Autonomic Pharmacology
I. Nervous System  Preganglionic neurons exit the spinal cord at the thoraco-lumbar
 The nervous system has several properties in common with
endocrine system:
o High-level integration in the brain
o Has the ability to influence processes in distant regions
of the body through the use of chemicals for the
transmission of information
o Makes extensive use of negative feedback
 By using drugs that mimic or block the action of
chemical transmitters, we can selectively modify
many autonomic functions
A. Central Nervous System (CNS)
 Brain
o Receives and processes sensory information, initiates
responses, stores memories and generates thoughts and
emotions
 Spinal cord
o Conducts signals to and from the brain and controls
reflex actions
B. Peripheral Nervous System (PNS)
 Somatic Nervous System
o Regulates activities under conscious control
o Acetylcholine is the NT released at the neuromuscular
junction
1. SENSORY DIVISION
 Afferent division
 Contains neurons and signals from the tendons, joints, skin,
skeletal muscles, eyes, nose and many other organs
 Signals are conveyed to the cranial and spinal nerves
2. AUTONOMIC NERVOUS SYSTEM
 Releases Ach
 Functional considerations:
o Mediates control of vegetative or involuntary functions
o Innervation of cardiac muscle, vascular and nonvascular
smooth muscle, and exocrine glands
o Functions in these systems often occur without control
 Anatomical considerations:
o In contrast to somatic efferent, it consists of 2 sequential
neurons: preganglionic and postganglionic neurons that
synapse in autonomic ganglia
II. Autonomic Nervous System
A. Sympathetic Nervous System
 Adrenal medulla is considered to be a modified sympathetic
ganglion
o Embryologically and anatomically homologous to the
sympathetic ganglia
 Catabolic
 Consists of one short preganglionic fiber synapsing with
several long postganglionic fibers in sympathetic ganglia
level to synapse with postganglionic nerves at the paravertebral
ganglia
 All the paravertebral ganglia provide sympathetic innervation to
blood vessels in muscle and skin, arrector pili muscles and
sweat glands
 Sympathetic trunk (22 pairs on each side of the spinal cord)
o Cervical (3)
 Superior Sympathetic Ganglion – innervates
viscera of the head
 Middle Cervical Ganglion and Stellate Ganglion
(Cervicothoracic Ganglion) - innervate viscera
of the neck, thorax and upper limbs
o Thoracic (10 or 11)
 Innervate the trunk region
o Lumbar (4)
o Sacral (4)
 Lumbar and sacral innervate the pelvic floor and
the lower limbs
o Coccygeal (Ganglion Impar) unpaired
 Greater ramification of sympathetic fibers compared to
parasympathetic
o Ratio of pre- to postganglionic fibers = 1:20
 Diffusion action: fight or flight response
o Not essential for life
 Normally active with the degree of activity varying from
moment to moment and organ to organ
 Adjust to changing environment, esp. during rage or fright
 Synapse of preganglionic neurons uses Acetylcholine as a
neurotransmitter
o All preganglionic nerves are cholinergic
 Synapse of postganglionic neurons with the target organ uses
Norepinephrine
o Except sympathetic postganglionic neuron that
terminates on the sweat glands (uses acetylcholine)
 Typical response:
o Increase HR (tachycardia)
o Shift blood flow to muscle
o Increase in blood glucose level
o Dilation of pupil
 Mydriasis (Pupil Dilation) happens during fight
or flight to be able to let more light enter your
eyes so you can see the threat even from a
distance
 Sweating, blushing, Goosebumps or Horripilation are stress
responses
 “Adrenaline Rush”
o Emergency, Exercise, Excitement, Embarrassment
o ANS response to fear, anger, stress
 Longitudinal muscles are relaxed while sphincters are
constricted
B. Parasympathetic Nervous System
  Anabolic
 Preganglionic neurons originate in cranial nerves and sacral
portion of spinal cord Sympathetic Parasympathetic
 Long preganglionic fiber; short postganglionic fibers (Adrenergo-) (Cholino-)
Agonist Adrenergomimetic or Cholinomimetic or
 More circumscribed than sympathetic system (1:1 ratio
(-mimetic) Sympathomimetic Parasympathetic
although but not always true)
 Preganglionic neurons synapse with postganglionic neurons in
Stimulates Sympathetic NS Stimulates
preaortic ganglia very close or in the organs innervated
Parasympathetic NS
o Discrete action
Antagonist Adrenergolytic or Cholinolytic or
 Essential for life (-lytic) Sympatholytic Parasympatholytic
 Cell bodies of the parasympathetic nervous system located in
the spinal cord (sacral region) and in the medulla Antagonize/Against Antagonize/Against
 In the medulla, CN III, VI, IX, and X form the preganglionic Sympathetic NS Parasympathetic NS
fibers
o Projects close to target organ and make a synapse
 Preganglionic synapses and postganglionic synapses use 1. SAME PHARMACOLOGICAL EFFECTS
Acetylcholine (cholinergic)  Sympathomimetic & Parasympatholytic
 Preaortic or Prevertebral Ganglion lies on the anterior o Both can cause tachycardia only in different mechanisms
surface of the aorta which retain a pattern of innervation that o Both stimulate different receptors
originates in the embryo o Examples:
o Celiac Ganglion  Sympathomimetic = NE
 Innervates structures from embryonic foregut  Parasympatholytic = Atropine (anticholinergic,
including stomach, liver, pancreas, duodenum Antimuscarinic)
and first part of the small intestine  Sympatholytic & Parasympathomimetic
o Superior Mesenteric Ganglia
 Innervates small intestine (from embryonic 2. PHARMACOLOGICAL ANTAGONISM
midgut)
 A type of antagonism between two drugs wherein one serves as
LOCATION OF GANGLIA an agonist at a particular receptor site and the other serves as an
 Parasympathetic NS Ganglia antagonist at the same receptor site
o Found closer to the organs o Examples
o Effects are more discrete for the specific organ  Sympathomimetic ANTAGONIST and
o Craniosacral Division Parasympathetic ANTAGONIST
 Sympathetic NS Ganglia
o Found paravertebral (closer to vertebral column and 3. PHYSIOLOGICAL ANTAGONISM
further away from the organs)  The sympathetic and parasympathetic systems usually do not
o Effect is usually all or none and usually all the organs are function independently
recruited in one quick response in order to respond to the o They are physiological antagonist = causes opposite
stressful situation effects
o Thoracolumbar Division  Often when one system INHIBITS a process, the other system
will AUGMENT the level of activity so that the total response
KEY POINTS: depends on the influence of BOTH SYSTEMS but this is not
 Peripheral Nervous System (PNS) transmits signals between always the case.
CNS and the rest of the body.  Integration of systems regulates function below the level of
o Motor Neurons - carry signals from the CNS that consciousness
control the activities of muscles and glands
o Sensory Neurons - carry signals to the CNS from the
sensory Signals
 Under Motor Neurons:
o Somatic Nervous System - controls voluntary
movements by activating skeletal muscles
o Autonomic Nervous System - controls involuntary
responses by influencing organs, glands and smooth
muscles
 Under Autonomic Nervous system:
o Sympathetic Division - fight or flight
 Adrenergic Receptors
o Parasympathetic Division - Rest and relaxation
 Cholinergic Receptors

