Transcript ANS Review+Qs

ANS PHARMACOLOGY
REVIEW
Neurotransmitters & Rcs at various sites of
ANS
-Memorize various NTs secreted at
Pre & post ganglionic level
-Figure out the Rcptrs at aforesaid
Levels
-Why Rcptors at various levels are
Different?
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Somatic
N

Sympathetic
Motor Fiber
Smooth Muscle
Postganglionic Fiber;N Cardiac Cells
Adrenergic
E Gland Cells
 α, β
Ganglion
Ach
Ach
Sympathetic
EPI/NE
Ach
Adrenal Gland
Parasympathetic
Ach Muscle
Ganglion
Ach
Sympathetic
N
 Skeletal
Ganglion
Ach
N
Sweat
Glands

M

Smooth Muscle
Cardiac Cells
Gland Cells
Ach
Which of the following receptors are
responsible for “stress-sweating” in 21-yearold man as he clicks the first question onto the
screen for his Step 1 USMLE exam?
A.
B.
C.
D.
E.
Alpha-adrenergic
Beta-adrenergic
Histaminergic
Dopaminergic
Muscarinic
Answer: A
Apocrine sweating
Drugs modifying autonomic neurotransmission at
various levels ,autonomic Receptors & their 2nd
Messenger System
-Know the specific moa of
-Figure out the Rcptrs at aforesaid
Levels
-Why Rcptors at various levels are
Different?
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Cholinergic Transmission
Acetylcholine (ACh)
 Synthesized (Step1) by choline acetyltransferase
(ChAT)
• Acetyl-CoA synthesized in mitochondria
• Choline transported into the neuron
• Blocked by hemicholinium (blocks uptake of
choline)
 ACh transported (Step2) into small clear vesicles
• Transporter can be blocked by vesamicol
(depletes neurotransmitter stores)
 Release (Step3) of transmitter is calcium-dependent
• Triggered by action potentials
• ACh release blocked by botulinum toxin
 Acetylcholine binds to receptors (Step4)
(cholinoceptor)
 Catabolized (Step5) by acetylcholinesterase
(AChE)
• Breaks ACh into choline and acetate
• Terminates the action of the transmitter
• Half-life of acetylcholine is very short
• AChE in other tissues, eg, red blood cells
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Examples of Drugs Affecting
Parasymp. Neurotransmission
Mechanism of action
Drugs Affecting Acetylcholine
Neurotransmission
Inhibit synthesis of neurotransmitter
Hemicholinium*
Prevent vesicular storage of
neurotransmitter
Vesamicol*
Inhibit release of neurotransmitter
Botulinum toxin
Increase release of neurotransmitter
Black widow spider venom (α-latrotoxin)*
Inhibit reuptake of neurotransmitter
-
Inhibit metabolism of neurotransmitter
Cholinesterase inhibitors (physostigmine)
Activate postsynaptic receptors
Acetylcholine, bethanechol, and pilocarpine
Block postsynaptic receptors
Atropine and tubocurarine (block
muscarinic and nicotinic receptors,
respectively)
*These agents have no current medical use.
A pack of girls were expediting their social research
in various countryside of Mexico. After few days
couple of girls developed various symptomatology
mimicking ‘cholinergic stimulation. That place is
quite known for black widow spider . What could be
the possible mechanism of such toxicity?
Cholinergic Receptors: Receptors Activated by Ach
Muscarinic Receptors
(Activated by muscarine from Amanita muscaria)
Nicotinic Receptors
(Activated by nicotine from tobacco)
M1
(Nerve Cells)
M2
NM
(Neuromuscular)
(Blocked by
NN
Tubocurarine) Autonomic ganglia,
(Heart & SM)
M3
(Vas. & other
SM)
M4
(SM & Glands)
(Blocked by Atropine)
M5
(?)
Adrenal medulla &
CNS
(Blocked by Trimethaphan
or Hexamethonium)
Muscarinic Receptors
M1 & M3 
Gq
Activation of
PLC
Formation of
IP3
Release of
Intracellular
Calcium
Formation
of DAG
Activation of
PKC
M2 & M4 
α subunit
Inhibition
of
Adenylyl
Cyclase
Gi
β
subunit
Opening of
Potassium
Channels
When acetylcholine is injected into an
experimental subject, which of the following
cholinergic-mediated mechanisms is
responsible for the formation endotheliumderived relaxing factor (EDRF) or nitric oxide
(NO) formation, the factor that initiates
vasodilatation?
A.
B.
C.
D.
E.
