8. MCMP 407
Autonomic Drugs
Drugs that produce their primary therapeutic effect by
mimicking or altering the functions of the autonomic
nervous system are called autonomic drugs.
These autonomic agents act either by stimulating
portions of the autonomic nervous system or by
blocking the action of the autonomic nerves.
8
10. MCMP 407
Introduction
Alpha & Beta adrenergic receptor antagonists
prevent the interaction of the endogenous
neurotransmitter norepinephrine (N.E) or
sympathomimetics (endogenous or synthetic
catecholamines, synthetic noncatecholamines)
with the corresponding adrenergic receptor.
10
11. MCMP 407
Receptor agonists activate signal transduction pathways
HO
NH3
HO CH CH2 NH2
OH
Norepinephrine
α 1 adrenergic
receptor
(+) Phospho -
Gq lipase C
PIP2
COOH IP3 Diacylglycerol
Increase Ca 2+ Activate Protein
Kinase C
Response
12. 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 alone
COOH
have on receptor activation?
16. MCMP 407
Alpha Blockers
Bind selectively to alpha receptors
Interfere with ability of catecholamines or other
sympathomimetics to provoke alpha responses on the heart
& peripheral vasculature
Inhibitory action of epinephrine on insulin secretion is
prevented too (insulin production is not reduced)
Side effects: orthostatic hypotension, baroreceptor-
mediated reflex tachycardia, impotence
Absence of Beta blockade allows maximum expression of
cardiac stimulation from N.E.
16
17. MCMP 407
Mechanism of Action (alpha
blockade)
Competitive Inhibition (reversible binding with receptors)
– Phentolamine
– Prazosin
– Yohimbine
Covalent Bond (irreversible & insurmountable blockade)
– Phenoxybenzamine
(once blockade in effect, even massive doses of sympathomimetics are
ineffective
UNTIL METABOLISM OF Phenoxybenzamine takes place
17
19. MCMP 407
α1 -adrenergic receptor antagonists
O
Acyl
Quinazoline ring moiety
Vary in half-life:
N R Prazosin 3 hrs
H3CO N N Terazosin 12 hrs
Doxazosin 20 hrs
N Piperazine ring
H3CO
Undergo extensive
metabolism, excreted
NH2
mainly in the bile
Vasodilators
Prazosin: R =
(Minipres) O Relaxation of smooth
muscle in enlarged
Terazosin: R =
prostate and in bladder
(Hytrin) O base
O “First-dose” effect
Doxazosin: R =
(Cardura)
O
20. MCMP 407
Dosage
Prazosin Terazosin
First dose 0.5mg at bed Initially 1mg at bed time
time , orally. orally.
Then 0.5mg BD or TDS , Titrate by approx. doubling
for 3-7 days. dose at weekly intervals.
Followed by 1mg BD or Usual maintenance dose is
TDS , for 3-7 days. 2-10 mg OD.
Therafter increase gradually
as required upto max. of
20mg / day.
21. MCMP 407
Mechanism Of Action
Selective blocked of postsynaptic alpha-1
adrenoseptor.
PHARMACOLOGICAL EFFECTS
CVS:
Decreases blood pressure
Only minimal changes in Cardiac output.
No reflex Tachycardia.
Kidneys:
Retension in salt & fluid when administered without a
diuretic or during long term Therapy.
22. MCMP 407
Clinical Uses
Mild to moderate chronic hypertension (more
effective when used in combination with a diuretic or
propanalol).
Acute congestive heart failure (Prazosin).
To relieve urinary obstruction ( Terazosin).
23. MCMP 407
Adverse Effect
CNS
Dizziness, headache
Resp.Tract
Nasal congestion.
GIT
GI hypermotility
Kidneys
Salt & Fluid
retension
29. MCMP 407
YOHIMBINE (Procomil, Yocon)
An alkaloid derived from the bark of the
tree Corynanthe yohimbi.It is an alpha-
adrenergic blocking agent that in excess
causes antidiuresis, increased blood
pressure, tachycardia, irritability, tremor,
sweating, dizziness, nausea, and vomiting.