C. Autonomic Nervous System Drugs

 Drugs acting on the ANS can be divided into four groups
o Adrenergomimetic or Sympathomimetic
o Cholinomimetic or Parasympathomimetic
o Adrenergolytic or Sympatholytic D. Homeostasis
o Cholinolytic or Parasympatholytic  Homeostasis is the dynamic balance between the autonomic
branches (SNS and PNS).
 o Effects blocked with non-depolarizing neuromuscular
blockers (e.g. curare, pancuronium, atracurium,
vecuronium)

B. Norepinephrine
1. NOREPINEPHRINE CHEMISTRY
 Norepinephrine is ultimately synthesized from tyrosine using
the enzyme tyrosine hydroxylase, which converts tyrosine to
E. Autonomic Nervous System Responses DOPA
 Aromatic L-amino acid decarboxylase converts DOPA to
Sympathetic Parasympathetic
dopamine
Eyes Mydriasis Miosis  Dopamine b-hydroxylase converts dopamine to norepinephrine
Glands Inhibit secretion Enhance secretion
Smooth muscles Relax Contract
Blood vessels in Dilate Constrict
muscles
Blood vessels in Constrict (EXCEPT for blush Dilate
skin areas of face and neck)
Hollow organs RETENTION EVACUATION
Longitudinal muscles: Relax Longitudinal muscles:
contract
Sphincters: Contract
Sphincters: Relax

III. ANS Neurotransmitters

A. Acetylcholine
1. ACETYLCHOLINE (ACH/CHOLINERGIC) SYNAPSES
 All preganglionic fibers outside the CNS (sympathetic and
parasympathetic)
 All parasympathetic postganglionic nerve endings (ACH is the
transmitter)
 Somatic motor neurons innervating the skeletal muscles

2. NORADRENERGIC (NE) SYNAPSES

 All postganglionic sympathetic fibers
o Exception: sympathetic postganglionic nerve endings of
sweat glands (release ACh).
 Adrenal medulla (norepinephrine and epinephrine)

