The document discusses the autonomic nervous system pharmacology. It begins by introducing the autonomic nervous system and its role in maintaining homeostasis through involuntary control of various effector cells. It then describes the anatomical differences between the autonomic and somatic nervous systems. The document goes on to discuss the neurotransmitters of the autonomic nervous system, including acetylcholine and norepinephrine. Finally, it examines cholinergic transmission and pharmacology, focusing on cholinergic agonists and antagonists as well as cholinesterase inhibitors.
3. Introduction
Autonomic NS
Operates involuntarily on reflex control
Functions to maintain the constancy of the internal
environment (homeostasis)
Innervates three types of effecter cells
1. Smooth muscle
2. Cardiac muscle
3. Exocrine glands
Somatic NS innervates skeletal muscle
Voluntary control of skeletal muscle
3
4. Anatomical differences: ANS-vs-SNS
• Neurons between CNS and effector cells
Two neurons in ANS
Only one neuron in somatic NS
• Synaptic junctions in ANS occur in ganglia which
lie out side the cerebrospinal axis while no such
structures occur in somatic NS.
• While efferent neurons in somatic NS are
myelinated, generally postsynaptic autonomic
neurons are nonmyelinated.
4
6. Autonomic Nervous System
• Has three divisions
Sympathetic nervous system (thoracolumbar)
Parasympathetic nervous system (craniosacral)
Enteric nervous system???
6
7. Fight or flight vs. Rest and Digest
7
Organ Symp. Parasymp.
Heart Rate and Force rate and force
Blood vessels Mostly constriction (dilates some skeletal
muscle arterioles and some veins)
no effect
Airway smooth
muscle
Dilatation constriction
GI tract Motility motility
Male sex
organs
Ejaculation erection
Eye (pupil) Dilatation constriction
Sailvary glands Secretion secretion
Ureters &
bladder
Relaxes detrusor & contract sphincter –
decreased urine output
Contraction of
detrusor & relaxation
of sphincter
Liver Glycogenolysis no effect
8. Acetylcholine (Ach) is neurotransmitter at:
All autonomic ganglia
All parasympathetic neuroeffector junction (NEJ)
Some sympathetic NEJ (those innervating sweat glands)
All somatic neuromuscular junctions.
Cholinergic neurons: Neurons that release Ach
Cholinoreceptors: receptors with which Ach interacts
Cholinomimetic drugs are those that mimic Ach on
interaction with cholinoreceptors
Cholinoreceptor antagonists are drugs that antagonize
the effects of Ach
8
9. • Norepinephrine (NE) and epinephrine (Epi)
NE is the NT at sympathetic postsynaptic neurons except
those innervating sweat glands
Adrenergic neurons: that release NE and/or Epi
Adrenoceptors: receptors with which NE or Epi
interacts
Adrenomimetic (sympathomimetic): drugs that mimic
NE/Epi on interaction with adrenoceptors
Adrenoceptor antagonists are drugs that antagonize
the effect of NE/Epi
9
11. Vesicular storage of Ach
Synthesized Ach (and ATP, Ca2+, and Mg2+) is actively
transported by vesicular transporter into vesicles in nerve
terminals (The process is inhibited by vesamicol).
Release of Ach on arrival of action potential at the nerve
terminal causes opening of voltage gated Ca2+ channels ↑
IC Ca2+ → fusion of vesicular membrane with the surface
membrane → Ach exocytosis into the synaptic space
(inhibited by botulinium toxin).
Inactivation of Ach action
Ach is rapidly inactivated in the synapse by the action
of AchE.
11
13. Nicotinic and Muscarinic Cholinoreceptors
Nicotinic receptors
They are ligand-gated ion channels and fall into three main
classes: ganglionic (Nn), muscle (Nm) and CNS subtypes
Mediate fast excitatory synaptic transmission at
neuromascular junction, autonomic ganglia, adrenal
medulla and the CNS.
Muscarinic receptors (M1, M2, M3, M4, and M5 )
Are G-protein coupled receptors found on tissues
innervated by postganglionic parasympathetic neurons and
on sweat glands
13
14. M1 (Neural)
Found mainly in the CNS, peripheral neurons and gastric parietal cells. They are selectively
blocked by pirenzepine---used for Rx of PUD.
M2 (Cardiac)
Found in the heart & presynaptic terminals of peripheral and central neurons. Selectively
blocked by gallamine.
M3 (Glandular)
Occur on exocrine glands, smooth muscles, endothelial cells and CNS
M4 and M5
Found in the CNS
All mAChRs are activated by acetylcholine and blocked by
atropine.
14
17. A. Choline Esters
Acetylcholine
Ester of acetic acid and choline
Choline group contains a quaternary ammonium gp that
confers high polarity (hydrophilicity)
Cholinesterases:
catalyze hydrolysis of Ach to acetate and choline
i.e. the only means of termination.
Two major types of cholinesterases:
Acetylcholinesterase (AchE) mainly found in the neuro-effector junction
(synaptic sites)
Pseudo-cholinesterase (Pseudo-ChE) [butyrylcholinesterase] mainly found in
liver and plasma
19
18. A. Choline Esters (C’tnd)
Derivatives of Ach
Methacholine, carbachol and bethanechol
Are too hydrophilic to cross membranes
The therapeutic usefulness of ACh is limited by
Lack of selectivity as an agonist for different types of Ach-Rs
Its rapid degradation by AchE.