It is used therapeutically to treat erectile
dysfunction.
30. MCMP 407
Blocks presynaptic alpha-2 receptors enhanced
release of N.E. from nerve endings
Toxic effect:
– Idiopathic orthostatic hypotension (rare)
– Impotence
– Crosses BBB, may cause muscle activity & tremor
– Overdosetachy, HTN, paresthesia
33. MCMP 407
Phentolamine (REGITINE)
Mechanism of Action
Non-selective alpha blockade
Inhibits response to Serotonin.
Stimulate Muscarinic receptor &, H1 H2 histamine reptor
Peripheral vasodilation (alpha-1 block) & decreased BP within
2 min (lasts 10-15 min) elicit baroreceptor- mediated
cardiac stimulation reflex
33
34. MCMP 407
Non-selective adrenergic receptor antagonists
Imidazolines
HO
Non-selective α receptor
N antagonist
N CH2 Competitive (reversible) blocker
N Potent vasodilator, but induces
H pronouced reflex tachycardia
Block of presynaptic α2 receptors
may promote release of NE
H3 C Also blocks 5-HT receptors, and is
Phentolamine (Regitine) a muscarinic and histamine
receptor agonist
35. MCMP 407
Pharmacological Effects
Glands
Stimulate Lacrimal, Slivary , Pancreatic &
Respiratory tract secreations.
CVS
Vasodilation through both alpha-adrenoceptor
blokade & an additional non-adrenergic action on
vascular smooth muscle
Decrease Peripheral resistance & Increase Venous
capacitance
Cardiac stimulaiton through Reflex effect & alpha-2-
36. MCMP 407
Phentolamine
(Clinical Uses)
Acute HTN emergencies
– Intraop manipulation of PHEOCRHOMOCYTOMA
– Autonomic NS Hyperreflexia
» 30 to 70 mcg/kg IV (prompt/transient dec in BP)
» Drip may be desirable to maintain steady state
Accidental extravascular injection of
sympathomimetic drug
– Local infiltration of phentolamine-containing solution
(2.5 to 5mg in 10ml)
Frost Bite.
36
To cause erection in male sexual Dysfunction.
37. MCMP 407
Adverse Effects
CVS Precautions
Severe tachycardia, Pts with coronary artery
arrhythmias, angina, disease.
postural hypotension. Pts with peptic ulcer.
GIT
Diarrhea , Increased
gastric acid production.
39. MCMP 407
α-ADRENOCEPTOR
ANTAGONISTS
Interaction with receptors:
A) Reversible B) Irreversible
• Phentolamine Phenoxybenzamin
• Tolozoline
• Prazosin
• Labetolol(both
alpha & beta )
• Ergot alkaloids
40. MCMP 407
LABETALOL ( Mixed alpha
& beta)
Labetalol (Normodyne, Trandate) is a mixed alpha/
beta adrenergic antagonist, which is used to treat
high blood pressure.
41. MCMP 407
Non-selective adrenergic receptor antagonist
β-Haloalkylamines
Non-selective α receptor
antagonist
CH3 Also blocks acetylcholine,
histamine, and serotonin
O receptors
N
Irreversible antagonist resulting
from covalent modification of
receptor
Cl
Phenoxybenzamine (Dibenzyline)
42. MCMP 407
Irreversible blokade long Duration (14-48 hrs)
Phenoxybenzamine(Dibenzyline)
Non-selective (alpha-1 & alpha-2 blocker) covalent
bond
Alpha-1 block > Alpha-2 block
Slow onset (up to 60 min to reach peak) IV or PO.
Long time required for structural change of the
molecule needed to render drug active
Elimination half-time: 24 hr (cumulative effect with
repeated doses)
Note:
Block can be overcome only by the synthesis of new
adrenoseptors.
