Antihypertensives

pharmacology

1. DRUG TREATMENT
OF
HYPERTENSION

2. HYPERTENSION
Hypertension can be
defined as the level of
blood pressure at which
there is risk to the organs
or vasculature.
Diagnosed on repeated &
reproducible
measurements of elevated
blood pressure.

3. A sustained increase in
blood pressure More
than or equal to 140/90
mm Hg.

4. HYPERTENSION
Category Systolic (mmHg) Diastolic (mm Hg)
optimal <120 < 80
normal < 130 < 85
high-normal
Hypertension
stage 1
stage 2
stage 3
130-139 85-89
140-159 90-99
160-179 100-109
> 180_ >110_

5. PRIMARY HYPERTENSION
The cause is unknown.
 Also referred to as Essential Hypertension
Includes approximately 90% of cases.

6. SECONDARY HYPERTENSION
The cause is known
Renal
Endocrine
Anatomic disorders
etc.
Includes approximately 10% of cases

7. Blood Pressure Regulation

8. BP= CO X TPR
CO= SV X HR
BP= SV X HR X TPR

11. BLOOD VESSELS CONTROLLING BLOOD PRESSURE
The major blood vessels controlling blood pressure are referred to
as

The Resistance vessels
The Capacitance vessels

12. RESISTANCE VESSELS
Arterioles are the primary resistance vessels,
Control mean arterial blood pressure
&
blood flow to specific tissues.
Vascular smooth muscle tone in these vessels is
controlled by the sympathetic nervous system
and local factors (metabolic need)

13. CAPACITANCE VESSELS
 Systemic venules and veins serve as a volume
reservoir for the circulatory system (approx.
50% of total blood volume is contained in
these vessels)
 Sympathetic and humoral regulation of these
vessels can significantly alter venous return
(preload) and fluid exchange in the
associated capillary beds

14. Blood pressure is closely regulated on
Short-term (seconds-to-minutes)
Long-term (days-to-weeks) basis
Mean arterial pressure is monitored by
Baroreceptors primarily in the aortic arch and carotid artery

15. SHORT-TERM REGULATION
Short-term changes in blood pressure are
mediated by the autonomic nervous
system

16. Changes in mean arterial pressure
are sensed by the baroreceptors and
processed by the vasomotor centers
in the medulla which differentially
regulate sympathetic and
parasympathetic nervous system
output.

17. If a drop in blood pressure is seen
by the baroreceptors, neuronal
activity to the vasomotor centers
is decreased, resulting in an
increase in sympathetic tone and
a decrease in parasympathetic
(vagal) tone.

18. A rise in mean arterial pressure
causes an increase in
baroreceptor neuronal activity
and gives rise to an increase in
vagal tone (activity of the vagus
nerve) and a decrease in
sympathetic tone.

19. 1.Increases in vagal tone lead to
lowering of heart rate.
2.Increases in sympathetic tone
result in increased peripheral
vascular resistance, increased
venous tone, increased heart rate,
and increased contractility of the
myocardium

20. LONG-TERM REGULATION
Long-term changes in blood pressure
(hours to days) are primarily mediated
by humoral factors that control blood
volume by regulating Na+ and water
retention.

21. Changes in renal blood flow and pressure, which are directly related to
mean arterial pressure, result in changes in renin secretion.
A drop in renal blood flow or pressure results in an increase in renin release
from the kidney.
High sympathetic outflow also causes an increase in renin secretion

22. 1.An increase in renin release leads to an increase in circulating angiotensin II.
2. The primary actions of angiotensin II are:
a)To stimulate the synthesis and secretion of aldosterone.
b)To raise blood pressure by direct vasoconstrictor effects (angiotensin II is one of
the most potent vasoconstrictors known).
c)Aldosterone acts on the kidney to retain Na+ (and therefore water), leading to an
increase in blood volume

23. BLOOD PRESSURE REGULATION
Renin-angiotensin system

24. In hypertensive patients,
the baroreceptors & renal
blood volume-pressure control
systems appear to be “set” at
a higher level of blood
pressure.

