There is a great deal of confusion regarding autonomic nervous system. In order to make the concepts a bit more clear, I've uploaded a presentation regarding the same which is a bit more comprehensive & which deals with various cholinergic, anticholinergic, adrenergic & anti-adrenergic drugs
4. ENS (3rd division of ANS)
• Submucosal, myenteric, and subserosal nerve
plexuses, is innervated by the sympathetic and
parasympathetic nervous systems.
• Synchronize propulsive contractions of gut muscle
(peristalsis).
• Parasympathetic activates the ENS
• Sympathetic inhibits the ENS
• ENS functions independently of autonomic
innervation after autonomic denervation
5. Neurotransmitters
Ach All autonomic ganglia, at parasympathetic
neuroeffector junctions, and at somatic NMJ, few
sympathetic neuroeffector junctions (sweat glands
and vasodilator fibers in skeletal muscle)
NE Sympathetic postganglionic neuroeffector
junctions
E Released from the adrenal medulla in activation
of sym.n.s.
Other neurotransmitters NPY, VIP, enkephalin,
substance P, serotonin, ATP, NO (vasodilatation)
In some tissues, ATP adenosine (activate
adenosine receptors) Nitric oxide is an important
12. Autonomic regulation of structures associated
with the eye
Dominant tone = Parasympathetic
Iris radial – contracted
via alpha-1
Iris circular –
contracted via M3
Ciliary muscle –
contracted via M3
13. Regulation of the heart
Dominant tone = parasympathetic
Sympathetic
Increases heart rate
and contractility via
beta-1 and 2
(primarily beta-1)
Parasympathetic
Decreases heart
rate and atrial
contractility via M2
14. Regulation of the blood vessels
Veins
Dominant tone =
parasympathetic
Arterioles/arteries
Dominant tone =
sympathetic
Contraction via
alpha1
Relaxation via
beta-2
15. Regulation of the liver
• Sympathetic
• Increase gluconeogenesis and glycogenolysis
• Provide glucose to fuel “flight or fight” response
• Primarily beta-2, possibly alpha-1
16. Control of stomach acid
Parasympathetic
• Increase histamine
release from ECL cell
via M3
• Increase H+
production from
parietal cell in
fundus via M3
• Decrease
somatostatin release
from D cell in
antrum
• Increases
gastrin release
from G cell
17. Regulation of the bladder
Parasympathetic
• Bladder wall
• Constriction via M3
• Relaxation via beta-2
• Sphincter
• Relaxation via M3
• Constriction via alpha-1
20. Physiological effects of autonomic innervation and
receptors that govern the effect
Parasympathetic Sympathetic
• Contracts the ciliary muscle
via M-3
• Decelerates the sinoatrial
node via M-2
• Decreases heart contractility
via M-2
• Releases EDRF in the
endothelium via M-3, M-5
• Contracts bronchiolar smooth
muscle via M-3
• Contracts GI walls via M-3
• Relaxes GI sphincters via M-3
• Increases GI secretions via M-
3
• Contracts the uterus via M-3
• Contracts the iris radial muscle via alpha-1
• Relaxes the ciliary muscle via beta
• Accelerates the sinoatrial node via beta-1,2
• Accelerates ectopic pacemakers via beta-1,2
• Increases cardiac contractility via beta-1,2
• Relaxes bronchiolar smooth muscle via beta-2
• Relaxes GI walls via alpha-2, beta-2
• Contracts GI sphincters via alpha-1
• Relaxes bladder wall via beta-2
• Contracts bladder sphincter via alpha-1
• Contracts uterus via alpha, relaxes uterus via
beta-2
• Contracts pilomotor smooth muscle via alpha
• Activates sweat glands via alpha, M
• Increases gluconeogenesis and glycogenolysis in
21.
22.
23.
24. Ach receptor agonists
1. Direct acting agonists Bind & activate Ach rec.
a) Choline esters Ach, Bethanechol, Carbachol
b) Plant alkaloids Muscarine, Nicotine,
Pilocarpine, Arecoline
c) Synthetic drugs Cevimeline, Varenicline,
Tremorine, Oxotremorine
26. Direct acting AchR agonists
1. Choline esters Quaternary ammonium
compds. (poorly abs. from GIT n BBB)
• Ach & Carbachol M + N; Bethanechol M only
• Resp. tract effects ↑ mucus secretion &
bronchoconstriction (caution in asthma, COPD)
• Cardiac effects ↓ impulse formation in SAN by
↓ the rate of diastolic depolarization (↓ HR) & ↑
PR interval (Time from SAN to AVN)
• Vascular eff. Vasodilation (NOS & cGMP); M3
• GIT eff. ↑ GI motility & secretions
• UT eff. + bladder detrusor muscle, relax the
internal sphincter of the bladder, and these effects
promote emptying of the bladder (micturition).
28. Loc. of receptors in bladder
• α1A bladder neck, urethra and prostate to enhance
bladder outlet resistance, in BPH
• β3- and β2-subtypes are important in the human
bladder and urethra, respectively.
