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I. E Receptor antagonists
1. Non SelectiveE Receptor Antagonists
2. Selective E1 receptor antagonists
3. Selective E2 receptor antagonists
II. Receptor antagonists
1. Non selective antagonists
2. 1 selective antagonists
In this picture, presynaptic receptors: 2 receptors
are for NE release, while E2 receptors inhibit NE
release. Postsynaptic 1 receptors are for NE and E
release.
E Adrenergic Antagonists
1. Non Selective E Receptor Antagonist
PhenoxybenzaminePhentolamineTolazolineErgot derivatives
o Ergotamineo Ergonovineo Dihydroergotamineo Methysergide
2. Selective E1 Receptor Antagonist
Prazosin*TamsulosinTerazosinAlfuzosinDoxazosin
3. Selective E2 Receptor Antagonist
Yohimbine*Prazosin
selective E1 receptor antagonist
affinity for E1 receptors is 1000x greater than
affinity for E2 receptors
duration of action of about 4 to 6 hours.
affects both arterioles and veins
Pharmacologic Actions:
1. Cardiovascular System
vasodilatation of arteries and veins
decrease total peripheral resistance
decrease preload
decrease blood pressure
Dilatation of arterial and venous smooth muscles
&decrease total peripheral resistance
In this picture, the presence of Prasozin dilates the
arterial and venous vascular beds. See last page for
bigger picture
Subject: PharmacologyTopic: ANS4Lecturer: Dr. Dela CruzDate of
Lecture: August 10, 2011Transcriptionist: Jobell M.Editor: Pinay
Pages: 13
SY
2011-2012
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E ffects on the Cardiovascular System
Effects on BP
BP = Cardiac Output x Total Peripheral
Resistance
SV HR (E1 effect)
(F1effect) (F2 effect)
EDV Fc
(F1effect)
Venous return
2. Metabolic effects
decrease LDL cholesterol and triglycerides
increase HDL
decrease hepatic glucose output
3. Genitourinary tract
decreases tone of smooth muscles in the
prostateand bladder neck
inhibit ejaculation
Adrenergic antagonist such as Prasozin inhibits A1
receptor so the effect in the prostate and bladder is
therefore decrease in tone of the muscles.
Pharmacokinetics:
well absorbed after oral administration
50-70% bioavailability
peak plasma conc. attained in 1-3 hrs
highly bound to plasma proteins (primarily to a1-
acid glycoprotein because the drug is basic)
5% as free drug
extensively metabolized in the liver
plasma half-life is approx. 2-3 hrs but duration of
action is 7-10 hrs
This is the case where the dose of the drug
will not determine the duration of its action
small fraction of the drug is excreted unchangedin the
kidneys
First dose phenomenonofPrasozin
marked postural hypotension and fainting 30-90
minutes after the first dose
associated with syncopal attacks
Measures:
start with the least effective doses
administer drug at bedtime (Must be
administered during bedtime because of the
supine position which will not pool the blood
down the extremities. In case of supine
position, the blood will be pulled down the
extremities by the gravity which can cause
syncopal attacks. Prasozin is usually
administered once a day.)
Terazosin
structural analog ofPrazosin
higher oral bioavalability (>90%)
longer plasma half-life (approx. 12 hrs)
induces apoptosis in prostate smooth muscles
(treatment for Benign Prostatic Hypertrophy)
&limits cell proliferation in the prostate
¬ related to E1 antagonism
Yohimbine
competitive E2 antagonist
an indolealkylamine alkaloid from bark of
Pausinystaliayohimbe and in Rauwolfia root
resembles structure of Reserpine an
anithypertensive drug
Pharmacologic Actions:
1. Cardiovascular System
increase central sympathetic outflow
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enhanced release of NE
&activation of 1 receptors in the heart
&activation of E1 receptors in the blood
vessels
&activation of 1 receptors in the JGA
increase cardiac output
increase heart rate
increase total peripheral resistance
fluid retention
increase blood pressure
The Renin Angiotensin Aldosterone System
In this picture: Just remember thatAldosterone from
the adrenal cortex causes sodium reabsorption by
the kidney so the important effects will be increase
in volume (water retention) and increase in arterial
blood pressure. See last page for bigger picture
2. vasodilatation due to postsynaptic E2 in blood
vessels
3. Inhibition of platelet aggregation
4. increase Insulin release
&decrease hepatic glucose output
a1 and a2 antagonist effects
Dilatation of arterial and venous smooth muscles
&decrease total peripheral resistance
&enhanced decrease in blood pressure
q
E2 antagonist effects Baroreceptor reflex
q q
enhance release of NE & Increase HR and CO
Fluid retention
q
BP
See last page for bigger picture
Phenoxybenzamine
binds covalently to alpha adrenergic receptor
non-competitive, irreversible blocker
slight selectivity for a1 receptor than for E2
receptor
mainly used in the control ofhigh blood pressureprior to surgery
for Pheochromocytoma
Pheochromocytoma means there is tumor in
adrenal medulla. If there is tumor in adrenal
medulla, therefore there is also increase in the
secretion of catecholamines. The net effect will be
increase in blood pressure.
