2. Nervous System
Divided into:
ā¢ Central Nervous System: brain and the spinal
cord
ā¢ Peripheral Nervous System
1. Somatic Nervous System
2. Autonomic Nervous System
4. Comparison of Autonomic and Somatic Motor Systems
Somatic motor system Autonomic nervous system
Effectors skeletal muscles cardiac muscle, smooth muscle,
and glands
Efferent
pathways
ā¢ Heavily myelinated axons of
the somatic motor neurons
extend from the CNS to the
effect āskeletal muscleā.
ā¢ Axons conduct impulses
rapidly
ā¢ no ganglia
Axons are a two-neuron chain
ā¢The preganglionic (first) neuron
has a lightly myelinated axon
ā¢The postganglionic (second)
neuron extends to an effector
organ
ā¢Conduction is slower due to
thinly or unmyelinated axons
Target
organ
responses
All somatic motor neurons release
Acetylcholine (ACh), which has
an excitatory effect
ā¢ Preganglionic fibers release
ACh
ā¢ Postganglionic fibers release
norepinephrine or ACh and the
effect is either stimulatory or
inhibitory
6. Divisions of the Autonomic Nervous System
ā¢ Sympathetic and parasympathetic divisions
ā¢ Innervate mostly the same structures
ā¢ Cause opposite effects
ā¢ Sympathetic ā āfight, or flightā
ā¢ Activated during exercise, excitement, and
emergencies
ā¢ Parasympathetic ā ārest and digestā
ā¢ Concerned with conserving energy
7. Anatomical Differences in Sympathetic and
Parasympathetic Divisions
ā¢ Issue from different
regions of the CNS
ā¢ Sympathetic ā also
called the
thoracolumbar division
ā¢ Parasympathetic ā also
called the craniosacral
division
8. Anatomical Differences in
Sympathetic and Parasympathetic Divisions
Sympathetic Parasympathetic
Thoracolumbar outflow Craniosacral outflow
Length of
preganglionic fibers
Short āsympathatic ganglia are
located billaterally to spinal cordā
long āparasympathatic ganglia
are located near effector organsā
Length of
postganglionic fibers
long postganglionic fibers short postganglionic fibers
Branching of axons highly branched few branches
Neurotransmitter
released by
preganglionic axons
Acetylcholine for both branches
(cholinergic)
Acetylcholine
Neurotransmitter
released by
postganglionic axons
release norepinephrine
Except sweat glands,
postganglionic sympathetic
neuron release ACh
release acetylcholine
11. Clinical relevance of ANS pharmacology
ā¢ Autonomic Drugs are very much Clinically Relevant in:
ā¢ Treatment of Angina (BBs)
ā¢ The treatment of Heart Failure (BBs)
ā¢ TTT of hypertension (alpha and BBs).
ā¢ TTT of arrhythmias (BBs)
ā¢ Anaphylactic shock (EP)
ā¢ Cardiogenic shock (dopamine)
ā¢ Benign prostatic hypertrophy
ā¢ Alzheimerās disease (Physostigmine)
ā¢ Asthma (adrenergic agonists)
ā¢ Preanesthetic medication (Atropine)
ā¢ Parkinsonism (Benzotropine; central anticholinergics)
12. NEUROTRANSMISSION
ā¢ Definition of Neurotransmitters:
ā¢ Chemical substances that transmit impulses across
junctions (synapses):
ā¢ neuron-neuron synapse= ganglion.
ā¢ neuron- effector synapse = synaptic cleft.
ā¢ Role of transmitters:
ā¢ Communication between nerve cells and between
nerve cells and effector organs.
ā¢ Steps in Neurohumoral Transmission
1. Synthesis 4. Receptor binding
2. Storage 5. Termination
3. Release
17. Termination of NE Action
1) Uptake mechanism: major mechanism.
ā¢ Neuronal uptake (uptake 1):
ā¢ NE is uptaken into the adrenergic neurons to be
metabolized by MAO enzyme.