• Contraction of the bladder involves direct contraction
via M3 receptors and an indirect ‘re-contraction’ via
M2-receptors whereby a reduction in adenylate cyclase
activity reverses the relaxation induced by β-
adrenoceptor stimulation.
• 3 Muscarinic receptors are also located on the
epithelial lining of the bladder (urothelium) where they
induce the release of a diffusible factor responsible for
inhibiting contraction of the underlying detrusor
smooth muscle. The factor remains unidentified but is
not nitric oxide, a cyclooxygenase product or adenosine
triphosphate.
29.
30. Effects of pilocarpine and atropine on the eye.
A, The relationship between the iris sphincter and
ciliary muscle is shown in the normal eye.
B, When pilocarpine, a muscarinic receptor
agonist, is administered, contraction of the iris
sphincter produces pupillary constriction (miosis).
Contraction of the ciliary muscle causes the
muscle to be displaced centrally. This relaxes the
suspensory ligaments connected to the lens, and
the internal elasticity of the lens allows it to
increase in thickness. As the lens thickens, its
refractive power increases so that it focuses on
close objects.
C, When atropine, a muscarinic receptor
antagonist, is administered, the iris sphincter and
ciliary muscles relax. This produces pupillary
dilatation (mydriasis) and increases the tension on
the suspensory ligaments so that the lens
becomes thinner and focuses on distant objects.
31. When the ciliary muscle is relaxed, the choroid acts like a spring pulling on the lens via the
zonule fibers causing the lens to become flat.
When the ciliary muscle contracts, it stretches the choroid, releasing the tension on the
lens and the lens becomes thicker.
32.
33. Acetylcholine
• Choline ester of acetic acid
• Uses
1. During cataract surgery (Miosis) NO topical
2. Diagnostic coronary angiography intracoronary
injection to cause coronary artery spasm
3. Vasospastic angina pectoris, however,
intracoronary injection of acetylcholine can
provoke a localized vasoconstrictive response,
and this helps establish the diagnosis of
vasospastic angina
34.
35. Clinical uses of direct acting AchR ag.
• Bethanechol
1. Urinary retention (Postoper. Or neurogenic bld.)
2. GIT atony (Expel gases, paralytic ileus)
3. Xerostomia (Salivary gland malfunc., Sjogren’s)
• Methacholine MCT (bronchial asthma)
• Carbachol Miosis during ophthalmic surgery
• Pilocarpine (Tertiary amine) sel. For Muscarinic R
1. Ophthalmic Glaucoma, mydr., break adhesions
2. Sialagogue Xerostomia (laryng. surg., radioth.)
37. Indirect acting AchR agonists
1. Drugs that inhibit AchE
1. Reversible chE inhibitors (shorter acting)
• Edro, neo, pyrido, physo, done, galant., rivast.
2. Quasi-reversible chE inhibitors (long acting)
• OP (Echothio, isofluro, malathion)
2. Type 5 PDE inhibitors
38.
39. Reversible chE inhibitors
1. Edrophonium (+vely charged alc. that reversibly
binds to a –vely charged anionic site on AchE)
• Duration of action 10 mins.
• Patients with myasthenia gravis may experience
muscle weakness from either undertreatment or
overtreatment with a cholinesterase inhibitor drug.
• Untreated - Edr ↑ Ach levels and muscle strength
• Overtreated - muscle weakness caused by ↑ Ach at
NMJ depol blockade similar to Sch (cholinergic
crisis) test dose of edr muscle weakness ↑
patient’s dose of chE inhibitor should be ↓
45. OPs form a tight covalently bound intermediate with the catalytic site of chE
The phosphorylated intermediate is then hydrolyzed very slowly by the enzyme,
accounting for the long duration of action of these compounds. The covalently
bound intermediate is further stabilized by a spontaneous process called aging, in
which a portion of the drug molecule (the “leaving group”) is removed
46. • OPs augment cholinergic neurotransmission at both
central and peripheral cholinergic synapses
• Excessive activation of nicotinic receptors by
organophosphate compounds leads to a
depolarizing neuromuscular blockade and muscle
weakness.
• Seizures, respiratory depression, and coma can
result from the overactivation of acetylcholine
receptors in the central nervous system.
47. Anti-chE poisoning
M Miosis
U Urination
S Sec. ↑ (Salivation, lacrimation & sweating)
C Cardiac contraction & conduction slows
A Abdominal cramps
R Redn. In i.o.t. (esp. in glaucoma)
I Inc. (↑) GI motility
N NO dependent vasodilatation
I Inc. sec. from GIT & tracheobronchial tract
C Constriction of tracheobronchial tract
48. Treatment
1. Termination of further exposure to the poison
2. Maintain patent airway PPV
3. Supportive measures
4. Specific antidotes
a) Atropine (musc.) Counteracts muscarinic
symptoms
Dose 2 mg i.v. every 10 mins. Till atr. Signs
b) ChE reactivator Pralidoxime (nicotinic,
Diacetylmonoxime; Dose 1-2 gms slow i.v.
infusion
49. Acetylcholine
• Choline ester of acetic acid
• Uses
1. During cataract surgery (Miosis) NO topical
2. Diagnostic coronary angiography intracoronary
injection to cause coronary artery spasm
3. Vasospastic angina pectoris, however,
intracoronary injection of acetylcholine can
provoke a localized vasoconstrictive response,
and this helps establish the diagnosis of
vasospastic angina
50. Atropine & Scopolamine (t.a.)
• t1/2 2 hrs (oral route)
• After topical ocular administration, they have
longer-lasting effects because they bind to
pigments in the iris that slowly release the drugs.