Methacholine
Is structurally -methylated Ach which renders the drug more
selective to muscarinic receptors and resistant to cholinesterase
activity
potency and duration of action relative to Ach
20
19. A. Choline Esters (C’tnd)
Carbachol
Differs from Ach only in the substitution of a carbamoyl group
for the terminal methyl group of Ach
This renders carbachol completely resistant to degradation by
cholinesterase
Its receptor selectivity is not improved for muscarinic Vs
nicotinic
Bethanechol
Combines the addition of a methyl group and the substitution of
the terminal carbamoyl group
It is selective agonist of muscarinic receptors and is resistant to
degradation by choline-esterases
21
20. A. Choline Esters (C’tnd)
• Bethanechol (cnt’d)
• Therapeutic application:
To stimulate contraction of GIT and urinary bladder in certain
cases of postoperative abdominal distention, gastric atony and
urinary retention in the absence of obstruction
To promote salivation in radiation induced xerostomia;
To reduce nausea and vomiting.
In paralytic ileus.
• GIT problems (10-25mg, 3-4 times/day PO)
• Urinary retention 5mg sc
22
21. A. Choline Esters (C’tnd)
• Bethanechol……
– Side effects:
• most are extensions of the pharmacologic effects
which includes, sweating, salivation, flushing,
decreased blood pressure, urinary urgency,
abdominal pain, diarrhea and bronchospasm.
23
22. B. Naturally Occurring Alkaloids
Naturally occurring alkaloids:
Pilocarpine, Muscarine, Nicotine, Lobeline
Pilocarpine, nicotine, lobeline are tertiary amines
and can readily cross-membranes, while muscarine,
a quaternary ammonium cpd does not cross
membranes
24
23. B. Alkaloids …
Pilocarpine
Exhibits muscarinic activity and is primarily used
in ophthalmology
• Actions: rapid miosis and contraction of the
ciliary muscle (vision is fixed at some particular
distance making it impossible to focus
(cyclospasm)
25
24. B. Alkaloids …
• Therapeutic use: in glaucoma
Is the drug of choice in the emergency lowering of
IOP
Effective in opening the trabecular meshwork, causing an
immediate drop in intraocular pressure as a result of the
increased drainage of aqueous humor.
Action lasts up to 1 day
It’s available as 0.5-4% eye drops
26
25. Pharmacologic effects (1)
Parasympathetic activation produces effect by two
mechanisms:
Released Ach interacts with muscarinic receptors on
effecter cell membrane
The Ach also interacts with pre-synaptic muscarinic
receptors to inhibit release of transmitters
Circulating cholinergic agonists act in the same
way to modulate parasympathetic & sympathetic
systems
27
26. Pharmacologic effects (2)
Effects on CVS
Vasodilation
Mediated by NO production up on activation of M3
receptors on endothelial cells.
Decrease in cardiac rate (-ve chronotropic)
Decrease in the rate of conduction in SA node and AV
conduction systems (-ve dromotropic)
Decrease in the force of cardiac contraction (-ve ionotropic)
28
27. Pharmacologic effects (3)
Effect on Gastrointestinal tract
Increased intestinal tone and peristaltic activity
Stimulation of salivation and acid secretion (M1)
Relaxation of most sphincters
Effect on Genitourinary tract
Stimulation of the detrusor muscle and relaxation of the
trigone and sphincter muscles of the bladder, thus
promoting voiding.
The human uterus is not notably sensitive to muscarinic
agonists.
29
28. Pharmacologic effects (4)
Effect on Respiratory System
Contraction of bronchial smooth muscle
(bronchoconstriction)
Stimulation of glands of the tracheobronchial mucosa →
secretion
Effect on Exocrine Glands
Stimulation of secretion (lacrimation, salivation,
sweating)
30
29. Pharmacologic effects (5)
Effect on the Eye
Contraction of two important muscles in the eye
Circular muscle (constrictor pupillae) of the iris
Smooth muscles of the ciliary body that controls the thickness of
the lens
Decrease in intraocular pressure due to two reasons
Ciliary muscle contraction puts tension on trabecular meshwork,
opening its pores and facilitating outflow of aqueous humor into
the canal of Schlemm
Contraction of the iris sphincter pulls the peripheral iris away
from the trabecular meshwork, thereby opening the path for
aqueous outflow.
31
30. Clinical Use
The therapeutic use of cholinomimetics is limited by
the paucity of drug selectivity for specific subtypes of
muscarinic receptors.
This lack of specificity combined with broad-ranging
effects of muscarinic stimulation on different organ
systems makes the therapeutic use of cholinomimetic
drugs a challenge.
32
31. Major therapeutic uses of the cholinomimetics
– Eye (glaucoma, accommodative esotropia)
– Gastrointestinal and urinary tracts (postoperative atony,
neurogenic bladder),
– Neuromuscular Junction (myasthenia gravis, curare-induced
neuromuscular paralysis)
– Heart (very rarely) (certain atrial arrhythmias).
– AchEIs: occasionally used in the treatment of atropine
overdosage.
– Several newer AchEIs are being used to treat patients with
Alzheimer's disease.
32. Clinical indications:
Glaucoma
Pilocarpine is the first choice among
cholinomimetics. It can be applied as gel in
chronic open-angle glaucoma and as drop in
emergency cases of angle-closure glaucoma.
Carbachol is sometimes effective in treating cases of
open-angle glaucoma that are resistant to pilocarpine.
34
33. Surgery of the Eye
Ach is used in cases where miosis is required for a short
period of time (10 min).
Carbachol is used for operations necessitating miosis for
longer than 10 minutes
Diagnosis of Bronchial Hyper-reactivity
Methacholine is indicated for the diagnosis of bronchial
airway hyper-reactivity in subjects who do not have
clinically apparent asthma
35
34. Urinary and GI Smooth Muscle Dysfunction
Urinary Retention
To treat postsurgical non obstructive bladder dysfunction
associated with the retention of urine
GI Atony
Treatment of postoperative ileus (atony or paralysis of the
stomach or bowel following surgical manipulation) and
congenital megacolon
Bethanechol most widely used for the purpose
36
35. Alzheimer’s Disease
Found to have a development of cholinergic
deficits.
