Download lec#6 ANS - DENTISTRY 2012

Autonomic Nervous System
(ANS)
Nervous System
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Central NS
- Brain
- Spinal cord
Peripheral NS
- Somatic NS
- Sympathetic (adrenergic)=Thoracolumbar
- Parasympathetic (Cholinergic)=Craniosacral
(III, IV, IX, X=Vagus)
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Pre-synaptic neuron: Where a neurotransmitter is
synthesized, stored and released upon cell
activation
Post-synaptic neuron or effector cells: Where
neurotransmitter is detected and its action
translated into cellular activities
Synapse: A junctional connection across which a
signal can pass
Ganglionic transmission is cholinergic and could
be blocked by ganglionic blockers

Sympathetic nervous system has the property of adjusting
the response to stressful situation, such as trauma, fear,
clod, exercise (Fight or flight response)

Stimulating this system results in an increase heart rate and
blood pressure, mobilize energy stores of the body,
increase blood flow to skeletal muscles and the heart and
dilates pupils and bronchi

The parasympathetic nervous system maintains essential
bodily functions, such as digestive processes and
elimination of wastes (feed and breed response)

It usually acts opposite or in balance with the sympathetic
division, and generally dominates in the rest situation
Classification of Autonomic Receptors
Sympathetic receptors (responses):
 α1-receptors (NE=NA; E=A;…agonists)
Mediate:
- Vasoconstriction of cutaneous; visceral; pulmonary;
coronary arteries and arterioles and veins
- Dilatation of pupils (mydriasis)
** α1-receptor antagonists (blockers) Phentolamine;
Prazocin…
 α2- receptors (Clonidine…agonist)
Presynaptic and inhibitory in nature

β1- receptors (NE; E, Isoproterenol =
Isoprenaline...agonists)
Mediate:
- Increased heart rate (+ve chronotropic effect)
- Increased heart contractility (+ve inotropic effect)
- Increased conduction velocity (+ve dromotropic
effect)
- Increased cardiac output
- Increased lipolysis
- Increased renin release...

β2-receptors (E; Isoprenaline; Salbutamol =
Albuterol...agonists)
Mediate:
- Bronchodilation
- Decreased GIT motility
- Increased glycogenolysis
- Relaxation of uterus
- Relaxation of skeletal and coronary blood vessels...

β3-receptors (Amibegron; Mirabegron...agonists)
Mediate:
- Increased lipolysis in adipose tissue
- Thermogenesis in skeletal muscle
- Anxiolytic effect
- Increase insulin effect
Beta3-Receptors are also found in the gallbladder and urinary
bladder. Their role in gallbladder physiology is unknown
but cause relaxation of the urinary bladder and prevent
urination
Possible uses:
Obesity; treatment of overactive bladder and DM

Responses to adrenergic and cholinergic nerve
stimulation
β-receptor blockers=antagonists:
- Cardioselective (e.g. Atenolol...)
Block only β1-receptors
- Nonselective (Propranolol…)
Block β1 & β2-receptors

Synthesis; storage; release and removal of NE
&E
Tyrosine
*Tyrosine hydroxylase
DOPA (Dihydroxyphenylalanine)
l-aromatic a.a decarboxylase
Dopamine
Dopamine β-hydroxylase
NE
Methyltransferase
(absent in nerve terminals)
(in adrenal medulla)
E
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Adrenal medulla contains more E
Adrenergic neurons synthesize only NE
* Tyrosine hydroxylase step is the rate
limiting one
Major inactivation of most
neurotransmitters is by a high specific
reuptake mechanism
TCA’s & Cocaine block NE & E reuptake
COMT
Epinephrine
Metanephrine
MAO
MAO
COMT
DHMA
*MHMA (VMA)
MAO
MAO
COMT
Norepinephrine
Normetanephrine
Metabolism of NE &E
Vanillylmandelic acid = VMA
A major metabolite to both NE & E, excreted
in urine (good indicator of the adrenal
medulla tumor pheochromocytoma)
 Little NE & E are excreted unchanged in
urine

