Regulation of BP and management of Hypertension

1. Dr. Irfan Ahmad Khan
JR-2
PHYSIOLOGICAL REGULATION OF BLOOD
PRESSURE
&
DRUG TREATMENT OF HYPERTENSION

2. Introduction
 Blood pressure (BP), sometimes called arterial blood pressure, is
the pressure exerted by circulating blood upon the walls of blood vessels,
and is one of the principal vital signs.
 During each heartbeat, blood pressure varies between a maximum
(systolic) and a minimum (diastolic) pressure.
 MAP = DBP + (SBP-DBP)/3
 Mean blood pressure drops over the whole circulation, although most of
the fall occurs along the small arteries and arterioles.
 Blood pressure (BP) is generated by cardiac contraction against the
vascular resistance.

3.  Stroke volume is related to myocardial contractility and to the size of
the vascular compartment.
Peripheral resistance is determined by functional and anatomic changes
in small arteries (lumen diameter 100–400 μm) and arterioles.

5. Cardiac output
 The output of the heart per unit of time is the cardiac output
 CO = Stroke Volume X Heart Rate
 Stroke volume is affected by preload, afterload and contractility
 Vascular volume is a primary determinant of arterial pressure over the
long term.
 Blood vol. depends on NaCl intake.It is kidney which regulates the
excess NaCl by increasing Na excretion.

6. Vascular mechanism of BP regulation
 Vascular radius and compliance of resistance arteries are also important
determinants of arterial pressure.
 Resistance to flow varies inversely with the fourth power of the radius.So
small decrease in lumen size significantly increase resistance.
 Regulation of BP involves:-
 Local Regulation
 Substances Secreted by the Endothelium
 Systemic Regulation by Hormones
 Systemic Regulation by The Nervous System

7. LOCAL REGULATION
1.AUTOREGULATION
 The capacity of tissues to regulate their own blood flow is referred to as autoregulation.
 Most vascular beds have an intrinsic capacity to compensate for moderate changes in
perfusion pressure by changes in vascular resistance, so that blood flow remains
relatively constant.
 This capacity is well developed in the kidneys but it has also been observed in the
mesentery, skeletal muscle, brain, liver and myocardium.
2.VASODILATOR METABOLITES
 Hypoxia,hypercapnia,↓pH,↑ temperature,↑K+, Lactate
3.LOCALIZED VASOCONSTRICTION
 Injured arteries and arterioles constrict strongly due to the local liberation of serotonin
from platelets that stick to the vessel wall in the injured area. Injured veins also constrict.
 ↓ local temperature

8. SUBSTANCES SECRETED BY THE ENDOTHELIUM
 They secrete many growth factors and vasoactive substances.
 The vasoactive substances include prostaglandins and thromboxanes,
nitric oxide, and endothelins.
1.Prostacyclin & Thromboxane A2
 Prostacyclin is produced by endothelial cells and thromboxane A2 by
platelets from their common precursor arachidonic acid via the
cyclooxygenase pathway.
 Thromboxane A2 promotes platelet aggregation and vasoconstriction,
whereas prostacyclin inhibits platelet aggregation and promotes
vasodilation.

9. 2.Nitric oxide (NO)
 Earlier k/a endothelium-derived relaxing factor (EDRF)
 NO is synthesized from arginine in a reaction catalyzed by nitric oxide synthase (NO
synthase, NOS). Three isoforms of NOS have been identified:
1.NOS 1, found in the nervous system;
2.NOS 2, found in macrophages and other immune cells; and
3.NOS 3, found in endothelial cells.
 NOS 1 and NOS 3 are activated by agents that increase intracellular Ca2+
concentrations, including the vasodilators acetylcholine and bradykinin.
 The NO that is formed in the endothelium diffuses to smooth muscle cells, where it
activates soluble guanylyl cyclase, producing cGMP, which in turn mediates the
relaxation of vascular smooth muscle.
3.Endothelins
 Endothelial cells also produce endothelin-1, one of the most potent
vasoconstrictor agents. (ETA receptor)

10. SYSTEMIC REGULATION BY HORMONES
 Many circulating hormones affect the vascular system.
 Vasodilator hormones include kinins, VIP, and ANP.
 Vasoconstrictor hormones include vasopressin, norepinephrine, epinephrine, and
angiotensin II.
1.Kinins
 Two related vasodilator peptides called kinins are found in the body.
 One is bradykinin and the other is lysylbradykinin, also known as kallidin .
 Lysylbradykinin can be converted to bradykinin by aminopeptidase.
 Both peptides are metabolized to inactive fragments by angiotensin-converting
enzyme.
 They relax vascular smooth muscle via NO, lowering blood pressure.