ā¢ Cocaine, TCA inhibit uptake 1.
ā¢ Relatively selective for NE.
ā¢ Vesicular uptake:
ā¢ NE escapes MAO enzyme is transferred from neuronal
cytoplasm to storage vesicles.
ā¢ Extraneuronal uptake (uptake 2):
ā¢ Non-selective and terminates all catecholamines (NE, EP,
dopamine & isoprenaline).
ā¢ Catecholamines are taken up by the surrounding tissues to
be metabolized by COMT in the liver.
19. Cont. Termination of adrenergic transmission
2) Enzymatic degradation: Minor pathway.
ā¢ MAO: in adrenergic nerve endings, brain, intestine & kidneys.
ā¢ COMT: in liver mainly
ā¢ Enzymatic degradation inactivates catecholamines to
inactive metabolites.
ā¢ Neuronal NE is metabolized by MAO
ā¢ Circulating catecholamines are metabolized by COMT.
20. Physiology of adrenergic Receptors
Pre-synaptic
a2
a2
NE
a2
a1
b1
b2 b3
a1
Post Synaptic Effector Cell
21. Location & functions of Autonomic receptors
i. a1 āreceptors
ā¢ Located post-synaptically in smooth muscles.
ā¢ Excitatory in function except GIT wall.
ā¢ Mediate the following effects:
ā¢ All B.V. ļ® V.C. ļ® ļ BP & ļÆ coronary blood flow.
ā¢ Radial muscle of the iris ļ® Contraction ļ® active mydriasis.
ā¢ GIT & urinary sphincters ļ® Contraction.
ā¢ Liver: glycogenolysis & gluconeogenesis.
ā¢ GIT wall (stomach & intestine) ļ® Relaxation
22. ii- a2- receptors
ā¢ both pre- & post-synaptics.
ā¢ Presynaptic a2- receptors are inhibitory & mediate
negative feed back inhibition of NE release from
adrenergic neurons.
ā¢ Postsynaptic a2- receptors are also inhibitory except in
platelet & BV.
ā¢ Stimulation of a2- receptorsļ®:
ā¢ ļÆ insulin secretion
ā¢ ļÆ central sympathetic outflow.
ā¢ GIT relaxation.
ā¢ ļ platelet aggregation.
ā¢ ļ vascular smooth muscle contraction.
23. iii- b1-receptors
ā¢ are excitatory in function.
ā¢ in heart & juxta-glomerular cells .
ā¢ mediate the following effects:
ā¢ cardiac stimulation
ā¢ ļ renin release.
24. iv- b2 & b3 āreceptors
ā¢ b2-receptors:
ā¢ Inhibitory to smooth muscles and excitatory to cardiac
muscles.
ā¢ Smooth muscles of bronchi, uterus, GIT, GUT and BV ļ®
relaxant effects
ā¢ Heart ļ® excitatory effects.
ā¢ Skeletal muscles ļ® glycogenolysis, tremors & K+ uptake.
ā¢ Liver: glycogenolysis & gluconeogenesis.
ā¢ Pancreasse ļ® ļinsulin secretion
N.B. b1-receptors ļ¾ b2-receptors in the heart.
ā¢ b3-receptors:
ā¢ In adipose tissues.
ā¢ Mediates lipolysis.
25. Molecular mechanisms of Adrenergic receptors
i) a1-adrenergic receptors:
- Activation of a1- receptors ļ®ļphospholipase C ā ļ Gs proteināļ®
formation of two second messengers:
1. IP3 ļ® ļ intracellular Ca++
2. DAG ļ® activates PKC.
ii) a2-adrenergic receptors:
-Activation of a2-adrenergic receptors ļ® activate Gi ļ®:
a) inhibit adenyl cyclase ļ® ļÆ cAMP ļ® ļÆ cAMP-dependent protein
kinases.
b) ļ K+ conductance & inhibit voltage-dependent Ca++ channels.
iii) b-adrenergic receptors:
Stimulation of b1 & b2 ļ® stimulates Gs protein ļ® activates adenylyl
cyclase ļ® ļcAMP ļ®ļ activity of cAMP-dependent protein kinase
which phosphorylates different cellular proteins ļ® b receptor effects.