COMT= Catechol-O-methyltransferase
Present in liver and peripheral tissues
 MAO= Monoamine oxidase
Present in liver; peripheral tissues and
neuronal mitochondria
MAO-A... Metabolizes NE & E
MAO-B... Specific for Dopamine (present in
brain)
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Sympathomimetic (adrenomimetic) agents
Directly acting:
-Norepinephrine=Noradrenaline (NE; NAD)
- Epinehrine=Adrenaline (E; AD)
- Isoproterenol (Isoprenaline)
- Dopamine
- Dobutamine
- Salbutamol (Albuterol); Terbutaline; Perbuterol
- Phenylephrine; Metaraminol; Methoxamine
 Indirectly acting:
- Ephedrine
- Amphetamine
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Norepinephrine (Noradrenaline) (α1; β1)
A catecholamine

NE actions:
- Its prominent effect is a widespread
vasoconstriction of both arterioles and veins
leading to significant increase in total
peripheral resistance and an increase in BP
- Leads to bradycardia (because direct effect
of NE on heart rate is masked by over
activity of parasympathetic system on the
heart and unmasked by Atropine)
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MOA of catecholamines:
Through a second messenger
- β-receptors: cAMP
Catecholamine → β-receptors → G-protein → adenylate
cyclase
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ATP → cAMP → activation of specific kinases that mediate
phosphorylation of many proteins → opening of Ca++
channels and activation of other enzymes leading to the
final physiological or pharmacological responses
cAMP is degraded by phosphodiesterase enzyme
- α-receptors: inisitol triphosphate (IP3) and
Diacylglycerol (DAG)
Catecholamine → α-receptor → G-protein →
phospholipase C → IP3 → opening of Ca++
channels from endoplasmic reticulum →
phosphorylate proteins → response
Catecholamine → α-receptor → G-protien →
phospholipase C → DAG → activation of protein
kinase C → phosphorylation of proteins →
response
Clinical uses to NE:
- Shock and severe drop in BP
- + local anaesthetics
Could be given SC and IV infusion
 Side effects to NE:
- Headache; tremors; ↑BP
- ↑ or ↓ in heart rate (↓ more likely)
- Palpitations and cardiac arrhythmias (overdose)

Epinephrine (Adrenaline)(α1 α2 ; β1 β2)
Effects:
- ↑ heart rate and contractility and ↑ CO
- ↑ systolic BP
- Bronchodilatation
- ↑ blood sugar
- ↓ GIT motility
- Dilatation of pupils
- ↓ salivary secretions
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Epinephrine clinical uses:
- Anaphylactic shock
- Open angle glaucoma (↑ drainage of eye fluid)
- + local anaesthetic
E is ineffective orally; given SC or IM
IV→ administration is contraindicated → fatal
ventricular fibrillation
Metabolized by MAO & COMT
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Epinephrine side effects:
Manifestations of sympathetic over activity
- Anxiety
- Nervousness
- Sweating
- Headache
- Palpitations
- Cardiac arrhythmias
- ↑BP
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Isoprenaline (Isoproterenol)
- A catecholamine; β1 & β2 stimulant
- ↑ heart rate; contractility and CO
- A good bronchodilator
- ↓ in peripheral resistance (due to predominant dilating effect
on skeletal muscle B.V’s and no α effect)
- No change or little ↑ in BP (due to ↑ in CO)
 Clinical uses:
- Bronchial asthma given by inhalation
- Shock & cardiac arrest given by an IV infusion
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Dopamine
A catecholamine; precursor to NE
Present in adrenergic neurons, adrenal medulla and
dopaminergic neurons and in the CNS
(neurotransmitter; and hormone); so it produces
unique cardiovascular effects through:
- ↑ release of NE
- Interacting with α and β1-receptors
- Interacting with specific dopaminergic receptors
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Dopamine pharmacological actions (dosedependent):
- Low doses (2-3 μg/Kg/min) dopamine acts as a
vasodilator increasing renal and splanchnic
(mesenteric) blood flow, keeps the kidney perfused
and leads to natriuresis and diuresis(D1 & D2
receptors)
- Intermediate doses (4-8 μg/Kg/min) it stimulates
β1 receptors → ↑ heart rate and contractility
- Large doses (more than 10 μg/Kg/min) it activates
α1-receptors → ↑BP