25. WHY TO TREAT HYPERTENSION ?

28. Hypertension - Clinical Significance
1. Heart disease
2. Stroke
3. Kidney failure
4. Blindness
Effects usually are not apparent until after 10 or more years of
sustained high blood pressure.

29. TREATMENT STRATEGIES
A.Lifestyle Modifications
low fat diet rich in vegetables and fruit
reduction of excess body weight
limited alcohol consumption
daily aerobic exercise
smoking cessation
reduction of sodium intake
B. Drug Therapy

30. C. Additional Risk factors for cardiovascular disease
smoking
dyslipidemia
diabetes mellitus
age older than 60
sex (men and postmenopausal women)
family history of cardiovascular disease

31. TREATMENT STRATEGIES
Risk Group A
No risk factors
No cardiovascular disease
No Target organ damage
Risk Group B
At least one risk factor not including diabetes mellitus
No cardiovascular disease
No target organ damage
Risk Group C
Cardiovascular disease
Target organ damage
Diabetes mellitus

32. TREATMENT STRATEGY
Blood PressureRisk group ARisk group BRisk group C
High-normal
Stage 1
Stage 2
lifestyle
modification
lifestyle
modification
lifestyle
modification
lifestyle
modification
lifestyle
modification
(up to 6 months)
drug therapydrug therapy
drug therapy
drug therapy
(140-159/90-99)
(130-139/85-89)
(160-179/100-109)

33.  CLASSIFICATION

34. A- Anti-Adrenergics
or
Sympathoplegics

35. 1- ALPHA-ADRENERGIC
BLOCKERS
a- Selective Alpha-1 Blockers
Prazocin
Doxazocin
Terazocin
Tamsuluson
b-Non-Selective Alpha Blockers
Phentolamine
Phenoxybenzamine

36. 2- BETA-ADRENERGIC BLOCKERS
a-Cardio-selective Beta-Blockers
Atenolol
Acebutolol
Metoprolol
b-Cardio-Nonselective Beta-Blockers
Propranolol
Nadolol
Timolol

37. 3- ALPHA & BETA
-ADRENERGIC BLOCKERS
Carvidilol
Labetolol

38. 4- CENTRALLY ACTING
SYMPATHOPLEGICS OR
ALPHA-2 AGONISTS
Alpha-methyldopa
Clonidine
Guanabenz
Guanfacine

39. 5- ADRENERGIC NEURON
BLOCKERS
Guanethidine
Guanadrel
Reserpine

40. 6-GANGLION BLOCKERS
Hexamethonium
Trimetaphan
Mecamylamine
Pempidine

41. 
B- Diuretics
1-Thiazide diuretics1-Thiazide diuretics
2-Loop diuretics2-Loop diuretics
3-Potassium sparing 3-Potassium sparing
diureticsdiuretics

42. C- Angiotensin Antagonists
1-ACE inhibitors1-ACE inhibitors
•CaptoprilCaptopril
•LisinoprilLisinopril
•Analapril Analapril
2-Angiotensin receptor blockers2-Angiotensin receptor blockers
•LosartanLosartan
•ValsartanValsartan
•saralasinsaralasin

43. D- VASODILATORS

44. 1-DIRECT VASODILATORS
a- Arteriolar dilators
Hydralazine
Minoxidil
Diazoxide
Fenoldopam
b-venodilators
Nitrates
Nitrites
c- Both Arteriolar & veno-dilators
Sodium Nitroprusside

45. 2-CALCIM CHANNEL BLOCKERS
Niedipine
Amlodipine
Verapamil
Diltiazem

46. 3- MISCELLANEOUS
1-ACE inhibitors
 2-Angiotensin receptor blockers
3-Alpha-Adrenergic Blockers
4-adrenergic neuron blockers
5-Ganglion blockers

