Download Pharmacology Block 3 Notes Autonomic Pharmacology I

Pharmacology Block 3 Notes
Autonomic Pharmacology I-III
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Autonomic nervous system
o A division of the PNS that is further subdivided into sympathetic and
parasympathetic components
o Is purely MOTOR!
o Involuntary (you don’t think about it), is regulated by areas of the brain stem
o Tissues it affects: smooth muscle, cardiac muscle, glands
Neuron pathways
o Three neuron types of concern:
 Sympathetic motor neuron:
 Preganglionic axon = short; Postganglionic axon = long
 At the synapse between the two, you have release of ACh which
binds to nicotinic receptors
o Nicotinic receptors: ion channel-linked receptors
 At the synapse between the postganglionic neuron and the target
tissue, you have release of norepinephrine (primarily) or ACh
which binds to adrenergic or muscarinic receptors
o Adrenergic receptors: can be alpha or beta
o Binds to muscarinic receptors if target is a sweat gland
 Alternative pathway: preganglionic neuron synapses with
chromaffin cells in the adrenal medulla, releasing ACh which in
turn causes the adrenal medulla to secrete epinephrine
 Parasympathetic motor neuron:
 Preganglionic axon = long; Postganglionic axon = short
 ACh still released at first synapse and binds to nicotinic receptors
 ACh released at synapse between postganglionic neuron and
target tissue, where it binds to muscarinic receptors
 Somatic motor neuron:
 One neuron system; neuron goes directly to target tissue
(probably skeletal muscle)
 Releases ACh at synapse where it binds to nicotinic receptors on
the muscle fiber
Enteric nervous system
o A division of the PNS that innervates the GI tract
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o Controls GI motility and secretion; operates independently but is still regulated
by the ANS and CNS
Autonomic nervous system
o Sympathetic division: fight or flight, thoracolumbar outflow (from T1-L2)
 Mydriasis: DILATION of pupils
 Stimulates SWEAT glands
 COMPLETELY innervate peripheral blood vessels
o Parasympathetic division: rest and digest, cranio-sacral outflow
 Cranial nerves: 3, 7, 9, 10; Spinal nerves S2-S4
 Miosis: CONSTRICTION of pupils
 Promotes secretions (except in sweat glands)
Acetylcholine
o Neurotransmitter released by CHOLINERGIC neurons
o Released at the following sites:
 Between pre and postganglionic neurons in sympathetic,
parasympathetic
 Between parasympathetic postganglionic neuron and target tissue
 Between somatic motor neuron and skeletal muscle (@ neuromuscular
junction)
 Between sympathetic postganglionic neuron and sweat glands
Norepinephrine
o Neurotransmitter released by ADRENERGIC neurons
o Released between sympathetic postganglionic neuron and target tissue
o Note: epinephrine is released by the adrenal medulla in response to sympathetic
stimulation
Drugs and Neurotransmitters
o Each type of neurotransmitter and drug has its own receptor it can bind to
 Affinity: the extent to which a drug/neurotransmitter binds to a receptor
 If it binds often, it has a high affinity
o Agonist and antagonist: refers to the activity a drug/neurotransmitter has on the
RECEPTOR (not the final physiologic effect)
 Agonist: something binds to the receptor and INCREASES the activity of
the receptor (promotes the normal effect of that receptor)
 Antagonist: something binds to the receptor and DECREASES/INHIBITS
the activity of the receptor (prevents the normal effect of the receptor)
o A drug or neurotransmitter can serve as both an agonist and an inhibitor of
function
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Example: a neurotransmitter binds to a receptor and increases that
