Transcript Clinical Pharmacology of Drugs for Controlling Vascular Tone

Clinical Pharmacology of Drugs
for Controlling Vascular Tone.
Clinical Pharmacology of
Cardiac Glycosides. Clinical
Pharmacology of Diuretics
FREQUENCY
of arterial hypertension (AH)
AP > 140/90 mm Hg
 20-30
% in population
 At elderly people - 45-50 %
Principles of treatment of arterial hypertension 1.
Treatment should be started as soon as possible and should be hold till the end of
life. Canceling antihypertensive drugs administration causes relapse of AH.
2. All the individuals with increased arterial pressure should obtain drugless treatment
(modifying lifestyle):
-rejection from smoking and alcohol;
-increasing of physical activity;
-restriction of salt consumption (less than 6 g per day);
-decreasing of body weight in a case of obesity.
3. Scheme of drug treatment should be the most availably simple – 1 tablet per day if
possible; it is better to use drugs with long duration of action (prophylaxis of
considerable fluctuation of blood pressure during the day).
4. Rapid decreasing of blood pressure to low figures is dangerous, especially for elderly
patients.
5. Main aim of the treatment is to decrease blood pressure to 140/90 mm Hg. To
improve life prognosis is the aim that has a more significant meaning than character
of drugs used to reach this aim. It is better to prescribe cheap and “non modern”
drugs than don’t treat the patient at all.
Treatment of arterial hypertension
Drugs of first row
-diuretics (furosemid, dichlothiazide, spironolacton)
-inhibitors of ACE (captopril, enalapril, ramipril)
-antagonists of angiotesine II receptors (АRА ІІ) (losartan)
-β-adrenoblockers (anaprilin, atenolol, thymolol)
-α-adrenoblockers (prasosine, terasosine)
-α-, β-adrenoblockers (labetolol, carvedilol)
-Ca ions antagonists (niphedipine, amlodipine, verapamil)
Drugs of second row :
-agonists of α2 –adrenoreceptors of central action (clopheline, methyldopa)
-sympatholytics (reserpin, octadin)
-direct vasodilators (molsidomin, hydralasin)
New drugs:
-imidasolines (moxonidine, rilmenidine)
-serotonin receptors blockers (ketanserin)
-monateril (calcium antagonist, α2 -adrenoblocker)
Mechanism of action of thiaside diuretics
in case of arterial hypertension
Dychlothiaside
(hypothiaside)
Oxodolin
(chlortalidon, hygroton)
Thiaside
diuretics
Holding sodium and
water
Volume of circulating
blood
Peripheral vascular
resistance
Decreasing of arterial
pressure
Cardiac output
FUROSEMIDE
High ceiling (loop) diuretic
 Properties :
1. diuretic action
2. dilation of peripheral venous
3. decrease left ventricular filling pressure
4. potent anti-inflammatory effect (similar
to indometacine and other NSAID)
 Administration: hypertensive emergencies,
long-term treatment of arterial hypertension
 Adverse reactions: dehydration,
hypokalemia, hearing loss - deafness,
hypocalcaemia

THIAZIDES and RELATED DIURETICS





Medium efficacy diuretics
Benzothiadiazines (chlorothiazide,
hydrochlorothiazide, clopamide), related
thiazide like (chlorthalidone, indapamide)
for long-term treatment of arterial hypertesion
(oral administration)
Duration of action (6-12 hours for
hydrochlorothiazide, 12-18 hours for
clopamide, 48-50 hours for chlorthalidone)
Adverse reactions: dehydration, hypokalemia,
hyperuricaemia (rise of blood urate level)
Furosemid
(diuretic)
Furosemid (diuretic)
Triampur
(triamteren + hydrochlorthiaside)
diuretic
Mechanism of action of beta-adrenoblockers
(anaprilin, atenolol, methoprolol etc.)
in case of arterial hypertension
activation of
β1-adrenoreceptors
of heart
βadrenoblockers
Cardiac
output
Peripheral resistance of vessels
Angiotensine
Renin
Decreasing of
blood pressure
ΙΙ
Aldosterone
Holding sodium
and water
Volume of
blood circulation
β-adrenoblockers