48. 1. DECREASE BLOOD VOLUME
Diuretics

49. 2. DECREASE HEART RATE &
FORCE
β-blockers

50. 3. DECREASE TPR
a. Vasodilators
Direct Vasodilators
Minoxidil
Hydralazine
Indirect Vasodilators
Calcium channel blockers
ACEI
AT Blockers

51. 3. DECREASE TPR
b. Decrease sympathetic tone
Central sympathoplegics
Ganglion Blockers
Adrenergic neuron blockers
Receptor blockers
Alpha blockers
Beta blockers

52. BP = CO X PVR
CCB = calcium channel blockers
CA Adrenergics = central-acting adrenergics
ACEi’s = angiotensin-converting enzyme inhibitors
cardiac factors circulating volume
heart rate
contractility
1. Beta Blockers
2. CCB’s
3. C.A. Adrenergics
salt
aldosterone
ACEi’s
Diuretics

53. BP = CO x PVR
Hormones
1. vasodilators
2. ACEI’s
3. CCB’s
Central Nervous System
1. CA Adrenergics
Peripheral Sympathetic
Receptors
alpha beta
1. alpha blockers 2. beta blockers
Local Acting
1. Peripheral-Acting Adrenergics

54. ADRENERGIC
NEURON BLOCKERS

55. Drugs which act at postganglionic adrenergic nerve endings &
inhibit their function by interfering with synthesis,storage or release
of Noradrenaline.
Do not control supine blood pressure.
Cause postural hypotension.
Used rarely in resistant hypertension.

56. CLASSIFICATION

57. DRUGS THAT PREVENT RELEASE
OF NORADRENALINE

Guanethidine
Bethanidine
Debrisoquine
Guanoxan
Guanadrel
Bretylium

58. 2-DRUGS THAT INHIBIT STORAGE OF
NORADRENALINE

Reserpine
Deserpidine
Syrosingopine
Methoserpidine

59. 3-DRUGS THAT INTERFERE WITH
SYNTHESIS OF NORADRENALINE
Methyldopa
Metyrosine

60. GUANETHIDINE
High doses----profound
sympathoplegia
Polar----------do not cross BBB
Long half-life----5 days

61. MECHANISM OF ACTION
It inhibits the release of noradrenaline(NE) from
Sympathetic nerve endings.
It is transported across the Sympathetic nerve
membrane by the same mechanism that
transports NE itself ( uptake 1),then it is stored in
vesicles, replaces the NE & released itself by
nerve stimulation.
Hypotensive action,
With early therapy----decrease CO,HR &
relaxation of capacitance vessels.
With long-term therapy---decrease PVR
Compensatory sodium & water retention
decrease

64. PHARMACOLOGICAL ACTIONS
 1-CVS
a-Blood pressure
Rapid I.V injection---
Triphasic response
1-rapid fall
2-Hypertention
3-progressive fall in B.P
b- Decrease concentration of catecholamine
in
Heart & blood vessels.
 2-CNS ,NO effect

65. 
3-GIT, increase motility
4- EYES, miosis
5-SUPERSENSITIVITY
CLINICAL USES
Rarely used
1-Moderate to severe HTN
2-Hyperreflexia of high spinal cord lesion
3-Glaucoma
4-Management of lid retraction in thyrotoxicosis

66. ADVERSE EFFECTS
Postural hypotension
Bradycardia
Diarrhea
Failure of ejaculation
Nasal congestion
Fluid retention & oedema
Heart failure
Hypertensive crisis in patients with
pheochromocytoma & taking cold remedies
containing directly acting sympathomimetics

67. DRUG INTERACTIONS
Drugs that block catecholamine uptake-
1 or displaces amines from the nerve
terminal block its effects
e.g.cocaine, tricyclic
antidepressants
Hypertension ---------sympathomimetcs

CONTRAINDICATIONS

Pheochromocytoma
Renal failure

68. BRETYLIUM
Quaternary ammonium compound
concentrated in adrenergic neurons.
Prevent release of NE
Now used as antiarrhythmic in resistant
ventricular arrhythmias.
Causes hypotension,nausea,parotid pain,
Bradycardia.