receptor’s activity (thus serving as an agonist); however when this
receptor is activated, the activity of the neuron is decreased (generating
an inhibitory effect)
 The receptor is thus an INHIBITORY RECEPTOR
 This is how molecules like GABA operate
The goal of neurons (and neurotransmitters) is to generate an action potential
o This is the way in which cells (primarily neurons) communicate with one another
o It involves changes in resting membrane potential
 Inside of the neuron is negative and high in K+ and anions
 Outside of the neuron is positive and high in Na+ and Ca++
o Depolarization: resting membrane potential becomes more positive, you get
closer to threshold and more likely to fire an action potential
o Hyperpolarization: resting membrane potential becomes more negative, you are
farther from threshold and less likely to fire an action potential
Neurotransmission
o Neurotransmitters are synthesized in the cell body (soma) of the presynaptic
neuron, packaged into vesicles, and transported down the axon where they are
stored in the axon terminal(s)
o Depolarization of the axon terminal via an action potential causes opening of
voltage-gated Ca++ channels, leading to an influx of Ca++ into the presynaptic
axon terminal
o The increase in intracellular Ca++ triggers release of neurotransmitter molecules
into the synaptic cleft via exocytosis
o Neurotransmitters cross the synaptic cleft and bind to receptors on the
postsynaptic cell
 Ionotropic receptors: associated with an ion channel
 Metabotropic receptors: associated with a G protein
 Note: either of these receptors can be excitatory or inhibitory
o Any neurotransmitter lingering in the synaptic cleft is removed via:
 Enzymatic degradation, with the metabolites being reabsorbed by the
presynaptic neuron
 Diffusion away from the synapse
 Reuptake of the neurotransmitter by the presynaptic neuron
o The signal generated in the postsynaptic cells is terminated through various
mechanisms
Acetylcholine
o Synthesized in the presynaptic neuron by reacting acetyl-CoA with choline
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 Note: the acetyl-CoA comes from mitochondria
 ACh contains a biological amine (very active subgroup)
o ACh is broken down in the synaptic cleft by the enzyme acetylcholinesterase into
acetate and choline
 Choline is then taken back up by the presynaptic neuron and recycled
Norepinephrine (NE)
o Synthesis: tyrosine to DOPA to dopamine
 Dopamine taken up into presynaptic vesicle where it is converted to
norepinephrine
o NE is NOT broken down in the synapse, instead is taken back up by the
presynaptic neuron or nearby glial cells
 If taken back up by the neuron, is broken down by monoamine oxidase
(MAO)
 If MAO is inhibited, you don’t get breakdown of NE in the neuron,
meaning more of it will be released into the synapse next time
 If taken up by cells other than neurons, will be broken down by catecholO-methyltransferase (COMT)
Receptors
o ACh receptors:
 Muscarinic: found between parasympathetic postganglionic neuron and
effector
 Nicotinic: found at all pre and postganglionic junction (sympathetic,
parasympathetic) and neuromuscular junctions
o Adrenoreceptors:
 Alpha-1 receptors: cause smooth muscle contraction
 Alpha-2 receptors: mediates sympathetic output
 Beta-1 receptors: cause cardiac stimulation
 Beta-2 receptors: promote smooth muscle relaxation
Sympathetic nervous system effects are performed by stimulating ADRENERGIC
receptors (alpha and beta)
Parasympathetic nervous system effects are performed by stimulating CHOLINERGIC
receptors (muscarinic; M2, M3, etc.)
