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ANS
Dr. Karun Kumar
JR – II
Dept. of Pharmacology
Nervous system hierarchy
Enteric
Nervous
System
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
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
M3  Smooth musc. Contraction (except sphincters) & gland secretion
Cholinergic neurotransmission
• Ach synth. from choline and acetate in neuronal
cytoplasm by chAT
↓
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
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
Regulation of the blood vessels
Veins
Dominant tone =
parasympathetic
Arterioles/arteries
Dominant tone =
sympathetic
Contraction via
alpha1
Relaxation via
beta-2
Regulation of the liver
• Sympathetic
• Increase gluconeogenesis and glycogenolysis
• Provide glucose to fuel “flight or fight” response
• Primarily beta-2, possibly alpha-1
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
Regulation of the bladder
Parasympathetic
• Bladder wall
• Constriction via M3
• Relaxation via beta-2
• Sphincter
• Relaxation via M3
• Constriction via alpha-1
Glandular secretion
Sweat
Salivary
Appocrine – increased via
alpha-1
Eccrine – increased via M
Increased via M3
Lacrimal gland (tear production) – increased via M
Predominant tones of major organ
systems
• Heart - parasympathetic
• Arterioles/arteries - sympathetic
• Veins - sympathetic
• Iris - parasympathetic
• Ciliary muscle - parasympathetic
• GI tract (ENS) - parasympathetic
• Smooth muscle - parasympathetic
• Bladder - parasympathetic
• Sweat glands - sympathetic
• Salivary glands – parasympathetic
• Lacrimal glands – parasympathetic
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
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
2. Indirect acting agonists (Anti-chE)
i) Reversible anti-chE
a) Natural alkaloid  Physostigmine
b) Others  Edrophonium, Neostigmine,
Pyridostigmine, Donepezil, Galantamine,
Rivastigmine, Ambenonium, Demecarium
ii) Irreversible anti-chE  OPs, Echothiophate,
Isoflurophate, Malathion,
Propoxur, Paraoxon, Carbaryl
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).
Urinary bladder
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.
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.
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.
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
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.)
• Nicotine  Smoking cessation programs (gum, t.d)
• Pilocarpine  Xerostomia, Glaucoma
• Cevimeline  Xerostomia (Sjogr., radiation ther.)
• Varenicline  Smoking cessation (Nicotinic ag.)
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
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 ↓
Neo, pyrido (Q. amine), physo 3oa
Clinical uses of reversible ChE
inhibitors
• Edrophonium  Diff. b/w myasthenic & c. crisis
• Donepezil, Galantamine & Rivastigmine (t.a.)  AD
• Neost., Pyridostigmine  Myasthenia gravis
• Neo, pyrido, and edro  Reverse eff. of curariform
drugs when muscle relaxation is no longer required
• Neostigmine (NO CNS penetration – Quat. Amine)
Muscarinic
1. Postop. Paralytic ileus
2. Postop. urinary retention
Nicotinic
1. Myasthenia gravis (Oral  15-30 mg; 0.5-2.5 mg i.m/s.c)
2. Cobra bite
3. Curare poisoning
• Physostigmine (CNS penetr. – Tertiary amine)
1. Antidote in atropine poisoning (2 mg i.m./i.v.)
2. Ophthalmic (Glaucoma, mydr., adhesions break)
Poisoning
• Organophosphates (lipid soluble)
1. Insecticides  Malathion (lice-p.c.), Parathion,
Dyflos
2. Nerve gases  Soman, Sarin
3. Ophthalmic agents  Echothiophate (glaucoma,
strabismus), Isoflurophate
• Carbamates
1. Reversible  Physostigmine, Neostigmine,
Pyridostigmine, Edrophonium,
Rivastigmine, Donepezil, Galantamine
2. Irreversible  Carbaryl, Propoxur
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
• 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.
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
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
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
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
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.
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
• 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.