3. ACETYLCHOLINE (CHOLINERGIC) RECEPTORS

 Muscarinic
o Glands
 Degradation is mediated by monoamine oxidase (MAO) or
o Heart
catechol-O-methyltransferase (COMT)
 Nicotinic
 When the substance has a 3,4-hydroxy substituent in the
o Muscles
benzene ring, it is called a catecholamine where degradation is
o Ganglia brought about by COMT.
o If one or all hydroxyl substituent/s is/are removed from
4. ACETYLCHOLINE and MUSCARINIC RECEPTORS the benzene ring of the substance, it is no longer a
 Postganglionic parasympathetic fibers innervating the heart, catecholamine. Instead, it is called a sympathomimetic
smooth muscles and exocrine glands amine
o Exception: postganglionic sympathetic fibers innervating
the sweat glands IV. Autonomic Nervous System Receptors
 Blocked by antimuscarinic agents (e.g. atropine) Nice to know:
 If the subscript is 1 or 3, the response is excitatory.
5. ACETYLCHOLINE and NICOTINIC RECEPTORS o Contraction (muscle), Constriction (blood vessels),
 Classically a biphasic response is observed with stimulation at Enhanced secretion (glands)
low doses and inhibition at high doses  If the subscript is 2, the response is inhibitory.
o Sympathetic and parasympathetic autonomic ganglia and o Relaxation (muscle), Dilatation (blood vessels),
the adrenal medulla Inhibited secretion (glands)
 Effects blocked with ganglionic blockers (e.g. trimethaphan,
hexamethonium) A. Muscarinic Receptors
6. NICOTINIC RECEPTORS MUSCARINIC RECEPTORS
 Neuromuscular junction of skeletal muscle Excitatory  M1
o Autonomic ganglia
o Central nervous system
 o Common in secretory glands (with M3)
 M3 V. Classification of Autonomic Nervous System Drugs
o Smooth muscles (Sympathetic Drugs)
o Glands See appendix for complete list of ANS Drugs
o Endothelium of blood vessels
A. Adrenergic Agonists/Sympathomimetic Drugs
Inhibitory  M2
o Heart/Supraventricular 1. CLASSIFICATION OF ADRENERGIC AGONISTS
(SYMPATHOMIMETIC)
B. Nicotinic Receptors  Direct acting
o Mixed alpha and beta (Norepinephrine, Epinephrine)
NICOTINIC RECEPTORS
Excitatory
o Alpha-2 selective (Clonidine)
 N1 (Nicotinic muscle – subtype)
o Neuromuscular junction o Beta-2 selective (Terbutaline, Isoproterenol)
 N1 (Nicotinic neuronal – subtype)  Indirect acting (Amphetamine, Cocaine)
o Neuromuscular junction  Dual-acting (Ephedrine)
Inhibitory  N2
o Postganglionic neuron 2. MEDICINAL CHEMISTRY OF SYMPATHOMIMETIC
o Activation produces EPSPs DRUGS
 Beta-phenylethylamine may be considered the parent
compound from which sympathomimetic drugs are derived and
consists of:
C. Alpha Receptors o Benzene ring with ethyl amine side chain
ALPHA RECEPTORS
Excitatory  Alpha 1
o Smooth muscles
o Glands
Inhibitory  Alpha 2
o Feedback inhibition of NE release

D. Beta Receptors
BETA RECEPTORS
Excitatory  Beta 1
o Heart (tachycardia)
 Beta 3
o Fat cells (degradation of fat cells into fatty
acids)
Inhibitory  Beta 2  Substitutions may be made on the:
o Smooth muscles and glands o Benzene ring
 Hydroxyl (-OH) groups at 3- and 4-positions of
POTENTIAL WAYS TO AFFECT AUTONOMIC
the ring converts benzene to catechol and thus,
NEUROTRANSMISSION
dehydroxylated
phenylethylamine/catecholamines.
REMEMBER! SSRRBB  Maximal alpha and beta effects
 Synthesis  Absence of one or the other substituent =
o Availability of precursors for the neurotransmitters marked diminution in potency (alpha
o Availability of synthesis enzymes effect is decreased by 100-fold and beta
 S-torage (vesicles) effect is negligible)
o Protects the neurotransmitters from degradation  Catecholamines are subject to
o Provides for the quantal release of neurotransmitters inactivation by catechol-O-
 R-elease (prevented by alpha2 agonists) methyltransferase (COMT)
o Ca2+ dependent exocytosis  Hydroxyl (-OH) groups at 3- and 5-positions
o Agents could interfere with or enhance the release of of the ring
neurotransmitters  Beta-2 selectivity (i.e. Terbutaline)
 R-euptake o Unsubstituted benzene ring
o Agents could interfere with the reuptake of  Removal of all substituents from benzene
neurotransmitters rings = non-catecholamines (aka
 B-inding to receptors (affected/inhibited by alpha sympathomimetic amines)
blockers/antagonists)  Loss of either of the two hydroxyl (-OH)
o Agonist - high affinity, high intrinsic activity groups enhances oral effectiveness and
o Antagonist - high affinity, no intrinsic activity duration of action because the drug is no
 Competitive → reversible by increasing the longer metabolized by COMT.
amount of agonist  Increased CNS effect and may produce
 Noncompetitive → irreversible anorexia
 B-reakdown (of neurotransmitters) o Amphetamines and
o Acetylcholine - metabolism in synaptic cleft via phentermine resins are
acetylcholine esterase examples
o Norepinephrine - reuptake into presynaptic neuron
  Noncatecholamines are primarily
metabolized by monoamine oxidase
(MAO)
o Substitution at the Alpha carbon
 Carbon attached to the amine side
 Noncatecholamines that have a substituted alpha
carbon have a longer duration of action because
they are NOT metabolized by either COMT or
MAO.
 Alpha-methyl compounds are also called
phenylisopropylamines
o Substitution at the Beta carbon 2. NON-SELECTIVE ALPHA ANTAGONIST
 Attached to the benzene ring  There is no feedback inhibition on the release of norepinephrine
 Typical of direct acting agonists so they can produce:
 Important for storage of sympathomimetic o Reflex tachycardia (Beta-1 stimulating effect)
amines in neural vesicles o Postural hypotension (Beta-2 stimulating effect)
 Example: Beta-hydroxylation of
dopamine to norepinephrine
o Amine side chain
 Increased beta-2 selectivity
 Decreased affinity for alpha receptors
 Protects against the metabolism by COMT
 Epinephrine - 1 methyl substituent
 Isoproterenol - 2 methyl substituents
 Terbutaline – 3 methyl substituents

