Antihypertensive drugs

Lecture 11
 Arterial pressure
the force with which blood presses
against the artery wall

BP is determined by :
1. Total peripheral vascular resistance
2. Heart output
3. Rheological properties of blood (TBV + viscosity)
Blood pressure measurement
Other instruments for measuring blood
pressure
Blood pressure monitoring
 Classification of hypertension by level of blood
pressure (WHO-MOG, 1999)
Category Systolic blood Diastolic blood pressure,
pressure, mm Hg mmHg.
Optimal < 120 < 80
Normal < 130 < 85
High normal 130 – 139 85 - 89
1st degree hypertension 140 – 159 90 - 99
(mild)
Subgroup: Border 140 - 149 90 - 94

Hypertension 2nd degree 160 – 179 100 - 109

(moderate)
Hypertension 3rd degree ≥ 180 ≥ 110
(severe)
Isolated systolic AH ≥140 < 90
 Epidemiology AH
Russia: high risk population
Arterial hypertension ≈ 40% of the population

20% of 16% of patients 25% of

patients + patients
+
+
coronary cerebral
atherosclerosis arteriosclerosis diabetes

76% of patients:
high chance of dying
in 10 years
 Arterial hypertension
Hypertension types

Secondary hypertension
Primary hypertension

Factors contributing hypertension development

Hypertensive heart disease ("essential hypertension")

Age Sex Genetics

 Arterial hypertension
Hypertension types

Primary hypertension Secondary hypertension

Background conditions and diseases

Kidney diseases Hormonal disorders

Disorders of the blood Pregnancy

vessel development

Narrowed vessels
 Complications (consequences) of hypertension
Angina pectoris

Transverse section of
coronary artery

Plaque

Coronary Myocardial infarction

atherosclesosis (heart stroke)
 Complications (consequences) of hypertension
congestive heart failure
 Complications (consequences) of hypertension

Stroke

Hemorrhagic stroke Ischemic stroke

Objectives of arterial hypertension Treatment :

1. In young people and middle-aged people, as

well as patients with diabetes mellitus - to
optimal blood pressure (130/85 mm Hg)

2. In elderly patients, to elevated normal blood

pressure (140/90 mm Hg)
“Stepwise” treatment of hypertension
Limit of NaCl –1 tsp (6 g sodium)
Treatment of hypertension
 Treatment of hypertension
Sedative Drugs
Tranquilizers

Smoking Cessation!
Mechanisms of blood pressure regulation
 Antihypertensive drugs

ACE
inhibitors

Diuretics BRA
1. Neurotropic
2. Humoral

Beta-blockers
3. Myotropic Compounds
affecting alfa
4. Diuretics receptors

Ca channel
blockers
Antihypertensives
CLASSIFICATION OF HYPOTENSIC DRUGS.
Neurotropic antihypertensive drugs :
1. The drugs lowering a tone of the vasomotor centers:
A. Imidazoline I1 receptor stimulants - Moxonidine;
B. Stimulants α2-adrenergic receptors - Methyldof;
B. Stimulants I1 and α2 receptors - Clonidine.
2. Ganglioblockers - Pentamine.
3. Sympatolytics - Reserpine, Guanethidine, Raunatin, Bretiliya tosylate.
4. Blockers of α-adrenoreceptors:
A. Central α1, α2-blockers - Butiroksan, Proroksan, Nicergolin;
B. Peripheral α1, α2-blockers - Phentolamine, Tropafen;
C. α1, α2 – blockers and partial agonists - Dihydroergotoxin, Vasobral;
D. α1-blockers - Prazosin.
5. Blockers of β -adrenoreceptors:
A. Nonselective β1, β2 –blockers - Propranolol, Sotalol, Pindolol;
B. Selective β1-blockers - Atenolol, Atsebutolol, Celiprolol.
6. Blockers of α and β-adrenoreceptors (“hybrid blockers”):
A. α1, β1, β2, blockers - Carvedilol, Procodolol;
B. α1, β1-blockers, β2-stimulants - Labetalol;
B. α1, β1, β2-blockers, α2-stimulants - Urapidil.
Alpha 2 mimetics
Alpha-1 blockers
 Neurotropic drugs
mechanism of action
 Antihypertensive drugs central neurotropic action
The mediocortic medulla dysplasia regulates blood pressure with the participation
of presynaptic imidazoline I1 and ą2AP.
Stimulation of I-1 and ą-2 AP leads to a decrease in the release of NA to the
pressor neurons.
• the endogenous ligand I-1P is the arginine metabolite - agmantine.
• I-1 P located in
• hypothalamus (decrease in the release of neuropeptide Y, decrease in blood
glucose);
• medulla oblongata (inhibitory effect on neurons of the SdTs);
• carotid glomeruli (increased function);
• kidneys, adrenal glands (reduced reabsorption of sodium and water in the
proximal tubules, reduced release of adrenaline and noradrenaline);
• pancreas (increased insulin secretion);
• adipose tissue (increased lipolysis).
 Antihypertensive drugs with central neurotropic
action