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In this picture: Just remember that in the presence
of an antagonist, the efficacy of NE is decreased.
Phenoxybenzamine is non-competitive so increase inNE will not
counteract the effect of the antagonist.
Phentolamine
a competitive antagonist
equal affinity for E1 and E2 receptors
antagonism for E2 receptors will cause the release
of NE from sympathetic nerve endings
also block 5-HT
effects on the cardiovascular system is similar to
those ofPhenoxybenzamine
Ergot Alkaloids
were the first adrenergic blocking agents to be
discovered.
Ergot is a fungus which grows on rye
Both Ergotamine, and Dihydroergotamine are
structural derivatives of a compound isolated from
ergot which have potent competitive alpha
antagonist effects.
Ergotamine is a prophylaxis for migraine and
Dihydroergotamine is used to contract uterus post
partum to stop bleeding.
GeneralTherapeutic Uses: E antagonists
1. Hypertension
2. Pheochromocytoma
3. Congestive heart failure (Alpha antagonist
decrease workload of the heart)
4. Peripheral vasospastic disease
e.g. Raynauds disease
5. Benign Prostatic Hypertrophy
Adrenergic Antagonists Adverse Effects:
1. Orthostatic hypotension
2. Reflex cardiac stimulation
tachycardia, cardiac arrhythmias
angina, myocardial infarction
3. Nasal congestion
4. Sexual dysfunction
F Adrenergic Antagonists
1. Non-subtype SelectiveF Receptor
Antagonist (First Generation)
PropranololTimololNadololPindolol
2. Selective F1 Receptor Antagonist (Second
Generation)
& Cardioselective Beta Blocker
AtenololMetoprololAcebutolol
3. Non-subtype Selective F Receptor Antagonist
(Third Generation) with additional CVS Actions
LabetalolCarteololCarvedilolBucindolol
4. SelectiveF1 Receptor Antagonist
(Third Generation) with additional CVS
Actions
BetaxololNebivololCeliprolol
Beta Blockers Pharmacologic Actions:
1. Cardiovascular system
decrease heart rate
(-) chronotropic effect
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decrease myocardial contractility
(-) inotropic effect
attenuate the expected rise in heart rate during
exercise or stress
negative dromotropic effect
slows conduction in the atria and A-V
node
decrease the spontaneous rate of
depolarization of ectopic pacemakers
increase refractory period in the A-V node
Decrease blood pressure due to:
decrease Cardiac output
(1 in the heart)
decrease renin secretion
(1 in the JGA) BB without ISA (Beta
Blocker without Intrinsic Sympathetic Action)
decrease central sympathetic outflow (presynaptic
2 receptor)
See last page for bigger picture
does not lower blood pressure in normal
individuals
reduce blood pressure in hypertensive patients
(because of the predominant effect in 1 receptors
more than 2 receptors so it causes decrease in
blood pressure)
chronic prophylactic therapy with a beta blocker in
patients who have had a myocardial infarct appears
to help prevent the recurrence of a second fatal
myocardial infarct
net effect in patients with coronary artery disease
is to decrease oxygen demand
improves exercise tolerance in patients with
angina
long term use decrease total peripheral resistance
2.Respiratory system
negligible effects on pulmonary function in normal
persons
bronchoconstriction in predispose patients
cardioselective beta blockers less likely to cause
respiratory problems in patients with
bronchospastic diseases
precaution still to be observed
Can also induce bronchospasm because it
also blocks 2 so there is contraction
3. Metabolic
Nonselective beta blockers cause most of the
metabolic effects such as:
mild impairment of glucose tolerance
inhibition of beta-receptor dependent glucose-
mobilization from the liver.
mild elevation of plasma triglyceride and VLDL
(less significant with drugs having ISA)
It increases glucose output so Beta blockers are notgood for
hypertensive patients with diabetes.