11. 2.Natriuretic Hormones
 Natriuretic peptides involved in vascular regulation, include atrial natriuretic
peptide (ANP) secreted by the heart, brain natriuretic peptide (BNP), and C-type
natriuretic peptide (CNP).
 They are released in response to hypervolemia.
 ANP and BNP inhibit Na reabsorption by the kidney.
 These peptides antagonize the action of various vasoconstrictor agents and lower
blood pressure.
3.Circulating Vasoconstrictors
 Vasopressin (ADH) secreted by posterior pituitary
 Potent vasoconstrictor (V1A receptor)
 Antidiuretic effect (V2 receptor)
 Catecholamines have vasoconstrictor action.
 Angiotensin II has a generalized vasoconstrictor action.It also increases water
intake and stimulates aldosterone secretion,Thus helps to maintain ECF volume. It
inhibits renin release due to Angiotensin II type 1 receptors on JG cells.

12. β 1 -
receptor
AT1
receptor
AT1
receptor

13. Systemic Regulation by The Nervous System

14. Autonomic Nervous System
 The autonomic nervous system maintains cardiovascular homeostasis via pressure,
volume and chemoreceptor signals.
 Adrenergic reflexes modulate blood pressure over the short term and adrenergic function,
along with hormonal and volume-related factors, contributes to the long-term regulation
of arterial pressure.
 The three endogenous catecholamines are norepinephrine, epinephrine, and dopamine.
All three play important roles in tonic and phasic cardiovascular regulation.
 Adrenergic receptors are α and β differentiated further into α1, α2, β1, and β2 receptors.
 α Receptors are occupied and activated more avidly by norepinephrine than by
epinephrine and the reverse is true for β receptors.
 α1 Receptors are located on postsynaptic cells in smooth muscle and elicit
vasoconstriction.
 α2 Receptors are located on presynaptic membranes of postganglionic nerve terminals
that synthesize norepinephrine. When activated by catecholamines, α2 receptors act as
negative feedback controllers, inhibiting further norepinephrine release.

15.  In the kidney, activation of α1-adrenergic receptors increases renal tubular
reabsorption of sodium.
 Different classes of antihypertensive agents either inhibit α1 receptors or act as
agonists of α2 receptors and reduce systemic sympathetic outflow.
 Activation of myocardial β 1 receptors stimulates the rate and strength of
cardiac contraction and consequently increases cardiac output.
 β1 Receptor activation also stimulates renin release from the kidney. Another
class of antihypertensive agents acts by inhibiting β1 receptors.
 Activation of β2 receptors by epinephrine relaxes vascular smooth muscle and
results in vasodilation.
 Chronic administration of agents that block adrenergic receptors may result in
upregulation, and withdrawal of those agents may produce a condition of
temporary hypersensitivity to sympathetic stimuli.

16. FEEDBACK CONTROL OF BP-BAROREFLEX
 The CVS is under neural influences coming from several parts of the brain, which
in turn receive feedback from sensory receptors in the vasculature (eg,
baroreceptors).

17. Medullary Control of CVS

18. Medullary Control Of Heart Rate By The Vagus Nerves
Baroreceptor Resetting
In chronic hypertension, the baroreceptor reflex
mechanism is "reset" to maintain an elevated
rather than a normal blood pressure.

19. ACE inhibitors
Clonidine
Methyldopa
Spironolactone
Ganglion
blockers
AT1 Antagonist
Diuretics
Renin inhibitors
Vasodilators &
CCBs
β-blocker
α-blocker
β-blocker
Vasodilators &
CCBs
↓BP
↑BP

20. HYPERTENSION
 Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension,
is a chronic medical condition in which the BP in the arteries is elevated.
 Clinically, hypertension may be defined as that level of blood pressure at which the
institution of therapy reduces blood pressure–related morbidity and mortality.
 30% adults worldwide are hypertensive & causes 6% death worldwide
 Risk factors include smoking,hyperlipidaemia,diabetes,CVD
 Hypertension is an independent predisposing factor for heart failure, coronary artery
disease, stroke, renal disease and peripheral arterial disease (PAD).

21.  Two types:1. Essential(Primary/Idiopathic) hypertension
2.Secondary hypertension
Essential hypertension
 80–95% of all hypertensive patients
 Familial and is likely to be the consequence of an interaction between
environmental and genetic factors.
 The prevalence of essential hypertension increases with age.
 In the majority of patients with established hypertension, peripheral resistance
is increased and cardiac output is normal or decreased.
Secondary Hypertension
 5-20%
 Identifiable etiology

22. Secondary Causes of Hypertension

23. DRUG TREATMENT OF HYPERTENSION
(Drug therapy is recommended for individuals with blood
pressures ≥ 140/90 mmHg.)

24. Classification of Antihypertensive Drugs by Their Primary Site or
Mechanism of Action

25.  Diuretics
1. Thiazides and related agents (hydrochlorothiazide, chlorthalidone,
chlorothiazide, indapamide, methylclothiazide, metolazone)
2. Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid)
3. K+-sparing diuretics (amiloride, triamterene, spironolactone)
 Sympatholytic drugs
1. β receptor antagonists (propranolol, metoprolol, atenolol, betaxolol,
bisoprolol, carteolol, esmolol, nadolol, nebivolol, penbutolol, pindolol,
timolol)
2. α receptor antagonists (prazosin, terazosin, doxazosin, phenoxybenzamine,
phentolamine)
3. Mixed α-β receptor antagonists (labetalol, carvedilol)
4. Centrally acting adrenergic agents (methyldopa, clonidine, guanabenz,
guanfacine)
5.Adrenergic neuron blocking agents (guanadrel, reserpine)