Activation of adenylyl cyclase
Activation of guanylyl cyclase
Inhibition of adenylyl cyclase
Opening of potassium channels
Release of intracellular calcium
Answer: E
Endothelial-nitric
oxide synthase
(eNOS) is a Ca2+
dependent enzyme
NE
Sympathetic Nervous System
(Thoracolumbar Outflow)
ACh
Pilomotor Muscles
Sweat Glands
ACh = thermal sweating
NE = nervous sweating
Radial Muscle of Iris
Ciliary Muscle
Sublingual/Submaxillary
& Parotid Gland
SA & AV Nodes
His-Purkinje System
Myocardium
Bronchi/Bronchial
Glands
Stomach
Kidneys
Blood Vessels
Intestines
Paravertebral Ganglia
Bladder//Genitalia
Prevertebral Ganglia
Receptor distribution On various organs –memorize ; Predicting outcome through various organsyou can figure out by putting yourself in “fight & flight” mode
Norepinephrine is typical product in SNS
• In adrenal, NE converted to epinephrine
• Dopamine stored in some CNS neurons
 Conversion of tyrosine to dopa is rate-limiting
• Tyrosine hydroxylase
• Inhibited by tyrosine analog metyrosine
 Dopa converted to dopamine
• Dopa decarboxylase (inhibited by
carbidopa)
 Dopamine converted to NE
• Dopamine-beta-hydroxylase
 Storage inhibited by reserpine
 Release blocked by guanethidine and
bretylium
 Uptake 1 (NET) transports catecholamines
into presynaptic neuron
• Inhibited by cocaine (and TCAs)
• Increases transmitter activity
 NE taken up postjunctionally by uptake 2
 Release is calcium-dependent
 Tyramine and amphetamines
• Enter via Uptake 1
NEpool
Examples of Drugs Affecting
Sympathetic
Neurotransmission
Mechanism of action
Drugs Affecting Sympathetic
Neurotransmission
Inhibit synthesis of neurotransmitter
Metyrosine (alpha-methyl-paratyrosine)
Prevent vesicular storage of
neurotransmitter
Reserpine
Inhibit release of neurotransmitter
Bretylium
Increase release of neurotransmitter
Amphetamine
Inhibit reuptake of neurotransmitter
Cocaine
Inhibit metabolism of neurotransmitter
Monoamine oxidase inhibitors
(phenelzine)
Activate postsynaptic receptors
Albuterol, dobutamine, and
epinephrine
Block postsynaptic receptors
Phentolamine and propranolol (block
α- and β-adrenoceptors, respectively)
*These agents have no current medical use.
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A cocaine addict was brought to ER with a
state of hypertensive crisis. What is the
possible pharmacologic mechanism through
which cocaine has raised BP in this patient?
Summary of Catecholamine Biosynthesis
Tyrosine
Rate limiting step 
DOPA
Dopamine
Norepinephrine
SYMPATHETIC
NERVE
ADRENAL
GLAND
Epinephrine
Inhibition of which of the following enzymes
would be the most appropriate in the treatment
of a 56-year-old man with pheochromocytoma?
A.
B.
C.
D.
E.
Catechol-O-methyltransferase
Dopa decarboxylase
Dopamine-beta-hydroxylase
Phenethanolamine-N-methyltransferase
Tyrosine hydroxylase
Answer: E
Rate limiting step
Adrenergic Receptors: Receptors Activated by EPI/NE
alpha-adrenergic
receptors
a
(Epinephrine>>Isoproterenol)
alpha1-adrenergic
receptors
(Phenylephrine>>Clonidine)
alpha2-adrenergic
receptors
(Clonidine>>Phenylephrine)
beta-adrenergic receptors
(Isoproterenol>Epinephrine)
beta1-adrenergic
receptors
(EPI >= NE)
beta 2-adrenergic
receptors
(EPI>>NE)
beta 3-adrenergic
receptors
(NE>EPI)
Signal Transduction by a1 - Adrenergic Receptors
Phenylephrine
Norepinephrine

Gq
q
Polyphosphoinositide
q
Signal Transduction by a2 - and  - Adrenergic Receptors
Isoproterenol

Clonidine

ADRENAL
MEDULLA
Chromaffin Cells
Epinephrine
(+) Dilates Airways
(+) Cardiac Output
(+) Muscle Contraction & Efficiency
(+) Fatty Acid Release
(+) Mental Alertness
(+) ACTH & TSH
(+) Glycogenolysis
(-) Intestinal Motility
Broad effects supporting “fight or flight”
Which of the following will occur in a 15-yearold boy after stimulation of adrenal
catecholamine release during a stress
response?
A.
B.
C.
D.
E.