28. Effects of drugs on adrenergic transmission
ā¢ Inhibition of vesicular storage of NE by reserpine.
ā¢ Inhibition of NE release by guanethidine.
ā¢ Increasing release of NE by indirectly acting
sympathomimetics e.g., tyramine, amphetamine and
ephedrine.
ā¢ Inhibition of reuptake 1 of NE by tricyclic antidepressants &
cocaine
ā¢ Blocking reuptake 2 by glucocorticoids.
ā¢ Inhibition of MAO or COMT by MAO inhibitors or COMT
inhibitors.
ā¢ Interaction with pre-or post-synaptic adrenergic receptors
e.g., a or b blockers .
31. Cholinergic Receptors
ā¢ The two types of receptors that
bind ACh are nicotinic and
muscarinic
ā¢ These are named after drugs
that bind to them and mimic
ACh effects
ā¢ Muscarinic receptors:
M1, M2, M3, M4, M5
ā¢ Nicotinic receptors:
Nn & Nm
32. Nicotinic Receptors (cholinergic)
ā¢ Nicotinic receptors are found on:
ā¢ Motor end plates (skeletal muscles)ā¦NM
ā¢ All preganglionic neurons of both sympathetic and
parasympathetic divisionsā¦.NN
ā¢ The hormone-producing cells of the adrenal
medulla ā¦.NN
ā¢ The effect of ACh binding to nicotinic receptors is
always stimulatory
33. Muscarinic Receptors (cholinergic)
ā¢ Muscarinic receptors occur on all effector cells
stimulated by postganglionic cholinergic fibers
ā¢ The effect of ACh binding:
ā¢ Can be either inhibitory or excitatory
ā¢ Depends on the receptor type of the target organ
34. Acetylcholine
Synthesis of Ach:
Acetyl-CoA+choline Choline acetyl transferase (CAT) ACh
stored in granules inside nerve terminals nerve impulse release of
ACh.
Removal of Ach:
ā¢ ACh is hydrolysed by acetylcholine esterase to choline and acetic acid, and
choline is reuptaked by neurons
ā¢ Acetylcholine esterase has two types:
ā¢ true (in neurons and different tissues)
ā¢ pseudo (in plasma and liver)
ā¢ Hemicholinum inhibits ACh synthesis.
ā¢ Excess Magnesium or lack of Calcium or botulinum toxin inhibit ACh
release.
35.
36. ACh
Primary transmitter in
1. All autonomic ganglia
2. Parasympathetic postganglionic neurons
3. Post-ganglionic sympathetic to thermoregulatory
sweat gland.
4. Neuro-muscular junction (Skeletal muscles)
37. Parasympathetic receptors
Receptor Action(s) Mechanism
Nicotinic
(N1 or NN)
1- stimulate all autonomic ganglia
2- secretion of NE and Epi from suprarenal gland
opening of Na+/K+
channels depolarization
Nicotinic
(N2 or NM)
1- Skeletal muscle contraction As N1
Muscarinic
(M1)
1- increase HCl secretion from stomach Act on Gs stimulates
phospholipase C increase
inositol triphosphate
(IP3) and Diacylglycerol
(DAG) increase
intracellular calcium
Muscarinic
(M2)
1- decrease heart rate, heart conductivity and atrial
contraction
2- presynaptic feed-back regulation (decrease ACh
release).
Act on Gi inhibit
adynylyl cyclase
Decrease cAMP
Muscarinic
(M3)
1- contraction of smooth muscles (miosis,
bronchoconstriction, contraction of urinary bladder and
GIT)
2- relaxation of ureter and sphincters of GIT and UT
3- increase secretion of glands (salivation, sweat, ā¦)
4- Vasodilation due to release of nitric oxide (NO)
As M1
38.