Clopheline (clonidine, gemiton, catapressan) - imidazoline derivative .

•Stimulates the I1 and ą2AP nuclei of the hypothalamus, the solitary tract,
the medulla oblongata and have an inhibitory effect on the neurons of the MVC
• The decrease in the activity of MVC reduces the flow of spontaneous
sympathetic impulses on the heart and blood vessels,
• enhances the nerve vagus tone;
• excites peripheral presynaptic ą2AP
• and reduces the secretion of renin and ON from varicose thickenings
• As a result, peripheral vascular tone and heart function decrease.
•OPSS + MOS = AD.
The pharmacologic effects of clopheline are due to a violation of the secretion of NA, D,
glutamic and aspartic acids, affects various brain structures and has:
• sedative and hypnotic action (contribute to the achievement of AHT action, but leads to the
development of drowsiness, decreased performance, sexual function, depression, impoverishes
cerebral blood flow);
• analgesia, in doses that do not cause a decrease in blood pressure, increases the release of EP and
EC, stimulates ą2AP A- and C-fibers, the posterior horns of the dorsal and medulla ,;
• decreased body temperature;
• increased appetite;
• decreased secretion of salivary glands, causing dry mouth (stimulate alpha-AR and increase
the viscosity of saliva), causes constipation;
• retains sodium and water in the body (impairs renal blood flow and GFR, causes swelling
- this is the mechanism for the formation of resistance to clonidine. To overcome resistance,
clonidine is administered with diuretics).
• potentiation of the action of CNS depressants, including alcohol, which is often used for
criminal purposes;
• children stop breathing;
• in the first 2-3 weeks of administration, an increase in growth hormone levels, a decrease in
insulin secretion;
• slowing of AV conduction, danger of bronchospasm (relative increase in vagus nerve
tone).
In addition, clonidine
when administered intravenously, it may briefly (5-10 min) increase blood pressure due to the
predominance of direct excitation of α-AR in the vessels over the central action;
abrupt cessation of treatment, especially without “covering” by other antihypertensive drugs, leads to
the development of withdrawal syndrome:
headache,
nausea
tachycardias, arrhythmias,
hypertensive crisis,
coronary ischemia.
Removal of the drug should be carried out gradually from 10 days to 1.5 months.
For knocking over used α- or α-, β-adrenergic blockers.
Chlorine poisoning:
lethargy, headache, weakness
hypothermia,
hyporeflexia and hypotonia of skeletal muscles,
short-term arterial hypertension is replaced by orthostatic hypotension,
bradycardia, AV blockade,
coma
Treatment:
tracheal intubation, oxygen therapy;
gastric lavage with activated carbon;
appointment of antagonists (naloxone, atropine, D2-P blocker — metoclopramide, 5HT3 receptor-ondansetron
blocker);
infusion therapy;
hemosorption
Indications for use : Contraindications:

• hypertensive crisis - parenteral • severe atherosclerosis of brain

and sublingual; vessels;
• AH course treatment - oral; • depression;
• migraine (provoked by chocolate • severe bradycardia;
and citrus); • weakness of the sinoatrial node,
AV-blockade of 2-3 degrees;
• for the treatment of opiate
• hypotension;
alcohol withdrawal;
• cardiogenic shock;
• for anaesthesia in surgery,
orthopaedics, myocardial infarction, • Chronic failure of vascular
childbirth; circulation
• professional restrictions
• sedation for anaesthesia
 Pharmacokinetics of clonidine :

• absorbed in the digestive tract,

• can be administered parenterally,
• maximum effect occurs in 1 to 2 hours
• Duration up to 6-8 hours, appointed 2-4 times a day, which is
not always convenient.
• excreted by the kidneys as metabolites.

