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MCMP 407
Sympatholytic pharmacology



Selective vs. Non-selective
Antagonist vs. Partial Agonist
Reversible vs. Irreversible
MCMP 407
Receptor agonists activate signal transduction pathways
HO
NH3
HO
CH
CH2
NH2
OH
Norepinephrine
a1 adrenergic
receptor
(+) Phospho-
Gq
lipase C
PIP2
COOH
IP3
Diacylglycerol
Increase Ca2+
Activate Protein
Kinase C
Response
MCMP 407
Receptor antagonists block agonist binding to the receptor
HO
HO
Antagonist
CH
CH2
NH2
OH
NH3
Norepinephrine
Gq
What effect would an antagonist
alone have on receptor
activation?
COOH
Phospholipase C
MCMP 407
Clinical pharmacology of a-adrenergic
receptor antagonists
Drug
Phenoxybenzamine
Phentolamine
Route of
Receptor admin.
Clinical uses
a1, a2
a1, a2
Prazosin
a1
Terazosin
a1
Doxazosin
a1
Oral
Pheochromocytoma, hypertensive crisis
Parenteral Pheochromocytoma, hypertensive crisis,
male impotence
Oral
Hypertension, benign prostatic
hypertrophy
Oral
Hypertension, benign prostatic
hypertrophy
Oral
Hypertension, benign prostatic
hypertrophy
Side effects of a1 receptor antagonists:
Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
MCMP 407
Non-selective adrenergic receptor antagonists
b-Haloalkylamines
R
N
CH2 CH2
R
R= aromatic, alkyl
X= Cl-, Br-, etc.
X
MCMP 407
Non-selective adrenergic receptor antagonists
b-Haloalkylamines
 Non-selective a receptor
antagonist
 Also blocks acetylcholine,
histamine, and serotonin
receptors
 Irreversible antagonist
resulting from covalent
modification of receptor
CH3
O
N
Cl
Phenoxybenzamine (Dibenzyline)
MCMP 407
Non-selective adrenergic receptor antagonists
b-Haloalkylamines: Mechanism of receptor inactivation
R
R
R Cl-
R
N
N
R
R Cl-
R
N
N
Nu
Cl
Aziridinium ion
R
receptor
Nu
alkylated
receptor
MCMP 407
Non-selective adrenergic receptor antagonists
Imidazolines
HO
N
N
CH2
N
H
H3 C
Phentolamine (Regitine)
 Non-selective a receptor
antagonist
 Competitive (reversible)
blocker
 Potent vasodilator, but
induces pronouced reflex
tachycardia
 Block of presynaptic a2
receptors may promote
release of NE
 Also blocks 5-HT receptors,
and is a muscarinic and
histamine receptor agonist
MCMP 407
1 M Phent
100
50
10 M Phent
a 1 Adrenergic
receptor activation
a 1 Adrenergic
receptor activation
Reversible vs. Irreversible receptor blockade
100
1 M Phenox
50
10 M Phenox
0
0
-10
-8
-6
-4
Log [Norepinephrine]
+ Phentolamine
-10
-8
-6
-4
Log [Norepinephrine]
+ Phenoxybenzamine
MCMP 407
a1-adrenergic receptor antagonists
O
Quinazoline ring
N
H3CO
N
N
N
Piperazine ring
H3CO
NH 2
Prazosin: R =
(Minipres)
Terazosin: R =
(Hytrin)
R
Acyl
moiety
O
O
O
Doxazosin: R =
(Cardura)
O
 “Quinazolines”
 Vary in half-life:
 Prazosin 3 hrs
 Terazosin 12 hrs
 Doxazosin 20 hrs
 Undergo extensive
metabolism, excreted
mainly in the bile
 Vasodilators
 Relaxation of smooth
muscle in enlarged
prostate and in bladder
base
 “First-dose” effect
MCMP 407
Other a adrenergic receptor antagonists
Ergot alkaloids
O
R'
N
O
N
R
O
NH
O
NCH3
N
H
 Derivatives of Lysergic Acid
 Product of the grain fungus
Claviceps purpura
 5 Major alkaloids based on R
and R’; Ergotamine the most
common
 Used in the treatment of
migraine
 Ergots possess strong oxytocic
action
MCMP 407
a2-adrenergic receptor antagonists
N
N
H
H
H
H
H3CO2C
Yohimbine (Yocon)
OH
 Indole alkaloid
 Found in Rubaceae and
related trees. Also in
Rauwolfia Serpentina.
 Blockade of a2 receptors
increases sympathetic
discharge
 Folklore suggests use in
the treatment of male
impotence
MCMP 407
b-adrenergic receptor antagonists
Aryloxypropanolamines
Note: non-carbon atom
in side chain
O
Ar
NH
R
OH
Ar = aromatic ring structure
R = bulky alkyl group (isopropyl or tert-butyl)
MCMP 407
b-adrenergic receptor antagonists
CH3
CH
O
N
H
OH
CH3



