concentration of digoxin in the blood, which
often leads to the appearance of side effects of the latter. Therefore,
when adding verapamil to therapy in a patient receiving digoxin, the
dose of digoxin should be preliminarily reduced. Diltiazem interacts
with digoxin to a much lesser extent than verapamil, and the
interaction of nifedipine and digoxin does not appear to be clinically
significant.
 Features of the use of calcium
antagonists
 One should not forget about the possibility of
pharmacodynamic interaction of calcium antagonists with
a number of other drugs. Thus, when verapamil or
diltiazem is prescribed together with beta-blockers, the
negative inotropic effect of these drugs may be
summarized, which often leads to a significant
deterioration in the function of the left ventricle. The
combined use of nifedipine and a beta-blocker, on the
contrary, is quite justified, since it neutralizes the
undesirable effects of both these drugs. Nifedipine, as a
rule, should not be prescribed together with nitrates,
since such a combination can lead to excessive
vasodilation, a significant decrease in blood pressure and
the appearance of side effects.
 DIURETICS (water pills)

o Thiazides and thiazide-like drugs

hydrochlorothiazide, bendroflumetazide,
chlorthalidone, indapamide
o Loop

furosemide, bumetanide, torsemide

o Potassium-sparing

spironolactone, amiloride, triamterene

 THIAZIDE AND THIAZIDE-LIKE
DIURETICS
• Main diuretics in the treatment of
hypertension

First generation drugs:

 - derivatives of benzothiadiazine
(hydrochlorothiazide, etc.) and
phthalimidine (chlorthalidone, etc.)
Second generation drugs:
 - derivatives of chlorobenzamide
(indapamide, xipamide, etc.) and
quinazolinone (metolazone^).

• Second-generation diuretics differ

from previous drugs in that they
have a significant sodium and
diuretic effect in any type of renal
failure .
 THIAZIDE AND THIAZIDE-LIKE
DIURETICS

• MECHANISM OF THE HYPOTENSIVE EFFECT

• Inhibit Na + reabsorption and Cl - in the initial segment of the distal tubules
• They reduce blood pressure by reducing blood volume and delayed
vasodilating effect :
 renal effect → ↓ Na → ↓ blood volume, ↓ C B
 extrarenal effects during long-term therapy due to the effect on blood vessels
→ ↓ Na + and ↓Ca++ in the cerebral vessels, ↓ pressor effects of NA and
Angiotensin → ↓ OPSS
• Thiazides enhance the effect of other antihypertensive
drugs, weakening the body's compensatory reactions -
retention of Na ,  blood volume, counteracting the drop in
blood pressure
 Enlighten Distal Interstitium -
ment – convolutes blood
urine

THIAZIDES
 THIAZIDE AND THIAZIDE-LIKE
DIURETICS

• Clinical pharmacology
 Thiazides are the first choice drugs for uncomplicated
hypertension
 They are also specially shown
 for systolic hypertension
 hypertension in the elderly and obese patients (salt-sensitive)
 hypertension complicated by heart failure
 Advantages
• Reduce mortality , stroke rate and cardiovascular complications of hypertension
• Potentiate the effects of other antihypertensive agents (RAAS inhibitors, beta-
blockers)
 THIAZIDE AND THIAZIDE-LIKE
DIURETICS

• Application
 Prescribed once a day in the morning, starting with low doses
 Onset of antihypertensive effect: 2-3 days
 Maximum effect: 2-4 weeks
 Low doses are effective in many patients without adverse
metabolic effects
 Synergistic with loop diuretics
 THIAZIDE AND THIAZIDE-LIKE
DIURETICS

• Side effects
– ↓ K+ , ↓ Mg++ , ↑ Ca ++ (!) in the blood
– ↓ glucose tolerance
– ↑ risk of developing type 2 diabetes
– ↑ atherogenic cholesterol (except indapamide)
– ↑ uric acid, provocation of gout attacks
– ↓ sexual potency ( ~ 10%)
Not effective in case of renal failure
Interactions : NSAIDs weaken antihypertensive effect
of diuretics
 Prevention of side effects of
thiazides
– 1. Reduce Na intake and increase K in the diet .
– 2. Use of low doses of thiazides ( to reduce negative metabolic
effects) .
– 3. Combinations with RAAS inhibitors (prevention of hypokalemia).
– 4. Combinations with potassium-sparing diuretics ( amiloride,
triamterene) or spironolactone in heart failure .
 Loop diuretics
• Furosemide, torasemide
– They have a rapid and strong
diuretic effect
– Effective in renal failure
– First line agents for heart failure
Furosemide
– Side effects :
•  Thiazide
• Unlike thiazides, they cause
hypocalcemia

