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CLASSIFICATION OF HYPERTENSION

Blood Pressure мм
stage
Systolic Diastolic
Normal 101-139 61-89
Boundary Hypertens. 140-159 90-94
160-179 95-109
I stage – mild
(functional, transint) No sings of infringement of
target organs
II stage – moderate 180-199 110-119
(initial systemic Hypertrophy of the LV,
infringement, labile) constriction of retina arteria
etc.
III stage – hard > 220 > 120
(systemic organic Disturbance of the cerebral,
infringement, permanent) coronary, renal blood flow
REGULATION OF BLOOD PRESSURE
capacity work of the pump
venules heart

CNS
resistance sympathetic n.s.
volume
arterioles kidneys

renin

aldosteron angiotensin
ANTIHYPERTENSIVE AGENTS
neurotropic:
tranquilizers,
on sympathetic neuroleptics,
transmission: psychosedatives
central 2-adrenomimetics (clonidine,
methyldopa)
selective agonist of imidazoline
receptors (moxonidin)
- & β-adrenoblockers
sympatholytics
on water- ganglioblockers
salt
balance miotropic
diuretics, ACE (vasodilators):
inhibitors, nonselective (papaverin, no-spa
antagonists of etc), selective (Са2+-channels
angiotensin II blockers, К+-channels activators
receptors etc)
CENTRAL 2-ADRENOMIMETICS
clonidine (clophelin), methyldopa,
guanfacin
 peripheral resistance (more in upright
position)
 heart beat and cardiac output (more in
horizontal position)
prevent left ventricle hypertrophy and heart
failure
dilation of the cerebral, renal and cardiac
blood vessels
 renin and aldosterone production
sedative, analgesic effects
adverse effects:
drowsiness, constipation, dryness of mouth, initial
hypertension (I.V.), bradycardia etc.
rebound syndrome, pseudotolerance, alcohol
potentiation
EFFECTS OF BETA-BLOCKERS
block of β-  sympathetic block of
receptors of nervous system cardiac β-
renal juxta- receptors
glomerular zone
 cardiac
contractility
and rate
 cardiac
 renin excitability
secretion and
 cardiac conductivity
output

 peripheral
vessels tonus  myocardial
oxygen
demand

hypotensive antianginal antiarrhythmic


PROPERTIES OF SEVERAL
BETA-RECEPTOR-BLOCKING DRUGS
Agents ISA MSA Bioavailability Elimina
tion T1/2
I. Nonselective β- (β1+β2) adrenergic agonists
Propranolol No Yes ≈ 30 3-6 hours
Timolol No No ≈ 50 4-5 hours
Pindolol Yes Yes ≈ 90 3-4 hours
Labetalol No Yes ≈ 30 5 hours
II. Selective β1 adrenergic agonists
Metoprolol No Yes ≈ 50 3-4 hours
Acebutolol Yes Yes ≈ 50 3-4 hours
Atenolol No No ≈ 40 6-9 hours
β-BLOCKERS
pharmacokinetics:
 Absorption: well-absorbed, peak concentration after
1-3 hrs. Significant first-pass effect
 Distribution: easily cross blood-brain barrier
(propranolol, metoprolol etc)

therapeutic uses:
hypertension
ischemic heart disease
arrhythmia - drugs with MSA
glaucoma - timolol
hyperthyroidism – propranolol
migraine, alcohol abstinence – propranolol
β-BLOCKERS
Adverse effects
cariovascular: arrhythmia (АV-block, bradycardia
etc), heart failure, hypotension, edema
bronchospasm
vasoconstriction («claudication»)
hypoglycemica
 LDLP
“down-regulation” of beta-receptors
rebound syndrome with tachycardia
pregnant uterus contraction
MIOTROPIC (VASODILATORS)

arterial: apressin (hydralazin), K+-


channels openers, Ca2+-channels
blockers etc.
arterial and venous: sodium
nitroprusside, papaverine, no-spa, -
adrenergic antagonists, ganglionic
blockers.
venous: nitrates
VASODILATORS
 systemic peripheral resistance

 Na+  BP  sympathetic n.s.