Propranolol
(Inderal)

Non-selective
Lipophilic
Local anesthetic
properties
Blockade is activitydependent
MCMP 407
b-adrenergic receptor antagonists
CH3
CH
O
N
H
OH
Propranolol
(Inderal)
CH3
Pharmacological effects
 Decreased cardiac output and
heart rate
 Reduced renin release
 Increase VLDL, Decrease HDL
 Inhibit lipolysis
 Inhibit compensatory
glycogenolysis and glucose
release in response to
hypoglycemia
 Increase bronchial airway
resistance
Therapeutic uses for b-adrenergic receptor antagonists:
Hypertension, angina, cardiac arrhythmias, migraine, stage fright,
thyrotoxicosis, glaucoma, congestive heart failure (types II and III)
MCMP 407
Non-selective b-adrenergic receptor antagonists
CH3
CH
O
N
H
HO


CH3

OH


HO
Nadolol (Corgard)
CH3
C
O
N
H
O
CH3
CH3
OH
N
N
N
S
Timolol (Timoptic, Blocadren)



Less lipophilic than propranolol
Long half-life: ~20 hours
Mostly excreted unchanged in
urine
Administered: Oral
Uses: Hypertension, angina,
migraine
Thiadiazole nucleus with
morpholine ring
Administered: Oral, Ophthalmic
Uses: Hypertension, angina,
migraine, glaucoma
How will b-blockers affect
pupil size?
MCMP 407
Non-selective b-adrenergic receptor antagonists
CH3
CH
O
N
H
OH
CH3




N
H

Pindolol (Visken)
Possesses “Intrinsic
sympathomimetic activity (ISA)
Partial agonist
Less likely to cause bradycardia
and lipid abnormalities
Administered: Oral
Uses: Hypertension, angina,
migraine
What would a pindolol dose-response curve look like?
MCMP 407
NE
100
100
% Inhibition of
%NE Response
b 1 Adrenergic
receptor activation
Dose-Response Curves and Partial Agonists
Pindolol
50
0
-10
-8
-6
Log [Drug]
-4
NE +
Pindolol
50
0
NE +
Propranolol
-10
-8
-6
Log [Drug]
-4
MCMP 407
Non-selective b-adrenergic receptor antagonists
CH3
O
OH
O
N C CH3
H
CH3
N
H
Carteolol (Cartrol, Ocupress)





Possesses “Intrinsic
sympathomimetic activity (ISA)
Partial agonist
Less likely to cause bradycardia
and lipid abnormalities
Administered: Oral, Opththalmic
Uses: Hypertension, glaucoma
MCMP 407
Selective b1-adrenergic receptor antagonists
O
OH
CH3
CH
N
CH3
H
R
Metoprolol (Lopressor, Toprol)
R= CH2 O CH3
CH3
Bisoprolol (Zebeta)
CH
R= O
CH2
CH2
O
CH3







“Cardioselective”
Less bronchconstriction
Moderate lipophilicity
Half-life: 3-4 hours
Significant first-pass metabolism
Administered: Oral, parenteral
Uses: Hypertension, angina,
antiarrhythmic, congestive heart
failure
MCMP 407
Selective b1-adrenergic receptor antagonists
CH3
CH
O
N
H
CH3
OH
NH 2
O
Atenolol (Tenormin)