39. Actions of ACh in the parasympathetic NS:
1. On CVS:
ā¢ bradycardia, decreases atrial contractility and heart
conductivity
2. On the eye:
ā¢Miosis by contraction of constrictor (circular) muscle (M3)
ā¢Contraction of ciliary muscle (accommodation to near vision)
(M3)
ā¢Decrease intraocular pressure (IOP) by opening of canal of
Schlemm, therefore increases aqueous humour drainage.
3. On UT:
ā¢ Facilitates urination by contraction of the walls and relaxation
of the sphincter of the urinary bladder.
40. Actions of ACh in the parasympathetic NS:
4- On GIT:
ā¢ Increases secretions (HCl, saliva, pancreatic, gastric,ā¦)
ā¢ Increases motility and relax sphincters thus facilitates
defecation.
5- On Respiratory tract:
ā¢ Bronchoconstriction
ā¢ Increases bronchial secretions
44. Direct acting parasympathomimetics
Mimic the effects of acetylcholine
by binding directly to
Cholinoceptors
1. Choline esters:
ACh, Carbachol, Bethanecol
2. Natural alkaloids:
Pilocarpine
All of the direct-acting cholinergic drugs have longer durations of
action than acetylcholine.
Pilocarpine and Bethanechol preferentially bind to muscarinic
receptors and are sometimes referred to as muscarinic agents
46. Acetylcholine
A quaternary ammonium compound that cannot
penetrate membranes
ā¢ Act on M + N receptors.
ā¢ Therapeutically ----- No importance.
Multiple actions rapid inactivation
by Cholinesterases
48. Effects of direct-acting cholinoceptors stimulants
organ effects
Heart : SA-node
Atria
AV-node
ventricles
--------------ve chronotropy (ā H.R.)
----------ve inotropic effect (ā force of contraction)
-----ve dromotropy (ā conduction)
-Small ā in contractility.
Blood vessels Non-innervated M3- receptors in the vessels
VD via endothelial derived relaxing factor (EDRF)
Skeletal muscles Contractions due to +++Of motor end plate.
Smooth muscles GIT --āā motility āā salivary & intestinal secretions
Bronchi ----- spasm & āā secretions.
Urinary bladder -- contract detrusor musc.
& relax sphincter.
Eye ------ miosis & contract ciliary muscle
āaccommodation to near visionā āā IOP
49. ACh vasodilatation
ā¢ ACh activates M3 receptors found on endothelial
cells of blood vessels.
ā¢ This results in the production of nitric oxide from
arginine.
ā¢ Nitric oxide then diffuses to vascular smooth muscle
cells to stimulate protein kinase G production, leading
to hyperpolarization and smooth muscle relaxation.
53. Bethanechol
ā¢ Not hydrolyzed by acetyl cholinesterase but hydrolysed slowly by
other esterases ---- long acting ( 1 h)
ā¢ Act on M- receptors
ā¢ No nicotinic action
ā¢ Major actions: smooth muscle of GIT, urinary bladder
Bethanechol Actions
1) GIT: āā intestinal motility & tone
2) Urinary bladder -- contract detrusor musc. & relax sphincter ----
urinary urgency
Bethanechol Uses
ā¢ to activate atonic bladder :
ā¢ postpartum & postoperative non-obstructive urinary retention
54. Carbachol
ā¢ Not hydrolyzed by acetyl cholinesterase but hydrolyzed slowly by
other esterases ---- long acting ( 1 h)
ā¢ Act on M + N receptors.