42
43. MCMP 407
Mechanism of Action
It bind covalently to alpha adrenoceptors (alpha-1 >
alpha-2)
It inhibits reuptake of released nor-epinephrine by
presynaptic adrenergic terminals.
It also blocks histamine (H1) , acetylcholine, &
serotonin receptors.
44. MCMP 407
Non-selective adrenergic receptor antagonist
β-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
45. MCMP 407
Cliniclal uses
To relieve vasospasm in Raynaud’s phenomenon
To relieve urinary obstruction
To control autonomic hyperreflexia due to spinal cord
transection.
– Preoperative treatment of HTN of pt with
PHEOCHROMOCYTOMA (0.5-1 mg/kg PO)
» With chronic alpha blockaderelieving intense peripheral
vasoconstriction, allows expansion of IV volume as reflected by a
drop in Hct
– Given to Pt with excessive vasoconstriction with associated
tissue ischemia (eg. hemorrhagic shock) but only after IV
fluid volume is replenished.
46. MCMP 407
Adverse Effect
CNS GIT
Fatigue, Sedation Nausea & vomiting
Eye (with oral
admisinstration)
Miosis
Reproduction
CVS
Inhibition of
Postural hypotension, ejaculation.
Reflex tachycardia.
Local
Resp.Tract
Local tissue irritation by
Nasal stifness injection.
48. MCMP 407
Clinical pharmacology of α -adrenergic
receptor antagonists
Route of
Drug Receptor admin. Clinical uses
Phenoxybenzamine α1, α2 Oral Pheochromocytoma, hypertensive crisis
Phentolamine α1, α2 Parenteral Pheochromocytoma, hypertensive crisis,
male impotence
Prazosin α1 Oral Hypertension, benign prostatic
hypertrophy
Terazosin α1 Oral Hypertension, benign prostatic
hypertrophy
Doxazosin α1 Oral Hypertension, benign prostatic
hypertrophy
Side effects of α 1 receptor antagonists:
Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
49. MCMP 407
Beta Blockers
Bind to Beta adrenergic receptors and block effects of
catecholamines & sympathomimetics on the heart &
smooth muscles of the airways & blood vessels
Beta blockers should continue during periop period to
avoid reflex SNS hyperactivity
49
56. MCMP 407
Classification
Nonselective for beta1 & beta2 receptors (propanolol,
nadalol, timolol, pindolol)
Cardioselective for beta1 receptors (esmolol,
metoprolol, atenolol, acebutolol, betaxolol)
Beta receptor selectivity is dose-dependent
Beta receptor selectivity is lost when large doses of
antagonist is given
56
58. MCMP 407
β -adrenergic receptor antagonists
Pharmacological effects
CH3
CH
Decreased cardiac output and
O N heart rate
H CH3
OH Reduced renin release
Increase VLDL, Decrease HDL
Inhibit lipolysis
Propranolol Inhibit compensatory
(Inderal) glycogenolysis and glucose
release in response to
hypoglycemia
Increase bronchial airway
resistance
Therapeutic uses for β-adrenergic receptor antagonists:
Hypertension, angina, cardiac arrhythmias, migraine, stage fright,
thyrotoxicosis, glaucoma, congestive heart failure (types II and III)
59. MCMP 407
Propanolol (Inderal la, INNOPRAN XL)
First Beta antagonist introduced clinically.
Nonselective for beta1 & beta2 receptors (equal
antagonism)
Pure antagonist (lacks sympathomimetic intrinsic
activity).
Mechanism of Action
Blocks both Beta 1 and Beta 2- Adrenoceptor
59
60. MCMP 407
Clinical use
Hypertension (most often used with either a diuretic
or a vasodilator).
Angina pectoris & prophylaxis of myocardial
infarction.
Supraventricular & ventricular arrhythmias.