26. Classification Contd...
 Ca2+ channel blockers (verapamil, diltiazem, nisoldipine, felodipine,
nicardipine, isradipine, amlodipine, clevidipine, nifedipine)
 Angiotensin-converting enzyme inhibitors (captopril, enalapril, lisinopril,
quinapril, ramipril, benazepril, fosinopril, moexipril, perindopril, trandolapril)
 AngII receptor antagonists (losartan, candesartan, irbesartan, valsartan,
telmisartan, eprosartan, olmesartan)
 Direct Renin Inhibitor (aliskiren)
 Vasodilators
1. Arterial (hydralazine, minoxidil, diazoxide, fenoldopam)
2. Arterial and venous (nitroprusside)

27. ACE inhibitors
Clonidine
Methyldopa
Spironolactone
Ganglion
blockers
AT1 Antagonist
Diuretics
Renin inhibitors
Vasodilators &
CCBs
β-blocker
α-blocker
β-blocker
Vasodilators &
CCBs
↓BP
↑BP

28. Diuretics
1.Thiazides and related agents
 First-line agents

29.  The initial action of these drugs decreases extracellular volume by enhancing Na+
excretion in the urine and lead to a fall in cardiac output.
 The hypotensive effect is maintained during long-term therapy due to decreased vascular
resistance; cardiac output returns to pretreatment values due to compensatory responses
such as activation of the RAS.Vasodilation is produced by:-
1.Indirect small persisting Na+ and vol. deficit
2.Open Ca2+-activated K+ channelshyperpolarization of vascular smooth muscle
cellsclosing of L-type Ca2+ channels decreased Ca2+ entryvasodilation.
 Greater effect at night by chlorthalidone is due to the much longer t1/2 of chlorthalidone
(>24 hours) compared to hydrochlorothiaze (several hours).
 Used in low dose-12.5 to 25 mg/day
 Urinary K+ loss can be a problem with thiazides. ACE inhibitors and angiotensin receptor
antagonists will attenuate diuretic-induced loss of K+ to some degree.

30.  Hypertensive patients may become refractory to sympatholytics or to vasodilator drugs,
because these drugs cause retention of salt and water50 mg/day dose of thiazide
/furosemide is used.
 Dietary Na+ restriction(2 g daily) is a valuable in minimizing the dose of diuretic that is
required. (hypokalemia and alkalosis)
 The effectiveness of thiazides as diuretics or antihypertensive agents is progressively
diminished when the GFR falls below 30 mL/min. One exception is metolazone, which
retains efficacy in patients with this degree of renal insufficiency.
 Most patients will respond to thiazide diuretics within about 4-6 weeks. Therefore, doses
should not be increased more often than every 4-6 weeks.
 Addition of a diuretic to a calcium channel blocker is less effective.

31. ADRs
 Hypokalemia
 HyperuricemiaGout
 Hypercalcemia
 Hypochloraemic alkalosis
 Erectile dysfunction in males
 Dyslipidemia
 Magnesium depletion
 Hyperglycaemia
 Increased incidence of sudden death: K+ depletion
1.Polymorphic ventricular tachycardia (torsades de pointes), quinidine.
2.Ischemic ventricular fibrillation

32. 2.Loop diuretics
 Less effective than thiazide diuretics due to short duration of action(4-6 hrs)
 Used in HTN complicated by:-
1.Chronic renal failure: thiazides are ineffective
2.CHF
3.Resistance to combination containing thiazide or marked fluid retention due to use of
potent vasodilator like minoxidil

33. ADRs
 Hypokalemia
 Dilutional hyponatremia
 GI disturbances
 Hearing loss(aminoglycisides)
 Alleric manifestation
 HyperuricemiaGout
 Hypercalcemia
 Dyslipidemia
 Magnesium depletion
 Glucose intolerance

34. 3.K+-sparing diuretics
spironolactone
Amiloride
Triamterene

35.  Amiloride blocks Li+ entry through Na+ channels in CD and mitigates diabetes
insipidus induced by Li+
 Spironolactone also lowers blood pressure but has some significant adverse
effects, especially in men (e.g., erectile dysfunction, gynecomastia, benign
prostatic hyperplasia).
 Eplerenone is a newer aldosterone receptor antagonist that does not have the
sexually related adverse effects induced by spironolactone. As a result of their
capacity to inhibit loss of K+ in the urine, these drugs are used in the treatment of
patients with hyperaldosteronism, a syndrome that can lead to hypokalemia.

