Hypertension PPT.pptx

Anti hypertensive agents
Antihypertensive agents are a class of drugs that are used to treat
hypertension.
Hypertension is a consequence of many diseases. Diseases which relate to
the central and peripheral nervous systems which regulate blood pressure
and abnormalities of the hormonal system and diseases of the kidney and
peripheral vascular network, which affect blood volume which can create a
hypertensive state in humans.
Hypertension are classified as :

Classification of Antihypertensive drugs
1. Adrenergic receptors antagonist : Timolol
2. Angiotensin converting enzyme Inhibitors ( ACE – INHIBITORS) -
Captopril , Lisinopril, Enalapril, Benazepril, Quinapril.
3. Centrally acting adrenergic drugs : Methyl dopa, Clonidine hydrochloride,
Guanabenz acetate.
4. Vasodilators : Sodium nitroprusside, Hydralazine hydrochloride, Diazoxide,
Minoxidil
5. Adrenergic neuron blocking agents : Guanethidine, reserpine]
6. Diuretics : Furosemide, Thiazides
7. Calcium channel Blockers : Amlodipine, Felodipine, Verapamil

Adrenergic receptors antagonist ( β – Blockers)
Beta –blockers are the most widely employed antihypertenives and the
treatment of Glaucoma.
Aryl oxy propyl amines.
Timolol :
CC(C)(C)NCC(COC1=NSN=C1N2CCOCC2)O
GI absorption High
BBB permeant No
P-gp substrate Yes
CYP1A2 inhibitor No
CYP2C19 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
CYP3A4 inhibitor No
Log Kp (skin
permeation)
-8.24 cm/s

Mechanism of action : It competes with adrenergic neurotransmitters such as
catecholamines for binding at Beta – 1 adrenergic receptors in the heart and vascular
smooth muscle and Beta -2 receptors in the bronchial and vascular smooth muscles.
Beta-2 Adrenergic Receptors (B2ARs) are a type of G Protein-Coupled Receptor
(GPCR). GPCRs are the largest family of integral membrane proteins in the human
body with over 1000 unique Isoforms. B2AR is activated by hormone ligands like
adrenaline (epinephrine) and noradrenaline and plays a critical role in cardiovascular
and pulmonary physiology. Binding of adrenaline by B2AR causes a sympathetic
nervous system response like the well-known “fight or flight response”, resulting in an
increased heart rate, pupil dilation, rapid energy mobilization and diversion of blood
to skeletal muscle. More precisely, upon binding a ligand, B2AR activates Adenylyl
cyclase through interaction with B2ARs C-terminus. Adenylyl cyclase subsequently
converts ATP into cAMP, which functions as a downstream signaling molecule
activating effectors like cAMP-dependent protein kinases, resulting in various bodily
responses.[
Uses : It is in oral form it is used to treat
hypertension

Angiotensin Converting Enzyme inhibitors ( ACE inhibitors)

RENIN ANGIOTENSIN ALDOSTERONE SYSTEM
Several pathophysiologic factors are involved in the relationship between HTN and
the other components of the CMS, including inappropriate activation of the renin
angiotensin aldosterone system (RAAS), oxidative stress, and inflammation.
The renin – angiotensin system is a hormonal system that plays a central role in the control of
sodium excretion and body fluid volume.
It interacts closely with the sympathetic nervous system and aldosterone secretion in the
regulation of the Blood pressure.
1. Renin is an aspartyl Protease cleaves the Leu –Val bond from the aspartic acid end of the
angiotensinogen polypetide molecule to release the decapeptide angiotensin –I.
2. The cleavage of dipeptide from the carboxy terminal of angiotensin –I by angiotensin
Converting enzyme to form octa peptide angiotensin –II.
3. Angiotensin –II is a potent vasoconstrictor that increases peripheral resistance through a
variety of mechanisms.
4. Angiotensin –II causes a slow pressor response resulting in long –term stabilization of arterial
Blood pressure.
5. This long term effect is accomplished by the regulation of renal function.
6. Angiotensin –II increases sodium reabsorption in the proximal tubule.
7. It also alters renal hemodynamics and causes the release of aldosterone from the adrenal
cortex.
8. Angitensin –III is formed by removal of the N –terminal aspartate residue of the angiotensin –
II, a reaction catalyzed by glutamyl amino peptidase.