Torasemide
 Clearance Thick segment Interstitium –
canal loops of Henle blood

Furosemide

Potential
Potassium-sparing diuretics
• Spironolactone, triamthene, amiloride
• Weak diuretics
• Used in combination with other diuretics (thiazides, loop diuretics)
to reduce the risk of hypokalemia and enhance the Na-uric
effect
• Increase the risk of hyperkalemia :
– in case of renal failure
– in combination with RAAS inhibitors, NSAIDs
• Spironolactone is an aldosterone antagonist.
–  drug of choice for hyperaldosteronism

24
Diuretic interactions

 Loop diuretics potentiate the ototoxicity

of aminoglycosides and the
nephrotoxicity of some cephalosporins.
 Indomethacin and other nonsteroidal
anti-inflammatory drugs reduce the
diuresis induced by furosemide and
possibly other diuretics, probably by
inhibiting the synthesis of vasodilatory
prostaglandins.
Diuretic dependence
 Sometimes, when diuretics and laxatives
are discontinued, psychological changes
characteristic of drug dependence (cause
addiction) occur. Often, drugs of this
group are used to reduce body weight,
including in patients with nervous
anorexia. The latter may develop chronic
conditions of sodium and potassium
deficiency with damage to the renal
tubules due to prolonged hypokalemia,
Rational combinations of antihypertensive drugs

- ACE inhibitor + diuretic // ARA + diuretic

- ACE inhibitor + calcium antagonist // ARA + calcium antagonist
- beta-blocker + diuretic (only nebivolol, carvedilol, bisoprolol +
hydrochlorothiazide or + indapamide)
- calcium antagonist + diuretic
- beta-blocker + dihydropyridine calcium antagonist
- beta blocker + alpha blocker

Irrational combinations
- a combination of drugs of the same class
- ACE inhibitor + potassium-sparing diuretic
- beta-blocker + centrally acting drug
- beta-blocker + non-dihydropyridine antagonist
calcium
 Benefits of Combination Therapy
Benefits of Combination Therapy

Potentiation of the action of Given the heterogeneity of the pathogenesis of

drugs hypertension, different mechanisms of increasing
blood pressure may be involved in one patient, and
the contribution of each of them may vary.
Inhibition of counter-regulatory For example, calcium antagonists have a
mechanisms pronounced vasodilating effect, thereby stimulating
the sympathoadrenal system and RAAS, which
makes their combination with β- blockers, ACE
inhibitors and ARBs logical.
Reducing the incidence of side One drug in a rational combination “counters” the
effects and improving treatment side effects of the other
tolerability

Prevention of target organ Reduction in the number of cardiovascular

damage complications in patients with hypertension
 Combined antihypertensive drugs
Trade name Composition of the drug
ACE inhibitor + Capozide captopril + hydrochlorothiazide
diuretic Ko-renitek enalapril + hydrochlorothiazide
Enap N enalapril + hydrochlorothiazide
Enap NL enalapril + hydrochlorothiazide
Noliprel perindopril + indapamide
Noliprel A forte perindopril A + indapamide
Fozikard N fosinopril + hydrochlorothiazide
Iruzid lisinopril + hydrochlorothiazide
ARA + diuretic Lorista N losartan + hydrochlorothiazide
Micardis plus telmisartan + hydrochlorothiazide
ACE inhibitors + Prestance perindopril A + amlodipine
AC Equator lisinopril + amlodipine
ARA + AK Tarka trandalopril + verapamil SR
Exforge valsartan + amlodipine
B-blocker + AK Logimax metoprolol + felodipine
Tenochek atenolol + amlodipine
B-blocker + D Tenoric atenolol + chlorthalidone
Adelphan-esidrex reserpine + dihydralazine + HCTZ