36.  Triamterene is a K+-sparing diuretic that decreases the risk of hypokalemia in
patients treated with a thiazide diuretic.
 These agents should be used cautiously with frequent measurements of K+
concentrations in plasma in patients predisposed to hyperkalemia. (use of K+-
containing salt substitutes )
 Renal insufficiency is a relative contraindication to the use of K+-sparing
diuretics.
 Concomitant use of an ACE inhibitor or an angiotensin receptor antagonist
magnifies the risk of hyperkalemia with these agents.

37. Diuretic-Associated Drug Interactions
 The K+- and Mg2+-depleting effects of the thiazides and loop diuretics also can
potentiate arrhythmias that arise from digitalis toxicity.
 Corticosteroids can amplify the hypokalemia produced by the diuretics.
 All diuretics can decrease the clearance of Li+, resulting in increased plasma
concentrations of Li+ and potentiate toxicity.
 NSAIDs that inhibit the synthesis of prostaglandins reduce the antihypertensive
effects of diuretics.
 NSAIDs, β blockers and ACE inhibitors reduce plasma concentrations of
aldosterone and can potentiate the hyperkalemic effects of a K+-sparing diuretic.

38. Sympatholytic drugs

39. β Adrenergic Receptor Antagonists
MOA
 Antagonism of β adrenergic receptors leads to a reduction in myocardial contractility,
heart rate, and cardiac output.
 Blockade of the β receptors of the juxtaglomerular complex, reduces renin secretion
and thereby diminishing production of circulating AngII.
 Reduction in central sympathetic outflow by blocking presynaptic β-receptors centrally
 Stimulation of prostacyclin synthesis in vascular beds
 ↑ in natriuretic peptide secretion caused by β blockade
 Some have additional mechanism like nebivolol promotes endothelial cell dependent
vasodilation via activation of the NO pathway
 Drugs without intrinsic sympathomimetic activity produce an initial reduction in CO
and a reflex-induced rise in peripheral resistance, generally with no net change in arterial
pressure. Peripheral resistance decreases gradually. So persistently reduced cardiac output
and possibly decreased peripheral resistance accounts for the reduction in arterial
pressure.
 Drugs with intrinsic sympathomimetic activity produce lesser decrease in HR and CO;
lower vascular resistance because of stimulation of vascular β2 receptors that mediate
vasodilation.

40.  Mild-moderate antihypertension
 Produce hypotensive response in 1-3 weeks
Adverse Effects and Precautions
 Fatigue, lethargy, dec. libido,cold extremities
 Avoided in patients with PVD, diabetics taking insulin, reactive airway disease (asthma)
or with SA or AV nodal dysfunction or in combination with other drugs that inhibit AV
conduction(verapamil).
 β blockers without intrinsic sympathomimetic activity increase triglycerides in plasma
and lower HDL. β blockers with intrinsic sympathomimetic activity have no effect.
 Sudden discontinuation lead to rebound hypertension,tachycardia and anginal pain of due
to upregulation of β receptors .So,tapered gradually over 10-14 days.
 NSAIDs such as indomethacin can blunt the antihypertensive effect of propranolol and
probably other β blockers. (inhibition of vascular synthesis of prostacyclin, as well as due
to retention of Na+).

41.  Epinephrine can produce severe hypertension and bradycardia when a nonselective β
antagonist is present. The hypertension is due to the unopposed stimulation of α receptors
when vascular β2 receptors are blocked; the bradycardia is the result of reflex vagal
stimulation. Such paradoxical hypertensive responses to β receptor antagonists have been
observed in patients with hypoglycemia or pheochromocytoma, during withdrawal
from clonidine, following administration of epinephrine as a therapeutic agent or in
association with the illicit use of cocaine.
Therapeutic Uses
 Effective therapy for all grades of hypertension
 Once- or twice-daily administration
 Effective especially in young nonobese hypertensive
 The β receptor antagonists usually do not cause retention of salt and water, and
administration of a diuretic is not necessary to avoid edema.
 β receptor antagonists are highly preferred drugs for hypertensive patients with
conditions such as MI, ischemic heart disease or congestive heart failure.

42. α 1 Adrenergic Receptor Antagonists
 Initially,dilates resistance and capacitance vesselsreflex ↑ in HR and plasma renin
activity.
 During long-term therapy, vasodilation persists, but cardiac output, heart rate, and plasma
renin activity return to normal.
 α 1 blockers cause a variable amount of postural hypotension, depending on the plasma
volume.
 α 1 Receptor antagonists reduce plasma concentrations of triglycerides and total LDL
cholesterol and increase HDL cholesterol. These potentially favourable effects on lipids
persist when a thiazide-type diuretic is given concurrently.
 Suitable for diabetics as improve carbohydrate metabolism(not when neuropathy is
present—postural hypotension)
 They are used primarily in conjunction with diuretics, β blockers, and other
antihypertensive agents.