For many years, α2-adrenomimetic clonidine has been the leading

central antihypertensive drug.
An analogue of clonidine is guanfacine (estulic), undesirable
effects of which are less pronounced, are prescribed 1 time per
day.
 Methyldopa (dopegit, aldomet)

According to the theory of a false mediator

Methyldopa is transformed into the central nervous system
in
stimulates I1 and ą2AP, reducing the activity of neurons of
the VMC,
reduces the flow of sympathetic impulses to the heart and
blood vessels;
reduces renin secretion;
in the brain tissues of NA, dopamine and serotonin

As a result, TPVR + MHO = BP.

 Pharmacological effects of methyldopa
• sedative (causes lethargy, lethargy, drowsiness, depression);
• unlike clonidine, improves cerebral blood flow; in young patients, it
does not reduce cardiac output;
• retain sodium and water in the body, causing edema (b
• autoimmune hemolytic anemia (regular hematological control is needed!
after 3-6 months of M.'s treatment, sometimes it requires glucocorticoid
prescription;
• hepatotoxicity (increased transaminase activity, cholestasis, hepatitis,
hyperbilirubinemia, hepatic necrosis);
• hyperprolactinemia with the development of gynecomastia,
galactorrhea, sexual disorders.
• orthostatic hypotension;
• nausea;
• flu-like condition, fever, headache (associated with the formation of
metabolites);
• skin rash, lupus syndrome, Coombs positive test.
Indications for use Pharmacokinetics of
the drug of the 2nd row, used when
AH with background Methyldopa
pregnancy • effective when taken orally;
hypertensive crisis and • the maximum of action comes
dissecting aortic aneurysm after 4-6 hours, lasts from 4-6
(w / w)
hours (w / w) to 8-24 hours
(inside);
Contraindications
• stands out mostly unchanged;
coronary insufficiency • damages the metabolic function
parkinsonism of the liver.
acute hepatitis
hemolytic anemia
The drugs of the central neurotropic action of the new generation are
moxonidine (fiziotenz, zint) and rilmenidine (albarel).

Pharmacological properties of moxonidine.

less clonidine affects α-AR.
is an analogue of agmantine, selectively excites the I-1P rostral and
ventrolateral region of the medulla oblongata and reduces sympathetic tone
reduces the level of angiotensin-II, aldosterone and ON;
TPVR + MHO (lesser degree) =  BP.
M. almost does not change the amount of cardiac output.
Reduces the heart's need for oxygen.
prevents development and reduces myocardial hypertrophy.
increases glucose tolerance, the flow of glucose into the cells, enhances the
synthesis of glycogen,
hypolipidemic effect;
not registered development of addiction and the development of withdrawal
syndrome.
Pharmacokinetics Indications
• Moxonidine is well
(about 90%) absorbed  Hypertension and symptomatic
in the digestive tract. hypertension, especially in
combination with type II diabetes and
• Excreted through the obesity.
kidneys in unchanged  Relief of hypertensive crises (quickly
and completely absorbed and when
form (to a lesser extent taken under the tongue, 0.4 mg once
through the liver). in powdered form).
• The effect lasts up to
24 hours, is prescribed
1 time per day.
Interaction with other drugs

•Enhances the effect of other antihypertensive

drugs.
•Clonidine enhances the effect of alcohol,
sedatives and hypnotic drugs, but such
combinations in any case should be avoided.
•It is combined with diuretics.
•May affect the action of hypoglycemic agents.
II. Humoral antihypertensive drugs :
1. Vasopeptidase inhibitors:
A. Inhibitors of angiotensin-converting enzyme (ACE)
B. ACE inhibitors and neutral endopeptidase - Omapatrilat.
2. Type 1 angiotensin receptor blockers (angiotensin II antagonists) - "- * sartan":
Losartan, Valsartan, Irbesartan.

III. Myotropic antihypertensives :

1. L-type calcium channel blockers (calcium antagonists) - Verapamil, Falipamil,
Diltiazem, Nifedipine, Amlodipine.
2. Activators of potassium channels - Diazoxide, Minoxidil, Nicorandil.
3. Nitro vasodilators - Sodium nitroprusside.
4. Antispasmodics of different groups - Apressin, Dibazol, Drotaverinum,
Magnesium sulfate.