Bradycardia
Bronchodilation
Decreased fatty acid release
Decreased skeletal blood flow
Increased intestinal motility Answer: B
Beta-2 activation
ANS Rcs their organ distribution & response
following agonism & antagonism
-predict responses on diff.organs
By visulaizing urself preparing
For ‘fight & flight’&’rest & digest’
Responses through various sub
types of adrenergic & cholinergic
Receptors respectively
-visualize 2nd MS used by various
types of SNS & PNS receptors
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Responses elicited in effector organs by sympathetic and
parasympathetic activation
Effector organ
Adrenergic response
Cholinergic response
Rate of contraction
Increase, β 1
Decrease, M2
Force of contraction
Increase, β1
Decrease, M2 (atrial contraction)
Atrioventricular conduction
Increase, β1
Decrease, M2
in myocardium
Vasodilatation, β 2 (α 1
constr*)
Vasodilatation, M3
in skeletal muscles
Vasodilatation, β2, M3
(contraction α1)
Heart
Arteries and arterioles
Endothelium
EDRF release ,vasodilatation
M3, M5 (cerebral blood vessels)
(See Note below)
Skin, splanchnic vessels
Contracts, α 1
Veins
Contracts, α 1
*Periphery as well
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Bronchodilatation, β 2
Bronchoconstriction, M3
motility
Decrease, α 2 (β 2, )
Increase, M3
sphincters
Contraction, α1
Relaxation*, M3
secretion
?Decrease, α
Increase, M3
Small secretion, α 1
Secretion, M3, M2
Bronchial muscles
Gastrointestinal
Exocrine glands
Salivary
Lacrimal
Digestive
Secretion, M3, M2
?Decreased secretion, α
Airway
Sweat
Secretion, M3, M2
Secretion, M3 ‘ M2
Secretion, α1 (Apocrine [
stress])
Secretion, M3 Eccrine sweat
glands (thermoregulatory)
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Pancreatic acini
Decreased secretion, α
Langerhans islets
Decreased secretion, α 2
Increased secretion, β 2
Lipid cells
Lipolysis, β 1 β 3
Liver glycogenolysis
↑ glycogenolysis &
gluconeogenesis, β 2 ,α 1
Secretion, M
Eye
Ciliary muscle
Contraction, M3 (near
vision)
Dilatator muscle of pupil (iris Contract., α 1 (Mydriasis)
radial muscle)
Sphincter muscle of pupil
(iris circular)
Contraction, M3 (Miosis)
Kidney
↑Renin secretion, β 1
↓Renin secretion α 1
Ureter-motility
Increase, α 1
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Urinary bladder
detrusor
Relaxation, β2
Contraction, M3
Sphincter/Trigone
Contraction, α 1
Relaxation, M3
male
Ejaculation, α 1
Erection, M3
uterus (pregnant)
Contraction, α 1
Relaxes β2
Genital organs
Adrenal medulla
Platelets
Pre junctional adrenergic
Neurons in brian
Secretion, N
↑ Aggregation
↓ Release of NE thus
sympatholysis
Ocular Pharmacology & Glucoma
-various therapeutic approaches
By exploiting physiological flow
Of aquas humor
-diff.drugs that are used in t/t.
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Table 10–3. Drugs Used in Open-Angle Glaucoma.
Mechanism
Methods of Administration
Ciliary muscle contraction, opening of trabecular meshwork; increased
outflow
Topical drops or gel; plastic film slow-release
insert
Increased outflow
Topical drops
Cholinomimetics
Pilocarpine, carbachol, physostigmine, echothiophate,
demecarium
Alpha agonists
Unselective
Epinephrine, dipivefrin
Alpha2-selective
Decreased aqueous secretion
Apraclonidine
Topical, postlaser only
Brimonidine
Topical
Beta-blockers
Timolol, betaxolol, carteolol, levobunolol, metipranolol
Decreased aqueous secretion from the ciliary epithelium
Topical drops
Decreased secretion due to lack of HCO3-
Topical
Diuretics
Dorzolamide, brinzolamide
Acetazolamide, dichlorphenamide, methazolamide
Oral
Prostaglandins
Latanoprost, unoprostone
Increased outflow
Topical
Structures of the anterior chamber of the eye
• Tonometric measurements in a 61-year-old patient revealing a
consistent increase in intra ocular pressure together with
abnormalities in central visual field testing, are diagnostic of
open-angle glaucoma. A number of pharmacologic treatments
can slow the progression of the disease, which can ultimately
lead to complete blindness if left untreated. Which one of the
following statements about such drug therapy is accurate?
(A)Beta blockers cause ciliary muscle contraction, increasing aqueous humor
outflow.
(B)Cholinomimetics causes miosis leads to better outflow of aqueous humor.
(C)Topical use of nonselective beta blockers will worsen glaucoma.
(D)Activation of alpha receptors leads to miosis.
(E)Topical use of AChE inhibitors leads to mydriasis.
Directly acting cholinomimetics-Pharmacology
-classification based on MOA
-ADME based on ter/quarter
-diff. in organ system effect in
-clinical uses & underlying MOA
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From: McGraw Hill’s AccessMedicine; Katzung; Table 7-2
Note methyl group blocks nicotinic activity
Note carbamoyl group blocks hydrolysis
Tertiary natural cholinomimetic alkaloids
• Pilocarpine
• Nicotine
• Lobeline is a plant derivative similar to nicotine in action
Muscarine - a quaternary amine
• Source – Amantia muscaria Mushrooms
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Clinical uses of choline esteres and alkaloid
Choline Ester
Clinical uses
Acetylcholine
chloride.
Short t1/2, no
clinical use
Methacholine
chloride
Dx-bronchial
hyperreactivity
Carbachol
chloride
Bethanechol
chloride
Rx-ileus
(postop/neurogenic)
, urinary retention
Choline
Alkaloid
Clinical uses
Muscarine
no clinical use,
toxological
importance
Nicotine
no clinical use,
toxological
importance
Lobeline
no clinical use,
toxological
importance
Pilocarpine
Rx-glaucoma
(topical),
xerostomia
• A 54-year-old woman recovering from abdominal surgery
receives bethanechol pharmacotherapy. Which of the
following symptoms could be expected to be observed in
this individual?