B. Adrenergic Antagonists/Sympatholytic Drugs

3. NON-SELECTIVE BETA ANTAGONIST -
1. CLASSIFICATION OF ADRENERGIC ANTAGONISTS PROPANOLOL
(SYMPATHOLYTIC)  Bradycardia (Beta-1 blocking effect)
 Alpha blockers  Bronchoconstriction (Beta-2 blocking effect)
o Nonselective (Phenoxybenzamine, Phentolamine)
o Alpha-1 selective (Prazosin)
 Beta blockers
o Nonselective (Propranolol)
o Beta-1 selective (Metoprolol)

C. Receptors Actions and Effects of Sympathetic Drugs

 Alpha-1, Beta-1 and Beta-2 are postsynaptic
 Alpha-2 receptor is presynaptic
o Stimulation causes feedback inhibition on the RELEASE 4. SELECTIVE BETA-1 ANTAGONIST -
of norepinephrine, so Clonidine an Alpha-2 agonist drug METOPROLOL
has an anti-hypertensive effect  Bradycardia (Beta-1 blocking effect)
 Leaves Beta-2 receptor unblocked → norepinephrine can still
stimulate the Beta-2
o NO bronchoconstriction

1. SELECTIVE ALPHA-1 ANTAGONIST - PRAZOSIN

 Leaves the Alpha-2 receptor unblocked hence norepinephrine
release is inhibited
D. Potential Ways to Affect Autonomic Transmission – Sympathetic
 Hence NO reflex tachycardia (Beta-1 effect)
Drugs
 NO postural hypotension (Beta-2 effect)
 SYNTHESIS
o Reserpine and Alpha Methyl-DOPA
 STORAGE
o Reserpine
 RELEASE
o Clonidine (Alpha-2 agonist)
 REUPTAKE
 o Duloxetine (Serotonin-Norepinephrine reuptake  Direct-acting drugs
inhibitor) o Act directly at the acetylcholine receptor
 BINDING  Indirect-acting drugs
o Agonist (Epi and NEpi) o Act indirectly through inhibition of acetylcholinesterase
o Antagonists (Alpha and Beta blockers) o Excess acetylcholine stimulates the cholinoreceptors
 BREAKDOWN  Act where acetylcholine is physiologically released
o MAO inhibitors  Amplifiers of endogenous acetylcholine