Ventricular ectopic beats, esp if precipitated by
catecholamines.
Obstructive cardiomyopathy (to increase stroke
volume)
Dissecting aortic aneurysm (to decrease rate of
development of systolic pressure).
63. MCMP 407
Contraindication:-
Cardiogenic shock
Right ventricular failure secondary to pulmonary
hypertension.
Congestive cardic failure
Asthma
Greater than 1st degree heart block
Hypotension
Raynaud’s phenomenon
Pts on MAO inhibitors.
64. MCMP 407
Precautions
Dose Precaution
20-80mg TDS or QID, Pts with asthma.
orally. Pts with diabetes
In emergency treatment mellitus esp IDDM.
of dysarrhythmias
1mg over 1 min, IV;
repeated at 2 min.
interval to a maximum
of 10mg
65. MCMP 407
Non-selective β -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 β-blockers affect
Timolol (Timoptic, Blocadren) pupil size?
69. MCMP 407
Effect of chronic β-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
70. MCMP 407
Effect of chronic β-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
71. MCMP 407
Selective β1 -adrenergic receptor antagonists
CH3
CH
O N CH3
H “Cardioselective”
OH
Less bronchconstriction
Moderate lipophilicity
Half-life: 3-4 hours
R Significant first-pass
Metoprolol (Lopressor, Toprol) metabolism
R= CH2 O CH3 Administered: Oral,
Bisoprolol (Zebeta) CH3 parenteral
R= O CH2 CH Uses: Hypertension,
CH2 O CH3 angina, antiarrhythmic,
congestive heart failure
72. MCMP 407
Selective β1 -adrenergic receptor antagonists
CH3
CH
O N
CH3
OH
H “Cardioselective”
Less bronchconstriction
Low lipophilicity
NH2
Half-life: 6-9 hours
Administered: Oral,
O parenteral
Atenolol (Tenormin) Uses: Hypertension,
angina
73. MCMP 407
Selective β1 -adrenergic receptor antagonists
CH3 Very short acting
CH Half-life: 9 minutes
O N Rapid hydrolysis by
H CH3
OH esterases found in red blood
cells
Administered: Parenteral
O
Note: incompatible with
CH3 sodium bicarbonate
O
Uses: Supraventricular
Esmolol (Brevibloc) tachycardia, atrial
fibrillation/flutter,
perioperative hypertension
77. MCMP 407
Adrenergic β3 Receptors
Antagonists
SR 59230A is a selective antagonist of the
beta-3 adrenergic receptor.
L-748,337 Selective β3 antagonist .
SR 59230A hydrochloride Potent and selective β3
antagonist.
Adrenergic receptor located primarily in the small
intestine, adipose tissue and vascular endothelium
79. MCMP 407
Mixed adrenergic receptor antagonists
Non-selective β receptor
antagonist, with potency
OH somewhat lower then that
H of propanalol.
N 1'
1 α1 receptor antagonist,
HO
CH3 with potency less then that
CONH2
of phentolamine.
β-blocking activity prevents
Labetalol (Normodyne, Trandate)
reflex tachycardia normally
associated with α1 receptor
antagonists
Administered: Oral,
parenteral
Uses: Hypertension,
80. MCMP 407
Mixed adrenergic receptor antagonists
OCH3
O
O N
H
OH
N Carvedilol (Coreg)
H
Non-selective β receptor β-blocking activity prevents
antagonist reflex tachycardia normally
α1 receptor antagonist associated with α1 receptor
Both enantiomers antagonize α1 antagonists
receptors Administered: Oral
Only (S)-enantiomer possesses Uses: Hypertension, congestive
β-blocking activity heart failure (Types II and III)
81. MCMP 407
Pharmacologic manipulation of the adrenergic system
Na+
Presynaptic neuron
Tyrosine
Na+
1
Dopamine
Tyrosine
2
Action Potential
H+ O
DA MA
NE NE
Ca2+
Uptake 1
3 Na+, Cl-
NE
NE NE NE
β
Effector organ
83. MCMP 407
Adrenergic Neuron Blocker
Drugs that reduce storage or release of NE
H Possess guanidino moiety
N NH2
N C (pKa > 12)
NH Effects can be blocked by
transport blockers
Guanethidine (Ismelin) Uses: Hypertension
84. MCMP 407
Mechanism of Action:
It inhibits nor epinephrine release from
sympathetic nerve endings.
