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Lecture 1, 2
Autonomic Pharmacology
• Explain the function and mechanism of action of all elements of the ANS
• Define the roles of cholinergic receptors, their differences, and systemic
responses
• Differentiate between the actions of muscarinic, nicotinic and adrenergic
receptors and their subtypes
• Identify and explain the mechanism of action for pharmacologic agents
used to manipulate these systems, and their role in pharmacotherapy
• Define the pharmacologic rationale for therapeutic application of
autonomic-acting agents
• Given a generic drug name, define mechanism of action, side effects, and
therapeutic utility
Peripheral Nervous System
Autonomic NS
• Regulates activity of:
– Smooth muscles
– Exocrine glands
• Some endocrine glands
– Cardiac tissue
– Metabolic activities
• Involuntary
• Regulated by brain stem
centers
Somatic NS
• Activates skeletal muscle
contraction
• Voluntary body movements
• Regulated by corticospinal
tracts & spinal reflexes
Side note: exocrine- section into external environment through ducts, e.g. (sweat, oil, wax, enzymes, etc.);
endocrine- secretion into internal environment with no ducts and hormones are secreted
Preganglionic autonomic
neurons and somatic
neurons are myelinated
Ach N- ANS preganglionic +
somaticNS
Ach M- ParaNS
postganglionic + SymNS
sweat glands **Exception
Adrenergic- SymNS
postganglionic
Concept: ganglia use
Ach/neuronal tissue
The adrenal medulla has
Ach receptors and acts like
a neuronal ganglia. It
releases NE (80%) and Epi
(20%)
**Epi is only made by the
adrenal medulla by SNS
Enteric Nervous System
- part of the PNS
• Meshwork of fibers innervating
the GI tract
• Controls GI motility and secretion
• Has
– Independent control!
– And highly regulated by the
autonomic nervous system
– And higher levels of the CNS
• “Brain of the Gut”
Autonomic Nervous System
• Sympathetic NS
– Nerves arise from the thoracic and lumbar spinal cord
– Short preganglionic fibers & long postganglionic fibers
• Parasympathetic NS
– Portions of cranial nerves III (oculomotor), VII (facial),
IX (glossopharyngeal) and X (vagus)  all are both
sensory and motor except CNIII which is just motor
– Long preganglionic fibers and short postganglionic
fibers
EPSP- Na+ influx- Nicotinics is Na+ channel
faster
IPSP- K+ efflux, Cl- influx
Muscarinic Receptors Regulate (slow
IPSP/EPSP)- 2nd messengers regulate K+ or Clchannels and are slower
Ganglia Phenomenon: have both receptors
and Ach can act on both– Nicotinic causes
EPSP. When Ach binds to muscarinic they
regulate the EPSP and these can be slow IPSP
or EPSP regulated by M1 receptors .
Neurotransmission
• 7 Steps of Synaptic Transmission
**all drug targets
–
–
–
–
–
–
–
Synthesis and storage
Action potential and depolarization
Activation of voltage-dependent Ca2+ channels
Vesicle fusion and release
Receptor binding
Signal termination in the synaptic cleft
Termination of postsynaptic intracellular
signaling
There are also autoreceptors that determine how
the cell will release the NT in presynaptic cellusually inhibitory
Synthesis-storage-inactivation of ACh
After the release of ACh and its interaction with its receptors, it is hydrolyzed by
acetylcholinesterase (AChE) to acetate and choline; the latter is taken back up into the
nerve terminal and is reused for ACh synthesis.
The acetyl CoA was donated by the Mitochondria. Choline +AcetylCoA become Ach via
acetylcholine transferase. There are massive amounts of Mito at the terminal.
Synthesis, Storage and Inactivation of NE
The action of NE is terminated by neuronal
reuptake into the nerve terminal
NE may be inactivated by monoamine oxidase
(MAO) w/i the nerve terminal or catechol-Omethyltransferase (COMT) extraneuronally
MOA
The rate limiting step is Tyr DOPA via tryosine
hydroxylase
COMT is also in the brain and glial cells but is
extraneuronal
COMT
You can’t give NE in mouth and it must be
peripheral b/c it will break down if given orally.
Receptors
Acetylcholine receptors  muscarinic or nicotinic (none to
blood vessels except certain glands**)
• Muscarinic – parasympathetic neuroeffector junctions (G-protein coupled,
metabotropic)
– Sweat glands use M2, M3 receptors
– Odds are G (alphaq, get constriction in smooth muscles) and evens are G (i, inhibit
adenylate cyclase and get constriction)
– M2- heart, respiratory, brain, inhibition of NE (heteroreceptor) and Ach
(autoreceptor)
– M3- eye, stomach (sphincter relaxation, secretion stimulation), bronchoconstriction,
vasodilation, emesis, GI (sphincter relaxation, increase sectretion), urinary bladder,
pancreas secretion, salivary gland blood vessels, these increase the blood to the
gland to get increase in section and this is ONLY area where blood vessels have
PARA that cause vasodilation!!!
• Nicotinic – all autonomic ganglia, somatic neuromuscular junctions & brain
[+sympathetic in the adrenal medulla]
Adrenoceptors  α and β
•
•
•
•
•
α1: contraction of vascular smooth muscle (vasoconstriction), the iris dilator muscle
(mydriasis), and urinary tract smooth muscle, increased peripheral resistance
– Found in vascular smooth muscle, Also found in exocrine glands and the CNS
α2: mediate smooth muscle relaxation by feedback inhibition of norepinephrine and Ach release
from nerve terminals [decrease outflow of NE] (ex. nasal decongestants work on this in the nose
to constrict), prejunctional , inhibit insulin release
– Also found in platelets and the pancreas
β1: cardiac stimulation  positive chronotropic ( HR), ionotropic ( contractility) &
dromotropic ( conduction velocity) effects, increase in lipolysis
– Found in the heart; Activation also increases renin secretion in the kidney
β2: mediate relaxation of bronchial (use these for asthma patients), uterine and vascular
smooth muscle (vasodilation)
– Skeletal muscle: mediate K+ uptake
– Liver: mediate glycogenolysis (increase in muscle and liver, increase blood sugar)
β3: enhances lipolysis
N.E.D mnemonic for catecholamines: norepinephrine, epinephrine, dopamine
Adrenoceptors  α and β
Domamine receptors 
• D1: mediate relaxation in vascular smooth muscle
• D2: modulate neurotransmitter release
• Imidazoline receptors: natriuresis (eliminating
Na+ in urine causes diuresis and water to follow
Na+) and decrease in sympathetic outflow from
the CNS (used for the eye and to regulate the
enteric NS)  these decrease sympathetics
“Rest and Digest”
Slows heart rate
Promotes digestion,
defecation, & micTurition
CNX- not sure of Para
functin in the kidney
so consider it null;
visceral organs,
parotid
CNIII- ciliary m. and
lacrimal gland
CN VII, IX- to salivary
gland, sublingual and
submandibular gland
“Fight or Flight”
Cardiovascular stimulation
Skeletal muscle activation
Glycogenolysis
Lipolysis
How DO I Remember All of This
Remember the parasympathetic
•
DUMBBELLS
–
–
–
–
–
–
–
–
–
Diarrhea
Urination
Miosis
Bradycardia
Bronchoconstriction, Bronchospasm
Erection (Excite skeletal muscle, Emesis)
Lacrimation
Lethargy
Salivation and Sweating
The Baroreceptor Reflex
Brody’s Human Pharmacology 5th ed.
Storage and Release
of Acetylcholine
•
1.