Renin Angiotensin system of blood Pressure control

Renin, also known as angiotensinogenase, is an aspartyl protease and belongs
to the protein family peptidase A1. Aspartyl proteases are endopeptidases that
typically use two aspartate residues in the active site to specifically cleave peptide
substrates using an acid-base hydrolysis mechanism. Mature renin circulates in
the blood stream and contains 340 amino acid residues and has a mass of
approximately 37 kDa. The function of renin is to cleave angiotensinogen to
produce angiotensin I.
Factor XII – coagulation
factor

The regulation action of the RAAS system is controlling sodium and
potassium balance and arterial blood pressure is modified by vasodilators
called kinins.
Callidin which is converted to bradykinin is activated in plasma by
noxious influences to act on a kinin, callidin which is converted to
bradykinin by tissue enzymes.

ACE inhibitors :
These compounds can be sub –classified in to three groups based on their
chemical composition.
1.Sulfhydryl – containing inhibitors : Captopril
2. Dicarboxylate containing Inhibitors : Enalapril, lisinopri;,Benazepril.
3.Phosphonate containing inhibitors : Fosinopril
SAR of ACE inhibitors :
1. The N-ring must contain a carboxylic acid to mimic the C-terminal
carboxylate of ACE substrates.
2. Large hydrophobic heterocyclic rings ( The N- ring) increase the
potency and alter the Pharmacokinetic properties.
3. The zinc binding groups can be either sulfhydryl (A), carboxylic acid
(B) or a Phosphinic acid ( C).
4. Sulfhydryl containing compounds produce high incidence of skin rash
and taste disturbances.
5. Sulfhydryl – containing compounds to form dimers and disulfides
which may shorten duration of action.

7. Compounds that bind to zinc through either a carboxylate or Phosphine
mimic the peptide hydrolysis transition state and enhance binding.
8. Esterification of the carboxylate or phosphine produces an norally
bioavailable pro drug.
9. X is usually methyl to mimic the side chain of alanine. With in the
dicarboxylate series , when X equals n- butyl amine this produces a compound
that does not require prodrug for oral activity.
10.Optimum activity occurs when stereochemistry of inhibitor is consistent with
L- amino acid sterochemistry present in normal substances.
MOA : The ACE inhibitors attenuate the effects of the renin angiotensin system
by inhibiting the conversion of angiotensin –I to Angiotensin –II. They also
inhibit the conversion of stimulate prostaglandin biosynthesis..

Sulfhydryl – containing inhibitors :
(2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid
Captopril is a potent, competitive inhibitor of angiotensin-converting enzyme
(ACE), the enzyme responsible for the conversion of angiotensin I (ATI) to
angiotensin II (ATII). ATII regulates blood pressure and is a key component of
the renin-angiotensin-aldosterone system (RAAS). Captopril may be used in
the treatment of hypertension.

Pharmacodynamics
Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic
mechanism for regulating hemodynamics, water and electrolyte balance. During
sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is
released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the
blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently
cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms.
First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels
to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases
sodium and water reabsorption by increasing the number of sodium channels and sodium-
potassium ATPases on cell membranes. Second, ATII stimulates the secretion of
vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland.
ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2
channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII
increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1
ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in
myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces
the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid
conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE
(also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a
vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may
sustain its effects by causing increased vasodilation and decreased blood pressure.

GI absorption High
BBB permeant No
P-gp substrate No
CYP1A2 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
CYP3A4 inhibitor No
Log Kp (skin permeation) -7.38 cm/s

Uses : For the treatment of essential or reno vascular hypertension.
Adverse effects : Skin rashes, and taste disturbances..
SAR of ACE inhibitors :
1. The N- ring must contain a carboxylic acid to mimic the C-terminal carboxylate of ACE susbstrates.
2. The zinc binding groups can be either sulhydryl (A). A carboxylic acid (B) or a phosphinic acid (C).
3. The sulfhydryl group shows superior binding to zinc (the side chain mimicking the Phe in carboxylate
and phosphinic acid compounds partially compensates for the lack of a sulfhydryl group).
4. Sulfhydryl – containing compounds produce high incidence of skin rash and taste disturbances.
5. Sulfhydryl – containing compounds can form dimers and disulfides which may shorten duration of
action.
6. Compounds that bind to zinc through either a carboxylate or phosphinate mimic the peptide hydrolysis
transition state and enhances binding.
7. Esterification of the carboxylate or phosphinate produces an orally bioavailable prodrug.
8. X is usually methyl to mimic the side chain of alanine.
9. Optimum activity occurs when stereochemistry of inhibitor is consistent with L- amino acid
stereochemistry present in normal substrates.