Dopamine is considered the best inotropic agent
in the management of shock states ± NE and it is
given in an IV infusion
 Dopamine side effects:
Tachyarrhythmias → IHD
 Effects of dopamine on:
- α-receptors are blocked by α-blockers
- β-receptors are blocked by β-blockers
- D-receptors are blocked by dopamine antagonists
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Terbutaline & Salbutamol (Albuterol) & Perbuterol
- Selective β2 agonists
- Good bronchodilators
- Have long DOA (not metabolized by MAO or
COMT)
- Salbutamol (Albuterol) is the most widely used one
in the management of bronchial asthma and
bronchospasm associated with bronchitis
- Given orally, by inhalation and SC
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Salbutamol side effects:
- Palpitations
- Tachycardia
- Sweating
- Tremors
- Headache
- Nausea & vomiting
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Phenylephrine; Metaraminol; Methoxamine
- Directly acting adrenomimetic agents
- Good α1 stimulants (have little effect on heart)
- Increase systolic and diastolic BP
- Used in cases of hypotensive states, especially
hypotension associated with spinal anaesthesia
and given IV
- Phenylephrine is also used as a nasal decongestant
and mydriatic in ophthalmology
- Could be used with L.A’s as vasoconstrictors
- Major side effect: Hypertensive crises
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Indirectly-acting sympathomimetic agents:
- Ephedrine
An alkaloid with marked CNS stimulant effect
Its peripheral actions are mainly due to ↑ NE release
Has little direct effects on adrenergic receptors
particularly β2
Unlike NE, it is not metabolized by MAO or COMT
so it has longer DOA and it is effective orally
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Ephedrine (Cont.)
- ↑ systolic and diastolic BP
- ↑ heart contractility and CO
- Leads to bronchodilatation
- Dilates pupils
 Ephedrine clinical uses:
- Bronchoconstriction of bronchitis and bronchial
asthma
- Nasal decongestant
- Mydriatic
Ephedrine (Cont.)
 Ephedrine side effects:
- Tachycardia
- Nervousness
- Insomnia
Ephedrine is contraindicated in patients with
hypertension, hyperthyroidism and patients
with heart disease
Amphetamine
- Has marked CNS stimulant effect > Ephedrine (disomer more potent than l-isomer)
- ↑ NE release
- ↑ BP
- ↑ alertness & thinking, ↑ activity, ↓ Fatigue
- Leads to addiction
- May be used in the management of severe
narcolepsy (frequent sleep) and hyperkinetic
syndrome
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Adrenergic Blockers=Antagonists
Sympatholytic Agents
1. β-adrenergic blockers (antagonists)
Their use (alone or with other
antihypertensives e.g. diuretics) proved to
↓ incidence of stroke, MI and CHF
Previously considered 1st line Rx for HTN
Recently diuretics are considered 1st line
Rx and β-blockers could be added for
proper ↓ in BP if required
Still β-blockers are considered 1st line therapy
in patients with hypertension and have
certain compelling indications e.g.:
Pts with high coronary risk or post myocardial
infarction...
β-blockers MOA:
a. Competitive inhibition of effects of
catecholamines at β-adrenergic receptors
→↓ HR and contractility→↓ CO →↓ BP
b. Inhibition of renin release →↓ plasma renin
levels →↓ angiotensin II levels
c. ↑ release of PG’s that have vasodilating
effect
d. ? CNS-mediated antihypertensive effect