Heart:
o Sympathetics: increase heart rate, electrical conduction, force of contraction
o Parasympathetics: decrease heart rate, electrical conduction
 Will SLIGHTLY decrease the force of contraction (but not much)
 If you block M2 receptors (those receptors that promote
parasympathetic activity in the heart) then you will have increased heart
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rate and electrical conduction, but force of contraction will not be
changed much
Remember the parasympathetics (b/c the sympathetics will be the opposite)
o DUMBBELLS
 Diarrhea, urination, miosis (pupil constriction), bradycardia,
bronchoconstriction/bronchospasm, erection, lacrimation, lethargy,
salivation/sweating
Baroreceptor reflex
o The way in which the body responds to elevated blood pressure (as a result of
sympathetic stimulation)
o Baroreceptors in your arteries detect the increased arterial pressure and send
info by way of afferent fibers to the vasomotor cortex in the medulla
o The medulla receives and interprets this information, ultimately sending info out
by way of efferent fibers:
 Decreases sympathetic output, resulting in vasodilation (b/c only
sympathetics go to blood vessels)
 Increases parasympathetic activity of the heart to decrease heart rate
and cardiac output
 End result = decreased blood pressure
Drugs that work on acetylcholine neurotransmission
o Hemicholinium and vesamicol
 Hemicholinium: prevents reabsorption of choline by the presynaptic
neuron (preventing it from being recycled to make more ACh)
 Vesamicol: prevents ACh from being taken up into presynaptic vesicles
 Note: neither of these have clinical use b/c they are NON-SELECTIVE
cholinergic antagonists
 If you were to use either of these, you would inhibit ALL ACh
systems in the body, preventing normal ACh activity, resulting in
mass paralysis (due to lack of muscle contraction)
o Tetrodotoxin (TTX)
 Blocks voltage-gated Na+ channels needed for depolarization to produce
the action potential
 No depolarization, no action potential, no neurotransmitter
release
o Alpha-Latrotoxin (derived from black widow spider)
 Creates pores in the axon’s plasma membrane, resulting in Ca++ flowing
in w/o stimulation from an action potential
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The initial increase in Ca++ causes a massive release of ACh from the
presynaptic neuron
 When an action potential is eventually produced, the ACh reservoir of the
presynaptic neuron will be depleted and you will lose normal ACh activity
at the postsynaptic cell (b/c you no longer have any ACh to release)
o Botulinum toxin
 Degrades SNAP-25 protein (needed for presynaptic vesicle to fuse
w/presynaptic membrane so ACh can be released into the synaptic cleft)
 Results in no ACh being released
o Atropine
 Is a muscarinic receptor antagonist
 Binds to muscarinic receptor for ACh on postsynaptic cell, preventing ACh
from binding
 Ultimately prevents ACh’s effect at the postsynaptic cell
o Physostigmine
 Acetylcholinesterase inhibitor
 Ultimately allows for increased concentrations of ACh in the synaptic
cleft, improving the likelihood that ACh will bind to a postsynaptic
receptor and exert its effects
o Dantrolene
 Binds to a receptor on the endoplasmic reticulum in the postsynaptic cell,
blocking the effects of Ca++ influx
 Example: in a muscle cell, by blocking Ca++ influx, you prevent
release of Ca++ from the sarcoplasmic reticulum of the muscle
cell, preventing muscle contraction
o Leading to muscle relaxation
Cholinergic agonists (molecules that bind to ACh receptors and promote the normal
activity of the receptor)
o Nicotinic receptor agonists: molecules that bind to the nicotinic ACh receptor
and stimulate its activity
 Nicotinic receptors are EVERYWHERE (these drugs therefore have
widespread effects)
 Classic example: Nicotine
 Sympathetic effects: increased heart rate, blood pressure
 Parasympathetic effects: diarrhea, urination
 CROSSES THE BLOOD-BRAIN BARRIER: resulting in alertness,
vomiting, tremors, convulsions, coma
 Varenicline
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Used for smoking cessation; reduces cravings and withdrawal
effects
 Cons: suicidal ideation, depression
 Is a PARTIAL AGONIST:
o Varenicline binds to the nicotinic receptor, promoting
SOME of its effect, but not to the same degree as would a
full agonist
 In this sense, it is also acting as an ANTAGONIST b/c
it is preventing nicotine from binding
o Muscarinic receptor agonists (molecule that binds to the muscarinic ACh
receptor and promotes the activity of the receptor)
 Five types of muscarinic receptors
 M1,3,5 are coupled to Gq which activates phospholipase C
o Phospholipase C in turn activates an EPSP
 M2,4 are coupled to Gi, which inhibits adenylate cyclase
o Shuts down the cell’s ability to mobilize Ca++
 Primarily promote parasympathetic nerve activity
 Bethanecol:
 Used for postoperative ileus, urinary retention
 Stimulates bladder/GI w/o affecting heart rate or blood pressure
 Pilocarpine
 Uses: glaucoma, xerostomia
o Lowers intraocular pressure by increasing aqueous humor
outflow
o Stimulates secretions of salivary glands
 Cevimeline
 Uses: xerostomia, Sjogren’s syndrome
o Stimulates salivary gland secretion
 Side effects:
 In high doses can cause acute circulatory failure and cardiac arrest
 Contraindications: asthma, COPD, UPD
o b/c parsympathetics cause bronchoconstriction
o Acetylcholinesterase inhibitors
 Are reversible and short-acting
 By inhibiting acetylcholinesterase, you are preventing the breakdown of
ACh in the synaptic cleft, therefore more of it will be available to bind to
cholinergic receptors (thus acetylcholinesterase inhibitors can be thought
of as cholinergic receptor AGONISTS)
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Edrophonium: used in the diagnosis of myasthenia gravis
Neo- and pyridostigmine: used to treat myasthenia gravis, neuromuscular
blockade, and postoperative urinary retention
 Physostigmine: used for glaucoma
 Donepezil, galantamine, rivastigmine: used in Alzheimer’s Disease
 Potentiates ACh effects in the hippocampus and other areas
responsible for memory
Myasthenia gravis
o An autoimmune condition where the body produces antibodies against the
nicotinic ACh receptors at the neuromuscular junction
o Therefore there are significantly fewer ACh receptors available on the muscle
cells, meaning the effects of ACh will be greatly hindered
o Results in skeletal muscle weakness (altered speech, dysphagia, problems
chewing, loss of facial expressions, ptosis, double vision, etc.)
o Diagnosis:
 Administer IV edrophonium (an acetylcholinesterase inhibitor)
 If patient has MG, they will show rapid but brief improvement in
muscle strength
 If patient does NOT have MG, they will experience fasciculations
(twitching beneath the skin)
o Treatment:
 Pyridostigmine: an acetylcholinesterase inhibitor
 Take PO QD
 Also given immunosuppressants at the same time (corticosteroids)
 AE: abdominal cramps, diarrhea
 Reasoning: you are increasing ACh levels system-wide, therefore
ACh will stimulate both nicotinic and MUSCARINIC receptors
o Muscarinic receptors = parasympathetic activity = GI tract
= increased peristalsis, bowel movements
Irreversible cholinesterase inhibitors
o Work by phosphorylation of acetylcholinesterase (forming a permanent covalent
bond)
o With acetylcholinesterase inhibited, acetylcholine accumulates in the synaptic
cleft, therefore its effects are potentiated
 Through triggering BOTH nicotinic and muscarinic receptors
o Examples:
 Organophosphates-pesticides, nerve gases
 Highly lipid soluble (absorbed via skin, mucous membranes, gut)
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o Organophosphate toxicity
 With this, you have knocked out your acetylcholinesterase, therefore you
have excess ACh in the synaptic cleft, and its effects are potentiated
 Symptoms:
 Miosis, salivation, sweating, bronchoconstriction, vomiting,
diarrhea
o All are parasympathetic effects triggered through ACh
stimulation of MUSCARINIC receptors
 CNS: cognitive disturbance, seizures, coma
 Neuromuscular blockade
 Treatment:
 Supportive care (especially for maintaining an open airway),
decontamination, atropine (large doses), benzodiazepines, 2-PAM
o Atropine: muscarinic receptor antagonist
 Prevents ACh from binding to muscarinic receptor,
decreasing muscarinic (parasympathetic) effects
o Benzodiazepines: for seizures
o 2-PAM: to regenerate acetylcholinesterase
Nicotinic receptor antagonists