• People with darker irises bind more atropine and
experience a more prolonged effect than do people
with lighter irises. The ocular effects gradually
subside over several days.
• “dry as a bone, blind as a bat, red as a beet, and
mad as a hatter.” Atr. toxicity
51. Effects
• Ocular eff. Myd. + cycloplegia
• Cardiac eff. ↑ HR & AV conduction velocity by
blocking the effects of the vagus nerve on SAN,AVN
Low i.v. atropine paradoxical slowing of HR
(stimulation of the vagal motor nucleus in the brain
stem). After full dose heart rate ↑
• Resp. tract eff. bronchial smooth muscle
relaxation and bronchodilation, inhibitors of
secretions in the upper and lower respiratory tract.
52. Indications
• Ocular Indications mydriasis (facilitate peripheral
retina), cycloplegia (refractive errors), iritis and
cyclitis (↓ muscle spasm and pain)
• Cardiac Indications Sinus bradycardia after MI.
AV block to ↑ AV conduction velocity
• Respiratory Tract Indications ↓ salivary and
respiratory secretions & prevent airway obstruction
in patients who are receiving general anaesthetics.
Glycopyrrolate is often used for this purpose today
53. • GIT Indications Relieve intestinal spasms & pain
• UT indications Relieve urinary bladder spasms in
persons with overactive bladder.
• CNS Indications A transdermal formulation of
scopolamine can be used to prevent motion
sickness (blocking Ach neurotransmission from the
vestibular apparatus to the vomiting center in the
brain stem). Also, PD.
• Other Indications
1. Prevent muscarinic side effects when chE
inhibitors are given to patients with myasthenia
gravis.
2. Reverse the muscarinic effects of cholinesterase
inhibitor overdose.
55. MUSCARINIC effects (OP poisoning)
M Miosis
U Urination
S Secretions ↑ (salivation, lacrimation, sweating)
C Cardiac contraction & conduction slows
A Abdominal cramps
R Redn. In i.o.t. esp. in glaucoma
I ↑ GI motility
N NO dependent vasodilatation
I Inc. secretion from GIT & tracheobronchial tract
C Constriction of tracheobronchial tract
56. Adverse effects of Atropine
(DHATURA)
1. Dry mouth, difficulty in swallowing & speaking
2. Hot dry skin & hypotension
3. Accommodation paralysis (blurring of near vision)
4. Tachycardia
5. Urinary retention & fecal retention (constipation)
6. Respiratory depression
7. Ataxia & acute congestive glaucoma may
precipitate
57. Type 5 PDE inhibitors
1. Sildenafil & Tadalafil ED, BPH, PAH
Ach activates M3 rec. in vascular endothelial cells
↓
↑ NO
↓
NO diffuses into vascular smooth muscle cells in the
corpus cavernosum
↓
NO activates g. c. & ↑ cGMP,
↓
Muscle relaxation and vasodilation
• Also, inhibit the breakdown of cGMP by type 5 PDE
58.
59.
60. BPH cGMP-mediated vasodilation in prostate and
bladder tissue, as well as relaxation of prostate and
bladder smooth muscle in a way that reduces
obstruction to urine outflow
PAH Due to impaired release of NO by vascular
endothelial cells, resulting in deficient cGMP levels in
pulmonary vascular smooth muscle. Sildenafi and
tadalafi increase levels of cGMP by inhibition of type
V phosphodiesterase, causing relaxation of
pulmonary vascular smooth muscle and decreasing
pulmonary artery pressure. Other treatments for
PAH include epoprostenol (prostacyclin) and
endothelin receptor antagonists such as bosentan
61. A/E of PDE 5 inh.
• headache, nasal congestion, dyspepsia, myalgia,
back pain, and visual disturbances
• Concurr. Admin. of 5-PDE inhibitors and NG can
cause profound hypotension, reflex tachycardia,
and worsening of angina pectoris.
• augment the hypotensive effects of other
vasodilators, including α-adrenoceptor antagonists
(e.g., doxazosin), that are used to treat symptoms
of urinary obstruction in men with BPH
63. • Drugs that selectively block either muscarinic or
nicotinic receptors.
• Muscarinic receptor blockers Relax smooth
muscle, decrease gland secretions, or increase
heart rate
• Nicotinic receptor antagonists Neuromuscular
blocking agents that are used to relax skeletal
muscle during surgery.
64. Musc. Rec. ant.,Anti-chol.,psymly.
• Belladonna Alkaloids Extracted from Atropa
belladonna (the deadly nightshade), Datura
stramonium (jimson weed), and Hyoscyamus niger.
