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.
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
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
24. In hypertensive patients,
the baroreceptors & renal
blood volume-pressure control
systems appear to be “set” at
a higher level of blood
pressure.
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 Pressure Risk group A Risk group B Risk group C
High-normal
Stage 1
Stage 2
lifestyle
modification
lifestyle
modification
lifestyle
modification
lifestyle
modification
lifestyle
modification
(up to 6 months)
drug therapy drug therapy
drug therapy
drug therapy
(140-159/90-99)
(130-139/85-89)
(160-179/100-109)
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
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.
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
62.
63.
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
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
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.
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.
80.
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
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.
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.