A. Dry mouth, abdominal cramps and tachycardia
B. Miosis, bronchospasm and fasciculations
C. Miosis, diarrhea and hypotension
D. Constipation, increased sweating and salivation
E. Hypotension, fasciculations and decreased urination
(A)
(B)
(C)
(D)
(E)
Calcium efflux
Increased cyclic adenosine mono phosphate (cAMP) concentration
Increased cyclic guanosine monophosphate (cGMP) concentration
Increased inositol triphosphate (lP 3) concentration
Potassium efflux
•
For each of the following pharmacologic effects, select the corresponding mechanism
of action.
•
Contraction of the iris sphincter muscle produced by pilocarpine
•
Vasodilation produced by sildenafil
•
Slowing of the heart rate by acetylcholine
•
A new acetylcholine receipt or inhibit or has just been approved by the FDA.
You consider the possible therapeutic implications of this agent and want to
review the autonomous nervous supply of various organs. Which of the
following nervous outputs is noradrenergic?
A. Sympathetic output to adrenals
B. Sympathetic output to sweat glands
C. Sympathetic output to the bladder
D. Parasympathetic output to the heart
E. Parasympathetic output to the bronchi
•
A strong, non-specific muscarinic agonist has recently been developed. This
new agent would most likely have which of the following actions?
A. Bladder wall relaxation
B. Kidney renin release
C. Gl sphincter contraction
D. Increased ventricular contractility
E. Release of endothelium-derived relaxation factor
• A new drug seems to have partial agonist/antagonist activity against
receptor X. When the drug is applied to cells expressing receptor X,
there is an immediate change in transmembrane sodium and
potassium flow thought secondary to the opening of receptorcoupled transmembrane ion channels. Receptor X is most likely
which type of receptor?
A. a1adrenoreceptor
B. β1 adrenoreceptor
C. β2 adrenoreceptor
D. Muscarinic cholinergic receptor
E. Nicotinic cholinergic receptor
Indirectly acting cholinomimeticsPharmacology
-classification based on MOA
-ADME based on ter/quarter
-diff. in organ system effect in
Comparision with DADs.
-clinical uses & underlying MOA
-toxicity & management
17
Indirect-Acting Cholinomimetics:
Basic Pharmacology

ACh effects terminated by Acetylcholinesterase
Indirect-acting cholinomimetics inhibit this enzyme

Cholinesterase inhibitors fall into three chemical groups:
(1) Simple alcohols bearing a quaternary ammonium group (doesn’t enter CNS);
compete for ACh at the enzyme
Edrophonium
(2) Carbamic acid esters of alcohols bearing quaternary (doesn’t enter CNS); or
tertiary ammonium (enter CNS); groups (carbamates); carbamoylate the active site
Neostigmine – quaternary
Physostigmine – tertiary (crosses BBB)
Carbaryl – high lipid solubility (rapid CNS effects); insecticide
(3) Organic derivatives of phosphoric acid (organophosphates); phosporylate the
active site
Echothiophate; used for glaucoma
Soman; nerve agent
Sarin; nerve agent
Malathion, parathion
Bioactivated to give active phosphorylating agent
used as insecticides.
Cholinesterase Inhibitors:
Absorption, Distribution, and Metabolism
 Absorption of quaternary carbamates is predictably poor
• Permanent charge renders them relatively insoluble in lipids
 The tertiary amine carbamates (physostigmine; carbaryl) are well
absorbed
• Distribute into the CNS (crossess BBB)
• Duration of their effect is determined by stability of inhibitorenzyme complex
 Organophosphates (except for echothiophate)
• Are well absorbed both topically and orally
• Are distributed to all parts of the body, including the CNS
Cholinesterase Inhibitors: Pharmacodynamics
 Acetylcholinesterase is primary target
 Butyrylcholinesterase is also inhibited
 Quaternary alcohols (edrophonium) reversibly bind to the active site
• Inhibition is short-lived (on the order of 2–10 minutes)
 Carbamate esters undergo a two-step hydrolysis
• Covalent bond of the carbamoylated enzyme is slowly hydrolyzed
(reactivated)
• Inhibition is longer (on the order of 30 minutes to 6 hours)
 Organophosphates
• Results in a phosphorylated AChE active site
• Covalent phosphorus-enzyme bond is extremely stable
• Inhibition lasts hundreds of hours
• Lifetime of enzyme protein
• “Aging” strengthens phosphorus-enzyme bond
• Before aging, pralidoxime (2-PAM) can restore enzyme function
(Reactivation)
Cholinesterase Inhibitors: Organ System Effects
 Most prominent effects are on:
• Cardiovascular and gastrointestinal systems
• Eye and skeletal muscle
 Actions amplify the actions of endogenous acetylcholine
 Effects are similar to direct-acting cholinomimetics
 Little effect on vascular smooth muscle and on blood pressure
• Remember PNS does not innervate peripheral vasculature!)