• Belladonna, which is an Italian expression meaning
“beautiful lady,” refers to the pupillary dilatation
(mydriasis) produced by ocular application of
extracts from these plants to women, which was
considered cosmetically attractive during the
Renaissance.
• Atropine, scopolamine, and hyoscyamine are
examples of belladonna alkaloids.
• In fact, atropine was named after Atropos, one of
the Fates in Greek mythology, who was known for
cutting the thread of life.
65.
66. Atropine & Scopolamine (t.a.)
• t1/2 2 hrs (oral route)
• After topical ocular administration, they have
longer-lasting effects because they bind to
pigments in the iris that slowly release the drugs.
• People with darker irises bind more atropine and
experience a more prolonged effect than do people
with lighter irises. The ocular effects gradually
subside over several days.
• “dry as a bone, blind as a bat, red as a beet, and
mad as a hatter.” Atr. toxicity
67. Effects
• Ocular eff. Myd. + cycloplegia
• Cardiac eff. ↑ HR & AV conduction velocity by
blocking the effects of the vagus nerve on SAN,AVN
Low i.v. atropine paradoxical slowing of HR
(stimulation of the vagal motor nucleus in the brain
stem). After full dose heart rate ↑
• Resp. tract eff. bronchial smooth muscle
relaxation and bronchodilation, inhibitors of
secretions in the upper and lower respiratory tract.
68. • GIT eff. Atropine ↓ lower esophageal muscle tone
(GERD), relaxed GI muscle (except sphincters), intestinal
motility, thereby increasing gastric emptying time and
intestinal transit time. They also inhibit gastric acid
secretion. Sufficient doses of these drugs can cause
constipation.
• UT eff. Atropine relaxes the detrusor muscle of the
urinary bladder and can cause urinary retention.
• CNS eff. Sedation and excitement. Scopolamine is
more sedating than is atropine and has been used as an
adjunct to anesthesia. Standard doses of atropine
typically cause mild stimulation,followed by a slower
and longer-lasting sedative effect. With higher doses
delirium & hallucinations.
• Other Effects Inhibit sweating, which can reduce
heat loss and lead to hyperthermia, especially in
children. The increased body temperature can cause
cutaneous vasodilatation, and the skin can become hot,
dry, and flushed.
69. Indications
• Ocular Indications mydriasis (facilitate peripheral
retina), cycloplegia (refractive errors), iritis and
cyclitis (↓ muscle spasm and pain)
• Cardiac Indications Sinus bradycardia after MI.
AV block to ↑ AV conduction velocity
• Respiratory Tract Indications ↓ salivary and
respiratory secretions & prevent airway obstruction
in patients who are receiving general anaesthetics.
Glycopyrrolate is often used for this purpose today
70. • GIT Indications Relieve intestinal spasms & pain
• UT indications Relieve urinary bladder spasms in
persons with overactive bladder.
• CNS Indications A transdermal formulation of
scopolamine can be used to prevent motion
sickness (blocking Ach neurotransmission from the
vestibular apparatus to the vomiting center in the
brain stem). Also, PD.
• Other Indications
1. Prevent muscarinic side effects when chE
inhibitors are given to patients with myasthenia
gravis.
2. Reverse the muscarinic effects of cholinesterase
inhibitor overdose.
71. Hyoscyamine
• levorotatory isomer of racemic atropine is
responsible for the pharmacologic effects of
atropine
• Formulations for oral or sublingual administration
are used to treat intestinal spasms and other
gastrointestinal symptoms
72. Semisynthetic & Synthetic Muscarinic
Receptor Antagonists
• Ipratropium & Tiotropium (Q.a.) OLD(Obstr. Lung
disease) not well absorbed from the lungs into the
systemic circulation (Few A/E)
• Unlike atropine, they do not impair the ciliary clearance
of secretions from the airways.
• Dicyclomine, Oxybutynin, Solifenacin Dicyclomine is
a synthetic amine used to relax intestinal smooth
muscle and thereby relieve irritable bowel symptoms,
such as intestinal cramping.
• Oxybutynin, tolterodine, darifenacin, solifenacin, and
trospium are used to reduce the four major symptoms
of overactive bladder:daytime urinary frequency,
nocturia (frequent urination at night), urgency, and
incontinence.
73. • Glycopyrrolate Blocks musc. rec.
1. preop. inhibit excessive salivary and respiratory
tract secretions.
2. It is also used during anesthesia to inhibit the
secretory and vagal effects of cholinesterase
inhibitors (e.g., neostigmine) that are used to
reverse nondepolarizing neuromuscular blockade
induced by curariform drugs (e.g., vecuronium).
3. Reduce chronic severe drooling in cerebral palsy.
• Tropicamide Mydriatic (pupillary dilator) Dur. Of
action (about 1 hour) and preferable to atropine
and scopolamine for short-term mydriasis.
• Pirenzepine Blocks M1 receptors on paracrine
cells and inhibits the release of histamine, a potent
gastric acid stimulant.