Enalapril
O
C
H3
O
NH
N
O
O
H
O
OC(=O)C1CCCN1C(=O)CNC(CC(=O)OCC)CCc1ccccc1
1-{2-[(1-ethoxy-1-oxo-5-phenylpentan-3-
yl)amino]acetyl}pyrrolidine-2-carboxylic acid
GI absorption High
BBB permeant No
P-gp substrate Yes
CYP1A2 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
CYP3A4 inhibitor No

MOA : It is a long acting ACE inhibitor. It requires activation by hydrolysis of its
ethyl ester to form the diacid enalaprilat.
Uses : It is used as an renovascular hypertension and symptomatic congestive
heart failure.
Adv effects : Hypotension,headache, dizziness and fatigue.
Lisinopril
OC(=O)C1CCCN1C(=O)C(CCCCN)NC(CCc1ccccc1)C(=O)O

Formula C21H31N3O5
Molecular
weight
405.49 g/mol
Num. heavy
atoms
29
Num. arom.
heavy atoms
6
Fraction Csp3 0.57
Num. rotatable
bonds
13
Num. H-bond
acceptors
7
Num. H-bond
donors
4
Molar
Refractivity
112.66
TPSA 132.96 Å²
GI absorption High
BBB permeant No
P-gp substrate Yes
CYP1A2 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
CYP3A4 inhibitor No
Log Kp (skin
permeation)
-10.80 cm/s

Uses : For the treatment of hypertension and symptomatic congestive heart
failure.
Benazepril Hydrochloride
[H][C@@]1(CCC2=CC=CC=C2N(CC(O)=O)C1=O)N[C@@H](CCC1=CC=CC=C1)C(=O)
OCC
2-[(3S)-3-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}-
2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid
InChI=1S/C24H28N2O5/c1-2-31-24(30)20(14-12-17-8-4-3-5-9-17)25-19-15-13-18-10-6-
7-11-21(18)26(23(19)29)16-22(27)28/h3-11,19-20,25H,2,12-16H2,1H3,(H,27,28)/t19-
,20-/m0/s1

Renin
Formula C24H28N2O5
Molecular weight 424.49 g/mol
Num. heavy atoms 31
Num. arom. heavy
atoms
12
Fraction Csp3 0.38
Num. rotatable bonds 10
Num. H-bond
acceptors
6
Num. H-bond donors 2
Molar Refractivity 120.24
TPSA 95.94 Å²

GI absorption High
BBB permeant No
P-gp substrate Yes
CYP1A2 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor Yes
CYP3A4 inhibitor Yes
Benazepril ADME
Uses : For the treatment of hypertension.
Adv.effects : Headache, dizziness, fatigue, postural dizziness, nausea and cough.

Quinapril Hydrochloride
(3S)-2-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-
phenylbutan-2-yl]amino}propanoyl]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@@H](
C)C(=O)N1CC2=CC=CC=C2C[C@H]1C(O)=O

Formula C25H30N2O5
Num. heavy atoms 32
Num. arom. heavy
atoms
12
Fraction Csp3 0.40
Num. rotatable
bonds
11
Num. H-bond
acceptors
6
Num. H-bond
donors
2
TPSA 95.94 Å²
MOA : Quinaprilat the principle active metabolite of quinapril competes with AT1
for binding to ACE and inhibits and enzymatic proteolysis of AT1 to AT2.
Decreasing AT2 levels in the body decreases blood pressire by inhibiting the
presence effects of AT2.

PAINS 0 alert
Brenk 0 alert
Leadlikeness
No; 2 violations:
MW>350, Rotors>7
Synthetic
accessibility
GI absorption High
BBB permeant No
P-gp substrate Yes
CYP1A2 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
Log Kp (skin
permeation)
-8.09 cm/s
Pan-assay interference
compounds (PAINS)
Uses : For the treatment of
hypertension and as an adjunct
therapy in the treatment of
congestive heart failure.
Adv.effects : Dizziness, cough,
chest pain, dyspnea, nausea and
vomiting

Dicarboxylate – containing inhibitors
The phosphinic acid is capable of binding to ACE in a manner similar to enalapril.
The interaction of the zinc atom with the phosphinic acid with sulfhydryl and
carboxylate groups
Fosinopril:
Fosinopril is a phosphinic acid-containing ester prodrug that belongs to the
angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly
hydrolyzed to fosinoprilat, its principle active metabolite. Fosinoprilat inhibits
ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to
angiotensin II (ATII). ATII regulates blood pressure and is a key component of the
renin-angiotensin-aldosterone system (RAAS). Fosinopril may be used to treat
mild to moderate hypertension, as an adjunct in the treatment of congestive
heart failure, and to slow the rate of progression of renal disease in hypertensive
individuals with diabetes mellitus and microalbuminuria or overt nephropathy.