Classes of β-blockers:
a. Cardioselective (block only β1 receptors)
Atenolol
Betaxolol (MSA)
Bisoprolol
Metoprolol (MSA)
Acebutolol (+ISA)
Esmolol
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b. Nonselective (block β1 & β2 receptors)
Propranolol (MSA)
Nadolol
Carteolol (+ISA)
Penbutolol (+ISA)
Pindolol (+ISA) (MSA)
Timolol (+ISA)
c. α & β blockers
Labetalol
Carvidolol
 β- receptors are located in most tissues
High concentrations of β1-receptors are
present in heart and kidney, stimulation of
which result in ↑ HR and contractility and ↑
renin release
High concentrations of β2-receptors are present in
lungs and vascular smooth muscles, stimulation of
which result in bronchodilatation, vasodilatation
and ↑ insulin release
Cardioselective β-blockers are safer in pts with
bronchial asthma, COPD, peripheral arterial
disease and diabetes mellitus
Large doses of cardioselective β-blockers block β2receptors as well (this effect is subject to great
individual variation)
ISA (Intrinsic Sympathomimetic Activity)
Some β-blockers have ISA (act as partial
agonists) which is weak as compared to
their β-blocking activity. Such blockers
would be advantageous in patients with
heart failure and bradycardia
β-blockers with ISA are rarely used because
they increase risk after MI
MSA (Membrane Stabilizing Activity)
β-blockers depress cellular membrane
excitability (they have Quinidine-like effect
or local anesthetic effect= they have
similarity in structure to LA’s)
In large doses all β-blockers have this property
This property is important when β-blockers
are used in the management of cardiac
arrhythmias
Pharmacokinetics of β-blockers:
- Well absorbed following oral administration
Differ in t1/2 & DOA (long t1/2 with Atenolol &
Nadolol, short with Esmolol)
- Protein binding (extensive with Propranolol
≈ 90%, modest with Metoprolol ≈ 10%)
- First-pass effect (extensive with Propranolol
& Metoprolol)
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- Route of elimination and metabolism
Propranolol & Metoprolol undergo extensive
hepatic metabolism and metabolites are
excreted renally, Atenolol undergoes little
metabolism and excreted mainly unchanged
by the kidney
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Remember that the duration of hypotensive
action of β-blockers does not correlate
always with their serum t1/2’s
Some β-blockers are given once daily despite
their short t1/2 e.g. Acebutelol’s t1/2 ≈ 4hrs
but metabolized to a pharmacologically
active metabolites with t1/2 ≈ 10hrs
- Lipid solubility:
All β-blockers are lipid soluble
Some have high lipid solubility e.g.
Propranolol which has the most lipid
solubility among β-blockers
Others have low lipid solubility e.g. Atenolol
which has the least lipid solubility among βblockers
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β-blockers with high lipid solubility
penetrate well the BBB (this accounts for
dizziness & headache side effects)
Lipid solubility has no effect on the
antihypertensive activity of β-blockers, but
has the benefit of utilizing highly lipid
soluble ones in the management of migraine
and essential tremors
β-blockers clinical uses:
- HTN
- Angina pectoris
- Mild to moderate HF
Not good for pts with HF with severe ↓ in CO
and bradycardia, but good in certain pts
with HF who are largely dependent on
enhanced sympathetic activity to maintain
sufficient CO
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- Cardiac arrhythmias
- Prevention of recurrent MI
- Hyperthyroidism
- Glaucoma (Timolol is particularly effective;
it ↓ production of eye fluid)
- Anxiety states
- Migraine
β-blockers side effects:
- High degree of atrioventricular block
- Bradycardia
- Acute HF
- ED
- Bronchoconstriction
- Raynaud's phenomenon
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- Hypoglycemia