Used for mostly mild to moderate cases
of AH (frequently in combinations with
other drugs)
Stable hypotensive response develops
over
1-3 weeks
Titration the effective dose
Antihypertensive action is maintained
over
24 hr after single daily dose
Withdrawal syndrome if discontinue
quickly
Contraindications: bronchial asthma,
peripheral vascular disease, diabetes
Atenolol
β - adrenoblocker
Anaprilin
β1- β 2 adrenoblocker
Vasocardin 100 mg
Methoprolol tartrate
Nadolol
( β1, β 2 - adrenoblocker )
Tenoretic
(atenolol + chlortalidon)
α1-adrenergic blockers
(prazosin, terazosin, doxazosin)



Do not block presynaptic α2-adrenoreceptors, so do not cause reflex
cardiac stimulation (as compared to
nonselective α-adrenoblockers)
Dilate resistance and capacitance
vessels
Adverse effects: postural hypotension
(“effect of first dose”), tolerance
Prasosine
(α1 –adrenoblocker)
α, β – adrenoreceptors blockers
(labetalol, carvedilol)


Labetalol is used for long-term
treatment of AH and for emergencies
(i. v. - hypertensive crisis, clonidine
withdrawal, cheese reaction)
Carvedilol – produces vasodilatation,
antioxidant/free radical scavenging
properties, it is used for HD and for
CHF
MECHANISM OF ACTION OF
IACE
ANGIOTENSINOGEN
sympathetic
tone
Renin (kidneys)
ANGIOTENSIN
(inactive)
Decrease
angiotensine II
production
ACE
IACE
Decrease
aldosterone
production
peripheral
vessels tone
retention of
Na+ and H2O
bradicinine
Decrease of
arterial
pressure
IACE (ANGIOTENSIN CONVERTING
ENZYME INHIBITORS)






Captopril, enalapril, ramipril, perindopril etc.
Decrease the levels of mortality and morbidity
When used for monotherapy control AP in 50% of
patients
Frequently combined with diuretics (not with
potassium-sparing diuretics !) and βadrenoblockers - the effectiveness of therapy grows
to 90%
Adverse effects: cause the retention of potassium
ions, dry persistent cough (requires discontinuation
of IACE or treatment with NSAID)
Contraindicated for the patients with bilateral renal
artery stenosis)
Captopril (IACE)
KOZAAR (Losartan)
АRА ІІ
CALCIUM CHANNEL BLOCKERS
(dihydropyridines – DHPs)






Short acting DHPs (nifedipine) can increase
mortality as a result of reinfarction (long term
controlled trials)
Retard forms of DHPs (Amlodipine) are used
widely for AH
Do not contraindicated in asthma, do not
impair renal perfusion, do not affect male
sexual function
Can be used during pregnancy
Can be given to diabetics
Adverse reactions: ankle edema, slight
negative inotropic / dromotropic action,
nifedipine decreases insulin release (diabetes
accentuating)
NIFEDIPINE
(calcium channels blocker)
NIFEDIPINE
(calcium channels blocker)
NIFEDIPINE
(calcium channels blocker)
NIFEDIPINE
(calcium channels blocker)
NORVASC (AMLODIPINE)
(calcium channels blocker)
Calcium channels blockers administration
DRUGS
diseases
Arterial
hypertension
Verapamil
Dilthiasem
Niphedipin
Ischemic
heart disease
Verapamil
Dilthiasem
Niphedipin
Supraventricule
tachicardia
Verapamil
Dilthiasem
Possibility to
combine with
beta-blockers
recommended drug
Dilthiasem
Дилтіазем
Niphedipin
to use carefully
Felodipin
Amlodipin
Amlodipin
Felodipin
Amlodipin
CLOPHELINE