4. Decrease intraocular pressure
decrease aqueous humor production by the ciliary
body
5. Block catecholamine induced tremor
6. Block catecholamine-induced inhibition of mast
cell degranulation
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Pharmacologic Characteristics of Blockers
Selectivity
relative rather than absolute
Non-selective
equal affinity for both 1 and 2 receptors
Cardioselective Selective 1
greater affinity for 1
at therapeutic doses only block 1
at higher doses may become non-selective
Lipid solubility
increases the ability to enter the CNS
affects presynaptic receptors to block release of
Norepinephrine
decrease central sympathetic outflow
e.g. Propanolol, Pindolol
Intrinsic sympathetic activity
blockers can activate b receptors in the absence
of catecholamines
partial agonist activity
intrinsic activity are less than that of the full
agonists
prevent bradycardia and decrease in force of
myocardial contraction in the resting heart (will not
produce excessive bradycardia)
e.g. Pindolol, Acebutolol
Membrane stabilizing action
Local anesthetic action (basically anti-arrhythmic
because it acts on contracting muscles)
Inhibits Phase 0 of action potential resulting in:
&impaired spontaneous firing of SA and
AV node (bradycardia)
&decreased AV node conduction (1,2,3 degree
heart block)
&decreased ventricular conduction (prolonged
QRS)
e.g. Propranolol, Acebutolol, Carvedilol
ComparativeProperties of Beta Blockers
Propanolol* ++ 0 High 30% 3-
5
90%
Pindolol + +++ Low 100% 3-
4
40%
Acebutolol + + Low 20-
60%
3-
4
26%
Metoprolol* + 0 Mod 40-
50%
3-
7
12%
Carteolol 0 ++ Low 85% 6 23-
30%
Labetalol* + + Low 33% 3-
4
50%
Betaxolol* + 0 High 80% 15 50%
Dilatation of blood vessels due to:
2 agonist effects
E1 antagonism
Ca+
entry blockade
Nitric oxide production
Additional CVS Action of Third Generation
Beta Blockers
Drug
NO
Product
ion
2
Agonist
Effect
E1r
ece
ptor
antagon
ism
Ca
e
ntry
blockad
e
Antioxid
ant
Action
Carteolol + +
Carvedilol + + +
Labetalol +
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Betaxolol
+
Propanolol
Pharmacokinetics:
highly lipophilic
almost completely absorbed after oral
administration
undergoes extensive first pass metabolism in the
liver.
25% bioavailability from oral route
metabolized to 4-hydroxypropranolol, an active
metabolite
90% of the drug in the circulation is bound to
plasma proteins.
plasma half-life 3-5 hours
well distributed
as antihypertensive agent, the full response on
the blood pressure is not observed until after
several weeks of administration.
Metoprolol
equipotent to Propranolol in affinity to the 1
receptor
50-100x less affinity to 2 receptor
Pharmacokinetics:
almost completely absorbed after oral
administration
only 40% bioavailability due to first pass hepatic
metabolism
primarily metabolized by CYP2D6
half-life is 3-4 hours
10% of the unchanged drug is recovered in the
urine
Labetalol
competitive antagonist to alpha and beta
receptors
more (5-10x) b receptor antagonism than a1
receptor antagonism
Pharmacokinetics:
completely absorbed from the GIT
presence of food in the stomach will increase
absorption
20-40% bioavailability
extensive metabolism in the liver by oxidation and
glucuronidation
elimination half-life 8 hours
small fraction of the drug is excreted unchanged
in the kidneys
Betaxolol
Pharmacokinetics:
completely absorbed from the GIT
presence of food or alcohol in the stomach does
not affect absorption
80% bioavailability
approx 50% bound to plasma proteins
elimination half-life 15 hours
15% of the drug is excreted unchanged in the
kidneys
Adrenergic Antagonists Therapeutic Uses:
1. Coronary artery disease
&reduce myocardial work load and oxygen demand
Anginareduce the frequency of anginal attacks
2. Hypertension (mild to moderate)
q Cardiac Output
qrenin secretion
q central sympathetic outflow
Not for severe hypertension because it does not
lower the blood pressure excessively
3. Congestive Heart Failure
recent evidence that beta blockers decrease
mortality in patients with CHF
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caution is necessary in initiating therapy due to
risk of worsening CHF(because of negative inotropic
effect)
blockers currently approved for treatment of
CHF:
Metoprolol
Carvedilol
Bisoprolol
4. Anti- arrhythmic
drugs withMembrane Stabilizing Action
e.g. Propranolol,Metoprolol, Acebutolol
5. Glaucoma
decrease the rate of synthesis of aqueous humour
e.g. Timolol
6. Reduce signs and symptoms ofhyperthyroidism
blocks enhanced responsiveness to
catecholamines
inhibit peripheral conversion ofT4 to T3