↓ blood glucose + mask manifestations of
Hypoglycemia
- ↑ serum triglycerides, ↓ HDL
More common with nonselective β-blockers
Pindolol (has the best ISA among β-blockers), ↑HDL
Combined α & β blockers have no effects on blood
lipids
- Central effects
Dizziness, headache, hallucinations, depression…
β-blockers contraindications:
- Pts with COPD, bronchial asthma
- Pts with severe CHF or LV dysfunction
- Allergy to β-blockers (not frequent)
- Diabetics on high dose of insulin or with
hypoglycemia
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β-blockers should not be stopped abruptly
Sudden withdrawal of β-blockers could lead
to unstable angina, ↑BP, MI and even death
Chronic use of β-blockers is usually
associated with increased β-receptor density,
therefore abrupt withdrawal → acute
withdrawal syndrome and life threatening
rebound hypertension
2. α-adrenergic antagonists
Chemically classified into:
- Haloalkylamines
Phenoxybenzamine O, I.V
- Imidazolines
Phentolamine
O, I.V
- Quinazoline derivatives
Prazosin
O
Terazosin
O
Doxazosin
O
Trimazosin
O
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Phenoxybenzamine and Phentolamine are
nonselective (block α1 & α2 receptors), effective
orally and IV mainly used in the management of
hypertension associated with pheochromocytoma
Quinazoline derivatives are selective α1-receptor
antagonists which replaced nonselective blockers
in the management of essential HTN
Selective blockers are less efficacious than
diuretics, Ca++ channel blockers and ACE
inhibitors in reducing primary end points of
cardiovascular disease, stroke or HF when used
alone in the management of HTN
Thus, α1-blockers are considered alternative
agents when other 1st line therapy fails to
control HTN and usually used in
combination with other antihypertensive
drugs
 α1-blockers MOA:
Competitive antagonism to postsynaptic α1receptors leading to arterial and venous
vasodilatation
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High doses of α1-blockers could lead to
blockade to α2-receptors → ↑ NE release →
↑ β-adrenergic receptors → cardiac
stimulation and ↑ renin release (this effect is
less prominent with Prazosin)
Also high doses of Prazosin lead to direct
vasodilating effect due to inhibition of
phosphodiesterase enzyme
α1-blockers clinical uses:
- HTN
Alone could be effective in mild HTN
Moderate to severe HTN, Prazosin + thiazide
or β-blocker
Prazosin has no effects on uric acid or blood
glucose levels (good to pts with gout or
diabetes)
- Benign hyperplasia of the prostate
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α1-blockers side effects:
- First-dose phenomenon
Severe drop in BP with the 1st dose more than
with subsequent doses
- Orthostatic hypotension (postural
hypotension), this leads to dizziness,
headache, drowsiness and syncope (so it is
advised to take these drugs at bedtime)
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Doxazosin is less effective than thiazides in
lowering systolic BP and may be associated
with a higher risk of cardiovascular disease
particularly HF and stroke in pts with HTN
Selective α1-blockers ↓ cholesterol and
triglycerides blood levels and ↑ HDL levels
(so they could improve the negative effects
on lipids induced by thiazides or β-blockers)
3. Agents with mixed properties
Labetalol Carvidolol
Have α and β antagonistic activity
β:α=3:1 orally β:α=7:1 IV (thus they are
considered β-blockers with some αantagonistic activity)
They have 1/10 potency of Phentolamine and
1/3 potency of Propranolol
α and β blockers clinical uses:
- HTN
- IHD ( Carvidolol has an antioxidant effect)
- Hypertensive emergencies (IV Labetalol)
The α-receptor antagonistic activity of
Labetalol ↓ with chronic administration &
disappears in few months