74. NICOTINIC RECEPTOR
ANTAGONISTS
1. Ganglionic blocking agents
• Their lack of selectivity for sympathetic or
parasympathetic ganglia & A/E Stopped
2. Neuromuscular blocking agents
75. N.m. Blocking Agents (Paralytics)
• Bind to NM & inhibit neurotransmission at skeletal
NMJ muscle
weakness and paralysis. Divided into :-
1. Nondepolarizing (Competitive) blockers
2. Depolarizing blocker Sch
• Extremely dangerous compounds (resp. failure in a
patient lacking external ventilatory support).
• Responsible for the rare occurrence of “anesthesia
awareness” during surgery, because they render a
patient immobile without affecting mental status
76.
77. Nondepolarizing Neuromuscular
Blocking Agents (Curariform drugs)
• atracurium, cisatracurium, pancuronium,
rocuronium, and vecuronium.
• Tubocurarine From plants used by native South
Americans as arrow poisons (curare) for hunting
wild game.
• +vely charged quaternary amines admin. only i.v.
• Eliminated by renal and biliary excretion (except
Cisatracurium elim. by Hoffman degradation &
given in impaired hepatic and renal function).
78. Mechanisms & effects
• Competitive antagonists of Ach at NMJ
• Paralysis sequence - Small & rapidly moving
muscles of the eyes and face Paralysis of larger
muscles of limbs & trunk. Intercostal muscles
and diaphragm resp. stops
• Respiratory function closely monitored
• Stimulate histamine release from mast cells & block
autonomic ganglia and muscarinic rec.
bronchospasm, hypotension, and tachycardia
• Doxacurium, cisatracurium, rocuronium, and
vecuronium Less histamine & autonomic s/e
80. Indications
1. Induce muscle relaxation during surgery &
facilitate surgical manipulations.
2. Adjunct to ECT to prevent injuries that might be
caused by involuntary muscle contractions.
3. Facilitate intubation of the respiratory tract so as
to enable ventilation and endoscopic procedures
(e.g., bronchoscopy).
• Degree of neuromuscular blockade small limb
contraction
81. Drug Selection
• Atracurium, cisatracurium, rocuronium, and
vecuronium provide duration of action (30 to 60
minutes).
• Doxacurium or pancuronium Longer duration of
action is required.
• Tubocurarine No longer used
82. Depolarizing Neuromuscular
Blocking Agents
• Succinylcholine 2 molecules of Ach
• Binds to NM transient muscle contractions
(fasciculations) Sustained muscle paralysis short
• duration of action 5 to 10 minutes
• sequence of muscle paralysis same as curare
• No antidote
• Indications Muscle relaxation before and during
surgery and to facilitate intubation of the airway
(emergency)administered in
• Nonemergent Interviewed (personal or family
history suggestive of atypical cholinesterase)..
83. Adverse effects
• Succinylcholine can cause hyperkalemia (burns and,
paralysis caused by spinal cord injury (up-regulation
of AchR at NMJ)
• Postoperative myalgia Muscles of neck, back,
and abdomen. (muscle fasciculations)
• Malignant hyperthermia
84.
85. Regulation of the heart
Dominant tone = parasympathetic
Sympathetic
Increases heart rate
and contractility via
beta-1 and 2
(primarily beta-1)
Parasympathetic
Decreases heart
rate and atrial
contractility via M2
87. 1. Ach Cardiac effects ↓ impulse formation in
SAN by ↓ the rate of diastolic depolarization (↓
HR) & ↑ PR interval (Time from SAN to AVN)
2. Atr Cardiac eff. ↑ HR & AV conduction velocity
by blocking the effects of the vagus nerve on sa,av
• Low i.v. atropine paradoxical slowing of HR
(stimulation of the vagal motor nucleus in the brain
stem). After full dose heart rate ↑
88. CVS eff. Of NE, E, Isoprenaline
• NE Activation of α1 receptors (V.c. & ↑ TPR)
Reflex bradycardia if blood pressure increases
sufficiently to activate the baroreceptor reflex
• E ↑ SBP but can ↑ or ↓ DBP
• Isoproterenol Activates β1 and β2 receptors
• Propranolol Blockade of β1 receptors
92. Dopamine
• Low doses (< 2 μg/kg per min) D1 dopaminergic
receptors in renal, mesenteric, and coronary
vascular beds. (vasodilation)
• Moderate dose (2–10 μg/kg per min) β1 recept.
• Higher dose (10 μg/kg per min) α1 receptors
93. Adrenaline
Uses (ABCD)
1. Anaphylactic shock (DOC) 0.5 mg (0.5 ml of 1
in 1000 solution for adult) i.m.
2. Bronchial asthma
3. Cardiac arrest 10 ml of 1:10000 i.v.
4. Control of local bleeding Adr 1 in 10,000
5. During LA combined with Lignocaine (1:50,000 or
1:2,00,000)
94. Adrenoceptor agonists
• Adrenoceptors α or β (potency of agonists)
• E & NE > iso at (smooth muscle) α
• Iso > E & NE (cardiac tissue) β
1. Direct-acting Bind and activate adrenoceptors.
2. Indirect-acting a ↑ stimulation of
adrenoceptors (↑ conc. of NE at neuroeffector
junctions)
1. Cocaine inhibits the catecholamine transporter ↑
conc.