α2 - adrenergic receptors agonist (in
brainstem stimulates α2 - adrenergic receptors
and imidazoline receptors)
decreases vasomotor centers tone - reduces
sympathetic tone - fall in AP
Increases vagal tone - bradycardia
Has analgesic activity
For hypertensive emergencies (i. v. dropply or
very slowly)
Side effects and complications: postural
hypotension, sedation, mental depression,
sleep disturbance, dry mouth, constipation,
withdrawal syndrome
CLOPHELINE
(decreases vasomotor centers tone)
SINEPRESS
(dihydroergotoxine + reserpine + hydrochlorthiaside)
TRIRESIDE
(reserpine + hydralasine + hydrochlorothiaside)
CRISTEPIN
(clopamide + dihydroergocristine + reserpine)
MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously)
Drug
Sodium
nitroprussid
Dose
0,5-10 mcg/kg/min (dropply)
Nitroglyceri
-num
5-10 mcg/kg (dropply)
Onset
immediate
ly
Side effects
nausea, vomiting,
muscles, sweating
2-5 min
tachicardia,
vomiting,
fibrillation of
flushing,
headache,
Diazoxidum
50-100 mg (quickly)
300 mg (during 10 min)
2-4 min
nausea,
vomiting,,
hypotension,
tachicardia, flushing, redness of skin,
chest pain
Apressinum
10-20 mg
10 min
flushing, redness of skin, headache,
vomiting
Furosemidu
m
20-60-100 mg during 10-15 sec
2-3 min
hypotension, fatigue
Clophelinum
0,5-1 ml 0,01 % solution (in 15-20 ml
0,9 % solution NaCI slowly)
15-20 min
somnolence
Anaprilinum
5 ml 0,1 % solution (in 20 ml 0,9 % NaCI
solution slowly)
20-30 min
bradicardia
Magnesium
sulfas
5-10-20 ml 25 % solution (i. v. very slowly
or dropply)
15-20 min
redness of skin
Labetololum
20-80 mg (slowly – 10 min) or 2 mg/kg
(dropply); the whole dose – 50-300 mg
5-10 min
nausea,
dizzeness
vomiting,,
hypotension,
Factors which promote
development of
INTOXICATION WITH HEART
GLYCOZIDES
DECREASING OF TOLERANCE TOWARDS HG – in case of
considerable damage of myocardium with pathological
process
(acute MI, myocarditis, chronic lung heart)
“Patients which need HG the most are the most sensitive of
diuretics (furosemis, dychlothiazide), GCS,
glucose with to them”
HYPOPOTASSIUMEMIA, HYPOPOTASSIUMHISTIA OF
MYOCARDIUM, HYPOMAGNESIUMEMIA
- administration insuline, amphotericine B
- secondary hyperaldosteronism, vomiting,
diarrhea
HYPERCALCIUMEMIA, KIDNEY, LIVER INSUFFICIENCY
Factors which promote development
INTOXICATION WITH HEART
GLYCOZIDES
Digitoxin is a choice drug when HI is
combined with kidney insufficiency, but
contraindicated if liver is damaged (it is
metabolized by liver)
 Digoxin is not contraindicated even in
case of liver cirrhosis (it is not
metabolized in liver), but
contraindicated in case of kidney
insufficiency (it is excreted by kidneys)

Intoxication with heart glycozides
Cardiac symptoms
Worsening of contractive function of
myocardium, increasing of circulation
insufficiency – relapse of HI (18-26 %)
Disturbance of heart rhythm
(90-95 %, у 65 % - single symptom of
intoxication)
- tachyarrhythmia (increasing of automatism)
- blockades
- combined disorders of rhythm
Intoxication with heart glycosides
Treatment of intoxication
with heart glycosides









Immediate quitting of HG introduction
Correction of hypopotassiumemia (KCl,
panangin)
Introduction of unitiol (1 ml of 5 % solution /
kg of weight i.m. 2-3-5 times per day)
Clearing of GI tract (vaseline oil,
cholestyramin, magnesium sulfate)
Treatment of arrhythmias (anaprilin,
verapamil, difenin, lidokain, atropine)
Na ЕDTA (trilon B), Na citrate
Calcitrin
Antibodies towards digoxin (Digibind)
Oxygen therapy
NONGLYCOSIDE CARDITONIC
DRUGS
Xantins, derivatives of isoquinoline
(ethophiline)
 Pyridines, and bipyridines (amrinon,
milrinon)
 Derivatives of imidazole (vardax)
 Derivatives of piperidine (buquineran,
carbazeran)
 Polypeptides (glucagon)
 Carboxyl antibiotics (lasolacid, calcimycin)
 Derivatives of other chemical groups: Lcarnitin, heptaminol, creatinol-o
NONGLYCOSIDE CARDIOTONIC
DRUGS
Dobutamin – beta1-adrenomimetic - in case of
acute and chronic heart insufficiency –
intravenously dropping – 2,5-5-10
mcg/(kg.min); in case of constant infusion
tolerance develops after 3-4 days; in case of
increasing of dose – heart arrhythmias
 Amrinon, milrinon – inhibitors of
phosphodiesterase – for temporary
improvement of patient’s condition in terminal
stage of HI