43.  α 1 Receptor antagonists are not the drugs of choice in patients with
pheochromocytoma because a vasoconstrictor response to epinephrine can still
result from activation of unblocked vascular α2 adrenergic receptors.
 α 1 Receptor antagonists are used for hypertensive patients with benign prostatic
hyperplasia because they also improve urinary symptoms.
ADRs
 Headache, drowsiness, palpitation, nasal blockade, blurred vision, rash, impaired
ejaculation
 Postural hypotension
 CHF(fluid retention)
 First-dose phenomenon, in which symptomatic orthostatic hypotension occurs
within 30-90 minutes of the initial dose of the drug or after a dosage increase.
After the first few doses, patients develop a tolerance to this marked hypotensive
response.

44. Combined α1 and β Adrenergic Receptor Antagonists
Labetalol
 Is an equimolar mixture of four stereoisomers. One isomer is an α1 antagonist
(like prazosin), another is a nonselective β antagonist with partial agonist activity
(like pindolol) and the other two isomers are inactive.
 Because of its capacity to block α1 adrenergic receptors, labetalol given
intravenously can reduce blood pressure sufficiently rapidly to be useful for the
treatment of hypertensive emergencies.
 Labetalol has efficacy and adverse effects that would be expected with any
combination of β and α1 receptor antagonists.
 It also has the disadvantages that are inherent in fixed-dose combination
products(unpredictable and varies from patient to patient).

45. Carvedilol
 is a β receptor antagonist with α1 receptor antagonist activity.
 The ratio of α1 to β receptor antagonist potency for carvedilol is approximately 1:10.
 It inhibits free radical induced lipid peroxidation and also prevents vascular smooth
muscle mitogenesis.
 Carvedilol undergoes oxidative metabolism and glucuronidation in the liver; the
oxidative metabolism occurs via CYP2D6.
 Carvedilol reduces mortality in patients with CHF associated with systolic dysfunction
when used as an adjunct to therapy with diuretics and ACE inhibitors.
 It should not be given to those patients with decompensated heart failure who are
dependent on sympathetic stimulation.
 As with labetalol, the long-term efficacy and side effects of carvedilol in hypertension are
predictable based on its properties as a α1 & β adrenergic receptor antagonist.

46. Centrally acting adrenergic agents

47. METHYLDOPA
Methyldopa
α -methyldopamine
L-aromatic amino acid
decarboxylase
1.α –Methyl NE is stored in the secretory vesicles substituting for NE itself. Consequently,
when the adrenergic neuron discharges its neurotransmitter, α –methyl NE is released instead
of NE.
2.α –Methyl NE stimulates central α2 receptors to inhibit adrenergic neuronal outflow from
the brainstem .
adrenergic
neurons
α -methylnorepinephrine

48.  Used largely in treatment of hypertension in pregnancy
 Methyldopa is a prodrug that is metabolized in the brain to the active form, its
concentration in plasma has less relevance for its effects.
 t1/2 ~2 hours
 Excreted in the urine primarily as the sulfate conjugate (50-70%) and as the parent
drug (25%). The remaining fraction is excreted as other metabolites.
 The peak effect of methyldopa is delayed for 6-8 hours and the duration of action
of a single dose is usually about 24 hours; this permits once- or twice-daily
dosing. (time required for transport into the CNS, conversion to the active
metabolite storage of α –methyl NE and its subsequent release in the vicinity of
relevant α 2 receptors in the CNS)

49. ADRs
 Sedation,lethargy,depression
 Dryness of the mouth,diminished libido, parkinsonian signs,
hyperprolactinemia gynecomastia and galactorrhea.
 Severe bradycardia and sinus arrest.
 Hepatotoxicity, sometimes associated with fever
 Positive Coombs test (antiglobulin test) that is due to autoantibodies directed
against the Rh antigen on erythrocyteshemolytic anemia
 Adverse effects that are even more rare include leukopenia, thrombocytopenia,
red cell aplasia, lupus erythematosus–like syndrome, lichenoid and
granulomatous skin eruptions, myocarditis, retroperitoneal fibrosis, pancreatitis,
diarrhea, and malabsorption
Interaction
TCA reverse its action by blocking its active transport into the adrenergic neurons

50. Clonidine, Guanabenz, and Guanfacine
 MOA:- Stimulate the α2A subtype of α2 adrenergic receptors in the brainstem, resulting in
a reduction in sympathetic outflow from the CNS .The decrease in plasma concentrations
of NE is correlated directly with the hypotensive effect.
 At doses higher than those required to stimulate central α2A receptors, these drugs can
activate α2 receptors of the α2B subtype on vascular smooth muscle cells
vasoconstrictionloss of therapeutic effect.(therapeutic window phenomenon)
 The α2 adrenergic agonists lower arterial pressure by an effect on both cardiac output and
peripheral resistance.
 In the supine position, when the sympathetic tone to the vasculature is low, the major
effect is to reduce both heart rate and stroke volume.
 In the upright position, when sympathetic outflow to the vasculature is normally
increased, these drugs reduce vascular resistance. This action may lead to postural
hypotension.
 The decrease in cardiac sympathetic tone leads to a reduction in myocardial contractility
and heart rate that could promote CHF in susceptible patients.