2.
3.
4.
5.
6.
7.
Drugs acting at each step of Synaptic
Transmission
Hemicholinium- block choline uptake
Tetrodotoxin- blocking AP Na+ channels
α-Latrotoxin*- form pores in lipid membranes
induce Ca2+ inflow (from black widow spider)
Botulinium toxin- - blocks synaptobrevin
preventing vesicle fusion
Atropine- muscarinic receptor antagonist
Physostigmine- ACHE inhibitor
Dantrolene- blocks ryanodine receptor which
are major mediators of intracellular Ca2+
release
• Do Hemicholinium and Vesamicol have a Clinical
Use?
• No, because they are nonselective cholinergic
antagonist causing complete depletion and
inactivation of all cholinergic systems.
Nicotinic Receptor Agonists
• Nicotine – prototype
• Activates sympathetic (vascular system) &
parasympathetic ganglia (GI tract)
•  blood pressure & heart rate
• Diarrhea & urination
• Crosses BBB  alertness, vomiting, tremors,
convulsions and coma
Nicotinic Receptor Agonists
• Varenicline (Chantix) – partial agonist in the brain
• Indicated for smoking cessation
• Reduces craving and withdrawal effects
BUT
• Associated with suicidal ideation, depression,
changes in behavior
Muscarinic Receptor Agonists
•
•
•
•
•
•
•
•
•
M1 - M5
Activate parasympathetic nerves
Constriction of iris (miosis)
Contraction of ciliary muscle
Constriction of airways
Increase in GI motility
Contraction of bladder and relaxation of its outlet
Decrease in heart rate
Increased secretions (sweat, saliva, lacrimal, etc.)
Muscarinic Receptor Agonists
Bethanecol (Urecholine)
• Stimulates bladder and GI w/o
affecting HR or BP
• Indicated for postoperative ileus,
urinary retention
Pilocarpine
• Lowers intraocular pressure by
increasing outflow of aqueous
humor (glaucoma)
• Stimulates salivary gland
secretion (xerostomia)
Cevimeline (Evoxac)
• Stimulates salivary gland
secretion (xerostomia)
• Indicated in patients with
Sjögren's syndrome
• Side effects – extension of the
parasympathomimetic actions
• If given in high doses or
parenterally, acute circulatory
failure & cardiac arrest
• CI: asthma, COPD, PUD
‘Shrooms
Amanita
muscaria
• Mushrooms - Inocybe and
Clitocybe contain muscarine
• Diarrhea, sweating,
salivation and lacrimation
• No current medicinal use
• Edibility: Toxic
Clitocybe dealbata
Clitocybe rivulosa
Inocybe erubescens
Heterotrimeric G proteins involved in the regulation of
smooth muscle tone. Gq/G11-coupled receptors
increase the intracellular Ca2+ concentration, leading
to Ca2+/calmodulin (CaM)-dependent MLCK activation
and MLC20 phosphorylation. Especially G12/G13coupled receptors mediate RhoA activation, thereby
contributing to Ca2+-independent smooth muscle
contraction. Relaxation is induced by activation of Gscoupled receptors, but the mechanisms underlying
cAMP-mediated relaxation are not clear. Gi-mediated
signaling might contribute to contraction by inhibiting
Gs-mediated relaxation. cGKI, cGMP-dependent
protein kinase I; DAG, diacylglycerol; IP3, inositol
1,4,5-trisphosphate; MLC20, regulatory chain of
myosin II; MLCK, myosin light-chain kinase; MPP,
myosin phosphatase; PIP2, phosphatidylinositol 4,5bisphosphate; PKA, cAMP-dependent kinase; PLC-β,
phospholipase C-β; RhoGEF, Rho specific guanine
nucleotide exchange factor; ROCK, Rho kinase; TRP,
transient receptor potential channel.
Acetylcholinesterase (AChE)
• Removes ACh from the synapse by degradation to
choline + acetate
• Terminates neurotransmission at cholinergic
synapses
• Time required is less than 1 millisecond
Cholinesterase Inhibitors
Reversible – short-acting
• Noncovalent – bind to the
anionic domain of AChE,
rapid hydrolysis
• Covalent – also bind to
AChE, but form a
carbamoylated enzyme that
undergoes slow hydrolysis
• Edrophonium – used in
diagnosis of myasthenia gravis
• Neo- and pyridostigmine –
myasthenia gravis, reversal of
neuromuscular blockade,
postoperative urinary retention
• Physostigmine - glaucoma
• Donepezil, galantamine,
rivastigmine – Alzheimer’s
disease
Myasthenia Gravis – “Grave muscle weakness”
Autoimmune disease
• Autoantibodies against the nicotinic
cholinergic receptor at the NM
junction  reduced numbers of
receptors  skeletal muscle
weakness
• Symptoms: drooping of one or both
eyelids (ptosis), double vision
(diplopia); altered speech, difficulty
swallowing, problems chewing, loss of
facial expressions
• Muscle weakness increases during
activity and improves after rest
Myasthenia Gravis: Diagnosis
• AChE inhibitors amplify the • Rapid but brief
effects of ACh, temporarily
improvement in strength
restoring muscle strength
after IV administration
• Edrophonium – blocks ACh
• Fasciculation (muscle
hydrolysis
twitch) generally occurs if
NOT Myasthenia
• Also used in myasthenic
crisis
Myasthenia Gravis: Treatment
• Pyridostigmine (Mestinon) taken orally every day
• Dose may vary on day to day basis (stress, infection,
etc.)