IV. Diuretics
1. Thiazide diuretics - Hypothiazide.
2. Loop diuretics - Furosemide.
3. Potassium-sparing diuretics - Spironolactone.
 Calcium channel blockers
5 types of potential-dependent calcium channels: L-type channels (myocardium,

CCB vascular muscles) open for a long time; T-type channels open for a short time;
N-type channels in the CNS and PNS neurons; P-type channels in the
cerebellum, R-type channels in the endothelium.

Primary membrane
chelation of calcium
(apressin)
 kinase phosphorylation LCM
Са 2+
- 6,4 – 12,2%
-
 LCM phosphorylation -

Na-Ca
sarcoplasm.
reticulum Actin / Myosin Conjugation

- Ca2+
 BLOCKERS Ca2 + channels
I generation 2nd generation
(3-4 times a day) (1 daily intake)
Diphenylalkylamines - affect primarily on the myocardium
Verapamil Gallopamil
Falipamil
Benzothiazepines - affect myocardium and vessels
Diltiazem Altiazem RР
1,4-dihydropyridines - affect primarily the vessels
(«-* dipin»)
Nifedipine Nitrendipine
Nimodipine Amlodipine
Ryodipine Felodipine
Isradipin Lacidipin
Nicardipine
 BLOCKERS Ca2 + channels
Inside Outside
cell cell

Calcium
channel

Muscular cell wall

BLOCKERS Ca2 + channels
DIURETICS
 Гипер-кинезия
BETA BLOCKERS
BATR-1
 BATR-1
• Competitive Antagonists :
Eprosartan, Tazosartan (active metabolite enoltazosartan)

• Noncompetitive antagonists :
Valsartan, Irbesartan, Kandesartan, Telmisartan,
Losartan (active metabolite)
The advantages of angiotensin receptor antagonists
in relation to ACE inhibitors

• A more complete and selective blockade of the

renin-angiotensin-aldosterone system

• More specific action - do not affect the activity of

other humoral systems

44
 Vasopeptidase inhibitors

Omapatrilat
Inhibits enzymes - neutral endopeptidase, enkephalinase,
neprilysin and angiotensin-converting enzyme, and as a result:
- the activity of endogenous vasodilating substances
increases
atrial natriuretic peptide
bradykinin
adrenomedullin
- reduced activity of the renin-angiotensin-aldosterone
system

45
Vasopeptidase inhibitors

46
 ACE Inhibitors
humoral antihypertensive drugs that reduce the
activity of angiotensin-converting enzyme (ACE,
ACF, di-peptidyl-carboxy-peptidase) in vascular
endothelium.

АТ-I ACE
АТ-II
 The total property of all ACE inhibitors - effect on the renin-
angiotensin-aldosterone and callecrein-kinin blood pressure regulation
systems
Kininogens
Callecreine
Prorenin Kinins (bradi-)
Angiotensinogen
Эндо-
Reninн пептидаза
Angiotensin - I Products
Angiotensin - I-7
ACE inactivation of
Angiotesin - III Angiotensin - II vasoactive
peptides
Carboxypeptidase Type I angiotensin receptor
+ -
Endopeptidase
Products myocyte
inactivation of of vascular wall
Aminopeptidase vasoactive
peptides
 Classification of ACE inhibitors (50, in Russia-32)
1. Sulfhydryl (SH-) - since the early 1970s.
Captopril * +, Altiopril **, Metiopril **, Alaceptril **,
Zofenopril **
2. Carboxyl (С=О)
Lisinopril + *, Enalapril ** +, Hinapril **, Quinapril **,
Ramipril **, Benazepril **, Perindopril **, Spirapril **,
Trandolapril **, Cilazapril ** +, Moexipril **
3. Phosphonyl (-РО2-)
Fozinopril ** +
4. Hydroxamine (NH2-)
Indrapril **
* - drugs of direct action
** - prodrugs - metabolized in the liver in the "-s" (-COOH)
+ - included in the state insurance list
 Pharmacological effects of an ACE inhibitor
1. Vascular :
Vasodilatation
•systemic arterial vasodilation (reduced afterload)
•venous vasodilation (reduced preload)
•coronary vasodilation
•prevention of vascular spasm
Vasoprotection
•restoration of vascular endothelium function
•decreased platelet aggregation
•fibrinogen level reduction
•reverse development of hypertrophy of artery walls and arterioles
2. Organ Protective :
 Cardioprotection - reduction of myocardial hypertrophy with an
increase in the ratio of myocytes / collagen
 Nephroprotection
 Primary pharmacological reactions
1. Interaction with the Zn atom in the ACE molecule.
ACE inactivation and suppression of circulating (plasma) and tissue
(local) angiotensin systems.
2 . Dose-dependent nature of ACE inhibition.
Perindopril at a dose of 2 mg inhibits ACE by 80% at the peak of
action and by 60% after 24 hours. At a dose of 8 mg, the inhibitory
ability increases to 95% and 75%, respectively..
3. Reduced plasma angiotensin II.
Reduces the release of NA from presynaptic terminations of the SNA.
Limits Ca2 + release from sarcoplasm. reticulum.
Reduces the production and release of aldosterone from the adrenal
glands (excretion of Na and water).
4. Decreased kininase activity.
Stimulation of bradykinin receptors promotes the release of ERF and
vasodilating PG (E2, I2).
The differences between the ACE inhibitors
are determined by their structure.

