MCMP 407
Sympatholytic pharmacologySympatholytic pharmacology
Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible
MCMP 407
NH3
COOH
Gq
Phospho-lipase C
(+)
PIP2
IP3 Diacylglycerol
Increase Ca2+ Activate ProteinKinase C
Response
Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways
1 adrenergic
receptor
HO
HO CH
OH
CH2 NH2
Norepinephrine
MCMP 407
Receptor antagonists block agonist binding to the receptorReceptor antagonists block agonist binding to the receptor
NH3
COOH
Gq
Phospho-lipase C
Antagonist
HO
HO CH
OH
CH2 NH2
Norepinephrine
What effect would an antagonist alone have on receptor activation?
MCMP 407
Clinical pharmacology of Clinical pharmacology of -adrenergic -adrenergic receptor antagonistsreceptor antagonists
Drug ReceptorRoute ofadmin. Clinical uses
Side effects of 1 receptor antagonists:
Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
Phenoxybenzamine Oral Pheochromocytoma, hypertensive crisisPhentolamine Parenteral Pheochromocytoma, hypertensive crisis,
male impotencePrazosin Oral Hypertension, benign prostatic
hypertrophyTerazosin Oral Hypertension, benign prostatic
hypertrophyDoxazosin Oral Hypertension, benign prostatic
hypertrophy
MCMP 407
Non-selective adrenergic receptor antagonistsNon-selective adrenergic receptor antagonists-Haloalkylamines
N CH2 CH2 XR
RR= aromatic, alkyl
X= Cl-, Br-, etc.
MCMP 407
-Haloalkylamines
NO
CH3
Cl
Phenoxybenzamine (Dibenzyline)
Non-selective receptor antagonist
Also blocks acetylcholine, histamine, and serotonin receptors
Irreversible antagonist resulting from covalent modification of receptor
Non-selective adrenergic receptor antagonistsNon-selective adrenergic receptor antagonists
MCMP 407
-Haloalkylamines: Mechanism of receptor inactivation
receptor alkylated
receptor
N
Cl
R RN
R R Cl-
Aziridinium ion
NR R Cl-
Nu
NR R
Nu
Non-selective adrenergic receptor antagonistsNon-selective adrenergic receptor antagonists
MCMP 407
Imidazolines
Phentolamine (Regitine)
Non-selective receptor antagonist
Competitive (reversible) blocker
Potent vasodilator, but induces pronouced reflex tachycardia
Block of presynaptic 2 receptors may promote release of NE
Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist
Non-selective adrenergic receptor antagonistsNon-selective adrenergic receptor antagonists
N
NH
N
HO
H3C
CH2
MCMP 407
Reversible vs. Irreversible receptor blockadeReversible vs. Irreversible receptor blockade
-10 -8 -6 -40
50
100
Log [Norepinephrine]
1
Ad
rene
rgic
rec
epto
r ac
tiva
tion
-10 -8 -6 -40
50
100
Log [Norepinephrine]
1
Ad
rene
rgic
rec
epto
r ac
tiva
tion1 M Phent
+ Phentolamine + Phenoxybenzamine
10 M Phent
1 M Phenox
10 M Phenox
MCMP 407 -adrenergic receptor antagonists-adrenergic receptor antagonists
“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
N
NH3CO
H3CO
NH2
N
N R
O
O
O
O
O
Prazosin: R =
Terazosin: R =
Doxazosin: R =
Quinazoline ring
Piperazine ring
Acylmoiety
(Minipres)
(Hytrin)
(Cardura)
MCMP 407
OtherOther adrenergic receptor antagonists adrenergic receptor antagonistsErgot alkaloids
N
N
O
R'O
R
O NH
O NCH3
NH
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
-adrenergic receptor antagonists-adrenergic receptor antagonists
Yohimbine (Yocon)
Indole alkaloid Found in Rubaceae and
related trees. Also in Rauwolfia Serpentina.
Blockade of 2 receptors increases sympathetic discharge
Folklore suggests use in the treatment of male impotence
NH
N
H
H
H3CO2C
H
OH
MCMP 407
-adrenergic receptor antagonists-adrenergic receptor antagonists
Ar
O NH R
OH
Ar = aromatic ring structure
R = bulky alkyl group (isopropyl or tert-butyl)
Aryloxypropanolamines
Note: non-carbon atom
in side chain
MCMP 407
-adrenergic receptor antagonists-adrenergic receptor antagonists
Non-selective Lipophilic Local anesthetic
properties Blockade is activity-
dependentPropranolol(Inderal)
O NH
OH
CH
CH3
CH3
MCMP 407
-adrenergic receptor antagonists-adrenergic receptor antagonists
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
Propranolol(Inderal)
Therapeutic uses for -adrenergic receptor antagonists:
Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)
O NH
OH
CH
CH3
CH3
MCMP 407
Non-selective Non-selective -adrenergic receptor antagonists-adrenergic receptor antagonists
Thiadiazole nucleus with morpholine ring
Administered: Oral, Ophthalmic Uses: Hypertension, angina,
migraine, glaucoma
O NH
OH
C
CH3
CH3
CH3
N S
NNO
Timolol (Timoptic, Blocadren)
O NH
OH
CH
CH3
CH3HO
HONadolol (Corgard)
Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine
How will -blockers affect
pupil size?
MCMP 407
Non-selective Non-selective -adrenergic receptor antagonists-adrenergic receptor antagonists
Pindolol (Visken)
Possesses “Intrinsic sympathomimetic activity (ISA)
Partial agonist Less likely to cause bradycardia and lipid
abnormalities Administered: Oral Uses: Hypertension, angina, migraine
O NH
OH
CH
CH3
CH3
NH
What would a pindolol dose-response curve look like?