• At NMJ:
• Low (therapeutic) concentrations increase force of contraction
• Higher doses produce depolarizing neuromuscular blockade
Cholinesterase Inhibitors: Clinical Uses
 Eye
• Glaucoma (closed & open angle)-(Physiostigmine,Ecothiophate)
• Reduce intraocular pressure
• Contraction of the ciliary body
• Facilitates outflow of aqueous humor
 Gastrointestinal and Urinary Tracts (Neostigmine,pyridostigmine)
• Clinical disorders related to inactivity of smooth muscle activity
• Postoperative ileus
• Congenital megacolon
• Urinary retention
• Neurogenic bladder
• Reflux esophagitis
• Insufficient salivary secretion
 Reversal of Non-depolarizing Neuromuscilar blockers (Neostigmine
,pyridostigmine)
Cholinesterase Inhibitors: Clinical Uses
(cont’d)
 Neuromuscular Junction (Dx-Edrophonium ); T/t: Neostigmine,
pyridostigmine)
• Myasthenia gravis
• Autoimmune disease affecting NMJ
• Cholinesterase inhibitors are valuable therapy
• Edrophonium (Tensilon test) – i.diagnostic test for MG
(improvement in muscle strength after inj.) ii.differential diagnosis
bet. MG & Cholinergic crisis.
 Atropine intoxication (physostigmine)
• Reversal of competitive blockade by cholinomimetics
• Physostigmine has tertiary structure so reverses both CNS and
peripheral effects
 Central Nervous System (Tacrine & donepezil )
• Alzheimer’s disease
• Tacrine & donepezil have anticholinesterase and cholinomimetic
actions
• Used in therapy for mild to moderate Alzheimer's disease
Cholinesterase Inhibitors: Acute Toxicity
“SLUDGE”
• Salivation
• Lacrimation
• Urinary incontinence
• Diarrhea
• Gastrointestinal cramps
• Emesis
DUMBBELSS
 Diarrhea
 Urination
 Miosis
 Bronchoconstriction
 Bradycardia
 Excitation; Emesis
 Lacrimation
 Salivation
 Sweating
• Can be reversed by atropine (muscarinic antagonist)
• Cholinesterase inhibitor poisoning also treated by:
• Maintenance of vital signs (respiration)
• Decontamination to prevent further absorption
• Atropine parenterally in large doses
• Therapy may also include treatment with pralidoxime to
“rescue” un-aged inhibited enzyme; but pralidoxime
contraindicated for carbamate intoxication
Irreversibly acting Cholinomimetics
These compounds phosphrylate
the esteric site of AchE,at
serine hydroxyl groups.
1.Phosphorylation-reversible by
pralidoxime (2PAM)
2.Removal of part of
organophosphate molecule
(aging). Complex no longer
reversible by 2PAM.
R-leaving group
P-organophosphate
A.
B.
C.
D.
E.
F.
G.
•
Bethanechol
Donepezil
Echothiophate
Malathion
Physostigmine
Pilocarpine
Pyridostigmine
For each patient described below, select the most appropriate drug for treatment.
•
A 22-year-old woman presents with eyelid and facial ptosis, loss of hand-grip strength, and
diplopia, which she says gradually developed over several months. These clinical manifestations
are rapidly reversed when intravenous edrophonium is given for diagnostic purposes.
•
A 60-year-old woman exhibits progressive dementia and complains of the loss of short-term
memory over the past year. Her clinical manifestations cannot be attributed to a specific cause.
•
A 45-year-old man has Sjogren's syndrome and suffers from chronic dry mouth.
• A 44-year-old woman returns to her physician for a follow-up
examination complaining of fatigue. On her last visit 1-month
ago she was diagnosed with myasthenia gravis and placed on
neostigmine pharmacotherapy. On questioning she states that
1 week ago she felt weak and increased her dosage of
neostigmine. Today, on challenge with edrophonium, a
decrease in muscle strength (3/4) is observed. Which of the
following is the recommended next step in the treatment of
this patient?
A. Maintain the current dosage of neostigmine
B. Reduce the current dosage of neostigmine
C. Increase the current dosage of neostigmine
D. Replace neostigmine treatment with physostigmine
E. Replace neostigmine treatment with isoflurophate (DFP)
• The administration of pralidoxime would be most useful in
treating a 29-year-old man 2 hours after an excessive
exposure to which to the following cholinergic drugs/poisions
?
(A)Soman
(B)Donepezil
(C)Pilocarpine
(D)Physostigmine
(E)Echothiophate
• A 24-year-old migrant farm worker is rushed to a nearby emergency
room after an accidental exposure to an organophosphate
insecticide. He is in respiratory distress and is bradycardic. Which of
the following drugs can be given to increase the activity of his
acetylcholinesterase?
A. Atropine
B. Deferoxamine
C. Dimercaprol
D. N-acetylcysteine
E. Physostigmine
F. Pralidoxime
Cholinoreceptor blocking drugs-Uses & a/e
-clinical uses & underlying MOA
-a/e & contraindications
18
Cholinoceptor-Blocking Drugs: Therapeutic
Applications
 Parkinson's Disease (benztropine, trihexphenidyl)
 Motion Sickness (scopolamine)
Patch behind the ear
 Preoperative medication – prevents laryngospasm
(glycopyrrolate); some are also amnestic (scopalamine)
 Relieves bronchodilation – asthma and COPD (ipratropium,
tiotropium)
 Relief of vagal syncope
 Traveler's diarrhea, mild GI hypermotility
• Combined with an opioid antidiarrheal (abuse deterrent)
Cholinoceptor-Blocking Drugs:
Therapeutic Applications
 Urinary urgency, frequency, incontinence (Oxybutynin;
Tolterodine – M3 selective)
Oxybutynin available as a patch
 Reversal of cholinergic poisoning
• Requires a tertiary (not quaternary) drug
• Large doses of atropine may be needed
• Drug may have to be repeated
 Ophthalmology (homatropine, cyclopentolate, tropcainamide,
scoplolamine, atropine)
• Retinal examination
• Prevention of synechiae after surgery
 Hyperhidrosis
• Relief is incomplete at best
• Understand ecccrine (cholinergic) vs. apocrine (adrenergic) glands
Cholinoceptor-Blocking Drugs:
Adverse Effects
 Atropine poisoning
• Dry mouth, mydriasis, tachycardia, flushed skin, delirium
• “Dry as a bone, blind as a bat, red as a beet, mad as a hatter."