• Immune suppressants given concomitantly
(corticosteroids)
• AEs: abdominal cramping, diarrhea
Cholinesterase Inhibitors
Irreversible – long-acting
• Phosphorylate AChE – strong
bond, very slow hydrolysis
• Organophosphates –
pesticides and nerve gases
• Highly lipid-soluble and
absorbed from skin, mucous
membranes and gut
• Activate both muscarinic and
nicotinic receptors
Therapeutic uses
• Echothiophate - glaucoma
• Malathion (Ovide) – pediculosis
capitis; kills ova and adult lice
Organophosphate Poisoning
• Toxic nerve gases – sarin,
soman, tabun and VX
• Insecticides – parathion and
malathion
• Agriculture major source of
intoxications
• Time to death - 5 min to 24 h if
untreated, depending on route of
exposure
Symptoms
• Initial - miosis, salivation,
sweating,
bronchoconstriction,
vomiting, diarrhea
• CNS – cognitive
disturbance, seizure,
coma
• Neuromuscular blockade
Treatment:
1) supportive care (airway), 2) decontamination, 3) atropine (large doses), 4)
benzodiazepines (for seizures), 5) pralidoxime [2-PAM] (regenerates ChE)
Cholinergic Transmission
Drugs that enhance cholinergic transmission:
1. Nicotinic receptor agonists, e.g., nicotine
2. Muscarinic receptor agonists, e.g., bethanechol
3. Cholinesterase inhibitor, e.g., physostigmine
Drugs that inhibit cholinergic transmission:
4. Inhibitors of vesicular ACh transport , e.g., vesamicol
5. Inhibitors of exocytotic release, e.g., botulinum toxin
6. Nicotinic receptor antagonists
7. Muscarinic receptor antagonists (e.g., atropine)
8. Inhibitors of high-affinity choline transport, e.g.,
hemicholinium
9. Inhibitors of pyruvate dehydrogenase, e.g.,
bromopyruvate
Nicotinic receptor antagonists
• Ganglionic blocking drugs – block nicotinic
receptors on postjunctional neurons in
sympathetic and parasympathetic ganglia
Effect depends on which is dominant:
• Sympathetic – hypotension
• Parasympathetic – dry mouth, blurred vision &
urinary retention
• Not used clinically
Role of Cholinergic Receptors of the
Autonomic Ganglia
Copyright © 2012 McGraw Hill Medical
PARASYMPATHETIC →
SYMPATHETIC →
Predominant Autonomic Tone and The Consequences
of Autonomic Ganglionic Blockade
SITE
PREDOMINANT TONE
EFFECT OF GANGLIONIC BLOCKADE
Arterioles
Sympathetic-adrenergic
Vasodilation, hypotension
Veins
Sympathetic-adrenergic
Dilation, peripheral pooling
Heart
Parasympathetic-ACh
Tachycardia
Iris
Parasympathetic-ACh
Mydriasis
Ciliary
Parasympathetic-ACh
Cycloplegia
GI
Parasympathetic-ACh
Reduced tone & secretions
Urinary
Parasympathetic-ACh
Urinary retention
Salivary
Parasympathetic-ACh
Xerostomia
Sweat
Sympathetic-ACh
Anhidrosis
Genital
Sympathetic & Para-
Decreased stimulation
Hexamethonium Man
He is a pink complexioned person, except when he has stood for a long time, when he may get pale and
faint. His handshake is warm and dry. He is a placid and relaxed companion; for instance he may laugh,
but he can’t cry because the tears cannot come. Your rudest story will not make him blush, and the
most unpleasant circumstances will fail to make him pale. His socks and his collars stay very clean and
sweet. He wears corsets and may, if you meet him out, be rather fidgety (corsets to compress his
splanchnic vascular pool, fidgety to keep the venous return going from his legs). He dislikes speaking
much unless helped with something to moisten his dry mouth and throat. He is long-sighted and easily
blinded by bright light. The redness of his eyeballs may suggest irregular habits and in fact his head is
rather weak. But he always behaves like a gentlemen and never belches or hiccups. He tends to get
cold and keeps well wrapped up. But his health is good; he does not have chilblains and those diseases
of modern civilization, hypertension and peptic ulcers, pass him by. He is thin because his appetite is
modest; he never feels hunger pains and his stomach never rumbles. He gets rather constipated so his
intake of liquid paraffin is high. As old age comes on he will suffer from retention of urine and
impotence, but frequency, percipitancy, and strangury will not worry him. One is uncertain how he will
end, but perhaps if he is not careful, by eating less and less and getting colder and colder, he will sink
into a symptomless, hypoglycemic coma and die, as was proposed for the universe, a sort of entropy
death.
W. D. M. Paton, Pharm. Rev. 6, 59 (1954)
Discussion and Questions?
• Is hexamethonium used to treat anything?
• No, however, trimethaphan and mecamylamine were the
first anti-hypertensive agents ever used. They were
developed and used during the 1950-1960. Today,
trimethaphan can be used to treat aortic dissection, to lower
blood pressure and block sympathetic response while
mecamylamine is an orphan drug for Tourette’s syndrome
• Is this how cigarettes work?
Discussion and Questions?
• Is hexamethonium used to treat anything?
• Is this how cigarettes work?
• Nicotine’s effects are a summation of its effects on sympathetic and
parasympathetic systems. This includes autonomic ganglia stimulation
followed by a depolarization block. It also effects sensory and chemo
receptors including the CTZ causing vomiting. It has the same biphasic
effect on epinephrine release from the adrenal medulla. It causes CNS
stimulation primarily at prejunctional nerve terminals causing
neurotransmitter release. This includes excitatory amino acids, leading to
it’s stimulatory action, and dopamine which leads to the addiction and
pleasure.
Nicotinic Receptor Antagonists
• Neuromuscular blocking drugs - bind to
muscle nicotinic receptors and inhibit ACh
neurotransmission at skeletal neuromuscular
junctions  muscle weakness and paralysis
• Remember this for later
Muscarinic Receptor Antagonists
• Competitive antagonists: compete with ACh at
parasympathetic neuroeffector junctions 
inhibit parasympathetic nerve stimulation
• AKA parasympatholytics
• Relax smooth muscle, increase heart rate, inhibit
exocrine gland secretion
• Generally not selective for different receptor
subtypes
Muscarinic Receptor Antagonists
Belladonna alkaloids
• Atropine
• Hyoscyamine
• Scopolamine
Semisynthetic/synthetic agents
•
•
•
•
•
Dicyclomine
Glycopyrrolate
Ipratropium
Oxybutynin
etc…
Case
• A 16-year-old male was brought to the ER by friends after
becoming highly agitated and experiencing visual
hallucinations, claiming that one of his friends had a mailbox
for a head
• He ingested some seeds from plants growing in a vacant lot;
denied EtOH or other substances
• PE: Dry skin and mucous membranes, absent bowel sounds,
sinus tachycardia, dilated pupils & blurred vision
• Labs: WNL; EtOH - 0
Case
• Gastric lavage was performed & activated charcoal was
administered to remove any unabsorbed substances
• The patient became more agitated and delusional
• An infusion of physostigmine was administered x 2
• His symptoms began to subside and 12 hours later he was
much improved
• 36 hours later he was discharged with normal vital signs and
mental status
• The plant material was identified as Datura stramonium
Anticholinergic Toxicity
• Jimson weed or locoweed (Datura stramonium)
• Hallucinogenic plant containing belladonna alkaloids found
throughout the U.S.
• Toxic via ingestion or inhalation
• Fatalities have occurred
Treatment
• Remove drug (plant material) from GI tract
• Supportive care
• Cholinesterase inhibitor (physostigmine);  ACh & counteracts
central nervous system toxicity (hallucinations, seizures)
Belladonna alkaloids
•
•
•
•
Atropa belladonna (deadly nightshade)
Datura stramonium (Jimson weed)
Hyoscyamus niger
Belladonna – “fair lady”, referred to pupil dilation
produced by extracts of these plants; considered
attractive during the Renaissance
• Atropine – Hyoscyamine - Scopolamine
Atropine/Scopolamine/Hyoscyamine
•
•
•
•
Well absorbed
Tertiary amines so distribute in to the CNS
Excreted via urine; t1/2 ~ 2 hours
Ocular t1/2 is longer; bind to iris pigmentation,
pigments slowly release drug over days; darker
irises bind more
• Toxicity: Dry as a bone, blind as a bat, red as a
beet and mad as a hatter
Atropine/Scopolamine/Hyoscyamine
Ocular:
Mydriasis
Cycloplegia
Dry eyes
Respiratory:
Dilation
 secretions
GI/Urinary:
 LES – reflux
 Motility
 Gastric acid
secretion
Urinary retention
CNS:
Sedation OR
stimulation
Delirium
Cardiac:
 HR (standard
dose)
 HR (low dose)
Misc:
 Sweating 
hyperthermia
Can’t see
Can’t pee
Can’t spit
Can’t s*%t
Atropine, et al: Indications
Ocular:
Mydriasis –
ophthalmoscopic exam
Cycloplegia – refractive
errors of lens
Iritis, cyclitis
Cardiac:
 HR– sinus bradycardia
(IV)
Respiratory:
Palliative care –
decrease respiratory
secretions
CNS:
Motion sickness
(scopolamine) blocks ACh from
vestibular to vomiting
center
Parkinson’s disease
GI/Urinary:
 Motility –
intestinal/urinary
spasm & pain
(hyoscyamine)
Misc:
SEs of myasthenia
gravis treatment
Reverse cholinesterase
inhibitor overdose
Semisynthetic/Synthetic Agents
• Pharmacologic effects similar to atropine-like agents but
pharmacokinetic profiles make them useful in specific
situations
• Ipratropium/tiotropium – administered via inhalation; few
systemic side effects; COPD
• Dicyclomine – symptoms of irritable bowel: intestinal cramping
• Oxybutynin, darifenacin, solifenacin, fesoterodine, tolterodine,
trospium – overactive bladder (frequency, nocturia, urgency,
incontinence)
Semisynthetic/Synthetic Agents
• Glycopyrrolate
– Preoperatively to inhibit secretions of salivary and respiratory
tract
– During anesthesia to inhibit secretory and vagal effects of
cholinesterase inhibitors used to reverse neuromuscular
blockade
– Manage oral secretions in terminally ill patients
• Tropicamide – mydriatic for eye exam; short duration of
action (~ 1 hour)
Muscarinic Receptor Antagonist
Contraindications
• Ophthalmic preps in elderly & • Urinary retention
those with narrow angles –
• Prostatic hypertrophy
can trigger acute angle• Co-administration with
closure glaucoma
other anticholinergic
• Bowel atony
agents
Ocular Effects of Muscarinic Drugs
A: Relationship between the iris sphincter and ciliary
muscle in the normal eye.