“Cardioselective”
Less bronchconstriction
Low lipophilicity
Half-life: 6-9 hours
Administered: Oral, parenteral
Uses: Hypertension, angina
MCMP 407
Selective b1-adrenergic receptor antagonists
CH3
CH
O
N
H
CH3
OH
O
O
CH3
Esmolol (Brevibloc)
 Very short acting
 Half-life: 9 minutes
 Rapid hydrolysis by esterases
found in red blood cells
 Administered: Parenteral
Note: incompatible with sodium
bicarbonate
 Uses: Supraventricular
tachycardia, atrial
fibrillation/flutter, perioperative
hypertension
MCMP 407
Side effects of b-blockers:
 Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
MCMP 407
Effect of chronic b-receptor blockade
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential
H+
DA
NE
NE
Uptake 1
NE
NE
NE
Effector organ
NE
MCMP 407
Effect of chronic b-receptor blockade:
Receptor up-regulation
Tyrosine
Na+
Dopamine
Tyrosine
Action Potential
H+
DA
NE
NE
Uptake 1
NE
NE
NE
Effector organ
NE
MCMP 407
Side effects of b-blockers:
 Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
Contraindications:
 Asthma, COPD, congestive heart failure (Type IV)
MCMP 407
Mixed adrenergic receptor antagonists
OH
1
H
N 1'
CH3
HO
CONH 2
Labetalol (Normodyne, Trandate)
 Non-selective b receptor
antagonist
 a1 receptor antagonist
 Two asymmetric carbons (1 and
1’)
 (1R, 1’R)-isomer possesses bblocking activity
 (1S, 1’R)-isomer possesses
greatest a1 receptor blocking
activity
 b-blocking activity prevents
reflex tachycardia normally
associated with a1 receptor
antagonists
 Administered: Oral, parenteral
 Uses: Hypertension,
hypertensive crisis
MCMP 407
Mixed adrenergic receptor antagonists
OCH3
O
O
N
H
OH
N
H
Carvedilol (Coreg)
 Non-selective b receptor antagonist
 a1 receptor antagonist
 Both enantiomers antagonize a1
receptors
 Only (S)-enantiomer possesses bblocking activity
 b-blocking activity prevents reflex
tachycardia normally associated
with a1 receptor antagonists
 Administered: Oral
 Uses: Hypertension, congestive
heart failure (Types II and III)
MCMP 407
Pharmacologic manipulation of the adrenergic system
Presynaptic neuron
Tyrosine
Na+
1
Dopamine
Tyrosine
2
Action Potential
H+
DA
NE
NE
Uptake 1
NE
NE
3
NE
Effector organ
NE
b
MCMP 407
HO
CH2
CH
NH2 TYROSINE
COOH
Inhibition of
norepinephrine
synthesis
HO
X
tyrosine hydroxylase
Metyrosine
HO
CH2
CH
NH2 DOPA
COOH
aromatic L-amino acid decarboxylase
HO
HO
CH2
CH2
NH2 DOPAMINE
dopamine b -hydroxylase
HO
HO
CH
CH2
NH2 NOREPINEPHRINE
OH
phenylethanolamineN-methyltransferase
HO
HO
CH
OH
CH2
NH
CH3
EPINEPHRINE
MCMP 407
Drugs that reduce storage or release of NE
Tyrosine
Na+
Dopamine
Reserpine
Guanethidine
Tyrosine
Action Potential
H+
NE
NE
NE
Guanethidine,
Bretylium
Effector organ
Guanethidine
b
MCMP 407
Catecholamine depleters
N
H3CO
N
H
H
H
O
OC
H
H3CO2C
OCH3
Reserpine (Serpasil)



Indole alkaloid obtained from the
root of Rauwolfia serpentina
Block vesicular monoamine
transporters
Deplete vesicular pool of NE




OCH3
OCH3
OCH3
Slow onset of action
Sustained effect (weeks)
Used in the treatment of
hypertension
May precipitate depression
MCMP 407
Drugs that reduce storage or release of NE

H
N
N
C
NH 2

NH
Guanethidine (Ismelin)




Possess guanidino moiety
(pKa > 12)
Resonance stabilization of cation
“spreads” positive charge over the
entire four atom system
Almost completely protonated at
physiological pH
“Pharmacologic sympathectomy”
Effects can be blocked by transport
blockers
Uses: Hypertension
MCMP 407
Drugs that reduce storage or release of NE
Tyrosine
Na+
Dopamine
Tyrosine
Guanethidine
Action Potential
H+
NE
NE
NE
Guanethidine,
Effector organ
Guanethidine
b
MCMP 407
Drugs that reduce storage or release of NE
CH3
CH
N
CH2CH3
O3S
CH3
Br
Bretylium tosylate (Bretylol)






Aromatic quaternary ammonium
Precise mechanism unknown
Displace and release NE and
prevent further release (depletion)
Local anesthetic
Administered: Parenteral
Uses: Antiarrhythmic (ventricular
fibrillation)
CH3
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