INHIBITORS OF ANGIOTENSINE
TRASFORMING ENZYME (IATE)
Captopril, enalapril, ramipril,
lysinorpil
In case of HI they brake pathological
consequences of activation of reninangiotesine system by inhibiting ATE:


production of angiotensine II decreases
(vasoconstrictor, inductor of aldosterone,
norepinephrine, endothelin secretion, myocardium
hypertrophy)
Accumulation of bradikin (inductor of
prostacycline and nitrogen oxide synthesis)
INHIBITORS OF ANGIOTESINE
TRANSFORMING ENZYME (IATE)
 Increase
duration and improve
quality of life of patients with
HI
 Increase tolerance towards
physical loads
 Decrease risk of recurring MI
 Brake development of
miocardium hypertrophy
CAPTOPRIL (CAPOTEN)
 Dose
titration: from 6,25-12,5 mg per
day to 12,5-50 mg 3 times a day until
appearance of effect
 Side effects: dry cough (can be
decreased by nonsteroid
antiinflammatory), considerable
decreasing of AP, worsening of
kidneys’ function,
hyperpotassiumemia, tachycardia,
neutropenia, aphtose stomatitis
 Contraindicated in case of bilateral
stenosis of kidney arteries, should not
ANTAGONISTS OF
ANGIOTESINE II RECEPTOS (АRА
II)
LOSARTAN (cosaar)
Blocks receptors of angiotensine II
Decreases mortality of patients with HI
on 50 %
Breaks development of myocardium
hypertrophy
It is approved to combine IATE with
АRА II
DIURETICS
Dichlotiazide, hyhrotone (oxodoline),
clopamide (brinaldix)
Furosemid, etacrine acid
Spironolacton
improve currency of the disease,
increase tolerance of patients towards
physical loads,
spironolacton decreases quantity of
relapses and mortality
PERIPHERAL
VASODILATORS
Arterial: hydralasin, calcium ions
antagonists, minoxydil
 Venous: nitrates, molsidomin
 Of mixed action (influence on tone of
arterioles and venules): sodium
nitropruside, prasosine, inhibitors of ATE,
ARA II

Isosorbide dinitrate (30-160 mg/day)
+
hydralasin (50-300 mg/day) – for
PERIPHERAL
VASODILATORS
Unfavorable action in case of
HI:
They activate sympatic-adrenalsystem
and intermediately renin-aldosterone
system
BETA-ADRENOBLOCKERS
Carvedilol, methoprolol, bisoprolol
They decrease mortality, improve disease
currency and quality of patients’ lives in case of
stagnant HI
Mechanism of treatment action in case of HI




Renewing of quantity and sensitivity of betaadrenoreceptors in heart, which leads to
increasing of systolic volume after 8-10 weeks of
regular administration (paradox of betaadrenoblockade)
Prevent calcium overload of myocardium, improve
coronary blood circulation
Decrease production of renin
Prevent arrhythmias
BETA-ADRENOBLOCKERS
Scheme of administration of betaadrenoblockers in case of HI
The treatment is started from a small dose
(3,175-6,25 carvedilol), every 2-4 weeks it is
doubled until obtaining the effect (usually develops
after 2-3 months).
Average effective doses:
carvedilol – 50 mg
metoprolol – 100 mg
bisoprolol – 5 mg
Administration of beta-blockers is possible only in
case of constant condition of the patient, before
development of stabile improvement of condition
temporary worsening may develop
DRUGS OF METABOLIC ACTION
 Vitamins:
Е, С, В group
 Ryboxin
 Mildronate
 Phosphaden,
ATP
 Creatinphosphate
 Potassium orotate, anabolic steroids
Drugs manifest cardiocytoprotective
action, improve energetic metabolism
in myocardium
PECULIARITIES OF TREATMENT OF
DIASTOLIC DISFUNCTION OF
MYOCARDIUM
Indicated:
IATE, АRА II,
Beta-adrenoblockers, calcium ions
antagonists
Contraindicated:
Nitrates, diuretics, heart
glycosides
Diuretics
Classifiction of diuretics
accordingly to power of action
І Strong (slowing down of Na+ reabsorbtion for
10-20%)
furosemide, etacrynic acid, clopamide, bufenox
ІІ Medial power of action (slowing down of Na+
reabsorbtion for 5-8%)
dichlothiaside, oxodoline
ІІІ Light (slowing down of Na+ reabsorbtion not
more than for 3%)
diacarb, spironolactone, amiloride, triamteren,
xanthines (theophylline)
Mannitol
15 % solution
rapid intravenous
introduction
dehydrating
action
diuretic
action
intravenous dropping
introduction
diuretic
action
Mannitol
Indicatoins
1. Brain oedema (in case of maintaining ofHEB permeability)
2. Toxic lung oedema (poisoning with gasoline, gass, formaline,
skipidar etc.)
3. Larynx oedema of allergic or inflammatory genesis
4. Holding of forced diuresis (poisoning with barbiturates,
salycylates, sulphonamides, PASA, metanole, boric acid,
haemolytic poisons, antifreezers; in case of trasfusing of
incompatible blood, massive hemoglobinuria etc.
5. In oliguric phase of acute nephral insufficiency
6. Burns, osteomielitis, peritonitis, sepsys
Contrainidications
Acute cardiac insufficiency, skull trauma, intracranial
hemorrhages, arterial hypertension
FUROSEMIDE
High ceiling (loop) diuretic
 Properties :
1. diuretic action
2. dilation of peripheral venous
3. decrease left ventricular filling pressure
4. potent anti-inflammatory effect (similar
to indometacine and other NSAID)
 Administration: hypertensive emergencies,
long-term treatment of arterial hypertension
 Adverse reactions: dehydration,
hypokalemia, hearing loss - deafness,
hypocalcaemia