Fozinaprilat
Captopril (phosphonylin group)

N СООН
Enalaprilat -прил -ат
(carboxyl group)
 Consequences of differences in the structure
of an ACE inhibitor
1. Ability to penetrate various tissues
- Quinapril - the most lipophilic - inhibits ACE in plasma, lungs, kidneys, heart, does
not enter the brain and gonads.
- Lisinopril - hydrophilic - does not "go" into adipose tissue, it is not metabolized in
the liver (for the obese, with liver damage).
-Ramipril, pranalopril and perindopril are superior to enalapril in their ability to
inhibit ACE in the tissues of the lungs, heart, kidneys, adrenal glands and in the
aorta.
2. The degree of penetration of drugs in the tissue
Highly lipophilic (quinapril), it is easier to penetrate into tissues
compared with enalapril, ramipril, perindopril.
3. The severity of the ACE suppression
- The affinity of quinapril to ACE is 30-300 times stronger than
captopril, lisinopril, ramipril or fosinopril.
- The ramipril-ACE complex is 72 times more stable than the
captopril-ACE complex.
 Differences between individual ACE inhibitors
4. Duration of the ACE suppression
Captopril (T1 / 2 = 2 hours) <Quinapril (3 hours) <Cilazapril (4 hours)
<Perindopril (9 hours) <Enalapril (11 hours) <Ramipril, Fosinopril (12
hours) <Lisinopril (13 hours) <Trandolapril ( 20 hours) <Benazepril (21
hours) <Spiapril (40 hours)
5. By therapeutic dose (по K.A. Johnson, 1995)
ACE inhibitor Average dose, mg
Captopril (Capoten) 25
Quinapril (Akkupro) 19.9 The higher the affinity for ACE, the lower
the dose, the longer the effect and the
Fozinopril (Monopril) 15.9 smaller daily fluctuations in blood pressure
Enalapril (Renitec) 10.2
Ramipril (Tritatse) 5,4
6. Excretion route
ACE inhibitors are mainly excreted by the kidneys (Trandolapril - the
liver). With double compensatory breeding (spirapril, quadropril,
fosinopril) - with  f kidneys (in 36.2% of the elderly).
ACE Inhibitors
 1st drug from the group of ACE inhibitors
(SH-groups -  insulin resistance)
drug generation I(short-range)

KAPTOPRIL
Tablets (5 different dosages) - 6.25 each; 12.5; 25; 50; 100 mg.
In the Russian Federation - 46 drugs,
registered under 22 trademarks :
Synonyms: Angiopril-25, Apo-Kapto, Acetene, Vero-Captopril, CapoCard, Capoten,
Capto, Captopril, Captopril Hexal, Captopril Herd International, Captopril SchenTon,
Captopril-Acri, Captopril-Biosintez, Captopril CM, Captopril MP, Captopril SchenTon,
Captopril Acry, Captopril-Biosynthesis S., Captopril-Teva, Captopril-Ferein, Captopril-FPO,
Captopril-Egis, Katopil, Rilcapton.