B: Effects of pilocarpine, a muscarinic receptor agonist:
pupillary constriction (miosis), contraction of the
ciliary muscle, relaxation of the suspensory ligaments
connected to the lens, increase in lens thickness. As
the lens thickens, its refractive power increases so that
it focuses on close objects.
C: Effects of atropine, a muscarinic receptor
antagonist: pupillary dilation (mydriasis), increased
tension on suspensory ligaments, lens becomes thinner
& focuses on distant objects.
*
*Do not penetrate BBB very well fewer CNS side effects
Brody’s Human Pharmacology 5th ed.
Review Questions
• The major neurotransmitter in the
parasympathetic nervous system is
_________, while the major neurotransmitter
in the sympathetic nervous system is
________.
• Acetylcholine and norepinephrine
• Norepinephrine and acetylcholine
Review Questions
• Reversible cholinesterase
inhibitor
• Malathion
• Edrophonium
• Irreversible
cholinesterase inhibitor
• Physostigmine
• Donepezil
• Echothiophate
Review Questions
• Which of the following are effects of
muscarinic receptor activation?
– Decrease in heart rate
– Increase in heart rate
– Decrease in GI motility
– Secretion of hydrochloric acid
– Bronchodilation
Review Questions
• A patient presents with confusion, blurred
vision, dry mouth and constipation. These are
symptoms of:
– Anticholinergic toxicity
– Cholinergic toxicity
– Myasthenia gravis
– Organophosphate poisoning
Lecture 3, 4, 5
Autonomic Pharmacology
• Explain the function and mechanism of action of all elements of the ANS
• Define the roles of cholinergic and adrenergic receptors, their differences,
and systemic responses
• Differentiate between the actions of muscarinic, nicotinic and adrenergic
receptors and their subtypes
• Identify and explain the mechanism of action for pharmacological agents
used to manipulate these systems, and their role in pharmacotherapy
• Define the pharmacologic rationale for therapeutic application of
autonomic-acting agents
• Given a generic drug name, define mechanism of action, side effects, and
therapeutic utility
Noradrenergic transmission
Drugs that enhance or mimic noradrenergic transmission
(sympathomimetics):
1. Facilitate release, e.g., amphetamine
2. Block reuptake, e.g., cocaine
3. Receptor agonists, e.g., phenylephrine
Drugs that reduce noradrenergic transmission
(sympatholytics):
4. Inhibit synthesis, e.g., 4a, α-methyltyrosine; 4b,
carbidopa; 4c, disulfiram
5. Disrupt vesicular transport and storage, e.g.,
reserpine
6. Inhibit release, e.g., guanethidine
7. Receptor antagonists, e.g., phentolamine
3 Classes of: Adrenoreceptor agonists
• Direct-acting: bind to and activate the receptors
– Catecholamines & noncatecholamines
• Indirect-acting: increase the concentration of
norepinephrine at neuroeffector junctions
• Mixed-acting: direct & indirect actions
Direct-acting agonists: Catecholamines
Naturally occurring
Synthetic
• Norepinephrine
• Epinephrine
• Dopamine
• Isoproterenol
• Dobutamine
Rapidly inactivated by monoamine oxidase (MAO) and catechol-O-methyltransferase
(COMT) in the gut, liver, & other tissues
Catecholamine basic structure must have –OH at 3 and 4 or lose activity
Low bioavailability, short half-life = parenteral administration required
Direct-acting agonists: Catecholamines
•
•
•
•
•
NE: α1= α2 , β1> β2 Activation of α1 receptors = vasoconstriction,  peripheral resistance; 
systolic & diastolic blood pressure  reflex bradycardia
EPI: α1= α2 , β1= β2
– Low dose: β2 receptor stimulation = vasodilation,  DBP; bronchodilation
– High dose: α1 stimulation = vasoconstriction,  SBP & DBP
Isoproterenol: β1= β2 >>>α Activation of β1& β2 = cardiac stimulation & vasodilation; 
DBP but  SBP by increasing heart rate & contractility; potent chronotropic effect may lead
to tachycardia and tachyarrhythmias; bronchodilation
Dopamine: D1> β1 >α
– Low dose: D1 = renal vasodilation;
– Mid dose: β1 =  cardiac contractility, cardiac output, tissue perfusion;
– High dose: α1 receptors = vasoconstriction
Dobutamine: β1> β2 >α β1 =  cardiac contractility, cardiac output; β2 = vasodilation, 
vascular resistance
SBP = systolic blood pressure; DBP = diastolic blood pressure
Mean Arterial Pressure
• Perfusion pressure seen by organs in the body
• Want MAP > 60 mmHg is enough to sustain the organs
of the average person (70 to 110 mmHg)
• If the MAP falls significantly below this number for an
appreciable time, the end organ will not get enough
blood flow, and will become ischemic
• MAP = 1/3(SBP-DBP)+DBP
Catecholamines: Indications
Shock
• Cardiogenic
• Neurogenic & Septic
• Anaphylactic
• Cardiac arrest (Epi)
• Bradycardia/AV block (Iso)
• Prolongation of local
anesthetic action (Epi)
• Acute heart failure (Dobu)
Note: Catecholamines that increase blood pressure are also called vasopressors
Shock
Profoundly decreased blood flow to vital organs
• Hypovolemic: inadequate blood volume; tx by giving fluid
saline
• Cardiogenic: inadequate heart function; called cold shock
• Neurogenic/septic: inadequate vasomotor tone
– Septic: pathogenic microorganisms produce toxins causing
massive vasodilation; called warm shock
• Anaphylactic: severe immediate hypersensitivity reaction
with hypotension and difficulty breathing
Shock: General principles
Fluid resuscitation if hypovolemic
• Cardiogenic shock: 1) dobutamine, 2) dopamine
• Neurogenic/septic shock: norepinephrine; often in
combination with dopamine to preserve renal blood
flow; goal MAP > 60 mm Hg
• Anaphylactic shock: epinephrine
Catecholamines: Adverse effects
Excessive vasoconstriction
• Tissue ischemia/necrosis
• Reduction of blood flow to vital organs
Excessive cardiac stimulation
• Arrhythmias
Glycogenolysis (β2)
• Hyperglycemia
Non-catecholamines
Do not contain a catechol moiety
Not substrates for COMT
May be resistant to degradation by MAO
Effective orally
Longer duration of action
Phenylephrine (the friend of the receptor)
• Well absorbed orally and topically; may also
be given IV
• Partly metabolized by MAO in the liver and
intestine
• Activates α1 receptors
Phenylephrine: Indications
• Viral/allergic rhinitis: nasal
decongestant
• Allergic conjunctivitis: ocular
decongestant
• Mydriasis: ophthalmologic
exam
Hypotension/shock due to:
• Excessive vasodilators
• Drug-induced
• Septic shock
• Neurogenic shock
• Maintenance of BP during
surgery (anesthesiainduced hypotension)
Midodrine
• Rapidly absorbed after oral administration
• Metabolized in the liver/tissues to active metabolite
(desglymidodrine)
• Activates α1 receptors = vasoconstriction, SBP & DBP
while standing, sitting & supine
• Indicated to treat postural (orthostatic) hypotension
when non-pharmacologic treatment fails
• AE: Hypertension, especially when supine
β2 agonists
• Selective β2 agonists, however, at higher doses
may stimulate β1 receptors as well
• Bioavailability 30-50% (incomplete absorption,
1st-pass metabolism)
• Metabolized to inactive compounds; renally
excreted
• PO, IV or via inhalation
β2 agonists: Indications
• β2: relaxation of bronchial,
uterine and vascular smooth
muscle
• Obstructive lung disease:
asthma, COPD
• Premature labor
• AEs: tachycardia, skeletal
muscle tremor, nervousness
•
•
•
•
•
•
•
Albuterol
Metaproterenol
Salmeterol
Formoterol
Bitolterol
Ritodrine
Terbutaline- relaxes
uterine muscles
More on these in the Cardio-Pulmonary Block!