VI. Classification of Autonomic Nervous System Drugs A. Direct-Acting Cholinomimetics

(Parasympathetic Drugs) See appendix for the list of direct-acting agonists
See appendix for complete list of ANS Drugs Direct acting drugs can be further subdivided based on:
A. Cholinergic Agonists/Parasympathomimetic Drugs  Spectrum of action
 Direct acting muscarinic o Whether they act on muscarinic, nicotinic, or both
o Naturally occurring alkaloids (Muscarine, Arecoline, receptors
Pilocarpine)  Chemical structure
o Synthetic alkaloids (Carbachol, Bethanechol) o Choline esters (e.g. Acetylcholine)
 Indirect acting muscarinic (acetylcholinesterase inhibitors) o Alkaloids (e.g. Muscarine and Nicotine)
o Acetylcholinesterase is the enzyme that breaks down ORGAN RESPONSE
ACh, so if you inhibit the enzyme that breaks down the Eye
ACh Sphincter muscle of iris Contraction (miosis)
 ACh levels will increase Ciliary muscle Contraction of near vision (accommodation)
o Short-acting alcohols (Edrophonium) Heart
Sinoatrial node Decrease in rate (negative chronotropy)
 Edrophonium - used for diagnosis of myasthenia
Atria Decrease in contractile strength (negative
gravis inotropy)
o Medium-acting carbamyl esters (Neostigmine, Decrease in refractory period
Physostigmine) Atrioventricular node Decrease in conduction velocity (negative
 Produce carbamylation of acetylcholinesterase dromotropy)
o Long-acting organophosphates (Echothipate, Malathion, Increase in refractory period
Parathion, Sarin) Ventricles Small decrease in contractile strength
 Noncompetitive inhibitors of Blood vessels
acetylcholinesterase; thus, long-acting Arteries, veins Dilation (via EDRF)
 Direct acting nicotinic Constriction (high-dose direct effect)
Gastrointestinal tract
o Depolarizing NMB (succinylcholine)
Motility Increase
 Stimulation of nicotinic receptors → initially,
Sphincters Relaxation
leads to muscle contraction causing Secretion Stimulation
fasciculation/muscle twitches Urinary bladder
 But due to prolonged depolarization, Detrusor Contraction
muscle relaxation occurs. Trigone and sphincter Relaxation
Glands
B. Cholinergic Antagonists/Parasympatholytic Drugs Sweat, salivary, lacrimal, Secretion
nasopharyngeal
1. CLASSIFICATION OF CHOLINERGIC ANTAGONISTS
(PARASYMPATHOLYTIC) B. Indirect-Acting Cholinomimetics
 Antimuscarinic See appendix for the list of indirect-acting agonists
o Belladonna alkaloids (Atropine, Scopolamine)  Three chemical groups of cholinesterase inhibitors
 Antinicotinic o Simple alcohol bearing a quaternary ammonium group
o Non-depolarizing NMB and ganglionic blockers o Carbamic acid esters of alcohols having quaternary or
 Because acetylcholine in the ganglia tertiary ammonium groups
bind to nicotinic receptors o Organic derivatives of phosphoric acid
 Effects are similar, but not always identical, to the effects of
VII. Cholinergic Agonists/Parasympathomimetic Drugs direct acting cholinomimetic agonists.
 Effects in the organ system:
ORGAN RESPONSE
Central Nervous System  Low concentrations: subjective
alerting response
 High concentrations: Generalized
convulsions → coma → respiratory
arrest
Eye Similar with direct-acting cholinomimetics
Respiratory tract
Gastrointestinal tract
Urinary tract
Cardiovascular system  Bradycardia
 Decrease atrial contractility
 Reduction in ventricular contractility
 Fall in cardiac output
 Drugs with acetylcholine-like effects  Increased vascular resistance → rise
 Have 2 major subgroups based on their mode of action: in blood pressure
 High/Toxic doses: VIII. Cholinergic Antagonists/Parasympatholytic Drugs
 Marked bradycardia
 Significant decrease in Cardiac output 1. TERTIARY AMINE
 Hypotension  Lipid soluble, can easily penetrate the brain
Neuromuscular junction Low therapeutic concentrations:  Well absorbed from the gut and conjunctival membranes
 Contraction  Naturally occurring alkaloids
Higher concentrations:
o Atropine
 Fibrillation of muscle fibers
depolarizing neuromuscular blockade o Darifenacin
followed by nondepolarizing blockade o Dicyclomine
o Oxybutynin
C. Toxicity o Scopolamine
 Toxic effects of Direct-acting muscarinic stimulants: o Solifenacin
o Nausea and Vomiting o Tolterodine
o Diarrhea  Synthetic Esters
o Urinary urgency o Dicyclomine
o Salivation
o Bronchial constriction 2. QUATERNARY AMINE
o Sweating  Water-soluble and does not penetrate the CNA well
o Cutaneous vasodilation  Examples:
o Anisotropine
 Toxic effects of Direct-acting nicotinic stimulants: o Clidinium
o Acute toxicity o Mepenzolate
 Convulsions → coma → respiratory arrest o Ipratropium
 Skeletal muscle end-plate depolarization → o Propantheline
depolarization blockade and respiratory paralysis o Glycopyrrolate
 Hypertension and cardiac arrhythmias
o Chronic nicotine toxicity
 Increased risk for cardiovascular disease
 High incidence of ulcer recurrences 1. Muscarinic Antagonists
See appendix for the list of muscarinic antagonists
 Organophosphate poisoning  Block the effects of parasympathetic autonomic discharge
o ○ Organophosphate  Effects in the organs:
 Inhibit the enzyme that breaks down ORGAN EFFECT MECHANISM
acetylcholinesterase; therefore, it is an CNS Sedation, anti-motion Block of muscarinic
acetylcholinesterase inhibitor sickness action, receptors, several
 Increased acetylcholine → stimulation of PNS antiparkinson action, subtypes
 Result: amnesia, delirium
 Increased bronchial gland secretion Eye Cycloplegia, mydriasis Block of M3 receptors
Bronchi Bronchodilation, especially Block of M3 receptors
 Increased salivary gland secretion
if constricted
 Bradycardia Gastrointestinal Relaxation, slowed Block of M1, M3
 Difficulty of breathing tract peristalsis, reduced receptors
 Miosis salivation
 Vomiting and diarrhea Heart Initial bradycardia, Tachycardia from block
 Cognitive disturbances, convulsions, especially at low doses, then of M2 receptors in the
tachycardia sinoatrial node
coma
Blood vessels Block of muscarinic Block of M3 receptors
 Depolarizing neuromuscular blockade vasodilation; not manifest on endothelium of
NOTE: When fumigation (an organophosphate) happens, allow time unless a muscarinic agonist vessels
for the organophosphates to diffuse first by opening the doors and is present
windows before going back in. Glands Marked reduction of Block of M1, M3
salivation; moderate receptors
 TREATMENT: reduction of lacrimation,
o Antimuscarinic drugs sweating; less reduction of
gastric secretion
o Atropine
Skeletal muscles None
 Cholinergic antagonist, specifically a muscarinic
antagonist
o Pralidoxime 1. ATROPINE TOXICITY
 It attaches to where the cholinesterase inhibitor  ”Dry as bone, blind as a bat, red as a beet, mad as a
attaches → attaches to the inhibitor → remove  hatter”
organophosphate from cholinesterase →  ”Blind as a bat, mad as a hatter, red as a beet, hot as Hades, dry
acetylcholinesterase works again as a bone, the bowel and bladder lose their tone, and the heart
o This is known as “regenerating” or “reactivating” runs alone”
acetylcholinesterase o Dry as a bone
o However, some inhibitors could develop a permanent  Sweating, salivation, and lacrimation are
bond with cholinesterase, known as aging reduced or stopped
 Here, oximes like Pralidoxime can’t reverse the o Blind as a bat
bond  Mydriasis or dilation of pupils and cycloplegia
 o Red as a beet 1. A child has swallowed the contents of 2 bottles of a nasal
 Dilation of cutaneous vessels of the arms, head, decongestant , the primary ingredient of which is an alpha
neck, and trunk → “atropine flush” adrenoceptor agonist drug. This signs of alpha activation that
o Mad as a hatter may occur in this patient include:
 CNS toxicity: sedation, amnesia, delirium, A. Bronchodilation
hallucinations, and convulsions may occur B. Tachycardia
o ○ Hot as a Hades C. Pupillary dilatation
 Blockage of thermoregulatory sweating → D. Vasodilatation
hyperthermia
 Most dangerous effect of antimuscarinic drugs in 2. K.L.,a 40 year old school teacher lives in a Manila
children condominium. One day the condominium management
o ○ Bowel and bladder lose their tone announced a scheduled fumigation and when she arrived home
 Relaxation of bladder wall, urinary retention late in the afternoon she experienced difficulty breathing and
o ○ Heart runs alone coughing with increased bronchial gland secretions. K.L. is
 Tachycardia most likely suffering from:
A. Acute muscarinic intoxication
2. TREATMENT B. Acute organophosphate toxicity
C. Myasthenia gravis
 Physostigmine
D. Autonomic hyperreflexia
o Should be used cautiously especially when there’s
severe tachycardia 3. Which of the following is a direct-acting cholinomimetic that is
 Cooling blankets lipid-soluble and is used to facilitate smoking cessation?
o To combat hyperthermia A. Physostigmine
B. Varenicline
2. Nicotinic Antagonists C. Acetylcholine
 Block the action of acetylcholine and similar agonists at D. Bethanechol
neuronal nicotinic receptors of both parasympathetic and E. Neostigmine
sympathetic autonomic ganglia
 Classified as a nondepolarizing competitive antagonists 4. What are the potential ways to affect autonomic
 Drugs of interest are synthetic amines neurotransmission?
 Effects in the organs: SSRRBB (Synthesis, Storage, Release, Reuptake, Binding,
ORGAN EFFECT Breakdown)
CNS Antinicotinic action may include reduction of
nicotine craving and amelioration of Tourette 5. If one or all hydroxyl substituent/s is/are removed from the
syndrome (mecamylamine only) benzene ring of the substance, it is no longer a catecholamine.
Eye Moderate mydriasis and cycloplegia Instead, it is called a
Bronchi Little effect; asthmatic patients may note some Sympathomimetic amine
bronchodilation
Gastrointestinal tract Marked reduction of motility, constipation may
be severe
Heart Moderate tachycardia and reduction in force
and cardiac output at rest; block of exercise-
induced changes
Blood vessels Reduction in arteriolar and venous tone, dose-
dependent reduction in blood pressure;
orthostatic hypotension usually marked
Glands Reductions in salivation, lacrimation, sweating,
and gastric secretion
Skeletal muscles No significant effect