Oxotremorine has been developed as a
muscarinic agonist which is able to pass
through the BBB and act centrally.
not yet available for clinical use.
37
36. C/Is & ADEs
Contraindications
• Major contraindications are:
– asthma, hyperthyroidism, coronary insufficiency, and
acid-peptic disease.
Adverse Effects (ADRs)
• ADR include
– sweating, abdominal cramps, urinary urgency, difficulty
in visual accommodation, headache, and salivation.
38
38. AchEIs
• Anti- Choline esteras drugs are indirect acting
parasympatomimetics
Inhibits AchEs and protect Ach from hydrolysis , hence are
indirect acting cholinergic drugs.
This results in the accumulation of acetylcholine in the
synaptic cleft
– Provoke a response at all cholinoceptros in the body,
including both muscarinic and nicotinic receptors of the ANS.
– Some of the AchE inhibitor drugs have intrinsic nicotinic
activity (quaternary ammonium cpds).
40
39. AchEIs
• Classified in to two groups:
– Reversible AchE inhibitors
– Irreversible AchE inhibitors
• Irreversible:
– poisons rather than drugs.
– Includes Organophosphates and organochlorides
41
Reversible:
• Physostigmine
• Neostigmine
• Pyridostigmine
• Edrophoniuim
• Rivastigmine
Irreversible:
• Parathion
• Malathion
• DDT
AchEIs
40. AchEIs are broadly classified into two:
1. Reversible
a. Non-covalent inhibitor drugs: simple alcohols
bearing a quaternary ammonium’ eg,
edrophonium.
b. Carbamic acid esters of alcohols bearing quaternary
or tertiary ammonium groups (E.g, Neostigmine).
2. Irreversible
Organic derivatives of phosphoric acid
(Organophosphates, eg, Echothiophate).
generally irreversible.
42
41. Nature of Interaction with AchE
Non-covalent inhibitors
Bind electrostaticaly & by hydrogen bonds to
the anionic active site, preventing access of
Ach (2-10’)
Edrophonium, Ambenenium, Tacrine and
Donepezil (with longer activity and more
lipophilicity)
43
42. Nature of Interaction with AchE
Carbamate esters
Same hydrolysis pattern, same as for Ach but
form carbamoylated enzyme, which is more
resistant to hydration, and enzyme takes
longer time to regenerate (in the order of 30
minutes to 6 hours)
Physostigmine, neostigmine, pyridostigmine,
rivastigmine
44
43. Organophosphates;
Undergo binding and hydrolysis, resulting in a
phosphorylated active site. The phosphorus-
enzyme bond is extremely stable (hundreds of
hours).
Phosphorylated enzyme complex may undergo
aging, which involves breaking of one of the
oxygen-phosphorus bonds further strengthening
the phosphorus-enzyme bond.
Sarin, Tabun, Soman, Malathion, Parathion,
Echothiophate are some of the drugs.
45
45. Effects on Autonomic Cholinergic
Synapses
↑ ed secretions from salivary, lacrimal, bronchial
and gastrointestinal glands,
Increased peristaltic activity, bronchoconstriction,
bradycardia and hypotension, pupillary
constriction, fixation of accommodation for near
vision, fall in intraocular pressure.
Large doses can stimulate, and later block,
autonomic ganglia, producing complex autonomic
effects 47
46. Effects on Neuromuscular Junction
Low (therapeutic) concentrations
Prolonged and intensified actions of physiologically
released Ach (ed strength of contraction)
At higher concentrations
Fibrillation of muscle fibers
With marked inhibition
Depolarizing neuromuscular blockade occurs and that
may be followed by a phase of non-depolarizing
blockade
48
47. Effects on the CNS
Tertiary compounds, such as physostigmine, and the
non-polar organophosphates penetrate the BBB freely
and affect the brain.
Initial excitation, which can result in convulsions,
followed by depression, which can cause
unconsciousness and respiratory failure.
Effects are mediated via the muscarinic receptors in
the CNS
49
48. Neurotoxicity of Organophosphates
Many organophosphates can cause a severe type
of peripheral nerve demyelination, leading to
slowly developing weakness and sensory loss.
This seems to result from inhibition of an esterase
(not cholinesterase itself) specific to myelin.
50
49. Cholinesterase Reactivation
Dephosphrylation of enzyme can be effected by
strong nucleophilic cpds like the oximes (pralidoxime,
obidoxime)
Used in organophosphate poisoning but they should
be used with in few hours following exposure.
Once aging has occurred reactivation of cholinesterase
is practically impossible.
51
50. Clinical Use
Myasthenia Gravis
Autoimmune disease in which the No of functional
nicotinic receptors on skeletal muscle es, with
consequent in the sensitivity of muscle to ACh.
Anticholinesterase used in diagnosis and therapy are:
Pyridostigmine, neostigmine, ambenenium
52
51. Smooth Muscle Atony
Non-obstructive paralytic ileus & atony of the urinary
bladder, which may result from surgery.
Neostigmine is most commonly used, and it can be
administered subcutaneously or intramuscularly
Antimuscarinic toxicity
Toxicities with antimuscarinic drugs (atropine and
scopolamine) and others with significant anticholinergic
effect
Physostigmine has been used in such acute toxicities
53
52. Alzheimer’s Disease
Functional changes in AD appear to result primarily from
the loss of cholinergic transmission in the neocortex
Tacrine, donepezil, rivastigmine, and galanthamine are
cholinesterase inhibitors approved in AD.
Produce modest but significant improvement in the
cognitive function of patients with mild to moderate AD
but do not delay the progression of the disease.