69. RESERPINE
Alkaloid in nature.
Obtained from Rauwolfia Serpentina
Used in Indo-Pakistan to treat mental illness
since ancient times.
Pure alkaloid was isolated in 1955.it was
popular antihypertensive in late 1950s &
early 1960s but now used as
pharmacological tool.
Well absorbed orally
Crosses BBB,placental barrier & excreted in
milk.

70. MECHANISM OF ACTION
It interferes with intracellular storage of
catecholamines.It acts at the membrane of
intraneuronal granules which stores monoamines
( NE,5-HT,DA) & irreversibly inhibits the active amine
transport ( ATP-Mg++ dependent uptake
mechanism).
Monoamines are gradually depleted & degraded
by MAO enzyme.
Occurs throughout the body even in adrenal
medulla.
Action not reversed until new vesicles are
synthesized
The effects last long after the drug is eliminated ( hit
& run drug) because tissue CA stores are restored
only gradually.

71. PHARMACOLOGICAL ACTIONS
1-CARDIOVASCULAR SYSTEM
B.P,
Causes slowly developing fall in B.P &
bradycardia,taking 2-3 weeks for full action.
The hypotensive action is due to peripheral as well as
central action.
salt & water retention
Decrease PR,CO & Cardiovascular reflexes are
partially inhibited.
Increase cutaneous blood flow.
Decreae Renin secretion
s

72. 2-CENTRAL NERVOUS SYSTEM
 It produces a characteristic sedation , tranquillizing
effect & a state of indifference to environmental
stimuli due to depletion of CA & 5-HT stores in brain.
Extra-pyramidal effects on prolong use of high doses
due to depletion of dopamine.
3-PARASYMPATHETIC OVERACTIVITY
Effects are similar to Acetylcholine

73. CLINICAL USES

HYPERTENSION MILD TO MODERATE
along with a thiazide diuretic & other
antihypertensive drugs.
Hypertensive emergencies
Now Not used as antipsychotic

74. ADVERSE EFFECTS
CVS
Postural hypotension
Bradycardia
Oedema
GIT
Increase salivation,GIT motility
Increase gastric acid secretion (peptic ulcer)
diarrhoea

75.  CNS
Parkinsonism-like extra-pyramidal syndrome
Nightmares
 sedation
 Most serious ---------psychic depression lead to
suicide
OTHERS
Weight gain
Nasal stffiness
Decreased libido (impotence)

76. CENTRALLY ACTING
SYMPATHOPLEGICS
Decrease sympathetic outflow from
vasopressor centers in brain

77. Patients with moderate to severe hypertension,most effective
drug regimens include an agent that inhibits function of
sympathetic nervous system.
These agents reduce sympathetic outflow from vasopressor
centre in the brain stem but allow these centres to retain or
even increase their sensitivity to baroreceptor control.

78. CLASSIFICATION
L-Dopa analog
Alpha-methyldopa
Imidazoline derivatives
Clonidine
Apraclonidine
Brimonidine
Relmenidine
Moxonidine
Others
Guanabenz
guanfacine

79. ALPHA-METHYLDOPA
(L- ALPHA-METHYL-3,4-DIHYDROXYPHENYLALANINE)
It is an analog of L-Dopa (precursor of
dopamine & NE) is converted to alpha-
methyl dopamine then to alpha-
methylnoradrenaline (selective alpha-2
agonist), stored in adrenergic nerve vesicles,
where it replaces NE & is released by nerve
stimulation to interact with postsynaptic
adrenoreceptors.
It probably acts as an agonist at presynaptic
alpha-2 receptors in brainstem to decrease
efferent sympathetic activity.