Imidazolines
• α1 receptor activation: oxymetazoline (non-selective αadrenergic agonist)
– Nasal & ocular decongestant
• α2 receptor activation: apraclonidine, brimonidine
–  intraocular pressure with ocular surgery –”onidines”
• α2- & imidazoline- receptor activation in the CNS
– Clonidine – hypertension
– Dexmedetomidine – sedation during mechanical
ventilation
Clonidine
• α 2-receptor agonist in the CNS (medulla) 
reduced sympathetic outflow
•  peripheral resistance, heart rate, and cardiac
output =  BP
• AEs: dry mouth, sedation, dizziness
• Abrupt withdrawal = sympathetic NS over activity
(HTN, tachycardia & sweating); “rebound HTN”
• Guanabenz & guanfacine
Indirect acting agonists
Amphetamine
Cocaine
• Inhibits the storage of norepi by • Blocks neuronal uptake of
neuronal vesicles  reverse
norepi at central and
transport back into the synapse
peripheral synapses 
stimulates the sympathetic NS
• Highly lipid soluble
• Vasoconstriction, pupillary
• Increases norepi in the CNS &
dilation, cardiac stimulation,
peripherally
 BP and CNS stimulation 
• Vasoconstriction, cardiac
cardiac damage/heart failure
stimulation,  BP and CNS
• Local anesthetic
stimulation
Mixed-acting agonists
Ephedrine & pseudoephedrine (isomer)
• Activate α1 receptors  vasoconstriction (nasal
decongestants),  BP & urinary retention
• Activate β1 receptors  tachycardia
• Activate β2 receptors  bronchodilation
• CNS stimulation  insomnia
Mixed-acting agonists
• Ephedrine derived from a naturally occurring
plant, Ephedra, AKA Ma Huang
• Well absorbed, lipid soluble
• Relatively resistant to MAO and COMT
metabolism = long duration of action
• Found in dietary supplements until banned by the
FDA due to deaths caused by hypertension and
cardiac stimulation
Adrenoreceptor antagonists
Reduce sympathetic stimulation; sympatholytics
Therapeutic effects
• Blocking α1 receptors =
vascular & smooth
muscle relaxation
• Blocking β1 receptors =
reduces sympathetic
stimulation of the heart
Adverse effects
• Blocking α2 receptors =
dizziness, headache,
nasal congestion
• Blocking β2 receptors =
bronchoconstriction,
inhibits glycogenolysis
Selective α1- antagonists
• Vasodilation,  BP; relax the bladder, urethra and
prostatic smooth muscle
• Indications – it is an o-sin to block alpha1
– Hypertension (doxazosin, prazosin & terazosin)
– Urinary symptoms (frequency, urgency & nocturia)
due to benign prostatic hypertrophy (alfuzosin,
tamsulosin)
• AEs: hypotension, dizziness, sedation
Selective α1- antagonists
• Prazosin – duration of action ~
6 hours; first-pass metabolism;
renal/biliary excretion
• Doxazosin – duration of action
~ 30 hours
• Terazosin – duration of action ~
20 hours
• Although indicated in the
treatment of HTN, not firstline
• AE: Orthostatic hypotension
• Alfuzosin/tamsulosin –
“uroselective”
• Relieve lower urinary tract
symptoms without as much
hypotension, dizziness &
sedation
Nonselective α-adrenergic antagonists
Phenoxybenzamine
• Spontaneous chemical
transformation to an active
metabolite  stable covalent bond
with the α receptor 
noncompetitive antagonism of
epinephrine & other adrenergic
agonists
• Gradual onset, duration ~ 3-4 days
•  Vascular resistance,  BP
• Indication: hypertension in
pheochromocytoma until surgery
Phentolamine
•
•
•
•
•
•
Imidazoline
Competitive antagonist
Onset immediate (IV), duration 1015 min
Hepatic metabolism, renal excretion
 Vascular resistance,  BP
Indications: hypertension caused by
α1-agonists; dermal necrosis &
ischemia caused by extravasation of
epinephrine. Perioperative use for
patients with pheochromocytoma.