54
53. Glaucoma
Long-lasting AChE inhibitors, such as demecarium,
echothiophate, and physostigmine are effective in
treating open-angle glaucoma though are largely
replaced by less toxic drugs
Reversal of Neuromuscular Blockade
Used post operatively to reverse effects of Non-
depolarising muscle relaxants
Neostigmine, pyridostigmine, and edrophonium are used
for this purpose.
55
54. Unwanted Effects
Acute toxicity result from accumulation of Ach
First muscarinic stimulation, followed by nicotinic receptor stimulation
and then desensitization of nicotinic receptors.
Excessive inhibition leads to cholinergic crisis
Gastrointestinal distress,
respiratory distress,
CV distress (bradycardia or tachycardia, A-V block, hypotension),
Visual disturbance,
Sweating,
loss of skeletal motor function,
CNS symptoms (agitation, dizziness, and mental confusion).
Death usually results from paralysis of skeletal muscles required for
respiration but may also result from cardiac arrest.
56
58. A. MUSCARINIC BLOCKERS
Most are Amino Alkaloid Esters of tropic acid with a
tertiary amine or quaternary ammonium group
Tertiary amines can cross membranes (including BBB)
• Antimuscarinics are competitive antagonists of
the binding of Ach to muscarinic receptors
60
59.
60. Clinical Use
Cardiovascular use
Carotid sinus syncope
Sinus or nodal bradycardia associated with excessive
vagal tone in acute myocardial infarction
As preanaesthetic medication
To reduce excessive salivary and bronchial secretion
induced by certain inhalational aneasthetics
62
61. Anticholinesterase poisoning
Atropine interferes with muscarinic effects and not the
nicotinic ones
Use in ophthalmology
Produce mydriasis (due to dilation of the pupil)
Produce cycloplegia (due to relaxation of ciliary muscles)
Funduscopic examination
Prevent synechia (adhesion) formation in uveitis and
iritis (Homatropine)
63
62. Use in GI disorders
Pirenzepine, telenzepine: more selective to M1 and are
used in acid-peptic diseases
As adjunctive therapy in the treatment of irritable bowel
syndrome and diarrhea
GI hypermotility (spasmolytics hyoscine, atropine
methonitrate)
64
63. Uses in Urology
Propantheline , Oxybutynin, Dicyclomine, used for
uninhibited bladder syndrome, bladder spasm, enuresis,
and urge incontinence.
Tolterodine, a non-selective muscarinic antagonist,
exhibits functional specificity for blocking muscarinic
receptors in the bladder
65
64. Respiratory Disorders
Ipratropium in chronic obstructive lung diseases (COPD)
Parkinsonism
There is an apparent excess of cholinergic activity in the
striatum of patients suffering from this disorder.
Benztropine mesylate, Biperiden, Procyclidine, and
Trihexyphenidyl hydrochloride
Prevention of motion sickness
Anticholinergic activity in the vestibular nuclei and reticular
formation may account for their effect
Scopolamine is used for the purpose
66
65. Antimuscarinic Poisoning
Lower doses
Signs of peripheral muscarinic blockade
Large doses
CNS effects (e.g., headache, restlessness, ataxia, and
hallucinations)
Can be managed by removing unabsorbed drug, treating
symptoms, and providing supportive therapy.
Use of physostigmine in life-threatening effects
(seizures, severe hypertension, hallucinations, or
lifethreatening arrhythmias)
67
69. Vesicular Storage of NE
• Dopamine hydroxylase is located only within the
vesicles
• There is a tendency for NE to leak from the
vesicles into the cytosol, where it is destroyed by a
mitochondrial enzyme, monoamine oxidase (MAO).
71
70. Vesicular Storage of NE
• However, most of the NE that leaks out of the
vesicle is rapidly taken up in to storage vesicles by
an active transport system.
Ensures regulated release of transmitters
Decreases intraneuronal metabolism
Decreases leakage of NE to the extracellular sites
72
71. Release of NE
• Action potential triggers exocytotic release of NE
containing vesicles.
• Neuropeptide Y and ATP are also released along
with NE.
73
72. Prejunctional Regulation of NE release
• Inhibit NE release:
– 2 to inhibit its further release
– NPY (Y2) and Adenosine derived from ATP (P1)
– muscarinic M2 & M4 receptors
• Increase NE release:
– 2-AR, Agt-II, nicotinic receptors
74
73. Removal of NE from the Synapse
• Termination of its transmitter role
• Three processes contribute to this process
1. Transport back into the noradrenergic neuron
(reuptake, uptake1) [87%]
2. Dilution by diffusion out of the junctional cleft (8%)
and uptake into extraneuronal sites (extraneuronal
uptake or uptake2) (5%)
3. Metabolic transformation
By MAO and COMT (catechol O-methyl transferase)
75
74. Adrenoceptors
• Can broadly be divided into two:
– -AR & -AR:
• comparative potency;
– -AR : EPI ≥ NE >>isoproterenol
– -AR: isoproterenol > EPI ≥ NE
• -AR: constitutes 1 & 2 subtypes
– 1A, 1B, and 1D
– 2A, 2B, and 2C
• -AR: constitutes 1 , 2 & 3 subtypes
• Are all GPCR’s
76
76. CLASSIFICATION OF
SYMPATHOMIMETIC DRUGS
• Direct acting
Act directly on one or more of the adrenergic receptors
• Indirect acting
Increase the availability of NE or Epi in synapses
Release or displace NE from sympathetic nerve varicosities
Block transport of NE into sympathetic neurons
Blocking metabolizing enzymes MAO or COMT.