α and β blockers side effects:
- Postural hypotension
- Liver damage
- Tremors
- Lupus like syndrome
- +ve ANA (antinuclear antibody test)
- Reflex tachycardia
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Parasympathetic System=Cholinergic System
Cholinomimetic agents
Acetylcholine (Ach)
 Major neurotransmitter at:
- Parasympathetic nerve terminals
- Sympathetic and parasympathetic ganglia
- Motor nerves
- Sympathetic terminals to sweat glands
- Sympathetic terminals to adrenal
Directly-acting parasympathomimetic
(cholinomimetic) agents
- Acetylcholine (an ester of choline & acetic
acid)
Methacholine
Carbachol
Bethanechol

Indirectly-acting parasympathomimetic
(cholinomimetic) agents
Inhibitors of acetylcholinesterase (ACHE) =
Anticholinesterases
A. Reversible competitive anticholinesterase
- Quaternary ammonium agents
Edrophonium
Ambenonium

- Carbamates
Neostigmine (quaternary amine; positively charged)
Pyridostigmine (quaternary amine)
Physostigmine (tertiary amine)
Quaternary amines are more polar and do not enter the CNS
readily
Reversible anticholinesterases bind anionic site of ACHE
B. Irreversible anticholinesterases
Organophosphates
(Malethion; Parathion; Sarin)
Mainly used as insecticides and bind esteratic site of ACHE
Acetylcholine (Ach)
 Synthesis; storage; release & metabolism
From choline and acetyl-CoA
Choline acetyl transferase
Choline + Acetyl-CoA
Ach
Ach degradation (metabolism) by ACHE=
acetylcholinesterase
- Plasma cholinesterase (pseudo cholinesterase)
- Tissue cholinesterase (true cholinesterase)
Acetylcholine (Ach)
Interacts with 2 major types of receptors
distributed allover the body
- Muscarinic receptors (5 subtypes M1 to M5)
- Nicotinic receptors (2 subtypes:
Nn=neuronal or ganglionic type &
Nm=neuromuscular or muscular type)
Muscarinic receptors
A. Stimulatory muscarinic receptors:
parasympathetic nerve terminal → release Ach
→ interact with muscarinic receptors → ↑
IP3, DAG and stimulation of adenylate
cyclase → all mediate stimulatory responses
of cholinergic system e.g. ↑ gland secretion
(salivation); contraction of smooth muscles
of GIT…etc

B. Inhibitory muscarinic receptors:
Ach → interaction with muscarinic receptors
→ ↓ activity of adenylate cyclase which
mediate the inhibitory effects of Ach e.g.
decreased heart rate
Nicotinic receptors
A. In voluntary muscles → Ach → nicotinic
receptors → depolarization of voluntary
muscles →↑ influx of Na+ and Ca++ →
generation of action potential → contraction
of voluntary muscles

B. In autonomic ganglia
Stimulation of nicotinic receptors in sympathetic and
parasympathetic ganglia results in a complex
sympathetic and parasympathetic activities
C. In CNS
Stimulation of CNS nicotinic receptors leads to
complex excitatory and inhibitory effects
D. In adrenal medulla
Stimulation of nicotinic receptors in adrenal medulla
leads to an increase in E release
Aetylcholine (Ach)
A quaternary positively charged ammonium
compound (present in the choline portion of
Ach), for this Ach is very hydrophilic and
hydrolyzed quickly, therefore it is not used
clinically
Ach actions
- Relaxation of arterial smooth muscles →
vasodilatation → ↓ BP
- ↓ heart rate (direct effect)
- Miosis; accommodation to near vision
- ↑ salivation
- ↑ gastric acid secretion
- ↑ GIT motility
- Relaxation of GIT and urinary system sphincters
- ↑ respiratory secretions and bronchoconstriction

Methacholine; Carbachol; Bethanechol;
Pilocarpine
- Synthetic; directly acting Ach-like agents
- Resist degradation by ACHE so they may have
prolonged action and could be given orally or SC
- IM & IV administration is contraindicated →
severe side effects (nausea, abdominal pain, severe
drop in BP with reflex tachyarrhythmias,
bronchoconstriction…etc)

Clinical uses to directly-acting
cholinomimetics:
- Glaucoma
Pilocarpine eye drops and ophthalmic gel → ↓
resistance to movement of aqueous humor
out of the eye → open angle glaucoma →↓
intraocular pressure
Carbachol could be used in patients resistant
to Pilocarpine therapy
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- Urine retention following surgery or child birth
Bethanechol is highly effective orally and SC
- Clear bowel gases before x-ray or surgery
Carbachol or Bethanechol, orally
- Diagnosis of bronchial hypersensitivity
Methacholine is given by inhalation to a patient and
if the patient develops exaggerated airway
contraction or bronchoconstriction he or she most
likely may develop the disease bronchial asthma
Side effects to directly-acting
cholinomimetics:
- Abdominal colic, nausea, diarrhea
- Vasodilatation and drop in BP
- Bronchoconstriction
- Sweating and salivation

Indirectly-acting cholinomimetics
- Physostigmine
Activates muscarinic and nicotinic receptors
(↑ Ach actions at all sites including
neuromuscular junction)
↑ intestinal movement
↑ bladder motility
Effective orally; SC and as an ophthalmic
drops