• Can be treated with physostigmine or symptom management
 Contraindications are relative:
• Glaucoma (especially narrow angle-closure glaucoma)
• Prostatic hyperplasia
• May increase gastric ulcer symptoms
• A 38-year-old traveler presents to your office for a routine check-up.
He will be leaving for a cruise next week, and asks for a drug that
would prevent the severe nausea and vomiting he experiences on
ships. What is the site of action of the most appropriate drug for this
patient?
• You have successfully prescribed neostigmine to a young patient
with myasthenia gravis, and her muscle strength has improved
markedly. However, she also exhibits cardiovascular and
gastrointestinal signs of excessive vagal tone, which you would like
to block with atropine. Which of the following risk factors in
prescribing atropine is MOST important to you?
A. Dry mouth
B. Ocular disturbances
C. Paralysis of the respiratory muscles
D. Tachycardia
E. Urinary incontinence.
• Atropine and other muscarinic receptor antagonists are
used to treat all of the following conditions EXCEPT
•
•
•
•
•
atrioventricular block
bradycardia
emphysema
gastroesophageal reflux
urinary incontinence
• Ocular effects that include mydriasis and fixed
far vision are characteristic of
A. mecamylamine
B. neostigmine
C. phentolamine
D. phenylephrine
E. timolol
• An 11-year-old boy was brought to the ER by some of his friends
because he "started going crazy" after eating seeds from a plant
while "trying to get high." The boy was incoherent; his skin was hot
and dry. His pupils were dilated and unresponsive to light. Blood
pressure was 180/105, pulse 150, and rectal temp 400C. The
presumptive diagnosis was drug toxicity due to the ingestion of a
compound similar to
• cannabis
• digoxin
• mescaline
• phencyclidine
• scopolamine
• Toxic doses of atropine typically cause all of the
following effects EXCEPT
(A) bronchospasm
(B) hallucinations
(C) hyperthermia
(D) palpitations
(E) urinary retention
Ganglionic blockers-predicting responses
-how to predict response on different
Organs following administration of
Ganglionic blockers?
-reflex control of HR & mechanism
19
Algorithm: Reflex control of Heart Rate
• The effects of a ganglion blocking agent may be predicted by
knowledge of ANS innervation of effector systems and which branch
of the ANS exercises dominance in terms of organ and tissue
responsivity. With this principle in mind, one can anticipate that
hexamethonium will cause
•
•
•
•
•
abolition of the circulatory reflex
cycloplegia
reduction of bladder tone
xerostomia
all of the above
Sympathomimetics & their specific adrenergic
Rc innervation
20
-required to read the autonomic
tracings
Adrenoceptor Agonists
Sympathomimetics
Anxiety, nervousness
Fear, fight, flight
Pupil dilated
Alpha = excitatory
Beta-1 = excitatory
Beta-2 = inhibitory (relaxation)
Direct acting
Catecholamines
Indirect acting
Releasers
tachyphylaxis Tyramine
Ephedrine
Amphetamine
Direct adrenoceptor
agonists
Epinephrine α1, α2, β1, β2
Norepinephrine α1, α2, β1
Isoproterenol β1, β2
Dobutamine β1 (α1)
Dopamine D1 (α1 and β1 at
high doses)
Methoxamine α1
Phenylephrine α1
Methyldopa α2 prodrug
Clonidine α2
Ritodrine β2
Terbutaline β2
Albuterol β2
Metaproterenol β2
MAO Inhibitors
Tranylcypromine (A)
Selegiline (B)
Reuptake inhibitors
Cocaine
Imipramine (TCA)
COMT inhibitors
Tolcapone
Entacapone
•
A medical student is conducting a
pharmacology experiment. He infuses Drug
X intravenously over different dose ranges
and measures several important
hemodynamic parameters. Graphs plotting
the recorded measurements of renal blood
flow and cardiac output change with
increasing doses of Drug X are shown
below. Which of the following is most likely
to be the drug used in the experiment?
A. Epinephrine
B. Phenylephrine
C. Dopamine
D. Edrophonium
E. Esmolol
Sympathomimetics & uses
21
-clinical uses & underlying MOA
Sympathomimetics: Clinical Applications
Conditions in which Blood Pressure is to be enhanced:
–
Hypotension (2o to cardiac arrhythmias, neurologic disease,
etc.)