Fosinopril is an ester prodrug that hydrolyzes in the liver to fosinoprilat, the
active metabolite form. Fosinoprilat then uses competitive inhibition to bind to ACE
resulting in decreased formation of angiotensin II, reduced aldosterone
concentrations, and diminished systemic vasoconstriction.
Formula C30H46NO7P
Molecular
weight
563.66 g/mol
Num. heavy
atoms
39
Num. arom.
heavy atoms
6
Fraction Csp3 0.70
Num. rotatable
bonds
16
Num. H-bond
acceptors
7
Num. H-bond
donors
1
Molar
Refractivity
157.56
TPSA 120.02 Å²

GI absorption Low
BBB permeant No
P-gp substrate Yes
CYP1A2 inhibitor No
CYP2C9 inhibitor Yes
CYP2D6 inhibitor No
Log Kp (skin
permeation)
-5.31 cm/s
Uses : For treating mild to moderate hypertension.

Centrally Acting adrenergic drugs
The use of agents that directly affect the peripheral component of the
sympathetic nervous system represents to the treatment of hypertension.
The second approach to modifying sympathetic influence on the
cardiovascular system is through inhibition of reduction of CNS control of
blood pressure.
Methyl dopate hydrochloride. (2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-
methylpropanoic acid
C[C@](N)(CC1=CC=C(O)C(O)=C1)C(O)=O

MOA : Methyl dopa on coonversion to alpha – methyl nor adrenaline which
acts on α2- adrenergic receptors to inhibit the release of nor adrenaline,
resulting in decreased sympathetic outflow from the CNS and activation of
parasympathetic out flow.
ADME :
Formula C10H13NO4
Num. heavy atoms 15
Num. arom. heavy
atoms
6
Fraction Csp3 0.30
Num. rotatable bonds 3
Num. H-bond acceptors 5
Num. H-bond donors 4
TPSA 103.78 Å²

GI absorption High
BBB permeant No
P-gp substrate No
CYP1A2 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
CYP3A4 inhibitor No
Log Kp (skin
permeation)
-9.19 cm/s
Uses : Management of moderate to
severe hypertension.
Adv.effects : 48 -72 hrs therapy and
can dissapear with continued
administration of the drug.

Adr effects : Drowsiness, sedation, orthostatic hypotension, Mental
depression, Night mares.
Guanabenz acetate
2,6 dichlorobenzylidene) amino) guanidine
monoacetate.

Guanabenz's antihypertensive effect is thought to be due to central alpha-
adrenergic stimulation, which results in a decreased sympathetic outflow to the
heart, kidneys, and peripheral vasculature in addition to a decreased systolic and
diastolic blood pressure and a slight slowing of pulse rate. Chronic administration
of guanabenz also causes a decrease in peripheral vascular resistance.

ADME :
Water solubility -1.818 Numeric (log mol/L)
Absorption Caco2 permeability 0.722 Numeric (log Papp in 10
-6
cm/s)
Absorption Intestinal absorption (human) 89.803 Numeric (% Absorbed)
Absorption Skin Permeability -2.815 Numeric (log Kp)
Absorption P-glycoprotein substrate No Categorical (Yes/No)
Absorption P-glycoprotein I inhibitor No Categorical (Yes/No)
Absorption P-glycoprotein II inhibitor No Categorical (Yes/No)

Distribution VDss (human) 1.084 Numeric (log L/kg)
Distribution Fraction unbound
(human)
0.543 Numeric (Fu)
Distribution BBB permeability -0.561 Numeric (log BB)
Distribution CNS permeability -2.893 Numeric (log PS)
Metabolism CYP2D6 substrate No Categorical (Yes/No)
Metabolism CYP3A4 substrate No Categorical (Yes/No)
Metabolism CYP1A2 inhibitior Yes Categorical (Yes/No)
Metabolism CYP2C19 inhibitior No Categorical (Yes/No)
Metabolism CYP2D6 inhibitior Yes Categorical (Yes/No)
Metabolism CYP3A4 inhibitior No Categorical (Yes/No)