Physostigmine clinical uses
- Myasthenia gravis
Autoimmune disease mainly due to antibodies directed
against nicotinic receptors leading to muscle weakness and
rapid fatigue
Physostigmine increases concentration of Ach at this site
- Paralytic ileus and urinary bladder atony which may occur
postoperatively or after child birth
- Glaucoma
- Overdose with anticholinergic drugs e.g. Atropine; TCA’s,
Phenothiazines...etc

Physostigmine side effects
- Convulsions
- Decreased heart rate
- Paralysis of voluntary muscles with large
doses

Neostigmine
- Has similar actions to Physostigmine but with more
effect on skeletal muscles
- Considered the drug of choice to treat myasthenia
gravis and as an antidote to d-tubocurarine
 Side effects
- Salivation
- Decrease in BP
- Bradycardia

Pyridostigmine
Mainly used in the management of myasthenia
gravis and has longer duration of action as
compared to Neostigmine
 Edrophonium
Produces similar actions to Neostigmine but more
rapidly acting and has longer DOA
Mainly used to diagnose myasthenia gravis
IV Edrophonium → rapid improvement in muscle
strength

Also, IV Edrophonium could differentiate
between over dosage with anticholinesterase
(cholinergic crisis) and inadequate
treatment with anticholinesterase
(myasthenia crisis)
Cholinergic crisis → IV Edrophonium →
more muscle weakness
Myasthenia crisis → IV Edrophonium → ↑
muscle strength
The use of anticholinesterases in Alzheimer’s
disease:
Alzheimer’s disease is characterized by progressive
loss of memory and dementia, believed to be due
to decreased or loss of cholinergic transmission in
the neocortex
Anticholinesterases found to be of benefit in such
patients include: Rivasigmine; Tacrine;
Galanthamine & Donepezil
Such agents produce reversible inhibition of ACHE,
they are lipid soluble, cross BBB well and improve
the cognitive function in patients with Alzheimer

The use of anticholinesterases in glaucoma:
Demecarium
Physostigmine
Isoflurophate
Echothiophate
Available as ophthalmic drops and gel
↑ drainage of eye fluid and possibly ↓ its secretion
Long use is not advised (may lead to cataract)

Organophosphates
- Cause irreversible inhibition of ACHE
- Many (Malathion; Parathion) are used as
insecticides
- Many others (Sarin) are used as chemical
weapons; known as nerve gases
- Therefore, toxicity with such agents should
be known well
- They are readily absorbed through skin

Toxicity with organophosphates
- Nausea & vomiting
- Abdominal pain & diarrhea
- Excessive salivation & sweating
- Respiratory distress, bronchospasm → death
- Drop in BP → death
- Muscle weakness → death
- Bradycardia, A-V block
- Agitation, dizziness...