Clinical Uses
Moderate to severe hypertension ( usually with
a diuretic & a vasodilator)
85. MCMP 407
Adverse Effects
CVS: Contraindication
Orthostatic hypertension Pheochromocytoma
& syncop esp. during
exercise.
Severe coronary
artery disease.
GIT:
Cerebrovascular
Diarrhea
insufficiency.
Sk,muscle
During MAO
Aching , weakness
inhibitor
Reroduction administration.
Delayed Ejecullation
86. MCMP 407
Catecholamine depleters
H3CO N
H
N OCH3
H H O
H OC OCH3
H3CO2C
OCH3 OCH3
Reserpine (Serpasil)
Indole alkaloid obtained Slow onset of action
from the root of Rauwolfia Sustained effect (weeks)
serpentina Used in the treatment of
Block vesicular monoamine hypertension
transporters May precipitate depression
Deplete vesicular pool of NE
87. MCMP 407
Mechanism of Action
Reserpine blocks the ability of adrenergic
transmitter vesicles to take up & store biogenic
amines by interfering with an uptake
mechanism that depend on Mg & ATP ,
Depletaion of nor epinephrine, dopamine &
serotonin in both central & peripheral neurons.
Also exerts a direct vasodilating effect on
vascular smooth muscle when administer
intraarterially.
88. MCMP 407 HO CH2 CH NH2 TYROSINE
COOH
Inhibition of nor HO
X tyro sine hydroxyla s e
Metyrosine
epinephrine synthesis HO CH2 CH NH2 DOPA
COOH
aromatic L-amino a cid de carboxyla s e
HO
HO CH2 CH2 NH2 DOPAMINE
dopamine β -hydroxyla s e
HO
HO CH CH2 NH2 NOREPINEPHRINE
OH
phenylethanolamine-
HO N-methyltran sfera s e
HO CH CH2 NH EPINEPHRINE
OH CH3
89. 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
β
Effector organ
93. MCMP 407
Methyldopa
Mechanism of Action
Converted into alpha methylnorepinephrine which is
stored in adrenergic nerve granules, where it is
stoichiometrically replaces norepinephrine &, is
released by nerve stimulation to interact with
presyneptic central alpha adrenoseptors, Decrease
sympathetic outflow Decrease arterial presure.
Inhibit Dopa decarboxylase decrease stor of
norepinephrine in the sympathetic nervous system.
Decrease BP.
94. MCMP 407
Clinical Uses:-
Mild to moderate severe hypertension.
Dosage
1-2 g orally in divided doses.
97. MCMP 407
2) CLONIDINE
Mechanism of Action
It stimulates presyneptic alpha-receptor in vasomotor
center of brain Decrease sympathetic outflow to
the peripheral vessels.
Dosage
0.2 - 1.2 mg/day
Clinical Uses
Fall in BP, decrease in cardiac output & heart rate.
Decrease plasma Renin activity
100. MCMP 407
Mechanism of Action
Decrease of aqueous humor production
Side Effects
Ocular irritation, contraindicated in
patients with asthma, obstructive air
disease, bradycarida, and congestive heart
failure.
101. MCMP 407
Side effects of β -blockers:
Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
May alter airway resistance, carbohydrate/lipid
metabolism, distribution of extracellular ions
Cross CNS/placenta
GI: N/V/D
Fever, rash, myopathy, alopecia,
thrombocytopenia with chronic use