• Mixed acting
Indirectly release NE & directly activate receptors
78
79. Epinephrine/Adrenaline:
pharmacological effects (1)
• Blood Pressure
Potent vasopressor
Rapid IV injection of pharmacological dose
BP rises to a peak that is proportional to the dose
As the response wanes, BP falls before returning to control
level
Small dose (0.1 g/kg rapid IV infusion) causes
fall in BP
Mechanisms of rise in BP
+ve ionotropy, +ve chronotropy and Vasoconstriction in
many vascular beds (skin, mucosa, kidneys and veins)
81
80. Epinephrine/Adrenaline:
pharmacological effects (2)
• Blood pressure (cont’d)
Slow IV infusion (10-30 g/min) or SC (0.5-
1.5mg)
Moderate in systolic BP (due to in cardiac output)
Peripheral resistance es (due to dominant 2), hence
diastolic BP es
82
82. Epinephrine/Adrenaline:
pharmacological effects (4)
• Cardiac effects
ed heart rate and altered rythm
Cardiac systole: shorter and stronger
ed cardiac output
Cardiac work and oxygen consumption es
ed cardiac efficiency
84
83. Epinephrine/Adrenaline:
pharmacological effects (5)
• Smooth muscle effects
GI smooth muscle
Relaxation due to both - & -AR mediated effects
Reduced intestinal tone and frequency and amplitude of spontaneous
contraction
Stomach relaxed, pyloric and ileo-cecal sphincter are contracted
Uterine smooth muscle
2 mediated inhibition of uterine tone and contraction during the last
month of pregnancy and parturition.
Urinary bladder
Relaxation of detrusor muscle ( mediated)
Contraction of trigone and sphincter muscle ( mediated)
85
84. Epinephrine/Adrenaline:
pharmacological effects (6)
• Respiratory effects
Strong bronchodialator
Also have 2-mediated inhibition of release of inflammatory
mediators from mast cells
Decreases bronchial secretion and congestion of mucosa (-
mediated)
• CNS effects
Too polar to cross the BBB
86
85. Epinephrine/Adrenaline:
pharmacological effects (7)
• Metabolic effects
Inhibition of insulin secretion
Predominant 2-mediated inhibition
2-mediated activation of release
ed glucose uptake by peripheral tissues
-mediated activated glycogenolysis
free fatty acid level (3-mediated lipolysis)
• Effects on the eye
Mydriasis, ed intraocular pressure
87
86.
87. Pharmacokinetics
• Orally not effective
• SC: slow absorption (due to vasoconstriction)
• More rapid absorption through IM
• IV used only in emergency conditions
• Inhalational aerosol to produce local effect
• Metabolism is via hepatic MAO and COMT
89
88. Adverse effects, contraindications
• Restlessness, throbbing headache, tremor,
palpitations cerebral hemorrhage, cardiac
arrhythmias
• Angina may be induced in coronary artery
disease
• Contraindicated in patients taking -AR blockers
90
89. Therapeutic uses
Has limited clinical use
• Anaphylactic shock
• Prolong action of local anesthetics
• Restore cardiac rhythm in patients with cardiac
arrest
• Topical hemostatic agent
• To lower intraocular pressure
91
90. Dopamine: pharmacological effects
(1)
• CVS
Dopamine exerts its cardiovascular actions by
1. Releasing NE from adrenergic neurons
2. Interacting with -and -ARs, and
3. Interacting with specific dopamine receptors
Low rates of dopamine infusion
D1-mediated vasodilation in
o renal, coronary and intercerebral vascular beds with little
effect on other blood vessels or on the heart.
ed GFR, renal blood flow, Na+ excretion (appropriate in
management of such states as CHF)
92
91. Dopamine: pharmacological effects
(2)
• CVS (cont’d)
Higher rate of infusion
1-mediated +ve ionotropy
Releases NE from nerve terminals
ed systolic BP
Even higher levels
Activates 1-ARs and cause a more generalized vasoconstriction
Does not have CNS effects.
Clinical uses
• Treatment of severe congestive failure
• Treatment of cardiogenic and septic shock.
93
92. Adverse effects, contraindications
• Nausea, vomiting, tachycardia, anginal pain, headache,
HTNH, and peripheral vasoconstriction.
• Extravasation of large amounts of dopamine cause necrosis.
• Contraindicated or used at a much reduced dosage with MAO
inhibitor.
• Careful adjustment of dosage is necessary in patients who are
taking tricyclic antidepressants.
94
94. Isoproterenol/Isoprenaline
• Non-selective receptor agonist with very low affinity
for receptors.
• Pharmacological Effects
– CVS
peripheral vascular resistance (potent
vasodilator)
Diastolic BP while systolic BP may have a
lesser or a slight rise
cardiac output
96
95. Pharmacological Effects Isoproterenol (Cont’d)
• Smooth muscles
• Relaxation especially those of the GI and bronchial
• Metabolized primarily by COMT
– relatively resistant to MAO
– uptaken in to sympathetic neurons to a lesser extent than
Epi & NE.
• Toxicity and Adverse effects
– Palpitations, tachycardia, headache, and flushing are
common and arrhythmias.
97
96. Isoproterenol (Cont’d)
• Therapeutic Uses
– Management of bronchospasm (inhalation)
– In emergencies to stimulate heart rate in patients with
bradycardia or heart block and asthma (I.V.)
98
97. Dobutamine
• Relatively 1 selective, but also acts on 1
• Actions are not due to
Release of NE from sympathetic neurons
Activation of dopamine receptor
• Dobutamine possesses a center of asymmetry
(-)- isomer is a potent agonist at 1 receptors
(+)- isomer is a potent 1 agonist & 1 receptor
antagonist, which can block the effects of (-)-dobutamine.