– Hypovolemic or cardiogenic shock
– Cardiac insufficiency
Conditions in which Blood Flow is to be reduced:
–
–
–
Hemostasis in surgery (cocaine)
Reducing diffusion of local anesthetics (Epi)
Reducing mucous membrane congestion (alpha1 agents)
Heart failure - may respond to positive inotropic effects
of dobutamine
• Tolerance/ desensitization limits use in heart failure
Sympathomimetics: Clinical Applications
Bronchial asthma (bronchodilation by beta2)
Anaphylaxis (bronchospasm, hypotension)
Fundoscopic examination of the retina (alpha1 – mydriasis)
Premature labor – uterus relaxed by beta2 agonists
(ritodrine, terbutaline)
Narcolepsy - amphetamines produce alertness and defer
sleep
Attention-deficit hyperactivity disorder (ADHD);
methylphenidate
Sympatholytics & uses
21
-clinical uses & underlying MOA
Alpha-Receptor Antagonists:
Clinical Uses
 Pheochromocytoma
• Tumor of the adrenal medulla
• Releases a mixture of epinephrine and norepinephrine
• Symptoms and signs of catecholamine excess
• Hypertension, headaches, palpitations, sweating
• Very severe cases treated with metyrosine
• Competitive inhibitor of tyrosine hydroxylase
 Hypertensive Emergencies
• Direct vasodilators (nitrates) are preferred
 Chronic Hypertension
• Effective, but may not prevent eventual heart failure
• Adverse effect - postural hypotension
 Urinary Obstruction due to benign prostatic hyperplasia (BPH)
• Poorly defined mechanism
Some B-Blockers & isolated characteristics
22
Some Beta Blockers
Beta blocker -Uses & a/e
-clinical uses & underlying MOA
-a/e & contraindications
23
Beta-blockers: Clinical Uses
 Hypertension (Any BB)
• Effective and well tolerated
• Often used in combination with diuretic or vasodilator drugs
 Ischemic Heart Disease (Any BB)
• Reduce the frequency of anginal episodes
• Improve exercise tolerance
• Decrease cardiac work
• Reduce myocardial oxygen demand
• Good evidence that long-term use prolongs survival after MI
 Cardiac Arrhythmias (only Class II Antiarrhythmics)
• Effective in supraventricular and sympathomimetic-driven
arrhythmias
• Post-MI survival may be due to suppression of arrhythmias
• Increase AV node refractory period
• Slows ventricular response rates in atrial fibrillation
• Reduce ventricular ectopic beats
Beta-blockers: Clinical Uses
Glaucoma (Timolol,Betoxolol)
• Topical administration reduces intraocular pressure
• Reduced production of aqueous humor by the ciliary epithelium
• Better tolerated than epinephrine-related drugs or pilocarpine in
open-angle glaucoma
 Hyperthyroidism (only Propranolol)
• Beneficial effects in limiting excessive catecholamine activity
Migraine,performance anxiety & essential tremor (only Propranolol)
Combined use
*CHF (Labetolol & Carvedilol ;Reversible alpha1 blocker +
nonselective beta blocker)
*Arrhythmia (Sotalol, Class III antiarrhythmics;K+channel
blocker+beta blocker)
Toxicity of the Beta-Receptor Antagonist
Drugs
 Drugs are relatively well-tolerated
 Minor toxic effects include:
• Rash, Fever ,Sedation & Depression
 Major adverse effects:
• Related to predictable consequences of beta blockade:
• Worsening of preexisting asthma and other airway
obstruction (B2)
• Vasospasm in patients with peripheral vascular disease (PID)
(B2)
• Depression of myocardial contractility and excitability
• May result in cardiac decompensation(B1)
Toxicity of the Beta-Receptor Antagonist
Drugs
Supersensitivity with abrupt discontinuation after
chronic use
– Gradual tapering of dosage can prevent hypertensive
crisis (B1)
– Can exacerbate hypoglycemic episodes in diabetics
(B2) & masks the symptoms of hypoglycemia (B1&
B2)
– BB overdose should be treated with Glucagon rather
than beta agonist to prevent development of receptor
supersensitivity
• A 43-year-old, insulin-dependent diabetic patient is diagnosed with
hypertension and begins therapy with an antihypertensive agent.
Three days later, he measures his blood glucose at home and finds
that it is 53 mg/dL. He recalibrates his glucose testing apparatus and
repeats the test, only to find that the first reading was accurate. He
is concerned that his hypoglycemia did not produce the normal
premonitory signs and symptoms. Which of the following
medications was most likely prescribed to treat his hypertension?
A. Acebutalol
B. Methoxamine
C. Methyldopa
D. Prazosin
E. Propranolol
ANS Trachings
24
Effect of an unknown drug on Heart rate
and blood pressure
Control drug effect
Increased diastolic
Decreased diastolic
Increased Heart rate
Decreased Heart rate
Increased pulse pressure
Increased TPR (Increased α1)
decreased TPR (increased β2, decreased α1, directly
acting vasodilators and cholinomimetics.
increased β1 (May be reflex *)
Increased Cholinergic (May be a reflex)
increased β1 (increased inotropic activity)
Effect of α1 activators on Heart rate and
blood pressure
•Systemically , increase mean blood pressure via vasoconstriction.
•Increased BP may elicit a reflex bradycardia.
•Cardiac output may be decreased but also offset by increased venous
return.
•No change in pulse pressure.
Effect of β activators on Heart rate and
blood pressure
•Systemically, decrease mean BP via vasodilation (β2) and increased HR
(β1)
•Increased Pulse pressure.