Selective α2-blockers
• Yohimbine (Yocon)
•
•
•
•
•
Competitive antagonist, α2 selective
Bark of Pausinystalia yohimbe
Enters CNS –  BP, HR, motor activity
Actions appear opposite that of clonidine
Used (herbal treatment) for male sexual dysfunction
• Neuroleptic Agents
• Dopamine (D2) receptor antagonists
• Chlorpromazine, haloperidol, phenothiazines
• Induce side effects via blockade of α2
•
•
•
•
•
•
•
Selective β1 - antagonists
β 1 > β2
Primarily located in cardiac tissue
β1-blockers AKA cardioselective β-blockers
However, as dose increases, β2 receptor blockade increases
Negative chronotropic, ionotropic and dromotropic effects
Decrease cardiac output and BP
Decrease aqueous humor secretion in the eye and
intraocular pressure
Drug
Lipid solubility
Bioavailability
Half-life
Indications
Acebutolol
Medium
40%
10-12 h
HTN
Arrhythmias
Atenolol
Low
50%
6-7 h
HTN, acute
MI, angina
Adverse effects
Bronchoconstriction
Betaxolol
Low
90%
14-22 h
HTN, HF,
Glaucoma
Fatigue
Bisoprolol
Low
80%
9-12 h
HTN, HF
Depression
Esmolol
Low
100% (IV)
10 min
Acute SVT
Bradycardia
Metoprolol
Medium
40%
3-4 h
HTN, HF,
angina, MI
Sexual
dysfunction
Nonselective β - antagonists
• Block β1-receptors in cardiac tissue and β2receptors in smooth muscle, liver, & other tissues
• Intrinsic sympathomimetic activity
• Membrane-stabilizing activity
• Inhibit epinephrine-stimulated glycogenolysis
• Mask signs of early hypoglycemia (sweating,
tachycardia)
Intrinsic sympathomimetic activity
ISA
• Partial agonist activity = smaller reduction in
heart rate when the patient is resting and
sympathetic tone is low
• Pindolol (non-selective) and acebutolol
(selective)
Membrane-stabilizing activity
• Local anesthetic activity
• Block sodium channels cardiac nerves = slow
conduction velocity, perhaps contributing to
antiarrhythmic effects
• Pindolol and propranolol (nonselective)
Drug
Lipid solubility
Bioavailability
Half-life
Indications
Adverse effects
nadolol
Low
35%
15-20 h
HTN, angina,
migraine HA
prophylaxis
Broncho-
pindolol
Medium
75%
3-4 h
HTN
constriction
Fatigue
Propranolol1st drug
discovered
timolol
High
Medium
25%
50%
4-6 h
4-6 h
HTN, angina,
essential
tremor,
migraine HA
prophylaxis
Depression
Bradycardia
Sexual
HTN, migraine dysfunction
HA
prophylaxis,
glaucoma
α- and β-antagonists- go to the lab
to carve out receptors lol
Drug
MOA
F
HalfLife
Effects
Indications
Carvedilol
β1 & β2-blocker;
α1- blocker
30%
6-8 h
Vasodilation, 
HR & BP,  CO
HTN
Heart Failure
Labetalol
β1 & β2-blocker;
α1- blocker
20%
6-8 h
Vasodilation, 
HR & BP
HTN
Review questions
• Activation of β1 receptors produces cardiac
stimulation while activation of β2 receptors
mediates smooth muscle relaxation.
Review questions
• Which of the following receptors are associated
with renal vasodilation when activated?
– α1
– β1
– D1
• Which catecholamine has this effect? dopamine
Review questions
• Catecholamine Z is injected. The patient’s BP
and peripheral resistance rises; the HR
decreases. Which catecholamine was given?
– Dopamine
– Epinephrine
– Isoproterenol
– Norepinephrine
Review questions
• A new patient of yours with episodic severe HTN is found to
have markedly elevated levels of epinephrine and
norepinephrine metabolites in his urine. What would you
prescribe to lower his blood pressure before surgery?
– Doxazosin
– Metoprolol
– Phenoxybenzamine
– Tamsulosin
Lecture 6
Neuromuscular Blocking Agents
• Define the mechanism of action of neuromuscular
blocking agents and know their indications
• Relate pharmacokinetic parameters to drug selection
• Convey information related to drug interactions and
side effects
• Explain the pharmacological rationale behind use of
these drugs in clinical settings
History
• In the 16th century, European explorers found that
South American natives in the Amazon basin were
using an arrow poison, curare, to produce skeletal
muscle paralysis in the animals they were hunting
• Active compound – d-tubocurarine
Nicotinic Receptors
•
•
•
•
•
N1 or NM and N2 or NN
Ligand-gated ion channel
Requires binding of two acetylcholine molecules
Composed of five subunits (pentamer)
Five different types of subunits
– α, β, γ, δ and ε
– 10 different α and 4 different β subunits
• NM receptors contain only α1 and β1 subtypes plus
δ and γ/ε
• NN receptors contain α2-10 and β2-4 subtypes
ε
Neuromuscular blocking agents
• Introduced in the 1940s
• Structural analogs of acetylcholine (ACh)
• MOA: Bind to the nicotinic acetylcholine receptor at the motor
end plate and inhibit binding of ACh at skeletal neuromuscular
junctions  muscle weakness and paralysis
• Do not cross the blood-brain barrier, thus a patient may be
paralyzed but completely aware
• Classified as either depolarizing or nondepolarizing
Classification
Depolarizing agents
– Occupy and activate the
nicotinic receptor for a
prolonged period of time,
leading to blockade:
nicotinic receptor agonists
• Structures resemble that of
acetylcholine (ACh)
Nondepolarizing agents
• Competitively antagonize
the actions of ACh at the
nicotinic receptor
• Majority of agents fall into
this classification
Peripheral Nerve Stimulator
• Contraction of the adductor
pollicis muscle
• Determine
–
–
–
–
Type
Onset
Magnitude
Duration
• ED95
– 95% suppression on a single
twitch
– Used to quantify the potency of
a neuromuscular blocker
Other pharmacologic actions
• Stimulate the release of histamine 
bronchospasm & hypotension (tubocurarine,
mivacurium and atracurium)
• Block autonomic ganglia  hypotension &
tachycardia (tubocurarine)
• Block cardiac muscarinic receptors  tachycardia
(pancuronium)
Pharmacokinetics
• Poor absorption from GI tract; only administered by intravenous
route
• Do not enter cells or cross blood-brain barrier; distribution volume is
similar to blood volume
• Eliminated in urine and bile primarily as unchanged compounds,
some as hepatic metabolites
• Atracurium & cisatracurium (a stereoisomer of atracurium) undergo
spontaneous nonenzymatic degradation (Hofmann elimination);
preferred for patients with impaired liver and kidney function
Drug
Histamine
release
Ganglionic
blockade
Onset of
action (min)
Duration of
action (min)
Elimination
Succinylcholine*depola
Minimal
None
1.5
Short (5-10)
Plasma
cholinesterase
Atracurium
Varies
Low
3
Intermediate (3060)
Plasma esterase
Cisatracurium
None
Low
3
Intermediate (3060)
Spontaneous
degradation
Pancuronium
None
Medium
3
Long (60-120)
Renal
Rocuronium
None
Low
1
Intermediate (3060)
Biliary/renal
Tubocurarine
High
High
2
Long (60-120)
Renal/biliary
Vecuronium
None
Low
2
Intermediate (3060)
Biliary/renal
Hepatic metabolism
rizing
Succinylcholine
• Persistent depolarization of the motor end plate due to lack of
metabolism by Acetylcholinesterase (AChE)
• Phase I block – initial muscle fasciculations over the chest and
abdomen  flaccid paralysis of eye and face muscles, arms, legs and
neck muscles, then intercostal muscles and diaphragm
• Phase II block – membrane repolarizes but is still unresponsive;
desensitized nicotinic receptor
• Recovery occurs in reverse order: diaphragm regains function first,
followed by limb and trunk muscles, and lastly small muscles
Succinylcholine MOA
Phase I – depolarizing
These effects cannot be reversed
by cholinesterase inhibitors
Phase II - desensitizing
Succinylcholine: Adverse effects
• Genetic variations in
butyrylcholinesterase activity 
either 1) lower concentrations of
the enzyme or 2) an abnormal
enzyme resulting in a longer
duration of activity and apnea
• May cause increased intraocular
pressure and intragastric pressure
• Hyperkalemia ( K+)
patients with burns, neuromuscular
disease or nerve damage, closed
head injury and other trauma may
release potassium into the blood,
rarely resulting in cardiac arrest
Indications of NM Blockers
• Endotracheal intubation
•  muscle contractility, decreasing the depth of
anesthesia required for surgery
• In patients on mechanical ventilation (ICU) to
decrease O2 consumption and prevent high airway
pressures if sedation alone is not enough
• Prevent bone fractures during electroconvulsive
therapy
Drug interactions
• Inhaled anesthetics potentiate neuromuscular blockade
Isoflurane
Sevoflurane
Desflurane
Enflurane
Halothane
Nitrous oxide
Malignant hyperthermia:
rare interaction with succinylcholine;
abnormal release of calcium from
skeletal muscle causes muscular
contraction, rigidity and heat production;
hyperthermia, metabolic acidosis, tachycardia
• Dose must be reduced when used together
Drug interactions
Antibiotics potentiate neuromuscular blockade
• Aminoglycosides (gentamicin, tobramycin) -  Ach release;
lower sensitivity to ACh
• Tetracyclines – chelate Ca++ and  Ach release
• Clindamycin – block nicotinic receptors; depress muscle
contractility
• Dose must be reduced when used together
Drug interactions
Local anesthetics
• Bupivacaine potentiates blockade by blocking
neuromuscular transmission and muscle contractions
• Lidocaine and procaine prolong the duration of
action of succinylcholine by inhibiting
butyrylcholinesterase
Drug-disease considerations
• Myasthenia gravis – resistance to succinylcholine but
increased sensitivity to nondepolarizing agents; avoid
long-acting agents
• Advanced age – prolonged duration due to decreased
clearance by the liver and kidneys
• Hyperkalemia – potentiates depolarizing agents;
antagonizes non-depolarizing agents
• Hypokalemia – potentiates non-depolarizing agents;
antagonizes depolarizing agents
Drug-disease considerations
• Renal disease – prolonged elimination of
compounds that depend on glomerular
filtration, tubular secretion and reabsorption
for clearance
• Hepatic disease – prolongs the duration of
blockade
Drug selection
Considerations
• Onset of action
• Duration of action
• Adverse effects (cardiovascular, respiratory)
• Renal/hepatic function
Reversal
• Nondepolarizing agents can be reversed by cholinesterase
inhibitors (neostigmine, physostigmine, pyridostigmine)
Which of the following NMBs is the
DOC for intubation due to its short
onset of action?