Greater +ve ionotropic effect than Isoprenaline
TPR doesn’t significantly decreased (1 activation)
99
98. Dobutamine (Cnt’d)
• Pharmacological Effects
– CVS
More prominent inotropic than chronotropic effects
compared to isoproterenol
Administration at 2.5 to 15 mg/kg/min
es cardiac contractility and cardiac output.
TPR is not greatly affected.
HR es only modestly.
100
99. Dobutamine (Cnt’d)
• Adverse Effects
Hypertension, tachycardia, Atrial fibrillation (especially if
there is preexisting condition), ventricular ectopic activity,
Increase in the size of a myocardial infarct by increasing
myocardial oxygen demand.
• Therapeutic use
Treatment of Cardiogenic shock
101
101. Selective 2-AR Agonists
These include:
Salbutamol/Albuterol
Terbutaline
Salmeterol
Formoterol and
Ritodrine.
103
102. 2-AR Agonists
bronchodilatation, vasodilatation and uterine
relaxation, without significant cardiac stimulation
primarily used for bronchial asthma
Others
as uterine relaxant to delay premature labour
(Ritodrine)
In hyperkalemic familial periodic paralysis -benefit
by enhancing K+ uptake into muscle
103. Adverse Effects of 2-Selective
Agonists
Tremor (tolerance develops with increased use),
restlessness, anxiety, tachycardia, increased
bronchial hypersensitivity,
104. Terbutaline
• Not a substrate for COMT.
• Effective orally, subcutaneously,
or by inhalation.
• Effects observed rapidly on
inhalation or parenteral
administration
• Therapeutic use
Long-term treatment of obstructive
airway diseases and acute
bronchospasm,
Emergency treatment of status
asthmaticus (Parenteral)
Control premature labor 107
105. Salbutamol/Albuterol
• Pharmacology & therapeutic
indications are similar to that
of terbutaline
• Produces significant
bronchodilation within 15
min, & effects persist for 3 to
4 hours (Inhalation)
• Used to treat asthma and
COPD
108
106. Metaproterenol
• Resistant to methylation by COMT
• a substantial fraction (40%) is absorbed in active
form after oral administration. It is also used by
inhalation
• Less selective to 2 than albuterol or terbutaline
• Therapeutic use
Long-term treatment of obstructive airway diseases,
asthma, and for treatment of acute bronchospasm
109
107. Salmeterol
• Has slow onset but prolonged duration of action
(>12 hours)
• has 50X greater selectivity for 2 receptors than
albuterol.
• also may have antiinflammatory activity.
• Salmeterol or Formoterol
– are the agents of choice for nocturnal asthma in
patients who remain symptomatic despite
antiinflammatory agents and other standard
management.
110
108. Ritodrine
• 2 receptor agonist developed specifically for
use as a uterine relaxant
• has high β2-selectivity
• is a tocolytic drug, was used to stop premature
labor.
• It is available in oral tablets or as an injection.
• Use: To arrest premature labor
(intravenously).
111
109. Other less commonly used 2 agonists
Isoetharine (acute bronchoconstriction)
Bitolterol
Formoterol (long acting~12hrs, used in COPD,
prophylaxis of exercise induced bronchospasm)
112
111. Phenylephrine
Pure 1 agonist
Causes marked arterial vasoconstriction
Used as a nasal decongestant, mydriatic, can
be used in hypotension
Not a catechol derivative, hence not a substrate
for COMT (acts longer than the catecholamines)
114
113. Other drugs:
– Midodrine
• Hydrolyzed to desglymidodrine (prodrug)
• For treatment of orthostatic hypotension (Rises in BP are
associated with both arterial and venous smooth muscle
contraction)
• Advantageous in the treatment of patients with autonomic
insufficiency and postural hypotension
– Methoxamine (prolonged increase in BP, also causes
vagally mediated vasoconstriction)
– Mephentermine (prevent hypotension during spinal
anaestheasia),
– Metaraminol
116
115. Alpha2-selective agonists
• clonidine, methyldopa, guanfacine,
guanabenz)
• Dexmedetomidine (CA2-SA)
– indicated for sedation of initially intubated &
mechanically ventilated patients during treatment in an
intensive care setting.
– It also reduces the requirements for opioids in pain
control.
116. Clonidine
• Activates central 2-ARs (and probably immidazoline1
receptors) to reduce sympathetic outflow to the
periphery.
• Also activates peripheral pre-synaptic 2-ARs
• Stimulates parasympathetic outflow
• IV infusion:
Acute rise in BP (mediated through 2-ARs in vascular
smooth muscle)
More prolonged hypotensive response (decreased
sympathetic outflow from the CNS)
119
117. Clonidine
• Well absorbed orally and has bioavaillability of about
100%
• Adverse effects
Dry mouth, sedation, sexual dysfunction, marked
bradycardia, Rebound hypertension following abrupt
withdrawal of clonidine therapy.
• Therapeutic use
Treatment of mild to moderate hypertension
120
118. Apraclonidine
– When applied topically, it reduces intraocular
pressure with minimal or no effects on CVS.
– It does not cross the BBB.
– Therapeutic use:
Short-term adjunctive therapy in glaucoma
To control or prevent elevations in intraocular pressure
after laser iridotomy
121
119. Brimonidine
Similar in actions and use as apraclonidine
Unlike apraclonidine, it can cross the BBB and
can produce hypotension and sedation,
although these CNS effects are slight compared
to those of clonidine.
122
120. Guanfacine
Is more selective for 2 than is clonidine.
The drug has a large volume of distribution (4 to
6 liters/kg). Has relatively longer half-life than
clonidine
Guanfacine and clonidine appear to have similar
efficacy for the treatment of hypertension.