SSRRBB DRUGS
S-ynthesis Muscarine, Arecoline, Pilocarpine
S-torage Muscarine
R-elease Ganglionic blockers (Trimetaphan.
Hexamethonium)
R-euptake Agonists (Carbachol, Betachenol at muscarinic
B-inding receptor) and (Succinylcholine at nicotinic
receptor)

Antagonists (Atropine at muscarinic receptor)

and (nondepolarizing neuromuscular blockers
at nicotinic receptors, e.g., curare,
pancuronium, atacurium)
B-reakdown Acetylcholinesterase inhibitors (edrophonium,
neostigmine, Organophosphates)

NOTE: Subscript 1 (odd number) - EXCITATORY

Subscript 2 (even number) – INHIBITORY

IX. Review Questions

 ADRENERGIC AGONISTS
MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
Epinephrine Acts directly on both alpha and beta Used in asthma and allergic diseases as it May cause a decrease in total peripheral
receptors (direct acting) relaxes the airway and reduces swelling resistance (TPR) which explains the fall in
Very potent vasoconstrictor and cardiac diastolic pressure in some cases
stimulant
Pseudoephedrine Causes release of norepinephrine (indirect Used as treatment for rhinitis NTK: Restricted drug due to it being a
acting) Used as decongestant for colds precursor in the manufacture of
methamphetamine (shabu)
Phenylephrine Acts directly on alpha receptors (direct Used as decongestant in rhinitis and colds Not inactivated by COMT
acting) Also used as a vasopressor (increases blood
Selective alpha-1 agonist pressure through vasoconstriction)
Amphetamines Causes accumulation of noradrenaline at the No longer used clinically EXCEPT for No substituents at benzene ring ➝ increased
synapses treatment for narcolepsy and attention CNS activity
deficiency hyperkinesis
Ephedrine Acts indirectly on both alpha and beta Used as a vasopressor
receptors causing release of endogenous
catecholamines (indirect acting)
Terbutaline Selective beta-2 agonist Used as a bronchodilator in asthma May increase maternal morbidity
Tocolytic agent in premature labor (relaxes
the uterus)
Clonidine Selective alpha-2 agonist (affects R-elease Used for the treatment of hypertension Though being an agonist, but because it is
in SSRRBB) found presynaptically, it inhibits the release
of norepinephrine

Inhibits adenylyl cyclase

Alpha-2 agonists affect

ADRENERGIC ANTAGONISTS
MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
Reserpine Blocks synthesis and storage of Used in the management of some types of
norepinephrine hypertension

Sedation is a side effect

Phenoxybenzamine Noncompetitive alpha blocker Used in the management of malignant Cannot be reversed by increasing dose of
hypertension secondary to agonist (norepinephrine/epinephrine)
pheochromocytoma
May cause tachycardia and myocardial
ischemia
Phentolamine Competitive alpha blocker Can be reversed by increasing dose of
agonist(norepinephrine/epinephrine)

Half-life: ∼45 minutes after IV injection

Prazosin Selective alpha-1 blocker Used in the management of some types of No reflex tachycardia and postural
hypertension hypertension because only alpha-1 receptors
are blocked (leaving alpha-2 receptors
unblocked ➝ controlled release of
norepinephrine)
Propranolol Nonselective beta blocker Used in hypertension, angina pectoris, Worsens asthma (since it’s a non-selective
 migraine, headaches, and mitral valve beta blocker, it can also block the beta-2
prolapse receptors causing bronchoconstriction)
Metoprolol Selective beta-1 blocker Used in hypertension, angina pectoris, Safer to prescribe in hypertensive patients
arrhythmia, glaucoma with asthma

DIRECT-ACTING CHOLINERGIC AGONISTS

MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
AT MUSCARINIC SITES
Acetylcholine Acts directly on muscarinic receptors  Used as eye drops in ophthalmology  Rapidly hydrolyzed by cholinesterase
to constrict the pupil of the eye, relax (ChE)
the iris  Poor lipid solubility
 Cholinergic ➝ Miosis
 Relaxes the radial muscles of the iris
 Contraction of the sphincter muscles
Bethanechol  Synthetic alkaloid  Used for the treatment of GI and  Resistant to ChE
 Acts directly on muscarinic receptors bladder atony  Longer duration of action: 30 mins –
2 hrs
Note: PNS is for contraction of urinary
bladder and GI muscles
Pilocarpine Acts directly on muscarinic receptors  Used as eye drops in ophthalmology  Good lipid solubility
to constrict the pupil of the eye, relax  Duration of action: 30 min – 2 hrs
the iris
 Used in the treatment of acute angle
closure glaucoma
AT NICOTINIC SITES
Succinylcholine Acts directly on nicotinic NMJ receptors  Depolarizing NMJ blocker  Highly polar
 Causes noncompetitive inhibition on  Duration: 5-10 minutes
nicotinic NMJ receptors
 Fasciculations followed by paralysis
is a hallmark
OTHERS
Carbachol  Synthetic alkaloid  Used topically almost exclusively for
 Nonselective, muscarinic and glaucoma
nicotinic agonist
Nicotine Acts directly on both nicotinic and  Medical use in smoking cessation  Highly lipid solubility
muscarinic receptors  Nonmedical use in smoking and in  Duration of action: 1-6 hrs
insecticides
Muscarine Same as bethanechol Mushroom poisoning of fast onset type  Low lipid solubility
 Readily absorbed in the gut
Varenicline A partial agonist at N receptors Smoking cessation  Highly lipid solubility
 Duration of action: ∼12 hours