Excretion Total Clearance 0.247 Numeric (log ml/min/kg)
Excretion Renal OCT2 substrate Yes Categorical (Yes/No)
Toxicity AMES toxicity Yes Categorical (Yes/No)
Toxicity Max. tolerated dose (human) 0.316 Numeric (log mg/kg/day)
Toxicity hERG I inhibitor No Categorical (Yes/No)
Toxicity hERG II inhibitor No Categorical (Yes/No)
Toxicity Oral Rat Acute Toxicity (LD50) 3.038 Numeric (mol/kg)
Toxicity Oral Rat Chronic Toxicity (LOAEL) 1.283 Numeric (log mg/kg_bw/day)
Toxicity Hepatotoxicity No Categorical (Yes/No)
Toxicity Skin Sensitisation Yes Categorical (Yes/No)
Toxicity T.Pyriformis toxicity 0.684 Numeric (log ug/L)
Toxicity Minnow toxicity 1.442 Numeric (log mM)

Pharmacodynamics
Guanabenz, a centrally acting α-2 adrenergic agonist, is indicated for treatment of hypertension.
Adverse effects : Clonidine
Vasodilators : Vasodilators drugs relax the smooth muscle in blood vessels which
causes the vessels to dilate. Dilation of arterial vessels leads to a reduction in
systemic vascular resistance which leads to a fall in arterial blood pressure.
Draw backs of use of vasodilators : 1. Vasodilators can lead to a baro-receptor
mediated reflex stimulation of the heart from systemic vasodilation and arterial
pressure reduction.
2.They can impair the normal baro –receptor mediated reflex vasoconstriction
when a person stands up which can lead to orthostatic hypotension and syncope
on standing.
3. They can lead to renal retention of sodium and water increasing blood volume
and cardiac output.

Antihypertensive agents that produce vasodilation of smooth muscle can be divided
in to two categories :
1. Direct acting : Hydralazine hydrochloride, sodium nitroprusside, potassium
channel openers, calcium channel – blocking agents.
2. Indirect acting : Reserpine, alpha – adrenergic antagonists – Prazosin
hydrochloride, ACE inhibitors and angiotensin –II receptor antagonists such as
saralysin.
Sodium Nitroprusside
O=N[Fe--](C#N)(C#N)(C#N)(C#N)C#N Nitroprusside a powerful vasodilator relaxes the
vascular smooth muscle and produce consequent
dilatation of peripheral arteries and veins. Other
smooth muscle (e.g., uterus, duodenum) is not
affected. Sodium nitroprusside is more active on
veins than on arteries.

One molecule of sodium nitroprusside is metabolized by combination with
hemoglobin to produce one molecule of cyanmethemoglobin and four CN- ions;
methemoglobin, obtained from hemoglobin, can sequester cyanide as
cyanmethemoglobin; thiosulfate reacts with cyanide to produce thiocyanate;
thiocyanate is eliminated in the urine; cyanide not otherwise removed binds to
cytochromes. Cyanide ion is normally found in serum; it is derived from dietary
substrates and from tobacco smoke. Cyanide binds avidly (but reversibly) to ferric
ion (Fe+++), most body stores of which are found in erythrocyte methemoglobin
(metHgb) and in mitochondrial cytochromes. When CN is infused or generated
within the bloodstream, essentially all of it is bound to methemoglobin until
intraerythrocytic methemoglobin has been saturated.
Sodium nitroprusside is further broken down in the circulation to release nitric
oxide (NO), which activates guanylate cyclase in the vascular smooth muscle.
This leads to increased production of intracellular cGMP, which stimulates calcium
ion movement from the cytoplasm to the endoplasmic reticulum, reducing the level
of available calcium ions that can bind to calmodulin. This ultimately results in
vascular smooth muscle relaxation and vessel dilation.