Carbachol Actions
ā¢ Nicotinic Stimulation ---- ganglion-stimulating activity
CVS & GIT ā---ā
----- ā Adrenal medulla (ā adrenaline release)
ā¢ Muscarinic Stimulation ----- locally in Eye miosis & C.M spasm
Carbachol Uses
Treatment of glaucoma: āā IOP locally in the eye as a miotic.
high potency & long duration
Locally ---- The adverse effects is v. little.
56. Direct Acting Cholinergic Agonists
Cholinomimetic Alkaloids
Pilocarpine
ā¢ Tertiary amine --- pass to CNS.
ā¢ āāā M- receptors.
ā¢ Used mainly in ophthalmology
Pilocarpine Actions
1. Eye: topically it produces miosis & ciliary muscle
contraction.
2. āā Secretions -----āā sweat , tears & saliva
57. Pilocarpine
Pilocarpine Uses
the drug of choice in the emergency lowering of IOP in ---------
narrow- angle and wide-angle glaucoma.
Open the trabecular meshwork around Schlemm canal ----
āādrainage of aqueous humor ----- immediate āā IOP
Pilocarpine Adverse effects
Enter the brain ------ CNS disturbances.
It āāprofuse sweating and salivation.
58.
59.
60. Indirect acting (Anticholinesterases):
1. Reversible:
Produce reversible inhibition of cholinesterase
1) Physostigmine
2) Neostigmine
3) Pyridostigmine
4) Edrophonium
2. Irreversible
Irreversible inhibition, bind covalently to the enzyme
1) lsoflurophate
2) Echothiophate
61. Indirect-acting
parasympathomimetics
ā¢ Act by inhibiting the enzymes,
cholinesterases, thus preventing
the hydrolysis of Ach and
producing its accumulation at
various cholinergic sites
ā¢ Ach stimulate both M+N receptors
62. 1. Physostigmine
ā¢ 3ry amine ---- CNS
ā¢ More specific on eye:
miosis, ā IOP, twitches
ā¢ Oral, passes BBB
ā¢ CNS stimulation
Therapeutic uses:
1. + pilocarpine in acute
Glaucoma
2. Atony of
intestine,bladder
3. IV--- atropine, TCA
toxicity
63. 2. Neostigmine
ā¢ a synthetic quaternary amine (does not enter the CNS).
ā¢ Direct skeletal muscle stimulant effect (on nicotinic receptors).
It reverses the neuromuscular blockade produced by curare.
(cholinesterase inhibition, a direct action on skeletal muscle
cholinergic receptors and the increased amounts of Ach released from
nerve endings)
ACTIONS
ā¢ EYE: miosis, spasm of ciliary muscles (accomodation), ā IOP
ā¢ GIT: ā tone, motility of the GIT
ā¢ Skeletal muscles: āpower of skeletal muscles in myasthenia gravis-
---due to accumulation of Ach and direct action (+ Atropine)
(autoimmune disease caused by antibodies to the nicotinic receptor at N -
M junctions-fewer receptors available for interaction with the
neurotransmitter).
64. Neostigmine Therapeutic uses:
1 - Symptomatic treatment of myasthenia
gravis
2 - Antidote to competitive neuromuscular
blockers (tubocurarine)
3 - Stimulate the bladder and GI tract:
Contraindicated in mechanical obstruction of the
intestine
66. ā¢ generalized cholinergic (muscarinic) stimulation:
salivation, sweating, lacrimation
hypotension, bradycardia, bronchospasm
nausea, abdominal pain, diarrhea, Miosis
Physostigmine overdose----convulsions (not in Neostigā¦)
ā¢ Cholinergic crises:
weakness of the muscles due to excessive depolarization
at the motor end plate
ā¢ Ttt: stop the drug, large doses of atropine, artificial
respiration
67.
68. 1. Insecticides: parathion, malathion
2. Nerve gases: soman, sarin
3. Isoflurophate: used in glaucoma
4. Echothiophate: used in glaucoma
69. ANTICHOLINESTERASES (IRREVERSIBLE)
ā¢ Synthetic organophosphate compounds bind
covalently to acetylcholinesterase -----long-lasting
increase in acetylcholine.
