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
1 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 CH CH2 NH2
Antagonist NH3 OH

Norepinephrine

Phospho-
Gq lipase C

What effect would an antagonist

COOH
alone have on receptor
activation?
 MCMP 407
Clinical pharmacology of -adrenergic
receptor antagonists
Route of
Drug Receptor admin. Clinical uses
Phenoxybenzamine   Oral Pheochromocytoma, hypertensive crisis
Phentolamine   Parenteral Pheochromocytoma, hypertensive crisis,
male impotence
Prazosin  Oral Hypertension, benign prostatic
hypertrophy
Terazosin  Oral Hypertension, benign prostatic
hypertrophy
Doxazosin  Oral Hypertension, benign prostatic
hypertrophy

Side effects of 1 receptor antagonists:

Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
 MCMP 407

Non-selective adrenergic receptor antagonists

-Haloalkylamines

R
N CH2 CH2 X
R
R= aromatic, alkyl
X= Cl-, Br-, etc.
 MCMP 407

Non-selective adrenergic receptor antagonists

-Haloalkylamines
 Non-selective  receptor
antagonist
CH3  Also blocks acetylcholine,
histamine, and serotonin
O
N receptors
 Irreversible antagonist
resulting from covalent
modification of receptor
Cl
Phenoxybenzamine (Dibenzyline)
 MCMP 407

Non-selective adrenergic receptor antagonists

-Haloalkylamines: Mechanism of receptor inactivation

R R
R R R R Cl- R R Cl-
N
N N N
Nu Nu

Aziridinium ion
Cl receptor alkylated
receptor
 MCMP 407

Non-selective adrenergic receptor antagonists

Imidazolines
 Non-selective  receptor
HO antagonist
 Competitive (reversible)
N
blocker
N CH2
 Potent vasodilator, but
N
H induces pronouced reflex
tachycardia
 Block of presynaptic 2
H3C receptors may promote
Phentolamine (Regitine) release of NE
 Also blocks 5-HT receptors,
and is a muscarinic and
histamine receptor agonist
 MCMP 407

Reversible vs. Irreversible receptor blockade

1 M Phent
100 100

receptor activation
receptor activation

 1 Adrenergic
 1 Adrenergic

1 M Phenox
50 50
10 M Phenox

10 M Phent
0 0
-10 -8 -6 -4 -10 -8 -6 -4
Log [Norepinephrine] Log [Norepinephrine]
+ Phentolamine + Phenoxybenzamine
 MCMP 407
-adrenergic receptor antagonists
 “Quinazolines”
O
Acyl  Vary in half-life:
Quinazoline ring moiety  Prazosin 3 hrs
N R  Terazosin 12 hrs
 Doxazosin 20 hrs
H3CO N N  Undergo extensive metabolism,
excreted mainly in the bile
N Piperazine ring  Vasodilators
H3CO  Relaxation of smooth muscle in
NH2 enlarged prostate and in bladder bas
 “First-dose” effect

Prazosin: R =
(Minipres) O

Terazosin: R =
(Hytrin) O
O
Doxazosin: R =
(Cardura)
O
 MCMP 407

Other adrenergic receptor antagonists

Ergot alkaloids
N
 Derivatives of Lysergic Acid
O  Product of the grain fungus
O
Claviceps purpura
N
R' R  5 Major alkaloids based on R and
O R’; Ergotamine the most common
NH
 Used in the treatment of migraine
O NCH3
 Ergots possess strong oxytocic
action

N
H
 MCMP 407
-adrenergic receptor antagonists

 Indole alkaloid
N
 Found in Rubaceae and
H related trees. Also in
N Rauwolfia Serpentina.
H H  Blockade of 2 receptors
H increases sympathetic
discharge
H3CO2C  Folklore suggests use in the
OH
treatment of male impotence
Yohimbine (Yocon)
 MCMP 407
-adrenergic receptor antagonists
Aryloxypropanolamines
Note: non-carbon atom
in side chain

O NH R
Ar OH

Ar = aromatic ring structure

R = bulky alkyl group (isopropyl or tert-butyl)