Absorption Caco2 permeability 0.056 Numeric (log Papp in 10
-
6
cm/s)
Absorption Intestinal absorption
(human)
78.855 Numeric (% Absorbed)
Absorption P-glycoprotein substrate Yes Categorical (Yes/No)

VDss (human) -0.604 Numeric (log L/kg)
(human)
0.669 Numeric (Fu)
Distribution VDss (human) -0.604 Numeric (log L/kg)
(human)
0.669 Numeric (Fu)

Metabolism CYP2D6 inhibitior No Categorical (Yes/No)

Excretion Renal OCT2 substrate No Categorical (Yes/No)
Toxicity AMES toxicity No Categorical (Yes/No)
Toxicity Oral Rat Chronic Toxicity (LOAEL) 0.346 Numeric (log
mg/kg_bw/day)
Toxicity Hepatotoxicity No Categorical (Yes/No)
Toxicity Skin Sensitisation No Categorical (Yes/No)

Uses : Reduction of BP of Hypertension, reduce bleeding and the treatment of
congestive failure.
ADV effects : Not available
Uses : Profound hypotension.

Hydralazine Hydrochloride
1-hydrazinophthalazine monohydrochloride
Hydralazine may interfere with calcium transport in vascular smooth muscle by an
unknown mechanism to relax arteriolar smooth muscle and lower blood pressure. The
interference with calcium transport may be by preventing influx of calcium into cells,
preventing calcium release from intracellular compartments, directly acting on actin and
myosin, or a combination of these actions. This decrease in vascular resistance leads to
increased heart rate, stroke volume, and cardiac output.
Hydralazine also competes with protocollagen prolyl hydroxylase (CPH) for free
iron. This competition inhibits CPH mediated hydroxylation of HIF-1α, preventing the
degradation of HIF-1α. Induction of HIF-1α and VEGF promote proliferation of
endothelial cells and angiogenesis.

Membrane primary amine oxidase
Hydralazine may interfere with calcium transport in vascular smooth muscle by an
unknown mechanism to relax arteriolar smooth muscle and lower blood pressure. The
interference with calcium transport may be by preventing influx of calcium into cells,
preventing calcium release from intracellular compartments, directly acting on actin and
myosin, or a combination of these actions. This decrease in vascular resistance leads to
increased heart rate, stroke volume, and cardiac output.
Hydralazine also competes with protocollagen prolyl hydroxylase (CPH) for free iron. This
competition inhibits CPH mediated hydroxylation of HIF-1α, preventing the degradation of
HIF-1α.12 Induction of HIF-1α and VEGF promote proliferation of endothelial cells and
angiogenesis.

Absorption Caco2 permeability 1.394 Numeric (log Papp in 10-6 cm/s)
Distribution VDss (human) -0.224 Numeric (log L/kg)
Distribution Fraction unbound (human) 0.313 Numeric (Fu)
Toxicity AMES toxicity Yes Categorical (Yes/No)

Uses : Treatment of essential Hypertension.
Adv.effects : Faintness, dizziness or weakness.
Potassium Channel opener
Minoxidil
2,4 –diamino -6-Piperidino pyrimidine -3-oxide
Minoxidil is thought to promote the survival of human dermal papillary cells (DPCs) or hair cells by
activating both extracellular signal-regulated kinase (ERK) and Akt and by preventing cell death by
increasing the ratio of BCl-2/Bax. Minoxidil may stimulate the growth of human hairs by prolonging
anagen through these proliferative and anti-apoptotic effects on DPCs. Minoxidil, when used as a
vasodilator, acts by opening adenosine triphosphate-sensitive potassium channels in vascular smooth
muscle cells. This vasodilation may also improve the viability of hair cells or hair follicles.

ATP-sensitive inward rectifier potassium channel 1
Minoxidil is thought to promote the survival of human dermal papillary cells (DPCs) or hair
cells by activating both extracellular signal-regulated kinase (ERK) and Akt and by preventing
cell death by increasing the ratio of BCl-2/Bax. Minoxidil may stimulate the growth of human
hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs.
Minoxidil, when used as a vasodilator, acts by opening adenosine triphosphate-sensitive
potassium channels in vascular smooth muscle cells. This vasodilation may also improve the
viability of hair cells or hair follicles.