Effect of Norepinephrine on Heart rate and
blood pressure
Exercise: Effect of norepinephrine after pre-tretment with
atropine.
Effect of Epinephrine on Heart rate and
blood pressure
• Dose dependent effects
– Low dose: β1 ,β2 stimulation.
– High dose: α1, β1 (β2).
• Β2 specific effects:
– Smooth muscle relaxation.
– Metabolic effects:
• Increased glycogenolysis
• Increased gluconeogenesis
• Increased mobilization and
use of fat.
• Exercise: Effect of epinephrine
after pre-treatment with α1
blocker.
Predicting Responses
β1 & β2
Epi reversal
β 1, β 2, & α
1
β 1, & α1
Use of α 1blocker to reverse hypertension to hypotension
(unmasking β2 action) in pt. receiving too much Epinephrine
(Vasomotor reversal of Dale)
Effect of an unknown drug (R) on Heart rate and blood pressure
3 logical questions to yourself
• R is
1.What does the drug do in control tracing?
2.Does the blocker changes drug response?
(compare with control)
3.In +ce of blocker can the drug still do
some changes? (compare baseline vs after
effect in the same tracing
A. epinephrine
B.
norepinephrine
.
C. phenylephrine
D. isoproterenol
E. terbutaline
Effect of an unknown drug (U) on Heart rate and blood pressure
Effect of an unknown drug (S) on Heart rate and blood pressure
Effect of an unknown drug (H) on Heart rate and blood pressure
Effect of an unknown drug (R) on Heart rate and blood pressure
Effect of an unknown drug (R) on Heart rate and blood pressure
•
•
•
•
•
•
Drug H is
Isoprotenol
Epinephrine.
Norepinephrine
Phenylephrine
Tyramine
Effect of an unknown drug (R) on multiple body parameters
•
•
•
•
•
Drug X and Y are, respectively
Isoproterenol and propranolol
Epinephrine and
phenoxybenzamine
Norepinephrine and
phentolamine
Terbutaline and phenylephrine.
Acetylcholine and
Effect
Effectofofananunknown
unknowndrug
drug(R)
(R)ononHeart
multiple
rate body
and blood
parameters
pressure
Effect of unknown drugs on Heart rate and blood pressure in vitro
•
•
•
Horner's syndrome is a clinical syndrome caused by
damage to the sympathetic nervous system.
PAMELa" for Ptosis, Anhidrosis, Miosis,
Enophthalmos and Loss of ciliospinal reflex.
Lesions
First-order neuron disorder: Central lesions that
involve the hypothalamospinal pathway (e.g.
transection of the cervical spinal cord).
Second-order neuron disorder: Preganglionic
lesions (e.g. compression of the sympathetic chain
by a lung tumor).
Third-order neuron disorder: Postganglionic lesions
at the level of the internal carotid artery (e.g. a
tumor in the cavernous sinus).
lesion of the post-ganglionic sympathetic
innervation of the right eye.
1. Alpha 1 agonist
2. Releaser / indirectly acting drug
3. Muscarinic receptor blocker
4. Alpha receptor blocker
Heart Rate Blood Pressure Look
at BP 1st
Low dose ACH
(2 mg)
ACH (50 mg)
Intermediate dose
(Atropine: Muscarinic Receptor Antagonist)
ACH (50 mg)
ACH (5 mg)
High dose
(Hexamethonium: Neuronal Nicotinic Receptor
Antagonist)
ACH (5 mg)
• A medical student is observing a pharmacology experiment where
drug A is being intravenously administered to a pregnant dog. Some
parameters that are being recorded during the experiment include
heart rate, pupil size and uterine contractions .The following
diagrams illustrate the measured parameters and observed changes
after infusing drug A. Characterize drug A?
HR
Cardiovascular effects of a new drug (X) that activates autonomic
receptors are shown in the table below:
Parameter
Systolic BP
Diastolic BP
Heart rate
Control
118 mm Hg
85 mm Hg
62/min
Drug X
114 mm Hg
54 mm Hg
122/min
The most probable receptor affinities of drug X are
A. α1, α2
B. α1, α2, β1
C. β1, β2
D. M2
E. NM
• A pharmacologist is investigating the cardiovascular
actions of Drug X. Alone Drug X causes an increase in
blood pressure and a decrease in heart rate when
administered iv. If an antagonist at ganglionic nicotinic
receptors is administered first, drug X causes an
increase in blood pressure and no change in heart
rate. Drug X most likely is?
A. Epinephrine
B. Isoproterenol
C.Norepinephrine
D.Phenylephrine
E. Propranolol
•
Three days after a 60-year-old man undergoes a bowel resection, he
begins hyperventilating and is found to have respiratory alkalosis. The
following day, his condition has worsened. Findings include
temperature that exceeds 40°C (>104°F), profound hypotension,
tachycardia, elevated blood urea nitrogen (BUN) and serum creatinine
levels, low urinary output, and a white blood cell count of 18,000/mm3
with a shift to the left. The patient’s sputum is purulent, and a Gram
stain shows the presence of gram-negative rods. What agent is the
most appropriate drug to give to this patient for hemodynamic support?
A.Aspirin
B.Dopamine
C. Furosemide
D.Isoproterenol
E.Nitroprusside