excretion via 1
kidney 2
2
 renin 2  rate
1
 cardiac
contractiiity
  angio-  vascular  venous
aldosteron tensin II resistance return

Na+ retention,
 BP  cardiac
 blood volume output
1 – diuretics 2 – β-blockers
MIOTROPIC (VASODILATORS)
non-selective:
phosphodiesterase inhibitors:
 isoquinolone derivative – papaverin, no-
spа (drotaverin)
 xanthine derivative – theophyllin,
aminophyllin (euphyllin)
mixed mechanism of action – apressin
(hydralazine), diabzol, nicotinic acid etc.
selective:
Ca2+- channels blockers – nifedipine,
verapamil, diltiazem
K+-channels openers – minoxidil,
diazoxide
nitrous oxide donators – sodium
nitroprusside
CALCIUM CHANNEL BLOCKERS
 Type I (cardiotropic) –phenylalkylamines
derivatives : verapamil and others.

 Type II (vasotropic) – dihydropyridines


derivatives:
 I-st generation – nifedipine
 II-nd generation – amlodopine,
nimodipine, isradipine and others.
 Type III (mixed) – benzothiazine
derivative: diltiazem
ARTERIAL SMOOTH MUSCLES
calcium channels
voltage-gated ligand-gated

Са2+
Сa2+- + calmodulin
channels
blockers Сa2+ + calmodulin
kinase of light kinase of
miosin chanes - light miosin
Сa2+ РО4 chanes
miosin (non- miosin - РО4
ATP-
aza active) (active)
+ actin
contraction
EFFECTS OF Ca 2+ CHANN. BLOCKERS
heart vessels
conductive myocardium coronary peripheral
system
AV-node SA-node  contractility dilation 
resistance

 excit-  Auto  workload


ability & macity and after-load  bloodflow
conducti
vity,
 ERP  heart  oxygen  oxygen
rate demand of supply  BP
myocardium

arrhythmic antianginal hypo-


tensive
PHARMACODYNAMICS OF CALCIUM
CHANNELS BLOCKERS
heart:
 «-» ino- & chronotropic effects
  oxygen demand & cardiac output
  automacity of SА-node, automacity &
conductivity of AV –node (verapamil,
diltiazem)
smooth muscles: relaxation 
  BP (arterioles > veins)
  spasm of coronary vessels
  cerebral vasoconstriction & outcomes
of stroke (nimodipine, cinnarizine)
  bronchospasm etc.
blood: antiaggregative,  cholesterol
COMPARATIVE CHARACTERISTICS OF
CALCIUM CHANNELS BLOCKERS
Function Verapamil Nifedipine

Coronary blood  
flow

Arterial BP  

Heart rate  

AV-conductivity  -
CALCIUM CHANNELS BLOCKERS
therapeutic uses:
hypertension
infringement of cerebral blood flow, migraine
(nimodipine, cinnarizine)
Paynaud’s phenomenon (amlodipine)
ischemic heart disease
supraventricular tachyarrhythmia (verapamil,
diltiazem)
adverse effects:
arrhythmia: bradycardia, АV-block etc.
(verapamil, diltiazem)
hypotension, reflective tachycardia
heart failure, edema
redness of skin, dizziness, headache,
constipation etc.
POTASSIUM CHANNELS OPENERS
MInoxidil, diazoxide
К+-channels opening
К+ outflux
hyperpolarization
block of voltage-gated
Сa2+- channels
 Сa2+ intracellular influx
 smooth muscles tonus
vasodilation
 BP
POTASSIUM CHANNELS OPENERS
therapeutic uses:
alternative agents for hypertension:
 severe hypertension, resistant to other agents
(minoxidil)
 hypertonic crisis (diazoxide)
Ischemic heart disease: variant angina
(nicorandil)
adverse effects:

 tachycardia with  myocardial oxygen demand 


risk of myocardial infarction
 heart failure
 orthostatic hypotension
 reversible hypertrichosis  minoxidil (rigein) at
allopecia
 hyperglycemia
NITROUS OXIDE DONATORS
sodium endothelial cells
nitroprusside
NO
Adverse effects:
 postural  guanilate cyclase
hypotension
 reflective
tachycardia GТP  cGMP
 rebound
syndrome
 intoxication with  content of cytosol free Са2+
metabolites ions
(cyanides etc)
 hypovitaminosis
В12 relaxation of
smooth muscles
AGENTS, ACTING ON RENIN-
ANGIOTENSIN SYSTEM (RAS)
angiotensionogen kininogen  prosta
renin kallikrein glandins
synthesis
angiotensin I bradykinin
ACE
аngiotensin II non-active
АТ1-receptors bradykinin
vasodila
tion
vasoconst secretion of ACE
riction aldosterone inhibitors

 angiotensin- peripheral
Na+ & Н2О resistance
peripheral receptor
resistance retention blocking
 BP agents  BP
STIMULATION OF АТ1-RECEPTORS
Organs Angiotensin II effects
heart increasing of cardiac contractility,
constriction of coronary vessels
peripheral blood Vasoconstriction and raising of BP,
vessels hypertrophy of smooth muscles
aldosterone secretion, increasing
adrenal gland of Na+ reabsorption and K+
secretion, increasing of CA
kidney сужение почечной артерии,
 ренина
pituitary andiuretic hormone production
hypothalamus activation of thirsty center
sympathetic n.s. stimulaion
AGENTS, ACTING ON RENIN-
ANGIOTENSIN SYSTEM(RAS)
inhibitors of angiotensin converting
enzyme (АCE):
short acting (6-12 hrs) that contain
sulfhydryl group – captopril
lond acting (24 hrs) that contain
carboxyl group – lisinopril, enalapril,
benzepril, ramipril etc.
ultra-long acting (36 hrs) that contain
phosphoryl group – fosinopril
angiotensin-receptor blocking agent:
losartan, valsartan etc.
INHIBITORS OF ANGIOTENSIN
CONVERTING ENZYME (ACE)
the results of  decreasing of serum RАS:
dilation of arteries & veins ( pre- & after-load)
increasing of renal blood flow & glomerular
filtration rate, potassium retention
dilation of coronary & cerebral vessels
improvement of myocardium oxygen supply
the results of  decreasing of tissue RАS:
decreasing of heart dilatation and hypertrophy
increasing сof ATP, creatine phosphate &
glycogen synthesis
angioprotective
improvement of perception & cognitive function
INHIBITORS OF ANGIOTENSIN
CONVERTING ENZYME (ACE)
the results of metabolic effects:
antiaggregative
decreasing of free radicals level (captopril)
increasing of glucose tolerance (ramipril)

adverse effects
hypotension (initial doses)
infringement of kidneys function
(proteinurea)
hyperkaliemia
edema
dry cough
dermal allergic reactions (10 % of patients)
embryotoxic
PHARMACODYNAMICS OF
ANGIOTENSIN-RECEPTOR BLOCKING
AGENT
 peripheral resistance & BP ( after-load)
 systolic & diastolic BP
 heart rate, hypertrophy of left ventricular
angioprotective action
 sodium & uric acid excretion
 aldosterone, NA, A production
 renin, angiotensin I & II level (negative
feedback)
unlike ACE inhibitors:
 don’t alter bradykinin, prostaglandins and
potassium level in blood
 less prominent adverse effects
HYPERTONIC CRISIS (EMERGENCY)
Route of Onset of Duration of
Agents admini action (min) action (hrs)
stration
Sodium I.V. Beginning of End of
nitroprusside infusion infusion
Diazoxide I.V. 1-5 1-12
Hydralazine I.V. 5-10 4-6
Subling. 15-30 3-6
Nifedipine
I.V. 1-5 3-6
Labetolol I.V. 1-5 6-24
also available:
 furosemide (lazix) I.V.
 neurotropic – diazepam (I.V.), amizine (I.V.,
I.M.), magnesium sulfate (I.V.) etc.
CLASSIFICATION OF HYPETENSIVE
AGENTS
 adrenomimetics – adrenalin, ephedrine,
noradrenalin, mesaton, dobutamine, dopamine
 glucocorticoids – prednisolone,
dexamethasone
 mineralocorticoids – DOCSA
 analeptics – caffeine, cordiamine,
sulfocamphocaine
 adaptogens – Ginseng, Eleuterococ,
Echinacea etc