51. ADRs
 Sedation,dryness of mouth, nose & eyes & parotid gland swelling and pain.
 Postural hypotension and erectile dysfunction
 Sleep disturbances with vivid dreams or nightmares, restlessness and depression.
 Symptomatic bradycardia and sinus arrest
 Contact dermatitis
 Withdrawal Syndrome
 Sudden discontinuation of clonidine may cause headache, apprehension, tremors,
abdominal pain, sweating, and tachycardia.
 The arterial blood pressure may rise to levels above those that were present prior to
treatment.
 Symptoms typically occur 18-36 hours after the drug is stopped and are associated
with increased sympathetic discharge.
 Tt:-α blocker with a β blocker,or a potent vasodilator - sod. nitroprusside or clonidine
itself

52. Adrenergic neuron blocking agents

53. Guanadrel
 Guanadrel is an exogenous false neurotransmitter that is accumulated, stored, and
released like NE but is inactive at adrenergic receptors.
 The antihypertensive effect is achieved by a reduction in peripheral vascular resistance that
results from inhibition of α receptor– mediated vasoconstriction.
 Because guanadrel can promote NE release from pheochromocytomas, it is contraindicated
in those patients.
 Because guanadrel must be transported into and accumulate in adrenergic neurons, the
maximum effect on blood pressure is not seen until 4-5 hours
ADRs
 Symptomatic hypotension during standing, exercise, ingestion of alcohol or in hot weather
is the result of the lack of sympathetic compensation for these stresses.
 Fatigue and lassitude
 Sexual dysfunction usually presents as delayed or retrograde ejaculation.
 Diarrhea
C/I:-Because guanadrel is actively transported to its site of action, drugs that block or
compete for the catecholamine transporter on the presynaptic membrane will inhibit the
effect of guanadrel. Such drugs include the TCA, cocaine, chlorpromazine, ephedrine,
phenylpropanolamine and amphetamine.

54. Reserpine
• Reserpine binds tightly to adrenergic storage vesicles in central and
peripheral adrenergic neurons and remains bound for prolonged periods of
time
• The interaction inhibits the vesicular catecholamine transporter, VMAT2, so
that nerve endings lose their capacity to concentrate and store NE and
dopamine.
• Catecholamines leak into the cytoplasm, where they are metabolized.
• So,little or no active transmitter is released from nerve endings, resulting in
a pharmacological sympathectomy.

55.  Both cardiac output and peripheral vascular resistance are reduced during long-
term therapy with reserpine.
 Because of the irreversible nature of reserpine binding, the amount of drug in
plasma is unlikely to bear any consistent relationship to drug concentration at the
site of action.
ADRs
 Most adverse effects of reserpine are due to its effect on the CNS
 Sedation and inability to concentrate or perform complex tasks,
 Psychotic depression that can lead to suicide.So the drug should never be given to
patients with a history of depression.
 Other adverse effects include nasal stuffiness and exacerbation of peptic ulcer
disease.

56. Ca2+ Channel Antagonists
 Cardiac contractility and contraction of vascular smooth muscle is dependent on the free
intracellular concentration of Ca2+, inhibition of transmembrane movement of Ca2+ through
voltage-sensitive L-type Ca2+ channels can decrease the total amount of Ca2+ that reaches
intracellular sites.
 All of the Ca2+ channel blockers lower blood pressure by relaxing arteriolar smooth muscle
and decreasing peripheral vascular resistance evoke a baroreceptor-mediated
sympathetic discharge.
 Cardiac depressant:- verapamil >diltiazem >nifedipine
 Vasodilatory effects:- nifedipine >verapamil >diltiazem
 Can be used safely in asthma,angina,PVD
 Don’t have effect on renin release and no adverse effects on lipid profile, uric acid levels or
glucose metabolism.
 Postural hypotension,first dose effect or rebound hypertension not seen
 No adverse effect on foetus

57.  In the case of the dihydropyridines, tachycardia may occur from the adrenergic
stimulation of the SA node.
 Tachycardia is typically minimal to absent with verapamil and diltiazem because of the
direct negative chronotropic effect of these two drugs.
 The concurrent use of a β receptor antagonist drug may magnify negative chronotropic
effects of these drugs or cause heart block in susceptible patients. Consequently, the
concurrent use of β receptor antagonists with either verapamil or diltiazem not done.
ADRs
 Nifedipineheadache,flushing,peripheral oedema, tachycardia, gingival hyperplasia
 Verapamilconstipation
C/I
 Nifedipineunstable angina, LV failure, aortic stenosis and obstructive cardiomyopathy
 Verapamilsick sinus syndrome, AV block and heart failure