MCMP 407
Dose-Response Curves and Partial AgonistsDose-Response Curves and Partial Agonists
-10 -8 -6 -40
50
100
Log [Drug]
1
Ad
rene
rgic
rec
epto
r ac
tiva
tion
-10 -8 -6 -40
50
100
Log [Drug]
% In
hib
itio
n o
fN
E R
es
po
nse
NE
PindololNE +Pindolol
NE +Propranolol
%
MCMP 407
Non-selective Non-selective -adrenergic receptor antagonists-adrenergic receptor antagonists
Possesses “Intrinsic sympathomimetic activity (ISA)
Partial agonist Less likely to cause bradycardia and lipid
abnormalities Administered: Oral, Opththalmic Uses: Hypertension, glaucoma
Carteolol (Cartrol, Ocupress)
NH
O
O NH
OH
C
CH3
CH3
CH3
MCMP 407
Selective Selective -adrenergic receptor antagonists-adrenergic receptor antagonists
“Cardioselective” Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours Significant first-pass metabolism Administered: Oral, parenteral Uses: Hypertension, angina, antiarrhythmic,
congestive heart failureR
OH
O NH
CHCH3
CH3
Metoprolol (Lopressor, Toprol)R= CH2
Bisoprolol (Zebeta)R= O
O CH3
CH2CH2
OCH
CH3
CH3
MCMP 407
Selective Selective -adrenergic receptor antagonists-adrenergic receptor antagonists
Atenolol (Tenormin)
“Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina
O NH
OH
CH
CH3
CH3
NH2
O
MCMP 407
Selective Selective -adrenergic receptor antagonists-adrenergic receptor antagonists
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
O NH
OH
CH
CH3
CH3
OCH3
O
MCMP 407
Side effects of -blockers: Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
MCMP 407
Action Potential
Na+
Effect of chronic -receptor blockade
Presynaptic neuron
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
DA
NE
Uptake 1Na+, Cl-
NE
NENENE
NE
MAO
MCMP 407
Action Potential
Na+
Effect of chronic -receptor blockade: Receptor up-regulation
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
DA
NE
Uptake 1Na+, Cl-
NE
NENENE
NE
MAO
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 antagonistsMixed adrenergic receptor antagonists
Labetalol (Normodyne, Trandate)
Non-selective receptor antagonist 1 receptor antagonist Two asymmetric carbons (1 and 1’) (1R, 1’R)-isomer possesses -blocking activity (1S, 1’R)-isomer possesses greatest 1 receptor blocking
activity -blocking activity prevents reflex tachycardia normally
associated with 1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension, hypertensive crisis
HN
OH
CH3HO
CONH2
11'
MCMP 407
Mixed adrenergic receptor antagonistsMixed adrenergic receptor antagonists
Carvedilol (Coreg)
Non-selective receptor antagonist 1 receptor antagonist Both enantiomers antagonize 1
receptors Only (S)-enantiomer possesses -
blocking activity
OCH3
ONH
O
OH
NH
-blocking activity prevents reflex tachycardia normally associated with 1 receptor antagonists
Administered: Oral Uses: Hypertension, congestive
heart failure (Types II and III)
MCMP 407
Action Potential
Na+
Pharmacologic manipulation of the adrenergic system
Presynaptic neuron
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
DA
NE
Uptake 1Na+, Cl-
NE
NENENE
NE
MAO
1
2
3
MCMP 407
Inhibition of Inhibition of norepinephrine norepinephrine synthesissynthesis
HO CH2 CH NH2
HO
HO CH
OH
CH2 NH
CH3
HO
HO CH
OH
CH2 NH2
COOH
HO CH2 CH NH2
COOH
HO
HO
HO CH2 CH2 NH2
TYROSINE
DOPA
DOPAMINE
NOREPINEPHRINE
EPINEPHRINE
tyrosine hydroxylase
aromatic L-amino acid decarboxylase
dopamine -hydroxylase
phenylethanolamine-N-methyltransferase
MetyrosineX
MCMP 407
Action Potential
Na+
Drugs that reduce storage or release of NE
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
NE
NE
NE
MAO
ReserpineGuanethidine
GuanethidineGuanethidine,
Bretylium
MCMP 407
Catecholamine depletersCatecholamine depleters
Slow onset of action Sustained effect (weeks) Used in the treatment of
hypertension May precipitate depression
NH
N
H3CO2C
H3CO
H
H
H
OC
OCH3
OOCH3
OCH3
OCH3Reserpine (Serpasil)
Indole alkaloid obtained from the root of Rauwolfia serpentina
Block vesicular monoamine transporters
Deplete vesicular pool of NE
MCMP 407
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
Guanethidine (Ismelin)
N
HN
CNH2
NH
Drugs that reduce storage or release of NEDrugs that reduce storage or release of NE
MCMP 407
Action Potential
Na+
Drugs that reduce storage or release of NE
H+
Effector organ
Ca2+
Na+
Tyrosine
Tyrosine
Dopamine
NE
NE
NE
MAO
Guanethidine
GuanethidineGuanethidine,
MCMP 407
Drugs that reduce storage or release of NEDrugs that reduce storage or release of NE
Aromatic quaternary ammonium Precise mechanism unknown Displace and release NE and prevent
further release (depletion) Local anesthetic Administered: Parenteral Uses: Antiarrhythmic (ventricular
fibrillation)
Bretylium tosylate (Bretylol)Br
CH N
CH3
CH3
CH2CH3 CH3O3S
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