7. Migraine prophylaxis
8. Essential tremor
9. Control signs and symptoms of Alcohol
withdrawal
10. Acute panic and anxiety symptoms
Adrenergic Antagonists Adverse Effects
1. Cardiovascular system
bradyarrhythmias
(may be life threatening)
abrupt withdrawal after chronic therapy can
produce rebound hypertension or angina
may exacerbate or cause heart failure
2. Central nervous system
lethargy, fatigue, nightmares
insomnia and depression
3. Respiratory system
negligible effects in normal persons
life threatening bronchoconstriction in patients
with bronchospastic diseases
4. Metabolic (Non selective b blockers)
&dyslipidemia
&blunts perception of hypoglycemic
symptoms (tachycardia, tremors,nervousness)
&blockcounterregulatory effects of
catecholamines secreted during
hypoglycemia
4. Metabolic
1 selective blockers improve serum lipid profile
and are less likely to interfere withhypoglycemia-
induced counter-regulatory mechanisms
AdrenergicNeuron Blockers
1. False Transmitter
Methyldopa
2. Prevents storage of Norepinephrine in granules
Reserpine
3. Prevents release of Norepinephrine fromvesicles
Guanethidine
Bretylium
In this picture: a-methyl NA is a false
neurotransmitter so it is not recognized by the
receptor but is acted upon by the same enzyme. See
last page for bigger picture
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Reserpine
an alkaloid obtained from Rauwolfiaplant
slow onset but long duration of action
also cause depletion of other biogenic amines
(serotonin, dopamine)
mainly used as Antihypertensive
Mechanism of action:
very low concentration, blocks the transport of
norepinephrine and other amines into synaptic
vesicles, by blocking the vesicular monoamine
transporter (VMAT2)
Norepinephrine accumulates in the cytoplasm,
where it is degraded by MAO
In this picture: VMAT2 is blocked by Reserpine so NE
is not transported to the vesicle. See last page for
bigger picture
Adverse Effects:
1. Central nervous system
mental depression
lassitude, sedation, nightmares
Parkinsonian syndrome
2. Gastrointestinal
abdominal cramps
increase gastric acid secretion
mild diarrhea
Guanethidine
Mechanism of action:
inhibit the release of norepinephrine from
sympathetic nerve terminals
causes a gradual and long-lasting depletion of
norepinephrine in sympathetic nerve endings
reduce or abolish the response of tissues to
sympathetic nerve stimulation
In this picture: Guanethedine and Bretylium prevent
the release of NE from the vesicles.
large doses lead to accumulation in the nerve
terminal that may cause structural damage to
noradrenergic neuron
no longer used clinically, now that better
antihypertensive drugs are available
associated with severe adverse effects due to loss
of sympathetic reflexes
AdverseR
eactions:
1.Orthostatic hypotension
2.Bradycardia
3.Nasal congestion
4.Failure of ejaculation
5. Diarrhea
oP
SNS activity on GIT
6.Denervation supersensitivity
marked BP response to sympathomimetics
may lead to hypertensive crisis
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END ofTRANSCRITION
What I added are the important things we need to know because
the Power Point in itself is already
comprehensive. I also included a practice test for you to assess
whether you will be confident in this final part of
ANS or you have to read again. J
Lets go 2014!All for the glory of God!
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Test your knowledge
Matching type
A.
____1. Ergotamine a. Selective A2
____2. Methysergide b. Ergot Alkaloids
____3. Yohimbine c. Selective A1
____4. Terasozine d. Non selective Alpha
____5. Phenoxybenzamine
B.
_____6. Labetalol a. 1st
Generation
_____7. Nebivolol b. 2nd
Generation
_____8. Propranolol c. 3rd
Generation
_____9. Metoprolol
_____10. Carteolol
C. Identification (ANS 3 and 4)
_______________11. An example of Quinazoline.
_______________12. An example of Imidazoline.
_______________13. An example of Haloalkylamines.
_______________14.Myocardial contractility is mainly an effect
of this receptor.
_______________15. Formula of Stroke Volume.
_______________16. A Beta blocker which undergoes extensive
first pass metabolism in the
liver.
_______________17. A Beta blocker with extensive metabolism in
the liver by oxidation and
Glucuronidation.
_______________18. A Beta blocker in which the presence of food
or alcohol in the stomach
does not affect absorption.
_______________19. Give one drug withMembrane Stabilizing
Action.
_______________20. A drug wh
ich
decreases th
e rate of synth
esis of aqueoush
umor.
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