ā¢ Echothiophate used clinically
ā¢ Highly lipid soluble-except echothiophate
ā¢ Well absorbed by all routes including GIT, skin,
mucus membranes, lungs except echothiophate
ā¢ Cross BBB except echothiophate
ā¢ Long duration of action especially echothiophate
71. Organophosphorus poisoning
ā¢ Accidental/ homicidal/ suicidal
ā¢ Signs and symptoms:
muscarininc and nicotinic actions
nausea, vomiting, diarrhea, sweating, āsalivary and
bronchial secretions, bronchospasm
muscular weakness and fasciculations (fine tremors)
Cause of death: respiratory failure
72. Treatment of Organophosphorus poisoning
1. Atropine in large doses:
2-4mg IV / IM, followed by 2mg every 5-10 minutes until the
muscarinic symptoms disappear--- pupillary dilatation
ā¢ Antagonizes muscarinic receptors, ganglionic and central actions
ā¢ Doesnāt affect neuromuscular paralysis which can be reversed by
cholinesterase reactivators
2. Cholinesterase reactivators
ā¢ Oximes are drugs that can reactivate the enzyme
ā¢ Pralidoxime (PAM)
Oximes should be given early before aging of the enzyme
73. Paralidoxime
ā¢ Aging is a chemical change
that makes the enzyme
recovery impossible
You should give paralidoxime
before aging of the enzyme
74.
75.
76. Definition
1. Antimuscarinic drugs
Atropine
2. Ganglionic blockers
Nicotine large dose, trimethaphan, hexamethonium
3. Neuromuscular blockers
NB. The nicotinic receptors in skeletal muscle are
blocked by d-Tubocurarine while hexamethonium
blocks ganglionic nicotinic receptors, i.e. they are
different.
77.
78. 1. Antimuscarinic agents
ļAtropine
ļAtropine substitutes
ļScopolamine
ļ¼ Block muscarinic receptors causing inhibition of
all muscarinic functions, very useful clinically
+
ļ¼ Sympathetic cholinergic to the sweat glands.
79. Atropine
ā¢ In Italian:
Belladonna=beautiful lady.
ā¢ Italian renaissance:
dilated pupils (considered
beautiful) achieved through
administration of eye drops
from plant extract
1. Antimuscarinic agents
80. Atropine
A competitive antagonist to Ach
Block all muscarinic receptors
Acts both central and peripheral
Actions last for 4 h except in the eye (last for days)
1. Antimuscarinic agents
81. Atropine Actions
Eye:
1.Persistent mydriasis with absence of light reflex
(passive mydriasis)
2. Cycloplegia: paralysis of ciliary muscle (loss of
accommodation)
3. Dangerous in narrow angle glaucoma
1. Antimuscarinic agents
82. Atropine Actions: cont.
GIT:
1. āmotility, can be used as an antispasmodic
2. HCl secretion is not affected
3. M1 muscarinic antagonist (pirenzepine)āHcl secretion
4. It also relaxes the smooth muscle of the biliary tract.
Urinary system:
āhypermotility of the urinary bladder while promoting
contractions of the sphincter; thus, favoring urinary retention.
Cardiovascular system:
1. Heart rate: block M2 receptors producing tachycardia
2. BP: unaffected, cautaneous vasodilatation at toxic doses
1. Antimuscarinic agents
83. Atropine Actions: cont.
Secretions:
1. ā salivation producing dryness of mucus membranes
(Xerostomia)
2. ā sweat secretions (hyperthermia in high doses)
3. ā lacrimal secretions (Sandy eyes)
Effects on the bronchi:
Atropine produces a slight bronchodilation.
Effects on the CNS:
Therapeutic doses exert a little effect on the CNS; however,
large doses can produce hallucinations and coma.