Atropine
Uses (ATROPA)
1. As mydriatic-cycloplegic in refraction error
testing, fundoscopy, iridocyclitis
2. Traveller’s diarrhea
3. Rapid onset mushroom poisoning
4. Organophospohorous poisoning
5. Preanaesthetic medication
6. Arrhythmias (brady-arrhythmias)
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
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
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
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
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
AchR antagonists
• 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.
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.
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
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.
• 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.
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
• 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.
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
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.
• 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.
NICOTINIC RECEPTOR
ANTAGONISTS
1. Ganglionic blocking agents
• Their lack of selectivity for sympathetic or
parasympathetic ganglia & A/E  Stopped
2. Neuromuscular blocking agents
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
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).
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
Interactions
• Potentiated  inhalational anesthetic agents (e.g.,
sevoflrane), aminoglycoside, tetracycline,CCBs, m.g.
• Reversed  neostigmine
• Sugammadex  Reversing rocuronium.
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
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
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)..
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
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
PREDOM
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 ↑
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
Baroreceptor reflex
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
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)
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.
Direct acting agonists
• Catecholamines  Naturally occurring (E, NE, DA)
& Synthetic (isoproterenol and dobutamine)
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)
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)
Respiratory Tract Effects
• E & Iso  potent bronchodilators.
• Nowadays  more selective β2 agonists
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
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
• 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.
• 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.
• 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
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)
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.
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)
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
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
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.
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
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)
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
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.
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
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.
• 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)
Propranolol (Uses  THAPPAD)
1. Thyrotoxicosis & Tremors
2. HTN & Hypertrophic cardiomyopathy
3. Angina & Acute MI
4. Prophylaxis of migraine
5. Phaeochromocytoma (along with alpha blockers)
6. Anxiety & Arrhythmias
7. Dissecting aortic aneurysm
8. Digitalis toxicity
Adverse effects of beta blockers
(BBC Loses Viewers in Rochedale)
• Bradycardia
• Bronchoconstriction
• Claudication
• Lipids (profile altered)
• Vivid dreams & nightmares
• Negative ionotropic action
• Reduced sensitivity to hypoglycemia
Contraindications of Propranolol
• Don’t Prescribe Him Propranolol
1. Diabetes mellitus
2. Pulmonary diseases (Asthma, COPD)
3. Heart block, bradycardia
4. Prinzmetal’s angina
5. Peripheral vascular disease
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)
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)

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Autonomic nervous sytem

  • 1. ANS Dr. Karun Kumar JR – II Dept. of Pharmacology
  • 3.
  • 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
  • 6. M3  Smooth musc. Contraction (except sphincters) & gland secretion
  • 7.
  • 8. Cholinergic neurotransmission • Ach synth. from choline and acetate in neuronal cytoplasm by chAT ↓
  • 9.
  • 10.
  • 11.
  • 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
  • 18. Glandular secretion Sweat Salivary Appocrine – increased via alpha-1 Eccrine – increased via M Increased via M3 Lacrimal gland (tear production) – increased via M
  • 19. Predominant tones of major organ systems • Heart - parasympathetic • Arterioles/arteries - sympathetic • Veins - sympathetic • Iris - parasympathetic • Ciliary muscle - parasympathetic • GI tract (ENS) - parasympathetic • Smooth muscle - parasympathetic • Bladder - parasympathetic • Sweat glands - sympathetic • Salivary glands – parasympathetic • Lacrimal glands – parasympathetic
  • 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
  • 25. 2. Indirect acting agonists (Anti-chE) i) Reversible anti-chE a) Natural alkaloid  Physostigmine b) Others  Edrophonium, Neostigmine, Pyridostigmine, Donepezil, Galantamine, Rivastigmine, Ambenonium, Demecarium ii) Irreversible anti-chE  OPs, Echothiophate, Isoflurophate, Malathion, Propoxur, Paraoxon, Carbaryl
  • 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.)