Adverse effects, including rebound hypertension,
are milder and occur less frequently with
guanfacine. 123
121. Guanabenz
Guanabenz and guanfacine are closely related
chemically and pharmacologically.
Guanabenz has a half-life of 4 to 6 hours and is
extensively metabolized by the liver.
Adverse effects are similar to those associated
with clonidine use.
124
122. -methyldopa
Methyldopa, an analog of DOPA, is decarboxylated to -
methyldopamine which is then actively transported to
vesicles where it is -hydroxylated to the 2-AR agonist
-methylnorepinephrine.
Use: treatment of hypertension (it is the
preferred agent during pregnancy)
Adverse effects: sedation, dry mouth,
bradycardia, hepatotoxicity, hemolytic anemia
125
126. Non-Selective Antagonists
Fall into the following chemical groups
-Haloalkylamines (non-selective irreversible -AR
blockers)
Imidazolines (non-selective reversible -AR blockers)
Quinazoline derivatives (selective 1-AR blockers)
Indole derivatives (selective 2-AR blockers. E.g.,
yohimbine)
127. Pharmacological effects
• CVS
1-AR antagonists
Inhibits vasoconstriction induced by catecholamines
The fall in BP opposed by baroreceptor reflexes
1-AR antagonist + phenylephrine abolished pressor
1-AR antagonist + NE pressor response incompletely
blocked (due to 1-mediated myocardial effects)
1-AR antagonist + Epi Depressor effect
130
128. … effects
• Pharmacological effects (CVS, cont’d)
2-AR Antagonists
release of NE from peripheral sympathetic neurons
sympathetic outflow from the CNS
Hence cause in BP
131
129. Phenoxybenzamine
• Irreversible non-selective inhibitors of -AR (slight selectivity
to 1)
• Restoration of cellular responsiveness to agonists requires
synthesis of new receptors.
Pharmacological effects;
• CVS
ed peripheral resistance
ed cardiac output due to
Reflex sympathetic stimulation
ed release of NE in sympathetic neuroeffector junction
132
130. Phenoxybenzamine …
• Therapeutic Uses
Treatment of pheochromocytoma /tumor of adrenal
medulla w/c causes overproduction of Adrenaline/
Treat patients in preparation for surgery
Prolonged treatment in patients with inoperable or malignant
pheochromocytoma
• Toxicity and adverse effects
Postural hypotension accompanied by reflex
tachycardia, reversible inhibition of ejaculation.
It is found to be mutagenic in experimental studies.
133
131. Phentolamine
• Therapeutic Use
Short-term control of HTN in patients with
pheochromocytoma
Relieve pseudo-obstruction of the bowel in
patients with pheochromocytoma
Used in hypertensive crises (abrupt withdrawal of
clonidine or ingestion of tyramine-containing
foods during use of nonselective MAO inhibitors)
134
132. Phentolamine …
• Toxicity and Adverse Effects
Hypotension, tachycardia, cardiac arrhythmias
Abdominal pain, nausea, and exacerbation of
peptic ulcer
should be used with caution in patients with
coronary artery disease or a history of peptic
ulcer.
135
134. Quinazoline derivatives (Prazosin,
Terazosin and Doxazosin)
• Prazosin is the prototype drug
• It has about a 1000 fold greater affinity for 1-AR
than that for 2-AR.
• Has similar potencies at 1A, 1B, and 1D
• It is an inhibitor of cyclic nucleotide
phosphodiesterases
137
135. Prazosine; Pharmacological properties
• Blocks 1-ARs in arterioles & veins fall in TPR
and venous return
• Does not increase heart rate
Does not affect 2-ARs and no increase in NE
release and hence no tachycardia
It es cardiac preload and thus has little
tendency to increase cardiac output and rate
138
136. Prazosin; Pharmacokinetics
• Well absorbed orally with bioavaillability of 50-70
%, extensively protein bound (95%)
• It has a duration of action of 7 to 10 hours in the
treatment of hypertension
139
137. Terazosin and Doxazosin
• Have same activity as prazosin and differ in
pharmacokinetic profiles
Terazosin is more hydrophilic with better
bioavaillability (>90%).
DoA extends to 18 hrs, enables once per day
administration
Duration of action of doxazosin extends to 36 hrs.
140
138. Tamsulosine
• An 1-AR antagonist with some selectivity for 1A
(and 1D) subtypes compared to 1B subtype
• Blockade of 1A receptors in prostate.
• It is efficacious in the Rx of BPH (benign prostatic
hyperplasia) with little effect on BP.
141
141. Yohimbine
• Indole alkylamine alkaloid which is selective
competitive antagonist of 2-AR.
• It readily enters the CNS, and acts to increase BP
and heart rate; it also enhances motor activity and
produces tremors
144
143. Introduction
• Most are competitive antagonists of -AR
• Useful in the treatment of hypertension, ischemic
heart disease, CHF, and certain arrhythmias
• Propranolol: prototype drug in this group
146
144. • -AR antagonists can be distinguished by
Relative affinity for 1 and 2 receptors
Non-selective antagonists (propranolol,
nadolol, timolol)
1-Selective antagonists (metoprolol,
atenolol, acebutolol, bisoprolol, and
esmolol): the selectivity is not absolute and is
dose dependent
147
145. -AR antagonists with ISA
Intrinsic sympathomimetic activity (ISA)
Pindolol and acebutolol:
activate -AR partially in the absence of catecholamines
Counter productive to the response desired from a -
antagonist
Prevent profound bradycardia or negative ionotropy in
a resting heart
Differences in lipid solubility
Pharmacokinetic properties
148
146. Nonselective -AR antagonists
Inhibit vasodilation caused by isoproterenol
Augment pressor response to epinephrine
Significant in patients with pheochromocytoma, in
whom receptor antagonists should be used only after
adequate receptor blockade has been established
(This avoids uncompensated receptor-mediated
vasoconstriction caused by epinephrine)
149
147. Pharmacologic effects (cont’d)
• Pulmonary effects
2-mediated increase in airway resistance
Little effect in individuals with normal pulmonary function
1-selective antagonists or antagonists with ISA activity
are less likely than propranolol to increase airway
resistance
Celiprolol: 1 receptor selectivity and 2 receptor
partial agonism
• Effects on the eye
Decrease in aqueous humor production
intraocular pressure
150
148. Pharmacologic effects (cont’d)
• Metabolic effects
Modify the metabolism of CHOs and lipids.