2. Amphetamine inhibit storage of NE
3. Mixed-acting agonists (e.g., ephedrine) have both
direct and indirect actions.
95.
96.
97.
98. Direct acting agonists
• Catecholamines Naturally occurring (E, NE, DA)
& Synthetic (isoproterenol and dobutamine)
99. Drugs with large
alkyl group (e.g.,
isoproterenol) have
greater affinity for β-
adrenoceptors than
do drugs with a
small alkyl group
(e.g., epinephrine)
100. Effects on CVS
1. NE Activation of α1 (vasoconstr. & ↑ TPR
[↑SBP & DBP]). Reflex bradycardia
2. E ↑ SBP (↑ HR & CO), ↑/↓ DBP (α1 and β2)
Lower doses E Gtr stimulation of β2 (Vasodil.
& ↓ DBP) High dose V.c. &↑SBP & DBP
3. Isoproterenol β1- and β2 (↓ DBP, MAP, ↑SBP)
4. Dobutamine ↑ myocardial contractility & SV
(HR unaff) ↓ vasc. resistance (β2 receptors)
5. Dopamine low doses (D1 receptors);slightly
higher doses (β1); more higher doses (α1)
102. Adverse Effects
1. Exc. V.c. (tissue ischemia and necrosis)
2. Reduce blood flow to vital organs, such as the
kidneys
3. Exc. cardiac stimulation that leads tachycardia
and other cardiac arrhythmias
4. β agonists (hyperglycemia) so NOT in diabetes
103.
104. Shock
• Shock Circulation to vital organs is profoundly
reduced as a result of
1. inadequate blood volume (hypovolemic shock)
2. inadequate cardiac function (cardiogenic shock)
3. inadequate vasomotor tone (neurogenic shock
and septic shock).
• Septic shock is associated with massive vasodilation
secondary to the production of toxins by
pathogenic microorganisms (“warm shock”)
4. Anaphylactic shock (immediate hypersensitivity
reaction) hypotension and bronchoconstriction
105. • Catecholamines that ↑ BP vasopressors
• Hypovolemia should always be corrected by i.v.
fluids coz vasopressors will not be effective if
hypovolemia is present.
• Cardiogenic shock, mechanical devices (e.g., the
intra-aortic balloon pump) are usually superior to
pharmacologic agents in their ability to improve
coronary artery perfusion and cardiac performance
while reducing myocardial ischemia and cardiac
work. Such devices are often used in conjunction
with vasopressor drugs in the treatment of this
condition.
• Dobutamine (inotropic agent) that also produces
vasodilation. cardiac stimulant during heart surgery,
acute HF and cardiogenic shock.
106. • Dopamine septic or cardiogenic shock (2 mg/kg/
min) with i.v. fluids & vasopressors
• Norepinephrine septic & cardiogenic shock. Also
hypotension caused by exc. Vasodilators
(Phenylephrine)
• In anaphylaxis epinephrine (DOC) counteracts the
effects of histamine and other mediators that are
released from mast cells and basophils during
immediate hypersensitivity reactions, reduce
bleeding during surgery and to prolong the action
of local anesthetics by retarding their absorption
into the general circulation. Epinephrine is also
used as a cardiac stimulant in the treatment of
cardiac arrest and ventricular fibrillation.
• Isoproterenol Refractory bradycardia & AV block
when other measures have not been successful.
107. • Noncatecholamines Do not contain a catechol
moiety, and they are not substrates for COMT.
Some of the noncatecholamines are also resistant
to degradation by MAO. For this reason,
noncatecholamines are effective after oral
administration and have a longer duration of action
than do catecholamines.
1. Phenylephrine
2. Midodrine
108.
109. Phenylephrine (α1-receptors
(smooth muscle contraction)
• Indications
1. Nasal decongestant in patients with viral rhinitis,
allergic rhinitis
2. Eye allergic conjunctivitis ocular decongestant
ophthalmoscopic exam. of the retina.
3. hypotension and shock (hypotension caused by
excessive doses of vasodilator drugs, drug-
induced shock, septic shock, and neurogenic
shock such as resulting from spinal cord injury).
4. Phenylephrine is also used to maintain blood
pressure during surgery (e.g., when hypotension
is induced by anesthetic agents)
110. Terbutaline
• Management of preterm (premature) labor, < 37
wks Delays delivery to enable corticosteroids to be
given to prevent neonatal respiratory distress
syndrome.
• The adverse effects of albuterol and other selective
β2- adrenoceptor agonists include tachycardia,
muscle tremor, and nervousness caused by
activation of β2-adrenoceptors in the heart,
skeletal muscle, and central nervous system.
111. Imidazoline Drugs
• Activate α and imidazoline receptors.