58. Angiotensin-Converting Enzyme Inhibitors
 Act by inhibiting the biosynthesis of AngII .
 Also inhibit degradation of bradykinin .Thus leading to vasodilation.
 The ACE inhibitors appear to confer a special advantage in the treatment of patients with
diabetes, slowing the development and progression of diabetic glomerulopathy.
 Effective in slowing the progression of other forms of chronic renal disease, such as
glomerulosclerosis.
 Patients with hypertension and ischemic heart disease are treated with ACE inhibitors;
administration of ACE inhibitors in the immediate post-MI period has been shown to
improve ventricular function and reduce morbidity and mortality.
 Because ACE inhibitors blunt the rise in aldosterone concentrations in response to Na+
loss, the normal role of aldosterone to oppose diuretic-induced natriuresis is diminished.
Consequently, ACE inhibitors tend to enhance the efficacy of diuretic drugs.(small dose)

59.  Contraindicated during pregnancy
 In patients with bilateral renal artery stenosis or stenosis in a sole kidney, the
administration of an ACE inhibitor will reduce the filtration fraction and cause a
substantial reduction in glomerular filtration rate.
 Young and middle-aged Caucasian patients have a higher probability of
responding to ACE inhibitors
ADRs
 Dry cough
 Angioneurotic edema
 Hyperkalemia
 Altered sense of taste

60. AT1 Receptor Antagonists
MOA
 By antagonizing the effects of AngII, these agents relax smooth muscle and
thereby promote vasodilation, increase renal salt and water excretion, reduce
plasma volume and decrease cellular hypertrophy.
 AngII-receptor antagonists also overcome some of the disadvantages of ACE
inhibitors, as they prevent ACE-mediated degradation of bradykinin and
substance P.
 AT1 Receptor Antagonism↑ renin & AngIIstimulate AT2 receptor anti-
growth and anti-proliferative responses
 ARAs are capable of blocking effects of AngII regardless of any biochemical
pathway for AngII formation
.

61. Adverse Effects and Precautions
 Hypotension, hyperkalemia, and reduced renal function
 Hyperkalemia may occur in conjunction with other factors that alter K+ homeostasis,
such as renal insufficiency, ingestion of excess K+ and the use of drugs that promote K+
retention.
 Cough, an adverse effect of ACE inhibitors, is less frequent with AT1 receptor
antagonists.
 Angioedema
 ACE inhibitors and AT1 receptor antagonists should not be administered during
pregnancy and should be discontinued as soon as pregnancy is detected.
 The combination of an ACE inhibitor and an AT1 receptor antagonist is not
recommended for the treatment of hypertension.

62. Direct Renin Inhibitors
 Aliskiren directly and competitively inhibits the catalytic activity of renin.
(Angiotensinogen AngI)
 Orally effective
 Aliskiren's inhibition of renin leads to diminished production of AngI—and
ultimately AngII and aldosterone—with a resulting fall in blood pressure.
 Aliskiren is poorly absorbed, with a bioavailability of <3%
 Taking the drug with a high-fat meal may substantially decrease plasma
concentrations.
 Aliskiren has an elimination t1/2 of at least 24 hours. Elimination of the drug may
be primarily through hepatobiliary excretion with limited metabolism via
CYP3A4.
 Dose150-300 mg/day
Toxicity and Precautions
 Diarrhea (higher doses)
 Cough (less than found with ACE inhibitors)
 Angioedema
 Not to be used in pregnant women.

63. Vasodilators

64. Hydralazine
 Hydralazine directly relaxes arteriolar smooth muscle by
1.a fall in intracellular calcium concentrations inhibiting IP3-induced release of Ca2+
from intracellular storage sites in arteries leading to diminished contraction.
2.promotes arterial dilation by opening high conductance Ca2+-activated K+ channels
3. NO mediated vasodilatation
 Hydralazine-induced vasodilation is associated with powerful stimulation of the
sympathetic nervous system which results in increased HR and contractility, increased
plasma renin activity and fluid retention; all of these effects tend to counteract the
antihypertensive effect of hydralazine.
 Because of preferential dilation of arterioles over veins, postural hypotension and
impotence are not common problem.

65.  The usual oral dosage of hydralazine is 25-100 mg twice daily
 Hydralazine is well absorbed through the gastrointestinal tract, but the systemic
bioavailability is low (16% in fast acetylators and 35% in slow acetylators).
 Hydralazine is N-acetylated in the bowel and/or the liver.
 t1/2 of hydralazine is 1 hour.
 The acetylated compound is inactive; thus, the dose necessary to produce a systemic effect
is larger in fast acetylators.
 The peak hypotensive effect of the drug occur within 30-120 minutes of ingestion
 Hypotensive effect of hydralazine can last as long as 12 hours.(hydralazine pyruvic acid
hydrazone)

66. Toxicity and Precautions
 Headache, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina
pectoris.
 Immunological reactions  drug-induced lupus syndrome(most common), serum
sickness, hemolytic anemia, vasculitis, and rapidly progressive glomerulonephritis
drug's capacity to promote DNA demethylation may be involved .
 Myocardial ischemia (increased O2 demand induced by the baroreceptor reflex-induced
stimulation of the sympathetic nervous system).
 If the drug is used alone, there may be salt retention with development of high-output
congestive heart failure.
 When combined with a β adrenergic receptor blocker and a diuretic, hydralazine is better
tolerated.