o Molecules that bind to the nicotinic receptor, blocking the normal activity of that
receptor
o Nicotinic receptors found at the synapse between the pre and postganglionic
neurons in both sympathetic and parasympathetic pathways
 Also found at synapse between somatic motor neuron and skeletal
muscle
o Depending on whether the blocking effect is greater at the sympathetic or
parasympathetic ganglion will determine the effects observed
 If blocking is greater at the sympathetic ganglion:
 You won’t get sympathetic activity
 Symptoms will be parasympathetic in nature
o Ex.) hypotension
 If blocking is greater at the parasympathetic ganglion:
 You won’t get parasympathetic activity
 Symptoms will be sympathetic in nature:
o Dry mouth, blurred vision, urinary retention
o These drugs are NOT used clinically (b/c of widespread systemic effects)
Excitatory postsynaptic potentials (EPSP)
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o If the accumulation of EPSPs is of sufficient magnitude, then an action potential
is generated
o ACh released from the preganglionic neuron binds to nicotinic ACh receptors in
the postganglionic cell membrane
o This subsequently causes opening of Na+ channels, leading to an influx of Na+ in
the postganglionic neuron, resulting in generation of an EPSP (thus you are more
likely to generate an action potential in the postganglionic neuron, allowing for
continued signal transmission)
Muscarinic receptor antagonists
o Molecules that bind to muscarinic receptors (ACh receptors found at the
junction between the parasympathetic postganglionic neuron and the effector
tissue) and block the activity at said receptor
o b/c muscarinic receptors facilitate PARASYMPATHETIC effects, and you are
blocking the muscarinic receptors, you are essentially blocking parasympathetic
activity
o Therefore the effects will be sympathetic in nature
o Two big classes of drugs:
 Belladonna alkaloids: atropine, hyoscyamine, scopolamine
 Semisynthetic/synthetic agents: dicyclomine, glycopyrrolate, ipratropium,
oxybutynin
Anticholinergic toxicity
o Anticholinergic: inhibiting cholinergic activity, i.e. ACh activity at muscarinic
receptors (parasympathetic)
 Symptoms will be mainly sympathetic in nature (b/c you have inhibited
parasympathetic activity)
o Example: Jimson weed
 Contains belladonna alkaloids (muscarinic receptor antagonists)
 Commonly ingested or inhaled
 Treatment: decontamination, supportive care, acetylcholinesterase
inhibitor
 Acetylcholinesterase inhibitor would prevent the breakdown of
ACh, meaning more of it would be in the synaptic cleft
 With more ACh in the synaptic cleft, it now has a greater chance
of binding muscarinic receptors, increasing parasympathetic
activity (thus counteracting the sympathetic related symptoms of
toxicity)
Note: quaternary amines do NOT cross the blood brain barrier; tertiary amines DO cross
the barrier
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o Belladonna alkaloids (example-atropine) are drugs that act as muscarinic
receptor antagonists, blocking the effects of ACh at the muscarinic receptor, thus
blocking parasympathetic activity and causing sympathetic related symptoms
 These compounds contain tertiary amines, so they WILL GET INTO THE
BRAIN!!
Belladonna alkaloids
o Atropine, scopolamine, hyoscyamine
o Are well-absorbed and cross the blood brain barrier (thus enter the CNS)
o Excreted renally, has a longer half-life in the eye than systemically
o Is a muscarinic receptor antagonist
 Dry as a bone: inhibits secretions
 Blind as a bat-causes pupillary dilation (mydriasis)
 Red as a beet- blood pressure increases along with heart rate
 Mad as a hatter- delirium
Semisynthetic/synthetic anticholinergic drugs
o Man-made drugs that bind and inhibit the activity of ACh muscarinic receptors
(thus you are intentionally trying to inhibit parasympathetic activity, and thus
indirectly promoting sympathetic activity)
o Ipratropium/tiotropium-inhaled, used for COPD
 Promotes bronchodilation (by inhibiting bronchoconstriction)
o Dicyclomine-used for symptoms of irritable bowel and intestinal cramping
 Decreasing peristalsis/digestion
o Oxybutynin-used for overactive bladder
 Inhibiting urine production and secretion (promoting urinary retention)