1. Antimuscarinic agents
84. Atropine Uses
ļ¾ Ophthalmic:
1.Mydriatic before fundus examination
2.Measurement of refractive error
Contraindicated in patients with narrow angle Glaucoma
ļ¾ Antispasmodic agents:
To relax GIT and bladder.
ā¼ Antisecretory:
Used to decrease secretions in respiratory tracts prior to surgery
ā¼ Antidote for cholinergic agonists:
1.Treatment of insecticides and some types of mushrooms poisoning
2. Blocks effects of excess Ach resulting from acetylcholineterase
inhibitors eg. physostigmine
1. Antimuscarinic agents
85. Atropine Adverse effects
Depends on the dose
ļ½Dilated pupils, resulting in photophobia
ļ½Dry mouth, blurred vision, sandy eyes,
tachycardia, constipation, Flushed skin
ļ½A rise in body temperature, especially in children.
ļ½CNS: restlessness, confusion, hallucinations and
delerium, depression
ļ½Collapse of the circulatory and respiratory
system and death
N.B:. Physostigmine is the antidote in case of
atropine poisoning.
1. Antimuscarinic agents
86. Dose-dependent effects of atropine
>10 mg
5 mg
2 mg
0.5 mg
Hallucinations, delirium, coma
āHR, dryness of the mouth,
mydriasis, blurring of vision
Bradycardia, some dryness
of the mouth, inhibition of
sweating
1. Antimuscarinic agents
87. Atropine substitutes
ā¢ Mydriatics, cycloplegic:
Cyclopentolate (return to normal in less than 24 hr.)
Tropicamide (is effective in less than 30 minutes and lasts less
than 4-6 h.)
Homatropine and Eucatropine (Mydriasis may persist for 4 days)
ā¢ For treatment of parkinsonism:
Benztropine
ā¢ Quaternary amine anticholinergic drugs
Do not readily cross the BBB. They are effective as
antispasmodics. Examples are Hyoscine-butylbromide
(Buscopan)
1. Antimuscarinic agents
88. Scopolamine
ļ± Peripheral effects: similar to atropine
ļ± Central effects: greater and longer than atropine
ļ The most useful drug in motion sickness
Uses
ļPrevention of motion sickness
ļ before anesthetics
1. Antimuscarinic agents
Ipratropium
ļ¾ quaternary derivative of atropine
Uses
ļ¾ used as inhalation in:
1. asthmatic patients who are unable to take adrenergic agonists
2. chronic obstructive pulmonary disease (COPD)
89. Uses of atropine substitute:
1- Treatment of peptic ulcer (EX. Pirenzipine).
2- Antispasmodic (atropine, propantheline).
3- Antiparkinsonian (benztropine).
4- Treatment of bronchial asthma (ipratropium).
5- Mydriatics/Cycloplegics (cyclopentolate).
6- Treatment of nocturnal enuresis (Oxybutynin).
7- Pre-anaesthetic medication (atropine) to prevent vagal
attack (block M2), prevent asphyxia through decreasing
bronchial secretions and saliva in addition to central
stimulation of respiratory center.
8- Antiemetic and for treatment of motion sickness
(hyoscine & scopolamine).
1. Antimuscarinic agents
90. 2. Ganglion blockers
ļ Act on the nicotinic receptors of both parasympathetic
and sympathetic ganglia
1. Depolarizing blockers:
ā¢ In small dose, they stimulate the ganglia (initial
depolarization), but in large dose they cause maintained
depolarization (block) leading to blocking or inactivating
of the N1 in ganglia.
ā¢ Ex. Nicotine and lobeline (large dose)
ā¢ Not used clinically
2. Competitive (non depolarizing) ganglionic blockers:
ā¢ They competitively block N1. Ex. Hexamethonium,
trimethaphan, mecamylamine.
91. Ganglionic Blockers
Actions:
They suppress both sympathetic and parathympathetic NS and the net
effect depends on the predominant tone (which of the 2 systems is
more active).