Catecholamines promote glycogenolysis and mobilize
glucose in response to hypoglycemia
Block glycogenolysis
the release of free fatty acids from adipose
tissue
151
150. Propranolol
• has 1- & 2-AR equal affinity, lacks intrinsic
sympathomimetic activity, and does not block -
ARs
• Highly lipophilic and is almost completely absorbed
after PO.
• Undergoes extensive first pass effect (only about
25% reaches the systemic circulation)
153
151. Propranolol
• Therapeutic use
Treatment of hypertension and angina
Treatment of supraventricular
arrhythmias/tachycardias, ventricular
arrhythmias/tachycardias, premature ventricular
contractions, digitalis-induced tachyarrhythmias,
myocardial infarction, pheochromocytoma
154
152. • Nadolol
A long-acting antagonist with equal affinity
for 1 and 2 receptors.
Has a relatively long t1/2 of 12 - 24 hrs.
Therapeutic use: treatment of hypertension &
angina pectoris.
155
153. • Timolol
Potent, non-subtype-selective antagonist.
Therapeutic use: Treatment of hypertension
CHF
Migraine prophylaxis
widely used in the t/t of glaucoma and intraocular
hypertension.
156
154. • Pindolol
Such drugs (-blockers with partial agonistic
activity) may be preferred as antihypertensive
agents in individuals with diminished cardiac
reserve or a propensity for bradycardia.
Such drugs produce smaller reductions in resting
heart rate and BP.
157
156. 1-Selective AR Antagonists
• Metoprolol
Devoid of ISA and membrane-stabilizing activity.
Therapeutic Uses
For the treatment of hypertension, treatment of stable angina.
Effective in chronic heart failure
• Atenolol
Devoid of ISA and membrane stabilizing activity
Too hydrophilic to penetrate the CNS
Therapeutic Uses
Treatment of hypertension, in elderly patients with isolated systolic
hypertension (in combination with a diuretic)
159
157. Esmolol
A 1-selective, very short acting
little ISA, & lacks membrane-stabilizing actions.
used (I.V.) when short acting agent is desired or in
critically ill patients in whom ADE (bradycardia, heart
failure, or hypotension) may necessitate rapid
withdrawal of the drug.
t1/2 8 minutes, peak effects occur within 6 to 10
minutes
Onset and cessation (within 20 minutes) of blockade
is rapid
160
158. • Acebutolol
Has some ISA and membrane-stabilizing activity.
Well absorbed, and undergoes significant first-pass
metabolism to an active metabolite, diacetolol,
Therapeutic Uses
Treatment of hypertension, ventricular arrhythmias
• Bisoprolol
A highly selective 1 receptor antagonist that does not have
ISA or membrane-stabilizing activity
Therapeutic uses:
For the treatment of hypertension,
161
159. -AR Antagonists with Additional CVS Effects
• Competetitive -antagonism + vasodilating effects
Labetelol (1 antagonist and 2 partial agonist)
Carvedilol (membrane-stabilizing activity)
Bucindolol (1 blocking as well as 2 & 3 agonistic
properties)
Celiprolol (weak 2 agonistic activity)
Nebivolol (NO mediated vasodilation)
Devoid of intrinsic sympathomimetic activity, inverse
agonistic activity, and 1 receptor blocking properties
162
160. Adverse effects and precautions
• Cardiovascular System
-AR blockade ( heart failure in susceptible
patients)
Bradycardia life-threatening bradyarrhythmias in
partial or complete AV conduction defects
Cold extremities
Abrupt discontinuation of -AR antagonists after
long-term treatment can exacerbate angina and
may increase the risk of sudden death
163
161. Adverse effects and precautions
(cont’d)
• Pulmonary Function
major ADE of receptor antagonists
Drugs with selectivity for 1-AR or those with
ISA at 2 AR may be somewhat less likely to
induce bronchospasm
• CNS
Include fatigue, sleep disturbances, and
depression
164
162. Adverse effects and precautions
(cont’d)
• Metabolism
may delay recovery from insulin-induced hypoglycemia
Used with great caution in patients with diabetes who are prone to
hypoglycemic reactions
1-selective agents may be preferable
• Over dosage
Common manifestations:
Hypotension, bradycardia, prolonged AV conduction time, and widened
QRS complexes
Seizures and depression may occur.
Hypoglycemia (rare) & bronchospasm (uncommon) in the absence
of pulmonary disease. 165
163. Adverse effects and precautions
(cont’d)
• Drug Interactions
Al-salts, cholestyramine, and colestipol may the
absorption of blockers
Phenytoin, Rifampin, and Phenobarbital, as well as smoking
(inducers) may decrease plasma concentrations of
blockers (e.g., propranolol).
166
Editor's Notes
Enteric NS. Though our focus will be on ANS, we will also deal with some aspects of SNS, as it makes use of Achlike PSNS
Cholinestrase regenerators=chemical antagonists of organophosphate AchEIs, not receptor blockers
Methoxamine is available for parenteral use, but clinical applications are rare and limited to hypotensive states.