MCMP 407
-adrenergic receptor antagonists

CH3
CH
O N
 Non-selective
H CH3
OH
 Lipophilic
 Local anesthetic
properties
Propranolol
 Blockade is activity-
(Inderal) dependent
 MCMP 407
-adrenergic receptor antagonists
Pharmacological effects
CH3
 Decreased cardiac output and
CH
O N heart rate
H CH3
 Reduced renin release
OH
 Increase VLDL, Decrease HDL
 Inhibit lipolysis
 Inhibit compensatory
Propranolol
(Inderal) glycogenolysis and glucose
release in response to
hypoglycemia
 Increase bronchial airway
resistance

Therapeutic uses for -adrenergic receptor antagonists:

Hypertension, angina, cardiac arrhythmias, migraine, stage fright,
thyrotoxicosis, glaucoma, congestive heart failure (types II and III)
 MCMP 407

Non-selective -adrenergic receptor antagonists

CH3  Less lipophilic than propranolol
CH  Long half-life: ~20 hours
O N  Mostly excreted unchanged in urine
H CH3
HO OH  Administered: Oral
 Uses: Hypertension, angina, migraine

HO
Nadolol (Corgard)

CH3
 Thiadiazole nucleus with
morpholine ring
C CH3
O N  Administered: Oral, Ophthalmic
H CH3
O OH
 Uses: Hypertension, angina,
N N migraine, glaucoma
N S How will -blockers affect
Timolol (Timoptic, Blocadren) pupil size?
 MCMP 407

Non-selective -adrenergic receptor antagonists

CH3
 Possesses “Intrinsic sympathomimetic
CH activity (ISA)
O N
H CH3  Partial agonist
OH  Less likely to cause bradycardia and lipid
abnormalities
 Administered: Oral
 Uses: Hypertension, angina, migraine
N
H
Pindolol (Visken)

What would a pindolol dose-response curve look like?

 MCMP 407
Dose-Response Curves and Partial Agonists

100 NE 100
receptor activation

% Inhibition of
NE Response
 1 Adrenergic

NE +
Pindolol Pindolol
50 50

NE +
Propranolol

%
0 0
-10 -8 -6 -4 -10 -8 -6 -4
Log [Drug] Log [Drug]
 MCMP 407

Non-selective -adrenergic receptor antagonists

CH3  Possesses “Intrinsic sympathomimetic

activity (ISA)
O N C CH3  Partial agonist
H  Less likely to cause bradycardia and lipid
OH CH3 abnormalities
 Administered: Oral, Opththalmic
 Uses: Hypertension, glaucoma
O N
H
Carteolol (Cartrol, Ocupress)
 MCMP 407

Selective -adrenergic receptor antagonists

CH3
CH
O N CH3
H  “Cardioselective”
OH  Less bronchconstriction
 Moderate lipophilicity
 Half-life: 3-4 hours
 Significant first-pass metabolism
 Administered: Oral, parenteral
 Uses: Hypertension, angina, antiarrhythmic,
congestive heart failure
R
Metoprolol (Lopressor, Toprol)
R= CH2 O CH3

Bisoprolol (Zebeta) CH3

R= O CH2 CH
CH2 O CH3
 MCMP 407

Selective -adrenergic receptor antagonists

CH3
CH
O N
H CH3  “Cardioselective”
OH  Less bronchconstriction
 Low lipophilicity
 Half-life: 6-9 hours
 Administered: Oral, parenteral
NH2
 Uses: Hypertension, angina

Atenolol (Tenormin)
 MCMP 407

Selective -adrenergic receptor antagonists

CH3
CH
O N  Very short acting
H CH3  Half-life: 9 minutes
OH  Rapid hydrolysis by esterases found in red
blood cells
 Administered: Parenteral Note: incompatible
with sodium bicarbonate
 Uses: Supraventricular tachycardia, atrial
O fibrillation/flutter, perioperative hypertension

CH3
O

Esmolol (Brevibloc)
 MCMP 407

Side effects of -blockers:

 Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
 MCMP 407
Effect of chronic -receptor blockade
Na+
Presynaptic neuron
Tyrosine
Na+
Dopamine
Tyrosine

Action Potential
H+ O
DA MA

NE NE
Ca2+
Uptake 1
Na+, Cl-
NE
NE NE NE

Effector organ
 MCMP 407
Effect of chronic -receptor blockade:
Receptor up-regulation Na+

Tyrosine
Na+
Dopamine
Tyrosine

Action Potential
H+ O
DA MA

NE NE
Ca2+
Uptake 1
Na+, Cl-
NE
NE NE NE

Effector organ
 MCMP 407

Side effects of -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

 Non-selective  receptor antagonist
 1 receptor antagonist
 Two asymmetric carbons (1 and 1’)
 (1R, 1’R)-isomer possesses -blocking activity
OH  (1S, 1’R)-isomer possesses greatest 1 receptor blocking
activity
H
N 1'  -blocking activity prevents reflex tachycardia normally
associated with 1 receptor antagonists
1  Administered: Oral, parenteral
 Uses: Hypertension, hypertensive crisis
CH3
HO
CONH2

Labetalol (Normodyne, Trandate)

 MCMP 407

Mixed adrenergic receptor antagonists

OCH3
O
O N
H
OH

N Carvedilol (Coreg)
H

 Non-selective  receptor antagonist  -blocking activity prevents reflex

 1 receptor antagonist
 Both enantiomers antagonize 1
receptors
 Only (S)-enantiomer possesses -
blocking activity
tachycardia normally associated
with 1 receptor antagonists
 Administered: Oral
 Uses: Hypertension, congestive
heart failure (Types II and III)
 MCMP 407
Pharmacologic manipulation of the adrenergic system
Na+
Presynaptic neuron
Tyrosine
Na+
Dopamine 1
Tyrosine

Action Potential
2
H+ O
DA MA

NE NE
Ca2+
Uptake 1

NE
3 Na+, Cl-

NE NE NE


Effector organ
 MCMP 407 HO CH2 CH NH2 TYROSINE
COOH

X tyrosine hydroxylase
Inhibition of HO
Metyrosine
norepinephrine HO CH2 CH NH2 DOPA

synthesis COOH

aromatic L-amino acid decarboxylase

HO

HO CH2 CH2 NH2 DOPAMINE

dopamine -hydroxylase
HO

HO CH CH2 NH2 NOREPINEPHRINE

OH

phenylethanolamine-
HO N-methyltransferase

HO CH CH2 NH EPINEPHRINE
OH CH3
 MCMP 407
Drugs that reduce storage or release of NE
Na+

Tyrosine
Na+
Dopamine
Reserpine Tyrosine
Guanethidine
Action Potential
H+ O
MA

NE NE
Ca2+
NE

Guanethidine, Guanethidine
Bretylium


Effector organ
 MCMP 407

Catecholamine depleters

H3CO N
H
N OCH3
H H O
H OC OCH3
H3CO2C
OCH3 OCH3
Reserpine (Serpasil)

 Indole alkaloid obtained from the  Slow onset of action

root of Rauwolfia serpentina  Sustained effect (weeks)
 Block vesicular monoamine  Used in the treatment of
transporters hypertension
 Deplete vesicular pool of NE  May precipitate depression
 MCMP 407

Drugs that reduce storage or release of NE

 Possess guanidino moiety (pKa > 12)

H  Resonance stabilization of cation “spreads”
N NH2
N C positive charge over the entire four atom
system
NH  Almost completely protonated at physiological
pH
 “Pharmacologic sympathectomy”
Guanethidine (Ismelin)  Effects can be blocked by transport blockers
 Uses: Hypertension
 MCMP 407
Drugs that reduce storage or release of NE
Na+

Tyrosine
Na+
Dopamine
Tyrosine
Guanethidine
Action Potential
H+ O
MA

NE NE
Ca2+
NE

Guanethidine, Guanethidine


Effector organ
 MCMP 407

Drugs that reduce storage or release of NE

CH3
CH N CH2CH3 O3S CH3
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)