Enalapril - tablets of 2.5, 5, 10, 20 mg - 28 titles 74 LP. + ampoules

for intravenous administration (1.25 mg in 1 ml)
Mechanism of hypotensive action
 formation of vasoconstrictor angiotensin II
 aldosterone secretion ( Na excrection)
 production of antidiuretic hormone (vasopressin)
 inactivation of atrial Na + -uretic hormone
 inactivation of the vasodilator bradykinin
 activity of the sympatho-adrenal system
 output from the endothelium nitric oxide (ERF)
 membrane phospholipase activity ( PGE2 synthesis)

Other effects of ACE inhibitors

 blood levels of potassium and magnesium
 cell membrane permeability to glucose
blood levels of HDL
hypertrophy, ischemia and myocardial hypoxia.
 ACE inhibitors and CHF
• ACE inhibitors are the only group of drugs known to be
able to improve the prognosis of life of patients with CHF:
according to 32 RCTs, their use has reduced mortality by
23% and reduced the total number of hospitalizations due
to CHF decompensation by 35%.
• Comparative RCTs show the advantage of therapy with
ACE inhibitors (enalapril) compared with
pharmacotherapy of SG (digoxin).
• The use of ACE inhibitors in the treatment of CHF allows
to achieve positive dynamics of the state during the
previous ineffective therapy.
 KAPTOPRIL and ENALAPRIL
Side effects :
Occurring frequently(> 1%) -
Hypotension - in 40% (dizziness, fainting) - usually occurs 1 hour
after taking 6.25 - 12.5 mg, (enalapril - in 15%)
Dry cough - at 2.7 - 37% (enalapril - at 5 - 68%)
Skin rash in 3.5–8% (<0.5%), Quincke’s edema (0.4%), headache
(enalapril in 20% B), hyperkalemia, taste disturbance (“burnt tongue”
syndrome ).
Proteinuria - at 1% when taking> 150 mg per day, (enalapril - 1.4%)
Hyperpotassemia - in 1.2%
Rarely encountered(< 1%) -
Chest pain, neutropenia, agranulocytosis, unusual fatigue (5.8% V),
nausea, diarrhea, hepatotoxic action, pancreatitis.
 KAPTOPRIL and ENALAPRIL
Overdose :
Hypotension (dizziness, fainting).
Treatment - correction of hypotension, dehydration and electrolyte
disorders.
Hemodialysis is possible..

Absolute contraindications :
Hypersensitivity, angioedema (against the background of ACE
inhibitors in history), porphyria, pregnancy, breastfeeding,
children's age.
 KAPTOPRIL and ENALAPRIL
Relative contraindications (carefully):
Bilateral renal artery stenosis, single kidney artery stenosis, condition
after kidney transplantation, severe renal failure (proteinuria> 1 g /
day), history of kidney disease (increased risk of proteinuria),

Liver failure,

Severe autoimmune diseases (SLE, scleroderma),

Oppression of bone marrow hematopoiesis,

Cardiogenic shock, hypotension, tachycardia, marked aortic or mitral

stenosis, cerebral ischemia. Angioedema in history.

Primary hyper aldosteronism, azotemia, hyperkalemia.

Pregnancy, breastfeeding.
 POSSIBLE COMBINATIONS
Diuretics (with hydrochlorothiazide - in the federal insurance list)
 - blockers
BKK
Prazosin
Reserpine
Methyldopa
Minoxidil

Hormone replacement therapy -

in women after menopause)
(moexipril -
 KAPTOPRIL and ENALAPRIL
Clinically significant interactions :
Alcohol, diuretics, blood pressure reducing agents -
increased hypotensive effect
NSAIDs (especially indomethacin), estrogens,
sympomimetics - weakening of hypotensive effect
Cyclosporine, potassium-sparing diuretics,
potassium-containing drugs, salt substitutes -
hyperpotassemia (requires frequent determination in
serum).
Lithium preparations - hyperlithiumemia.
Sulfonylurea - increased hypoglycemia
Bone marrow suppressants - increased risk of
neutropenia and / or agranulocytosis
 Hemodynamic effects of antihypertensive
drugs

Drugs Heart Heart TPVR TBV

rate output
Central action
   
Sympatholytics
   
β-blockers    
Vasodilators
   
Affecting RAAS
- -  
Diuretics
- -  
65
Diuretics
 … Water is a slave of
electrolytes …

Diuretics
(diuretics, natriuretics, saluretiki) –
medicines that have the ability to increase the amount of
urine and change the electrolyte composition of body fluids
by
• increased filtering (primary urine formation) and/or
• inhibition of reabsorption electrolytes and water
which, ultimately, leads to an increase in natriuresis,
diuresis, anti-edema and hypotensive effect.
Nephron structure
Nephron structure
Diuretic action scheme
The point of application of diuretics
 By predominant localization of action
diuretics are divided :

I. Diuretics acting on the proximal tubule segment:

diacarb, osmotic diuretics.
II. Diuretics acting throughout the loop of Henle:
furosemide, uregit, bumethamide.