Management of organophosphate toxicity
- Support of ventilation
- Atropine SC
- Pralidoxime IV
Cholinesterase reactivator
Quaternary amine does not activate CNS
CHE
Effective only in the 1st 12-24 hrs of poisoning
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Parasympatholytic agents
Antimuscarinic; Anticholinergic agents
Prototype: Atropine
Effective orally, locally and parenterally (SC;
IV)
Atropine is a belladona alkaloid (plant Atropa
Belladona)
Blocks selectively muscarinic receptors; has
no Ach intrinsic-like activity and has no
effect on nicotinic receptors
Atropine pharmacological actions
- Small doses produce slight bradycardia; therapeutic
and large doses lead to tachycardia & ↑ CO
- ↓ salivation; ↓ gastric acidity; ↓ biliary and
pancreatic secretions
- ↓ intestinal movement (↓ spasm)
- ↓ respiratory secretions and dilates bronchi
- Dilates pupils & leads to cycloplegia (relaxation of
ciliary muscles)=loss of accommodation to near
vision
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Atropine pharmacological actions (Cont.)
- ↓ sweating
- Urinary retention
- CNS effects:
Drowsiness,
Sedation, ataxia, hallucinations, coma,
↓ concentration and memory…
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Clinical uses to anticholinergics:
- Bradycardia
- Preanaesthetic medication to ↓ salivary & bronchial
secretions
SC or IM Atropine; IM Glycopyrrolate bromide =
Atropine-like associated with less postoperative
agitation
- Overdosage of ACHE inhibitors
- Bronchial asthma
Ipratropium bromide; given by inhalation
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Clinical uses to anticholinergics (Cont.)
- Locally in ophthalmology to produce mydriasis &
cycloplegia
Atropine DOA 7-10 days; Scopolamine DOA 3-7 days;
Homatropine DOA 1-3 days; Cyclopentolate DOA
1 day; Tropicamide DOA 2-6 hrs (preferred)
- Parkinson’s disease
Trihexyphenidyl=Benzhexol (Artane®)
Benztropine mesylate
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Clinical uses to anticholinergics (Cont.)
- Abdominal spasm & pain & diarrhea
- Atropine; Scopolamine; Propantheline;
Dicyclomine; Oxybutynin...
- Motion sickness
Scopolamine (oral & transdermal patches)
- Congenital pyloric stenosis (Atropine relaxes the
pylorus)
- Peptic ulcer disease
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Clinical uses to anticholinergics (Cont.)
- Urinary uses
Urinary bladder spasm; enuresis;
incontinence...
Propantheline
Oxybutynin
Dicyclomine
Tolterodine
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Side effects to anticholinergics (Anticholinergic
manifestations)
- Dry mouth
- Blurred vision
- Tachyarrhythmias
- Headache; restlessness; hallucinations; delirium
- Constipation
- Difficulty in micturition
- Loss of accommodation
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Management of anticholinergics overdosage
- Rx of severe manifestations (e.g.
hypertension; cardiac arrhythmias)
- ↓ absorption of tablets
- Antidote
ACHE inhibitor
Physostigmine
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Nicotine & ganglionic blockers
Ganglionic transmission is very complex
Nicotine is not used clinically, likewise clinical
uses to ganglionic blockers are limited
because of lack of selectivity to either symp.
or parasymp. ganglia
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Nicotine
Its clinical use is restricted to smoking cessation
programs
Its importance lies in the fact that it is a CNS
stimulant and it is an abused substance and
consumed by many people through smoking
In low doses, Nicotine stimulates ganglia by
depolarization and in large doses it blocks ganglia
both in periphery and in CNS
It has no effect on neuromuscular junction
Nicotine is very lipid soluble
Actions to nicotine
- Euphoria; arousal, improves attention, learning and
problem solving
- In high doses could lead to medullary paralysis and
↓ BP & respiratory depression
- ↑ BP due to action on symp. ganglia in periphery
- ↑ heart rate
- Vasoconstriction of coronary arteries → IHD
- ↑ GIT motility (parasymp. ganglia)
- Large doses ↓ GIT motility and lead to urine
retention (block parasymp. ganglia)
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Side effects to Nicotine
- Irritability
- Tremors
- ↑ heart rate and ↑ BP
- Diarrhea
- Induction of metabolism of drugs
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Withdrawal manifestations to Nicotine
- Irritability
- Anxiety
- Insomnia
- Restlessness
- Difficulty in concentration
- Abdominal pain
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Trimethaphan & Mecamylamine
Competitive nicotinic ganglionic blockers
They could also block nicotinic receptors at
neuromuscular junction
Their use is limited because of lack of
specificity to ganglia and development of
tolerance to their beneficial effects and due
to severe side effects they produce
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Trimethaphan is given in an IV infusion and
was used to treat hypertensive crisis caused
by pulmonary edema or dissecting aortic
aneurysm
Mecamylamine is orally effective
Ganglionic blockers are also used to induce
hypotension needed in certain plastic
surgeries and ophthalmic surgeries
Ergot alkaloids
Ergotamine
Used in migraine, has no analgesic effect
MOA:
Constriction of cerebral blood vessels
Given orally ± Caffeine (↑ effect of Ergotamine); by inhalation
& rectally
Side effects:
Peripheral vasoconstriction → ↑ BP; gangrene; vomiting &
diarrhea
 Ergometrine
Contracts the uterus; has no α-adrenergic activity and used
IM in the management of postpartum hemorrhage
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