1. Oxymetazoline and similar drugs α1. never be
used for more than 3 to 5 days, to avoid rebound
congestion that results from excessive
vasoconstriction and tissue ischemia. Also cause
CNS & CV depression if they are absorbed into
the systemic circulation and distributed to the
brain. (used with caution in children under 6
years of age and in the elderly)
112. 2. Apraclonidine and Brimonidine. (α2 receptors in
ciliary body); high rate of tachyphylaxis
3. Clonidine (α2 & imidazoline receptors in CNS.
Activation of these receptors leads to a reduction in
sympathetic outflow from the vasomotor center in
the medulla, and clonidine is used to treat
hypertension
• Also used to facilitate abstinence from opioids in
persons being treated for drug dependence
• The activation of α2-adrenoceptors in the central
nervous system is also responsible for the sedative
and analgesic effects of clonidine
113. Indirect-acting Adrenoceptor
Agonists
• Amphetamine high lipid solubility and ↑
synaptic conc. of NE in CNS & PNS (vc,card.+, ↑BP,
and CNS +. Tyramine Bananas.
• Cocaine LA & + Sym. NS by blocking the
neuronal reuptake of norepinephrine at both
peripheral and central synapses (vc,card.+,↑BP)
• Cocaine abusers Severe HTN & cardiac damage,
ischemia & necrosis of nasal mucosa
114. Mixed-acting Adrenoceptor
Agonists
• DA, ephedrine, and pseudoephedrine
• Ephedrine Ephedra; lipid solubility to enter CNS
resistant to metabolism by MAO and COMT; its
duration of action is several hours.
• Pseudoephedrine Isomer of ephedrine (nasal
decongestant)
• α(α1) and β(β2) by direct and indirect mechanisms.
also CNS + & insomnia.
115.
116. α adrenoceptor antagonists
1. Nonselective α-Blockers Phenoxybenzamine
(nc) phentolamine (compet. Antag.)
• Phenoxybenzamine forms a long-lasting covalent
bond with α-receptors, resulting in noncompetitive
receptor blockade
• Indications hypertensive episodes in patients
with pheochromocytoma until surgery can be
performed to remove the tumor
• Phentolamine Imidazoline compound
117. Uses of Phentolamine
1. Acute HTN episodes caused by α agonists
2. Counteract localized ischemia caused by
accidental injection or extravasation (leakage
from an intravenous infusion) of epinephrine or
other vasopressor amines.
3. Accidental injection of a finger with an
epinephrine autoinjector may result in localized
vasoconstriction, ischemia, and necrosis. This
condition can be treated by injecting the finger
with phentolamine.
• NOT useful in treating chronic HTN (reflex
tachycardia and may cause dizziness, headache,
and nasal congestion)
118.
119. Selective α1-Antagonists
• Prazosin HTN & BPH
• The selective α1-blockers do not cause as much
reflex tachycardia as do phentolamine and other
agents that nonselectively block both α1- and α2-
adrenoceptors. This is because blockade of α2-
adrenoceptors on sympathetic neurons prevents
feedback inhibition of norepinephrine release and
thereby leads to increased activation of cardiac β1-
adrenoceptors and tachycardia
• A/E hypotension, dizziness, and sedation
120.
121.
122.
123.
124. β adrenoceptor antagonists
• Nonselective β1, β2 (nadol,pindolol, Ppnl, Timo)
some exhibit ISA & membrane stabilizing (LA)
• Uses
1. HTN
2. Glaucoma (β2 effects)
3. In the liver, β2-adrenoceptor blockade inhibits
epinephrine stimulated glycogenolysis and can
thereby reduce hepatic glucose output during
hypoglycemia resulting from excessive insulin
administration.
125. Hypertension
• Acute Not effective (baroreceptor reflexes)
• Chronic Effective (↓ renin release ↓ ang. II &
ald. renal loss of Na+ and H2O ↓ BP)
• Hypertension in some patients is caused by
emotional stress, which causes enhanced
sympathetic activity. Beta-blockers can be very
effective in these patients.
• Preop. mx of hypertension caused by a
pheochromocytoma, which results in elevated
circulating catecholamines
126.
127.
128.
129. Pindolol (only for HTN)
• Has intrinsic sympathomimetic activity, (partial
agonist activity), which enables it to exert a weak
agonist effect on β-adrenoceptors.
• Eff. Obs. when the patient is resting & sympathetic
tone is low, and it can result in a smaller reduction
in heart rate than that caused by β-blockers
without intrinsic sympathomimetic activity.
• When sympathetic tone is high, pindolol acts as a
competitive receptor antagonist to inhibit
sympathetic stimulation of the heart in the same
manner as other β-blockers.
130.
131.
132. • Pindolol & Ppnl Memb. stabilizing activity/LA
(block Na channels in nerves and heart tissue and
thereby slow conduction velocity)
• Nadolol HTN, angina, prevent migraine
headache
• Timolol HTN, ac. MI, prevent migraine headache,
glaucoma
• Selective β1-Blockers acebut, aten, esm,meto.
(caution in pts. with asthma) high dose (β2 block)
137. Specific Properties
• Acebutolol HTN & cardiac arrhythmias (vent.
premature beats)
• Atenolol Lower lipid solubility and ↓ CNS s/e
(e.g., vivid dreams, tiredness, and depression) HTN,
angina & acute MI
• Esmolol (shorter t1/2) i.v. (HTN & SVT during surg.)