Furosemide (lazix)
Effective even in case of decreased glomerular filtration
less than 10 ml/min. (norm – 127ml/min)
Indications
1. Acute left ventricular insufficiency, lung oedema
2. Chronic cardiac insufficiency
3. Arterial hypertension, including hypertensive crisis
4. Brain oedema of any etiology
5. Acute nephral insufficiency
6. Performing of forced diuresis
7. For excretion of Calcium ions (hypervitaminosis D)
Side effects of furosemide
1. Hypopotassiumaemia, hypopotassiumhystia
2. Hypovolemia, vascular collapse, hyposodiumaemia,
hypocalciumaemia, hypochloraemia, metabolic alkalosis
3. Ototoxic action
4. Contrinsular action (manifestation of latent diabetes mellitus)
5. Formation of oxalate and phosphate stones in urinary tracts
6. Decreasing of secretion of uric acid (acute attack of gout)
It should not be combined with antibiotics, aminoglycosides and
cephalosporines!
Furosemide (diuretic)
THIAZIDES and RELATED DIURETICS





Medium efficacy diuretics
Benzothiadiazines (chlorothiazide,
hydrochlorothiazide, clopamide), related
thiazide like (chlorthalidone, indapamide)
for long-term treatment of arterial hypertesion
(oral administration)
Duration of action (6-12 hours for
hydrochlorothiazide, 12-18 hours for
clopamide, 48-50 hours for chlorthalidone)
Adverse reactions: dehydration, hypokalemia,
hyperuricaemia (rise of blood urate level)
Dichlotiaside (hypothiaside)
Indications
1.
2.
3.
4.
Oedema in case of chronic cardiac insufficiency
Oedema in case of chronic pathology of liver and kidneys
Treatment of arterial hypertension
Diabetes insipidus
Side effects
1. Hypopotassiumaemia, hypopotassiumhystia
2. Hypochloraemic alkalosis
3. Retention of uric acid - artralgy, acute attack of gout, chronic
nephropathy
4. Hyposodiumaemia of dilution: nausea, vomitting, diarrhea,
weakness
5. Pancreatitis
Indapamide
(ariphone – sulphamoil benzamide)
Pharmacokinetics of some diuretic drugs
Drug
Way of
administration
Latent
period
Duration of
action
Sulfonyl derivates
Oxololin (chlortalidon,
hyhroton)
peroral
2-4 hours
Till 3 days
Clopamide
peroral
1-3 hours
8-18 (till 24)
hours
Bufenox (bumetanide)
intravenous
20-40
min.
2-5 min.
4-6 hours
1-3 hours
Potassium-, magnesium-sparing
Spironolactone
peroral
2-5 days
2-3 days
Triamteren (pterophen)
peroral
20-30
min.
6-8 hours
Amiloride
peroral
2 hours
till 24 hour
Spironolactone
(aldactone)
Combined administration of diuretics
1. Mannitol + furosemide (etacrynic acid)
2. Dichlotiaside + triamteren (spironolactone)
3. Furosemide + spironolactone
4. Furosemide (excretes Calcium ions) +
dichlotiaside
(retains Calcium ions)
Triampur
(triamteren + hydrochlorthiaside)
Blue corn-flowers (Flores Centaureae cyani)
Juniper berries
(Fructus Juniperi)