a.
b.
c.
d.
Pancuronium
Vecuronium
Succinylcholine
Atracurium
Which of the following NMBs would
you avoid in a patient with renal
insufficiency (ClCr ~ 25 mL/min)?
a.
b.
c.
d.
Atracurium
Cisatracurium
Pancuronium
Rocuronium
Which of the following NMBs would
you avoid in a patient with a history of
malignant hyperthermia?
a.
b.
c.
d.
e.
Atracurium
Cisatracurium
Pancuronium
Rocuronium
Succinylcholine
A 22-year-old patient underwent a surgical procedure.
Anesthesia was provided by isoflurane, supplemented
by intravenous midazolam (a benzodiazepine sedative)
and pancuronium. Which of the following will reverse
the effects of the pancuronium at the end of the
procedure? What is its MOA?
a.
b.
c.
d.
Aminoglycoside
Bupivicaine
Nitrous oxide
Physostigmine
Lecture 7
Skeletal Muscle Relaxants
• Explain the mechanism of action of muscle
relaxants
• Describe indications and contraindications for
this group of drugs
• Describe the most common adverse effects for
these drugs
Introduction
• Musculoskeletal pain is common
• Surveys indicate a yearly prevalence of low-back symptoms in
50% of working age adults
• 15% to 20% seek medical care
• 1 of 7 primary-care visits is prompted by musculoskeletal
pain or dysfunction
• Musculoskeletal disorders are leading causes of disability and
work absenteeism
• In 1990, an estimated $192 million were spent on
medications for back pain in the United States
Beebe et al. American Journal of Therapeutics 2005; 12:151-171.
Spasmolytics
Antispasticity drugs
Antispasmodic agents
•  muscle cramping and
tightness in neurological
disorders, e.g., multiple
sclerosis and cerebral
palsy, spinal cord injury
and disease
• Prevent use-related
minor muscle spasms
• AKA centrally active
muscle relaxants
ANTISPASTICITY DRUGS
Baclofen - Diazepam - Tizanidine – Dantrolene
Diazepam – Tizanidine- also anti-spasmotics
Spasticity
• Common neurological problem in patients with damage
of central motor pathways
• Characterized by hyperexcitability of α-motorneurons in
the spinal cord due to a loss of normal inhibitory function
and an imbalance of excitatory and inhibitory
neurotransmitters
• Antispasticity drugs alter the activity of
neurotransmitters in the CNS and
peripheral neuromuscular sites
Management of spasticity
Identify specific patient and caregiver objectives:
• Improve gait, activities of daily living, hygiene
• Provide pain relief, ease of care
• Decrease spasm frequency and pain
CMAJ 2003;169(11):1173-9
Management of spasticity
Initiate comprehensive spasticity management program:
• Removal or treatment of noxious stimuli
• Physical/occupational therapies; proper positioning &
regular stretching
• Oral drug therapy
• Injection of botulinum toxin type A
• Intrathecal baclofen
• Surgical intervention
Start at the top and work your way down.
CMAJ 2003;169(11):1173-9
Sites of antispasticity drug action
Drug
Mechanism of action
Baclofen
Binds to GABAB receptors on presynaptic terminals of spinal interneurons resulting in
hyperpolarization of the membrane, decrease in Ca++ influx, decrease in excitatory
neurotransmitters
Diazepam
Acts on GABAA receptors to enhance inhibition at pre- and postsynaptic sites in the
spinal cord; it also acts in the brain
Tizanidine
Acts presynaptically at α-2 adrenergic receptors to inhibit spinal motor neurons
Dantrolene
Reduces Ca++-mediated excitation-contraction coupling through block of release
channels on the sarcoplasmic reticulum of skeletal muscle
Baclofen: pharmacokinetics
•
•
•
•
Well absorbed; relative bioavailability: 70%–80%
Time to peak concentration: 2–3 h
Onset of action: hours to weeks (3 – 4 d)
Widely distributed; crosses blood-brain barrier readily;
protein binding: 30%
• Metabolism: minimal hepatic (15% of dose)
• Excretion: 70%–80% (parent compound in urine/feces)
• Elimination t 1/2: 2.5–4 h
Baclofen: adverse effects
•
•
•
•
•
•
•
Drowsiness initially; tolerance develops with chronic use
Hypotension
Elevated transaminases (ALT, AST, alkaline phosphatase)
May cause positive stool guaiac
Increase in serum glucose (hyperglycemia)
Avoid abrupt withdrawal (hallucinations, seizures)
Caution recommended in patients with seizures or renal
impairment
Baclofen
• Continuous intrathecal
baclofen is an option for
patients unable to tolerate
or unresponsive to oral
therapy
Pump/reservoir implanted between the
muscle and skin of the abdomen
A catheter carries baclofen from the
pump to the spinal cord and nerves
Diazepam (valium): pharmacokinetics
•
•
•
•
•
•
•
•
Well-absorbed
Time to peak concentration: 1-2 hours
Onset of action: 15 – 30 minutes
Widely distributed; crosses blood-brain barrier readily
Metabolism: hepatic via CYP450 to n-desmethyl-diazepam (active metabolite)
Multiple drug interactions!