o Glycopyrrolate- used preoperatively and in terminally ill patients to inhibit
secretions of salivary and respiratory tract
 Secretions are a parasympathetic response
o Tropicamide-used in eye exams to cause pupil dilation (mydriasis)
 You are inhibiting miosis (pupil constriction, a parasympathetic activity)
Contraindications for muscarinic receptor antagonists
o i.e. when do you NOT want to inhibit parasympathetic activity
o bowel blockage-you do NOT want to inhibit peristalsis during this time
o urinary retention/prostatic hypertrophy-you do NOT want to inhibit urine
production and secretion (they’re already having trouble urinating)
Miosis and Mydriasis in relation to drugs
o Miosis = constriction of the pupils (parasympathetic response)
o When you give a muscarinic receptor agonist……
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Ciliary muscles of the eye contract, suspensory ligaments that hold the
lens in place relax, the lens becomes thicker, allowing for accommodation
of the eye
o Mydriasis = dilation of the pupils (sympathetic response)
o When you give a muscarinic receptor antagonist
 Suspensory ligaments of the eye tighten, the lens becomes thinner and
you are now able to focus on distant objects
Autonomic Pharmacology IV-V
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Noradrenergic transmission
o The process by which the neurotransmitter norepinephrine is synthesized,
stored, released and acts within a synaptic pathway
o Norepinephrine is released by postganglionic sympathetic motor neurons and
acts on adrenoceptors, which have both alpha and beta forms and subtypes
o Again since norepinephrine is released by SYMPATHETIC motor neurons, its
targets are: smooth muscle, cardiac muscle and glands
Alpha adrenoceptors
o Alpha -1: mediates contraction of
 Vascular smooth muscle (causing vasoconstriction)
 Iris dilator muscle (causing mydriasis, i.e. pupil dilation)
 Urinary tract smooth muscle (causing urinary retention)
o Alpha-1 receptors are also found in exocrine glands and the CNS
o Alpha -2 receptors:
 INDIRECTLY mediates smooth muscle relaxation
 Reasoning:
 In the environment you have high levels of norepinephrine
 This then acts via a negative feedback loop through stimulating
alpha-2 receptors, which tells the noradrenergic neurons to stop
producing norepinephrine
 Eventually norepinephrine levels decrease, and thus their
sympathetic effects (in this case smooth muscle contraction)
decrease
o Causing smooth muscle relaxation
o Alpha-2 receptors are also found in platelets and the pancreas
Beta adrenoceptors
o Beta-1: responsible for cardiac stimulation
 Will increase heart rate, force of contraction and electrical conduction
velocity
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o Beta-1 receptors are also found in the kidney
 When stimulated will cause release of renin
 Begins the renin-angiotensin-aldosterone system which ultimately
increases blood pressure
o Beta-2: mediate relaxation of
 Bronchial smooth muscle (causing bronchodilation)
 Uterine smooth muscle
 Vascular smooth muscle (causing vasodilation)
o Beta-2 receptors are also found in:
 Skeletal muscle where they mediate K+ uptake
 Liver where they mediate glycogenolysis
 Glycogenolysis is the breakdown of glycogen to glucose
o The glucose is then released into circulation, where it is
available to be utilized by cells during sympathetic
responses
REMINDER: blood vessels are ONLY under SYMPATHETIC control
o Sympathetics act on vascular smooth muscle to cause vasoconstriction, thus
increasing blood pressure
o If you want to decrease blood pressure through vasodilation, you have to have
sympathetic stimulation of beta-2 receptors
Other misc. receptors
o D-1: mediate smooth muscle relaxation in blood vessels (causing vasodilation)
o D-2: modulate neurotransmitter release
o Imidazoline receptors: promote natriuresis (removal of Na+ via urine) and
decrease sympathetic outflow from CNS
Adrenoreceptor agonists: molecules that stimulate activity at the adrenoreceptors
(alpha and beta norepinephrine receptors) ; thus stimulate sympathetic activity
o Direct-acting agonists: molecules that they themselves actually bind to the
receptors and stimulate its activity
 Example: catecholamines and noncatecholamines