INDIRECT-ACTING CHOLINERGIC AGONISTS/CHOLINESTERASE INHIBITORS

MECHANISM OF ACTION CLINICAL APPLICATION
Edrophonium  Short-acting reversible
 Acts on both muscarinic and
nicotinic receptors
 Acts on the Nicotinic sites
 Alcohol, binds briefly to active site
of acetylcholinesterase (AChE) and
prevents access of acetylcholine
(ACh)
Neostigmine  Intermediate-acting reversible
 Acts on both muscarinic and
nicotinic receptors
 Acts on nicotinic sites
 Forms covalent bond with AChE, but
hydrolyzed and released
 It also has modest direct action to
neuromuscular nicotinic
cholinoreceptors
Physostigmine  Same with Neostigmine BUT it’s
natural alkaloid tertiary amine +
enters CNS
Pyridostigmine  Same with Neostigmine BUT longer
acting
Diagnostic aid and acute treatment for
myasthenia gravis
 Used to reverse nondepolarizing
NMJ blockers
 Myasthenia gravis
 Postoperative and neurogenic ileus
and urinary retention
 Used to reverse nondepolarizing
NMJ blockers
 Used in myasthenia gravis
FEATURES
 Alcohol
 Quaternary amine
 Poor lipid solubility
 Duration of action: 5-15 minutes
 Carbamate
 Quaternary amine
 Poor lipid solubility
 Duration of action: 30 minutes – 4
hours
 Carbamate
 Tertiary amine
 Good lipid solubility
 Duration of action: 30 mins – 2 hrs
 Same with Neostigmine
 Duration of action: 4-6 hours

Echothiopate  Same with Neostigmine BUT longer  Obsolete – was used in glaucoma  An organophosphate – thiocholine
acting + released more slowly derivative
 Moderate lipid solubility

parathion  Long-acting
 Acts on both muscarinic
nicotinic receptors
Sarin
Malathion  Long acting
Organophosphate  Long acting irreversible
 Insecticide – agricultural use
and
 Used in warfare and terrorism
 Medical use as ectoparasiticide
 Used as insecticides
 Poisoning with organophosphates is
treated with anticholinergic drugs
 Duration of action: 100 hours
 More stable in aqueous solution
 An organophosphate -thiophosphate
derivative
 High lipid solubility
 Duration of action: 7-30 days
 Used as insecticide
 An organophosphate – thiophosphate
derivative
 Very high lipid solubility
 Nerve gas
 An organophosphate – thiophosphate
derivative
 High lipid solubility

ANTIMUSCARINIC, NONSELECTIVE
MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
Atropine Competitive antagonist  Mydriatic, cycloplegic  Tertiary: Naturally-occurring
 Antidote for cholinesterase inhibitor alkaloids
toxicity  Lipid soluble
 Duration: 5-6 days
 Effects on the iris and ciliary muscle:
≥ 72 hours
Scopolamine Unknown mechanism in CNS  Anti-motion sickness via transdermal  Tertiary: Naturally occurring alkaloid
patch  IM injection for postoperative use
 Duration: 3-7 days
Benztropine Competitive antagonist  Antiparkinsonian
Homatropine  Topical ophthalmic use to produce Shorter duration of action that atropine: 12-
mydriasis, cycloplegia 24 hours
Ipratropium Competitive antagonist  Prevention and relief of acute  Quaternary
Aclidinium episodes of bronchospasm  Aerosol canister
Tiotropium  Aclidinium, Tiotropium, and
Umeclidinium Umeclidinium: Longer duration of
 Bronchodilation in asthma, COPD
action
Propantheline Acts directly as competitive antagonist at  Used as an antispasmodic by Quaternary
muscarinic receptors decreasing gastric motility
Glycopyrrolate  Used as preoperative medication to Quaternary
reduce salivation and maintain heart
rate during surgery

ANTIMUSCARINIC, SELECTIVE
MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
Darifenacin Like atropine, BUT modest selectivity for M3  Urinary urgency  Tertiary amines
Fesoterodine receptors  Incontinence  Duration: 12-24 hours
Solifenacin
Tolterodine

Dicyclomine Competitive antagonism at M3 receptors  Used for irritable bowel syndrome  Tertiary: synthetic ester
 Minor diarrhea  Short half-life
 Duration of action: 6 hours
Oxybutynin Slightly blocks M3 receptors  Urinary urgency
 Incontinence
Pirenzepine Significant M1 selectivity  Peptic disease Taken orally
Telenzepine

ANTINICOTINIC GANGLION BLOCKERS

MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
Hexamethonium Selectively blocks 𝑁𝑛 receptors Obsolete – used for hypertension Oral, parenteral
Trimethaphan Selective antagonist Hypertension and controlled hypotension  IV only
 Not anymore available for clinical use

Mecamylamine Non-competitive agonist Smoking cessation  Oral

 Enters CNS

NONDEPOLARIZING NEUROMUSCULAR JUNCTION BLOCKERS

MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
Gallamin
Pancuronium Competitively inhibits Ach at nicotinic Causes nondepolarizing block of the NMJ Block can be reversed by increasing the amount of Ach at
Atracurium NMJ sites the NMJ
Vecuronium
Rocuronium
Botulinum toxin Used for spastic conditions and cometic
purpose

ACETYLCHOLINESTERASE REGENERATOR 
MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
Pralidoxime  Very high affinity for phosphorus atom BUT does not enter  Relieve skeletal muscle end plate block Intravenous every 4-6
the CNS  Antidote for early stage cholinesterase inhibitor hours
poisoning