81. PHARMACOLOGICAL EFFECTS
Blood pressure
In young patient------decrease PVR
In older patient ------- decrease PVR & CO as a result of
decrease HR & stroke volume.
Fall in B.P is maximum 6-8 hours after an oral or I/V dose
Postural hypotension is less common
RBF is maintained
Renin is reduced
Salt & water retention blunt antihypertensive effect
(pseudo tolerance)

82. PHARMACOKINETICS
Prodrug
Absorbed by active amino acid transporter on oral adminstration.
Peak concentration in plasma occurs after 2-3 hrs
Vd is small
Half life is 2hrs ( 4-6hrs in renal failure)
Transport in CNS is also a active process.
Peak effect occurs in 6-8hrs
Duration of action is 24hrs so given in once & twice daily dosing
This discrepancy is related to time required for
1-transport into CNS
2-conversion into active metabolite
3-storage
4-release in vicinity of relevant alpha-2 receptors in CNS

83. Sedation, nightmares, movement disorders,
hyperprolactinemia

84. CLONIDINE

85. MECHANISM OF ACTION:
Clonidine, when given I/V , causes an acute rise
in B.P. probably due to activation of post-
synaptic alpha2 receptors in vascular smooth
muscle (arterioles).It is classified as Partial agonist
at alpha receptors because it also inhibits pressor
effects of other alpha agonists.

86. Clonidine is a partial agonist with high
selective affinity and high intrinsic activity at
alpha 2 receptors, especially alpha 2A
subtype which are mainly present in
hypothalamus and lower brain stem regions,
especially nucleus tractus solitarius which
regulates sympathetic activity. Activation of
central pre-synaptic alpha 2 receptors inhibit
the release of noradrenaline from
adrenergic neurons, decreases sympathetic
outflow and produces a fall in B.P.
Alternatively, Clonidine may act on post-
synaptic alpha 2A receptors in medulla
(vasomotor centre)

87. Clonidine also binds to a non-adrenoceptor
site, the imidazoline receptors which are
present in brain as well as in periphery.
Clonidine may first stimulate central
imidazoline receptors which then trigger
medullary alpha2A receptors to reduce
sympathetic outflow.
Clonidine increases parasympathetic tone
and results in fall of B.P. and bradycardia.
The reduction in B.P. is accompanied by a
reduction in catecholamine levels. This
suggests that Clonidine sensitizes brain stem
pressor centres to inhibition by baroreflexes.


88. PHARMACOLOGIC
EFFECTS
CVS:
Decreases B.P. & H.R.
High doses-Inc. B.P.
Dec. renal vascular resistance
Inc. renal blood flow
Inc. GFR
Relaxation of veins
Dec. C.O.

89. Abrupt withdrawal-rebound hypertension
Causes salt & water retention
CNS ???

90. PHARMACOKINETICS
Absorbed by oral route
Bioavailability- 75-100%
Lipid soluble-enters brain
Peak plasma level: 1-3 hrs.
T1/2 6-24hrs. Mean 24hrs.
Excretes unchanged in urine

91. ADVERSE EFFECTS
Dry mouth, sedation
Sexual dysfunction
Marked bradycardia
Contact dermatitis
Withdrawal reaction

92. THERAPEUTIC USES

93. Hypertension.
Pre-anaesthetic medication:
 Stimulation of central alpha 2 adrenoceptors produces sedation and
analgesia. Administered before surgery, clonidine reduces
anaesthetic requirement and improves cardiovascular stability.
 Opioid withdrawal :
Clonidine suppresses exaggerated transmitter release that
occurs during withdrawal of opioids. Clonidine also facilitates
alcohol withdrawal and smoking cessation.

94. Clonidine has been used to substitute morphine for intrathecal
and epidural analgesia.
Clonidine attenuates vasomotor symptoms of menopausal
syndrome such as hot flushes.
Clonidine has been used to control diarrhea due to diabetic
neuropathy.
Prophylaxis of migraine.

95. DRUG INTERACTIONS
Tricyclic anti-depressants
DOSE:
0.2-0.8 mg/day
Max. 2.4 mg