67. KATP Channel Openers: Minoxidil
 Efficacious in patients with the most severe and drug-resistant forms of hypertension.
 MOA
 Minoxidil is metabolized by hepatic sulfotransferase to the active molecule, minoxidil
N-O sulfate.
 Minoxidil sulfate relaxes vascular smooth muscle where the parent drug is inactive.
Minoxidil sulfate activates the ATP-modulated K+ channel. By opening K+ channels in
smooth muscle and thereby permitting K+ efflux, it causes hyperpolarization and
relaxation of smooth muscle.
 Minoxidil produces arteriolar vasodilation with essentially no effect on the capacitance
vessels leads to reflex increase in myocardial contractility and in cardiac output.
 Minoxidil increases blood flow to skin, skeletal muscle, the gastrointestinal tract and the
heart more than to the CNS.
 Minoxidil is well absorbed from the GI tract.
 Although peak concentrations of minoxidil in blood occur 1 hour after oral administration,
the maximal hypotensive effect of the drug occurs later, possibly because formation of the
active metabolite is delayed.

68.  The bulk of the absorbed drug is eliminated by hepatic metabolism; ~20% is excreted
unchanged in the urine.
 The major metabolite of minoxidil is the glucuronide conjugate.
 t1/2 of 3-4 hours, but its duration of action is 24 hours.The persistence of minoxidil in
vascular smooth muscle is responsible for this discrepancy.
Adverse Effects and Precautions
 Retention of salt and water (increased proximal renal tubular reabsorption)
 Increase in heart rate, myocardial contractility and myocardial O2 consumption
myocardial ischemia (baroreceptor reflex-induced stimulation of the sympathetic nervous
system).
 Increased pulmonary artery pressure, pericardial effusion
 Hypertrichosis(consequence of K+ channel activation)
 Rashes, Stevens-Johnson syndrome, glucose intolerance, serosanguineous bullae,
formation of antinuclear antibodies and thrombocytopenia.

69. Sodium Nitroprusside
 Is safe and useful for the short-term control of severe hypertension
 Sodium nitroprusside is effective in improving cardiac function in patients with left
ventricular failure.
MOA
 Nitroprusside is a nitrovasodilator that acts by releasing NO.
 NO increases intacellular cGMP, leading to vasodilation .
 Nitroprusside dilates both arterioles and venules.
 Regional distribution of blood flow is little affected by the drug.
 Unlike minoxidil, hydralazine, diazoxide and other arteriolar vasodilators, sodium
nitroprusside usually causes only a modest increase in heart rate and an overall reduction
in myocardial O2 demand.

70.  Sodium nitroprusside is an unstable molecule that decomposes under strongly alkaline
conditions or when exposed to light.
 Its onset of action is within 30 sec; the peak hypotensive effect occurs within 2 min and
when the infusion of the drug is stopped, the effect disappears within 3 min.
 The metabolism of nitroprusside by smooth muscle is initiated by its reduction, which is
followed by the release of cyanide and then NO.Cyanide is further metabolized by liver
rhodanase to form thiocyanate, which is eliminated almost entirely in the urine.
Uses
 To lower blood pressure during acute aortic dissection
 Improve cardiac output in CHF, especially in hypertensive patients with pulmonary
edema that does not respond to other
 To decrease myocardial oxygen demand after acute MI.
 Nitroprusside is used to induce controlled hypotension during anesthesia in order to
reduce bleeding in surgical procedures.

71. Toxicity and Precautions
 Hypotension due to excessive vasodilation
 Severe lactic acidosis(cyanide) administration of sodium thiosulfate
 Signs and symptoms of thiocyanate toxicity include anorexia, nausea, fatigue,
disorientation and toxic psychosis.(should not be allowed to exceed 0.1 mg/mL).
 Excessive concentrations of thiocyanate may cause hypothyroidism by inhibiting iodine
uptake by the thyroid gland.
 In patients with renal failure, thiocyanate can be removed readily by hemodialysis.
 Nitroprusside can worsen arterial hypoxemia in patients with COPD because the drug
interferes with hypoxic pulmonary vasoconstriction and therefore promotes mismatching
of ventilation with perfusion.

72. stage drug
Uncomplicated stage 1
hypertension
1.Diuretics as preferred initial therapy for most
patients
2.Other drugs:- β receptor antagonists, ACE
inhibitors/AT1-receptor antagonists, and Ca2+
channel blockers.
Uncomplicated stage 2
hypertension
2 drug therapy:- early introduction of a diuretic
and another drug from a different class.
Isolated systolic hypertension Diuretics ,Ca2+ channel blockers and ACE
inhibitors.

73. Newer drugs
 Moxonidine and rilmenidine
 newer congeners of clonidine
 Longer t1/2
 Rebound hypertension much less
 FK-453investigational K+-sparing diuretics

74. Thank you

76. Factors effecting CO

77. Factors affecting activity of the Vasomotor area of medulla

78. Factors Affecting Heart Rate