Absorption Caco2 permeability -0.064 Numeric (log Papp in 10-6 cm/s)
DistributionVDss (human) 0.105 Numeric (log L/kg)
DistributionFraction unbound (human) 0.866 Numeric (Fu)
DistributionBBB permeability -0.331 Numeric (log BB)
DistributionCNS permeability -3.058 Numeric (log PS)
Toxicity AMES toxicity No Categorical (Yes/No)
Toxicity Oral Rat Chronic Toxicity (LOAEL) 0.69 Numeric (log mg/kg_bw/day)
Toxicity Hepatotoxicity Yes Categorical (Yes/No)
Toxicity Skin Sensitisation No Categorical (Yes/No)

Uses : Treatment of severe hypertension and in the topical treatment of
androgenic alopecia.
Adv.effects : Sudden weight gain, rapid –heart beat, faintness or dizziness.
Diazoxide :
7-chloro -3- methyl -2H – 1,2,4 benzothiadiazine -1,1 dioxide.
Diazoxide is a non diuretic benzothiadiazine indicated for the management of
hypoglycemia in patients who produce an excess of insulin caused by a variety of
conditions.
Diazoxide inhibits insulin release from the pancreas, by opening potassium channels in
the beta cell membrane. Diazoxide is chemically related to thiazide diuretics but does
not inhibit carbonic anhydrase and does not have chloriuretic or natriuretic activity.
It also exhibits hypotensive activity by reducing arteriolar smooth muscle and vascular
resistance

ATP-sensitive inward rectifier potassium channel 1
Diazoxide inhibits insulin release from the pancreas, by opening potassium channels in the
beta cell membrane. Diazoxide is chemically related to thiazide diuretics but does not inhibit
carbonic anhydrase and does not have chloriuretic or natriuretic activity. It also exhibits
hypotensive activity by reducing arteriolar smooth muscle and vascular resistance.
Carbonic anhydrase
GI absorption High
BBB permeant Yes
P-gp substrate No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
CYP3A4 inhibitor No
Uses : Treat Hypertensive
emergencies

Adrenergic neuron blocking agents

1.Depleting the stores of the neurotransmitter.
2.Reducing the number of impulses travelling the symapthetic nerves.
3. Anatgonzing the actions of the neurotransmitter on the effector cells.
4. Inhibiting neurotransmitter release.
Guanethidine monosulphate
2-hexahydro-1-2H-azocinylethyl guanidine sulfate

Guanethidine acts at the sympathetic neuro effector junction by inhibiting or interfering with
the release and/or distribution of norepinephrine (NE), rather than acting at the effector cell by
inhibiting the association of norepinephrine with its receptors. It is taken up by norepinephrine
transporters to be concentrated within the transmitter vesicles in place of NE, leading to
gradual depletion of NE stores in the nerve endings. Guanethidine at the nerve terminal
blocks the release of noradrenaline in response to an action potential. In contrast to
ganglionic blocking agents, Guanethidine suppresses equally the responses mediated by
alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since
sympathetic blockade results in modest decreases in peripheral resistance and cardiac
output, Guanethidine lowers blood pressure in the supine position. It further reduces blood
pressure by decreasing the degree of vasoconstriction that normally results from reflex
sympathetic nervous activity upon assumption of the upright posture, thus reducing venous
return and cardiac output more.
Sodium-dependent noradrenaline transporter

GI absorption High
BBB permeant No
P-gp substrate No
CYP1A2 inhibitor No
CYP2C9 inhibitor No
CYP2D6 inhibitor No
CYP3A4 inhibitor No
Uses : Guanethidine is used in the management of moderate to severe
hypertension.
Adv.effects : Dizziness, waekness and post –exercise hypotesnion.

Reserpine
Serpasil
An alkaloid found in the roots of Rauwolfia serpentina and R. vomitoria. Reserpine inhibits the uptake of
norepinephrine into storage vesicles resulting in depletion of catecholamines and serotonin from central
and peripheral axon terminals. It has been used as an antihypertensive and an antipsychotic as well as
a research tool, but its adverse effects limit its clinical use.
Reserpine's mechanism of action is through inhibition of the ATP/Mg2+ pump responsible for the
sequestering of neurotransmitters into storage vesicles located in the presynaptic neuron. The
neurotransmitters that are not sequestered in the storage vesicle are readily metabolized by
monoamine oxidase (MAO) causing a reduction in catecholamines.

Reserpine's mechanism of action is through inhibition of the ATP/Mg2+ pump responsible for the
sequestering of neurotransmitters into storage vesicles located in the presynaptic neuron. The
neurotransmitters that are not sequestered in the storage vesicle are readily metabolized by
monoamine oxidase (MAO) causing a reduction in catecholamines.
Uses : Mild to moderate hypertension
Synaptic vascular amine transporter

Hypertension PPT.pptx

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Hypertension PPT.pptx