Excretion: urine as glucuronide conjugates
Elimination t 1/2: > 48 hours
Anything that causes sedation is a drug interaction for ALLL of the drugs in this
presentation (ex. anti-histamines, sedatives, hypnotics, etc…) and metabolized via
CYP450
Diazepam: adverse effects
•
•
•
•
Sedation, lightheadedness, ataxia, lethargy
Impaired mental and psychomotor function
Anterograde amnesia
Physical dependence and withdrawal upon abrupt
discontinuation
• Abuse potential (C IV)
• Pregnancy Category D: freely crosses the
placenta and accumulates in fetal circulation
Tizanidine: pharmacokinetics
• Bioavailability is 40% due to extensive hepatic first-pass
metabolism (95%)
• Peak effect: 1–2 h
• Metabolism: hepatic via CYP 1A2; avoid with ciprofloxacin
• Excretion: urine (60%); feces (20%)
• Elimination t1/2: 2.5 h
• Caution in patients with renal insufficiency as clearance is
reduced by 50%
Tizanidine: adverse effects
• Tizanidine is an α-2 agonist similar to clonidine
• Dose-related hypotension, sedation and dry mouth
• Rare but severe hepatotoxicity; monitor
transaminases (ALT, AST)
• Withdrawal and rebound hypertension with abrupt
discontinuation; tapering is recommended
Dantrolene
Pharmacokinetics
Adverse effects
• Well absorbed
• Metabolism: hepatic
CYP450
• Excretion: urine/bile
• Elimination t 1/2: 15 h
• Hepatotoxicity with chronic
use
• Drowsiness, dizziness,
weakness, malaise, fatigue
Drug of Choice (DOC) for malignant hyperthermia:
high fever, tachycardia, hypertension, rigidity
MOTOR NERVE BLOCKER
Botulinum toxin
Botulinum toxin type A
• Produced by anaerobic bacterium Clostridium botulinum
• MOA: Blocks the release of ACh from the motor nerves resulting
in long-lasting muscle paralysis (~3 months)
Used IM for:
• muscle disorders of the eye (blepharospasm, strabismus)
• elective cosmetic purposes
• spasticity, e.g., cerebral palsy
Best for small areas of focal spasm
• Contraindicated in pregnancy & lactation
ANTISPASMODIC
DRUGS
Chlorzoxazone – Cyclobenzaprine – Diazepam - Metaxalone – Methocarbamol –
Orphenadrine - Tizanidine
Indications
Painful musculoskeletal conditions including:
• Low back pain
Myofascial pain syndrome
• Fibromyalgia
• Tension headaches
Fast facts
• Among the top 200 drugs dispensed in 2006
• However, NOT recommended as first line
therapy
• Acetaminophen & NSAIDs are the DOC
• Use as adjuncts to physical therapy
Pharmacology
• Unknown! Do not act on motor neurons or
the muscle itself
• Act on the brain, maybe spinal reflexes
• CNS depressants  induce sedation
• Diazepam enhances the effects of GABA at
receptors in the brain
Chlorzoxazone: pharmacokinetics
• Readily absorbed
• Peak concentration: 1–2 h
• Metabolism: extensive hepatic phase II to
glucuronides
– CYP 450 Substrate: 1A2, 2A6, 2D6, 2E1, 3/4
– CYP 450 Inhibitor: 2E1, 3A4
• Excretion: urine (conjugates); <1% excreted
unchanged
Chlorzoxazone: adverse effects
•
•
•
•
Dizziness, drowsiness
Red or orange urine
Hepatotoxicity (rare); monitor LFTs
Contraindicated in patients with hepatic
dysfunction
• FDA Pregnancy category C
Cyclobenzaprine: pharmacokinetics
•
•
•
•
•
GOLD STANDARD DRUG= DRUG OF CHOICE
Absorption: oral, complete
Peak concentration: 3–8 h
Protein binding: 93%
Metabolism: extensive; conjugation to glucuronide
– CYP450 Substrate: 1A2, 2D6, 3A4
• Elimination: renal (50%) inactive metabolites; unchanged drug in
feces via bile
• Elimination t1/2: 1–3 d
Cyclobenzaprine: adverse effects
•
•
•
•
•
•
•
•
5-HT2 receptor antagonist, related structurally to cyclic antidepressants
Tachycardia, hypotension, arrhythmias (rare), MI (rare)
Drowsiness, lethargy, lightheadedness, dizziness
Dry mouth, urinary retention,  intraocular pressure
Seizures (rare)
MOST evidence for efficacy
Avoid with other serotonergic agents, recent MI, arrhythmias, glaucoma
QT prolongation and possible torsade de pointes have been reported with
fluoxetine, a CYP4502D6,3A4 inhibitor
• FDA Pregnancy Category B
Metaxalone: pharmacokinetics
• Well absorbed; peak levels: 2-3 h
• Metabolism: hepatic
– CYP450 substrate 1A2, 2A6, 2D6, 2E1, 3/4A
– CYP450 inhibitor: 2E1, 3A4
• Elimination: metabolites via kidney
• Elimination t1/2: 2.4h (fat meal) to 9.2 h (fasting)
Metaxalone: adverse effects
•
•
•
•
Drowsiness, dizziness, headache, nervousness
Leukopenia, hemolytic anemia (rare)
 hepatic transaminases
Contraindications: significant renal/hepatic
impairment; hypersensitivity
• FDA Pregnancy Category C
Methocarbamol: pharmacokinetics
•
•
•
•
•
•
Absorption: rapid and complete
Peak serum concentration: 1 - 2 h
Distribution: widely throughout the body
Metabolism: hepatic (first pass)
Elimination t1/2: 1–2 h
Elimination: renal 3d after 1 dose
Methocarbamol: adverse effects
• Black, brown, or green urine
• Lightheadedness, dizziness, drowsiness
• FDA Pregnancy category C; fetal abnormalities
have been reported
Orphenadrine: pharmacokinetics
• Readily absorbed from GI tract, variable in overdose due
to anticholinergic effects
• Peak effects: 2–4 h
• Widely distributed; protein binding: 20%
• Metabolism: hepatic
• Elimination: primarily renal (60%) metabolites, 8% parent
compound
• Elimination t1/2: 14–16 h
Orphenadrine: adverse effects
• Drowsiness, dry mouth, urinary retention, increased
intraocular pressure
• Aplastic anemia (rare)
• Confusion
• Tachycardia
• Contraindications: glaucoma, myasthenia gravis
• Reduce dose in older patients
• FDA Pregnancy Category C
Carisoprodol
• Brand name: Soma
• Metabolized to meprobamate, a C III controlled
substance  physical & psychological dependence
• No better than any other SMRs
• DO NOT USE!!!
Safety
• Sedation – caution when driving or operating heavy
machinery
• Additive effects with alcohol or other sedativehypnotics
• Caution in elderly
Evidence of effectiveness
Studies are not well-designed:
•
•
•
•
Inadequate randomization
No mention of allocation concealment
Not using intention-to-treat methods
Incomplete reporting of compliance
Evidence of effectiveness
A formal literature synthesis concluded that oral SMRs
• are effective in acute low-back pain and roughly
equivalent to NSAIDs but found little evidence of
effectiveness in chronic low-back pain
• it is not clear to what extent pain relief is affected by
muscle relaxation versus the sedative effect of SMRs
• combinations of an SMR with an NSAID show increased
efficacy over single agents
SORT: Key Recommendations for Practice
Clinical recommendation
Evidence
rating
Skeletal muscle relaxants are not considered first-line therapy for musculoskeletal conditions.
C
Skeletal muscle relaxants may be used as adjunctive therapy for acute low back pain.
B
Antispasmodic agents should be used short-term (two weeks) for acute low back pain.
C
There is no clear evidence that one skeletal muscle relaxant is superior to another for
musculoskeletal spasms.
B
Choice of skeletal muscle relaxant should be based on individual drug characteristics and patient
situation.
C
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patientoriented evidence; C = consensus, disease oriented evidence, usual practice, expert opinion, or case
series. For information about the SORT evidence rating system, see
See et al. Am Fam Physician 2008; 78:365-70.
http://www.aafp.org/afpsort.xml.