III. Diuretics acting on the cortical segment of the

loop of Henle: thiazides, chlorthalidone, clopamide.
IV. Diuretics acting on the distal tubule: veroshpiron,
amiloride, triamteren.
 Carbonic anhydrase inhibitors
membrane
Basement

Apical membrane
СО2+Н2О Н2СО3 НСО3+Н+
Na+ С
АСО CARBONIC ANHYDRASE Na+
Н
Ribosome
HCO3
Na+ С
АСО RNA
Н
Mitochondria
Cl-
K+
Na + Aldosterone
Na+
С DNA
АСО
Н Nucleus

tubule
 Carbonic anhydrase inhibitors
Carbonic anhydrase accelerates the reaction between carbon dioxide
and water to form carbonic acid:

CO2 + H20 = H2CO3 + H + + HCO3 -

which without enzyme is slow. This reaction underlies the process of

acid formation and alkali secretion.
As a result, the level of sodium bicarbonate in the urine increases and it
acquires an alkaline reaction. Increased sodium excretion leads to
increased diuresis.
Tolerance develops rapidly, as the long-term loss of bicarbonates is
accompanied by metabolic acidosis, as a result of which, without the
participation of carbonic anhydrase, a sufficient amount of hydrogen
ions enters the canalicular fluid.
During this period, diuresis is terminated, therefore carbonic anhydrase
inhibitors are effective only in treatment with intermittent courses; as
saluretics, they have no clinical value.
 Carboanhydrase inhibitors. Application

1. Reduction in intraocular pressure.

- not associated with a diuretic effect.
The formation of intraocular fluid is an active process, it requires bicarbonate
ions, which are provided by carbonic anhydrase .. This action is local and
does not depend on changes in acid-base balance in other media of the body.
- Tolerance to this effect does not develop.
 Carboanhydrase inhibitors. Application

2. Prevention of acute altitude sickness

Height over 3000 m Lack of oxygen Hyperventilation

Carbonic anhydrase inhibitors Acidosis Alkalosis

NORM
 DIURETICS classification
(the severity of the diuretic effect)

Powerful, fast-acting inhibit the

reabsorption of sodium filtered in the glomeruli Average force of
Weak drugs
by 10–25% (urine excretion rate of more than action
8 ml / min); increase in diuresis
by 40 - 300%

“loop” diuretics –
• Furosemidum (lasix, furantil),
• bumetanide (bufenox),
• ethacrynic acid (uregit)
 Loop diuretics
– Powerful natriuretic effect (over 15-20%)
– Effective in renal failure, can increase renal blood flow and glomerular filtration
– To a lesser extent, cause hypokalemia.
– Increase calcium excretion.
– Diuretic effect when ingestion occurs after 30-60 minutes;
– the peak of action is in 1-2 hours, but the effect is shorter (6 hours);
– The presence of acidosis or alkalosis does not affect efficacy.
– Bumetamide is more active than furosemide 40-60 times.
– Ethacrynic acid is more often prescribed to patients with hypersensitivity to sulfonamides.
 Loop diuretics. Application
• Hypertensive crisis with the development of pulmonary edema, incl.
in patients with renal failure, liver cirrhosis, circulatory failure
• Poisoning with barbiturates, salicylates
• Myocardial infarction with left ventricular failure
• Traumatic brain injury (reduces intracranial pressure) because
furosemide reduces the production of cerebrospinal fluid and
increases cerebral blood flow
• Late toxicosis (edema) of pregnant women
• Bronchial asthma attack (inhalation) - associated with the effect of
furosemide on mast cells, leukocytes and, mainly, on the transport of
sodium, chlorine, potassium in the epithelial cells of the bronchi
 Classification of diuretics
(the severity of the diuretic effect)