  • 36. • Nicotine  Smoking cessation programs (gum, t.d) • Pilocarpine  Xerostomia, Glaucoma • Cevimeline  Xerostomia (Sjogr., radiation ther.) • Varenicline  Smoking cessation (Nicotinic ag.)
  • 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 ↓
  • 40. Neo, pyrido (Q. amine), physo 3oa
  • 41. Clinical uses of reversible ChE inhibitors • Edrophonium  Diff. b/w myasthenic & c. crisis • Donepezil, Galantamine & Rivastigmine (t.a.)  AD • Neost., Pyridostigmine  Myasthenia gravis • Neo, pyrido, and edro  Reverse eff. of curariform drugs when muscle relaxation is no longer required
  • 42. • Neostigmine (NO CNS penetration – Quat. Amine) Muscarinic 1. Postop. Paralytic ileus 2. Postop. urinary retention Nicotinic 1. Myasthenia gravis (Oral  15-30 mg; 0.5-2.5 mg i.m/s.c) 2. Cobra bite 3. Curare poisoning • Physostigmine (CNS penetr. – Tertiary amine) 1. Antidote in atropine poisoning (2 mg i.m./i.v.) 2. Ophthalmic (Glaucoma, mydr., adhesions break)
  • 43.
  • 44. Poisoning • Organophosphates (lipid soluble) 1. Insecticides  Malathion (lice-p.c.), Parathion, Dyflos 2. Nerve gases  Soman, Sarin 3. Ophthalmic agents  Echothiophate (glaucoma, strabismus), Isoflurophate • Carbamates 1. Reversible  Physostigmine, Neostigmine, Pyridostigmine, Edrophonium, Rivastigmine, Donepezil, Galantamine 2. Irreversible  Carbaryl, Propoxur
  • 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.
  • 54. Atropine Uses (ATROPA) 1. As mydriatic-cycloplegic in refraction error testing, fundoscopy, iridocyclitis 2. Traveller’s diarrhea 3. Rapid onset mushroom poisoning 4. Organophospohorous poisoning 5. Preanaesthetic medication 6. Arrhythmias (brady-arrhythmias)
  • 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
  • 79. Interactions • Potentiated  inhalational anesthetic agents (e.g., sevoflrane), aminoglycoside, tetracycline,CCBs, m.g. • Reversed  neostigmine • Sugammadex  Reversing rocuronium.
  • 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
  • 90.
  • 91.
  • 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)
  • 101. Respiratory Tract Effects • E & Iso  potent bronchodilators. • Nowadays  more selective β2 agonists
  • 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)
  • 133.
  • 134. Propranolol (Uses  THAPPAD) 1. Thyrotoxicosis & Tremors 2. HTN & Hypertrophic cardiomyopathy 3. Angina & Acute MI 4. Prophylaxis of migraine 5. Phaeochromocytoma (along with alpha blockers) 6. Anxiety & Arrhythmias 7. Dissecting aortic aneurysm 8. Digitalis toxicity
  • 135. Adverse effects of beta blockers (BBC Loses Viewers in Rochedale) • Bradycardia • Bronchoconstriction • Claudication • Lipids (profile altered) • Vivid dreams & nightmares • Negative ionotropic action • Reduced sensitivity to hypoglycemia
  • 136. Contraindications of Propranolol • Don’t Prescribe Him Propranolol 1. Diabetes mellitus 2. Pulmonary diseases (Asthma, COPD) 3. Heart block, bradycardia 4. Prinzmetal’s angina 5. Peripheral vascular disease
  • 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

  1. 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.
  2. The high affiity of pralidoxime for phosphorus enables it to break the phosphorus bond with cholinesterase and thereby regenerate the enzyme
  3. 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.
  4. 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
  5. 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.
  6. 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
  7. 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.
  8. 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.
  9. Carvedilol & Labetalol  Both are b1,b2 & a1 (both used in HTN)