1- Heart:
Tachycardia (by blocking parasympathetic NS)
Decreased contractility and orthoststic hypotension (by blocking the
sympathetic NS)
2- Eye:
Mydriasis & cycloplegia (by blocking parasympathetic NS)
3- GIT & UT:
Decreased motility leading to constipation and urine retention (by
blocking parasympathetic NS)
- Little used now, only trimethaphan (short duration) is used as IV
infusion to control hypertension. They were used as antihypertensive.
94. Neuromuscular blockers (NMBs)
They block neuromuscular junction (motor-end plate) leading to relaxation
of skeletal muscles.
Uses of NMBs:
1- Surgical operations (pre-anaesthetic medications).
2- Electroshock theapy and certain types of convulsions.
3- Endoscopy and endotrachial intubation.
Classification:
A- Competitive NMBs:
They block N2 receptors at motor-end plate decrease opening of sodium
Channelsā¦ā¦ā¦ no depolarization ā¦ā¦ā¦relaxation.
Ex. 1- Long acting : Pancuronium,
2- Intermediate : Vecuronium, Atracurium
3- Short acting : Mivacurium.
NB. D-tubocurarine, gallamine not used now.
95. B- Depolarizing (non-competitive) NMBs:
They initially produce stimulation of N2 receptors persistent opening
of sodium channels sodium channels stay in the open state which
cannot respond to any stimuli (inactivated) muscle paralysis.
Ex. Suxamethonium (succinylcholine) and decamethonium.
Actions of NMBs:
1- Relaxation of skeletal muscles (eye muscles, face, neck, hands, feet,
limbs, and finally respiratory muscles). Recovery is in the opposite
direction.
2- Other effects: atropine like-effects and hypotension due to release of
histamine.
Neuromuscular blockers (NMBs)
96. Adverse effects:
1- Histamine release leading to hypotension and allergic reactions.
2- Atropine-like effects.
3- Prolonged apnea if pseudocholinesterase is genetically deficient no
hydrolysis of succinylcholine paralysis of respiratory muscles and
Apnea
4- Malignant hyperthermia (succinylcholine): usually when given with
halothane in this case patient treated by cooling and by administration
of dantrolene
5- Increased toxicity if used with aminoglycosides antibiotics because
aminoglycosides have neuromuscular blocking effect.
6- Hyperkalemia: Succinylcholine increases potassium release from
intracellular stores- dangerous in burn patients or patients with
massive tissue damage in which potassium has been rapidly lost from
within cells
Neuromuscular blockers (NMBs)
97. ā¢ Cholinesterase inhibitors: neostigmine, physostigmine,
pyridostigmine, and edrophonium -can overcome the action of
nondepolarizing neuromuscular blockers
ā¢ Halogenated hydrocarbon anesthetics: halothane- enhance
neuromuscular blockade by exerting a stabilizing action at the
neuromuscular junction.
ā¢ Aminoglycoside antibiotics: gentamicin or tobramycin- inhibit
acetylcholine release from cholinergic nerves by competing with calcium
ions, hence enhance actions of these agents.
ā¢ Calcium-channel blockers: These agents may increase the
neuromuscular block of competitive blockers as well as depolarizing
blockers.
Neuromuscular blockers and Drug interactions:
98. Types of skeletal muscle relaxants:
A- Central: acting on cerebral cortex and/or spinal cord:
Barbiturates, Benzodiazepines & Baclofen
B- Peripheral:
1- NMBs:
ļ Competitive NMBs
ļ Depolarizing NMBs
2- Direct skeletal muscle relaxant:
ļ± Dantrolene: decreases Ca2+ release from endoplasmic reticulum.
3- Other Motor-end-plate blockers:
ļ± Botulinum toxin: decrease ACh release.
ļ± Ī²-bungarotoxin, Mg2+ and aminoglycosides: decrease ACh release
and block N2
ļ± Local anaesthetics: block nerve action potential propagation