Medium force of action

Powerful These drugs inhibit the reabsorption of Weak
sodium by 5-10%;
increase in diuresis - +20 - 30%

•carbonic anhydrase inhibitors - Acetazolamidum

(diacarb, Fonurit);

• thiazide and thiazide-like drugs -

Hydrochlorothiazidum (dichlothiazide, hypothiazide),
clopamide (brinaldix), chlorthalidone (hygroton,
oxodoline), indapamide (aryphone);

• osmotic diuretics - Mannitum pro injectionibus

(mannitol, mannitol), urea (karmamid);

• derivatives of purines - theophylline, aminophylline

 Thiazide and thiazide-like diuretics
• Moderately pronounced natriuretic effect (Na fraction is 5-10%).
• Not effective in the presence of renal failure.
• Reduce excretion by the kidneys of calcium (the mechanism is not
clear).
• They are used in cases when it is necessary to remove Na and water
from the body not sharp and fast, but long in time.
• The manifestation of the effect begins after 1-2 hours, reaches a
maximum of 4/6 hours and lasts 12 hours (in oxodoline, 48-72 hours).
• Metabolic alkalosis or acidosis does not affect efficacy.
• Absorbed when taken by 60-80%.
 Thiazide diuretics
Application
 Hypertonic disease
 Edema in cardiovascular diseases
 Diabetes insipidus (exhibit antidiuretic
effect)
 Hypoparathyroidism
 Treatment with vitamin D; osteoporosis
 Classification of DIURETICS
(the severity of the diuretic effect )

Weak drugs
Powerful Average inhibit sodium reabsorption by less
than 3%.
diuresis increase - + 15 - 20%

• potassium-sparing agents -
Spironolactonum (veroshpiron, aldactone),
Triamterenum (pterofen, triampur), amiloride,
triampur compositum;

• acid-forming diuretics - ammonium

chloride;

• drugs of medicinal herbs - leaves of

strawberry, lingonberry, ortosifona (kidney tea),
bearberry, corn silk, horsetail grass
 Types of effects on the body
Diuretics

Diuretic

Antihypertensive Hyponitrogenic

Dehydration
(anti-edema)
Anti -
epileptic
 The main areas of application in clinics

Acute heart failure Edema syndrome

I/v are introduced strong, (Chronic circulation failure, nephrotic syndrome,
"Loop" diuretics - Liver cirrhosis)
furosemide, uregit, With moderately severe edema syndrome
bumethamide. Less in / in enter drugs of choice are hypothiazide,
osmotic diuretics - clopamide, chlorthalide. When expressed
mannitol but normal swelling apply "loopback" diuretics-furosemide,
Blood pressure when persists Uregit - sufficiently large doses;
glomerular filtration in large vines hypothiazide. If necessary
the kidneys. potassium-sparing diuretics are prescribed.
“Looped” diuretics and thiazide diuretic
prescribed by intermittent scheme,

Brain edema,
Arterial hypertension syndrome glaucoma, poisoning
Used diuretics average
In acute situations apply
forces (if "loop", then in smaller doses,
osmotic diuretics, lasix i/v. For
than with edema). Effective combination
Planned Glaucoma Therapy - Diacarb.
saluretik and veroshpiron.
Usage method usually intermittent
 Major side effects of diuretics
• Potassium deficiency
• Magnesium deficiency
• Hypovolemia with overdose.
• Urinary retention
• Hyponatremia
• Uric acid salt retention
• Reduced carbohydrate tolerance
• Alkalosis
• Calcium Homeostatic Regulation
• Dependence on diuretics
 UNDESIRABLE OR SIDE EFFECTS OF
DIURETICS
• Loop and thiazides - hypopotassemia, hypochloremic
alkalosis, hyponatremia, hyperuricemia, hyperglycemia.

• Carboanhydrase inhibitors - hypopotasslemia,

metabolic acidosis.

• Osmodiuretics - hyposodiumremia, hypervolemia.

• Potassium-saving - hyperpotassemia, hyponatremia.

 Rare complications
of the diuretics use:

- Interstitial nephritis (thiazides, furosemide)

- Pancreatitis (thiazides)
- Decrease in hearing acuity (loop diuretics)
- Anemia, leukopenia, thrombocytopenia (thiazides)
Hasta la vista