• Metoprolol HTN, ang, AMI
• Betaxolol ↓ aqueous humor secretion (POAG)
138. α- and β-adrenoceptor antag.
• Carvedilol (β1,β2,α1) & has antioxidant activity:-
1. inhibition of lipid peroxidation in myocardial
membranes
2. scavenging of free radicals
3. inhibition of neutrophil release of O2
• In addition, it has antiapoptotic properties that can
prevent myocyte death and reduce infarct size in
persons with myocardial ischemia. (MI)
• “third-generation β-blocker and neurohumoral
antagonist,” (HTN, AMI, HF)
Editor's Notes
The solution also can be used in other types of ophthalmic surgery that require rapid and complete miosis. Topical ocular administration of acetylcholine is not effective, because acetylcholine is hydrolyzed by corneal cholinesterase before it can penetrate to the iris and ciliary muscle.
The high affiity of pralidoxime for phosphorus enables it to break the phosphorus bond with cholinesterase and thereby regenerate the enzyme
The solution also can be used in other types of ophthalmic surgery that require rapid and complete miosis. Topical ocular administration of acetylcholine is not effective, because acetylcholine is hydrolyzed by corneal cholinesterase before it can penetrate to the iris and ciliary muscle.
The increased systolic pressure results partly from an increased heart rate and cardiac output. The effect on diastolic pressure depends on the relative stimulation of α1- and β2-adrenoceptors. which mediate vasoconstriction and vasodilation, respectively. Lower doses of epinephrine produce greater stimulation of β2-receptors than α1-receptors, especially in the vascular beds of skeletal muscle, thereby causing vasodilation and decreasing diastolic blood pressure. Higher doses produce
more vasoconstriction throughout the body and can increase both diastolic and systolic pressure. And produces vasodilation and cardiac stimulation. It usually
lowers the diastolic and mean arterial pressure, but it can increase the systolic pressure by increasing the heart rate and contractility. Its potent chronotropic effect can cause tachycardia and cardiac arrhythmias. For this reason, an alternative drug (e.g., dobutamine) is usually administered to increase cardiac output in cases of heart failure. Dobutamine selectively increases myocardial contractility and stroke volume while producing a smaller increase in heart rate.
reduces sympathetic stimulation of the heart, causing a negative chronotropic, inotropic, and dromotropic effect. Because the β-blockers reduce cardiac output and blood pressure (see Fig. 9-2), they can be used to treat arterial hypertension
The baroreceptor reflx. A, Increased arterial pressure activates stretch receptors in the aortic arch and carotid sinus. B, Receptor activation initiates afferent impulses to the brain stem vasomotor center (VMC). C, Via solitary tract fiers, the VMC activates the vagal motor nucleus, which increases vagal (parasympathetic) outflw and slows the heart. At the same time, the VMC reduces stimulation of spinal intermediolateral neurons that activate sympathetic preganglionic fiers, and this decreases sympathetic stimulation of the heart and blood vessels. By this mechanism, drugs that increase blood pressure produce reflex bradycardia. Drugs that reduce blood pressure attenuate this response and cause reflex tachycardia.
Vasomotor reversal of Dale. Comparison of the cardiovascular effects of four catecholamines when a low dose of each drug is given by intravenous infusion. Arrows
indicate when the infusion was started and stopped. The blood pressure recordings show systolic, diastolic, and mean arterial pressure. Peripheral resistance
is expressed on an arbitrary scale, ranging from 0 to 4 units. The reflex mechanism, adrenoceptors (α1, β1, and β2), or dopamine (D1) receptors responsible
for changes in the heart rate and peripheral resistance are illustrated. Norepinephrine increases peripheral resistance and blood pressure, and this leads to
reflex bradycardia. Epinephrine increases heart rate while reducing peripheral resistance, and the mean arterial blood pressure increases slightly. Isoproterenol
increases heart rate but significantly lowers peripheral resistance, and the mean arterial pressure declines. Dopamine increases heart rate (and increases
cardiac output) while lowering vascular resistance, and the mean arterial pressure increases.
Vasomotor reversal of Dale
The heart is innervated by vagal and sympathetic fibers. The right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node; however, there can be significant overlap in the anatomical distribution. Atrial muscle is also innervated by vagal efferents, whereas the ventricular myocardium is only sparsely innervated by vagal efferents. Sympathetic efferent nerves are present throughout the atria (especially in the SA node) and ventricles, including the conduction system of the heart.
Sympathetic stimulation of the heart increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects. Sympathetic and parasympathetic effects on heart function are mediated by beta-adrenoceptors and muscarinic receptors, respectively.
The mechanism of the beneficial effect of beta-blockers is to improve diastolic function by lengthening of diastole, reducing outflow-obstruction, and inducing a beneficial remodelling resulting in a larger left ventricular cavity, and improved stroke volume.
Carvedilol & Labetalol Both are b1,b2 & a1 (both used in HTN)