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.

1. Autonomic Nervous
System Pharmacology
1

2. 2

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

5. Neurotransmitters at d/t peripheral sites

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

10. Cholinergic Transmission
 Synthesis of Acetylcholine
10

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

12. 12
Vesicular storage of Ach and Termination Ach action

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

15. Cholinergic Agonists
15

16. Pilocarpine
Muscarine
Bethanichol
Carbacol
Methacholine
Neostigmine
Physostigmine
Edrophonium
d- tubocurarine,
Succinylcholine

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

37. Cholinesterase Inhibitors
39

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

44. Pharmacological Effects of
AchE Inhibitors
46

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

55. ANTICHOLINERGIC DRUG
PHARMACOLOGY
57

56. Anticholinergic/ Parasympatholytics/
Cholinoceptor antagonists
 Selectively antagonize the actions of Ach or other
cholinergic agonists at muscarinic (muscarinic
blockers) and/or at nicotinic (nicotinic blockers)
receptors.
 Muscarinic blockers
 Nicotinic blockers
1. Ganglion blockers
2. NMJ blockers
58

57. Classification of Anticholinergic
drugs

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

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

66. Side Effects
68
Constipation
Dry mouth
Hypohidrosis (decreased sweating)
Mydriasis (dilated pupils)
Urinary retention
Precipitation of glaucoma
Decreased lacrimation
Tachycardia

67. Adrenergic
Pharmacology
69

68. 70

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

75. SYMPATHOMIMETIC
DRUGS
77

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

77. Classifications

78. Endogenous
Catecholamines
80

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

81. Epinephrine/Adrenaline:
pharmacological effects (3)
• Vascular Effects
 Constriction of cutaneous, mucosal and renal blood
vessels (1 mediated)
 Dilatation of blood vessels supplying skeletal
muscle (2 mediated)
 Epinephrine + -AR antagonists
 ed TPR and ed MAP
 Epinephrine + -AR antagonists
 ↑ Pressor effect
83

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

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

93. -AR AGONISTS
95

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

100. Selective 2-AR Agonists
102

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

110. Selective 1-AR Agonists
113

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

112. Xylometazoline & Oxymetazoline
• Direct-acting 1 agonist
• Topical decongestant (constrict the nasal
mucosa)
• Oxymetazoline has 2A Affinity
– Causes hypotension (large doses) = Clonidine-like effect

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

114. Selective 2-AR
Agonists
117

115. Alpha2-selective agonists
• clonidine, methyldopa, guanfacine,
guanabenz)
• Dexmedetomidine (CA2-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

123. ADRENERGIC ANTAGONISTS

124. AR Antagonists
127

125. Non-Selective
-AR Antagonists
128

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

133. 1-AR Selective
Antagonists
136

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

139. Adverse Effects
• First-dose effect; marked postural hypotension,
(quinazolines)
• Impaired ejaculation (tamsulosine)
142

140. Therapeutic uses
• Treatment of hypertension (prazosin and congeners)
• Congestive heart failure
• Benign prostatic hyperplasia (especially
tamsulosine)
143

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

142. -AR Antagonists
145

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

149. Non-Selective
-AR Antagonists
152

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

155. 1-Selective AR
Antagonists
158

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