o Indirect-acting agonists: increase the concentrations of norepinephrine in the
synapse
 More epinephrine at the synapse means more of it will bind to
adrenoreceptors and thus stimulate the receptor’s activity
o Mixed-acting agonists: molecules that have both direct and indirect effects
Direct acting adrenoreceptor agonists: molecules/drugs that bind to adrenoreceptors
and stimulate their activity
o Catecholamines:
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Natural: norepinephrine, epinephrine, dopamine
Synthetic: isoproterenol, dobutamine
Are rapidly inactivated by monoamine oxidase (in postganglionic
neurons) and COMT (in nearby glial cells) in gut, liver, other tissues
 These drugs have a low bioavailability and short half life
 Therefore you give parenterally to maximize on the concentration
of the drug, thereby improving its effects
 Norepinephrine:
 Acting on alpha-1 receptors: vasoconstriction, leading to
increased systolic and diastolic blood pressure (which in turn
generates a reflex arc leading to bradycardia i.e. slow heart rate)
 Epinephrine:
 Low dose: activates beta-2 receptors: vasodilation, leading to
decreased diastolic blood pressure and also bronchodilation
 High dose: activates alpha-1 receptors: vasoconstriction which
increases systolic and diastolic blood pressure
 Dopamine:
 Low dose: activates D-1 receptors: vasodilation of renal blood
vessels
 Mid dose: activates beta-1 receptors: increased force of
contraction/cardiac output/tissue perfusion
 High dose: activates alpha-1 receptors: vasoconstriction
 Isoproterenol: activates beta-1,2 receptors: cardiac stimulation (beta-1)
and vasodilation (beta-2), decreases diastolic blood pressure but
increases systolic blood pressure (via increasing heart rate, contractility)
 May result in tachycardia and tachyarrhythmias; bronchodilation
 Dobutamine: activates beta-1 receptors leading to increased force of
contraction and cardiac output; activates beta-2 receptors leading to
vasodilation and decreased blood pressure
Mean arterial pressure
o Perfusion pressure seen by organs (organs require a certain blood pressure in
order to be supplied vascularly)
o MAP greater than 60 mm Hg is enough to sustain the organs of an average
person
o If MAP significantly decreases, the organs will not receive enough blood flow,
leading to ischemia and serious injury
o MAP = 1/3 (SBP – DBP) + DBP
 SBP = systolic blood pressure (top number)
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 DBP = diastolic blood pressure (bottom number)
Catecholamines
o Are direct-acting adrenoreceptor agonists (meaning they will bind to
adrenoreceptors and stimulate the natural activity of that receptor, often times
promoting sympathetic actions)
o Indications for usage:
 Shock (cardiogenic, neurogenic/septic, anaphylactic), cardiac arrest,
bradycardia/atrioventricular block, prolongation of local anesthetic
action, acute heart failure
o Catecholamines that result in an INCREASED blood pressure = vasopressors
Shock
o Profoundly decreased blood flow to vital organs (can lead to ischemia = bad)
o Different types of shock:
 Hypovolemic: decreased blood volume
 Cardiogenic: inadequate heart function
 Neurogenic/septic: inadequate vasomotor tone (the blood vessels are
not constricted to the degree needed to perfuse organs)
 Septic: pathogens release toxins that cause massive vasodilation
 Anaphylactic: severe immediate hypersensitivity reaction leading to
hypotension (low blood pressure) and difficulty breathing
o Treatment:
 Hypovolemic shock: fluid resuscitation (but gradually so as not to cause
cerebral edema)
 Cardiogenic shock: dobutamine first (to stimulate beta-1 receptors) and
then possibly in addition/in place use dopamine (again to stimulate beta1 receptors)
 Neurogenic/septic shock: norepinephrine (to activate alpha-1 receptors);
often used with dopamine to preserve renal blood flow (through
activating D-1 receptors)
 Get their MAP over 60 mm Hg
 Anaphylactic shock: epinephrine (activates alpha-1 receptors to cause
vasoconstriction and increase blood pressure; also activates beta-2 to
cause bronchodilation)
Adverse effects of catecholamine treatment
o Excessive vasoconstriction (through overstimulating alpha-1 receptors)
 Tissue ischemia, leading to necrosis
 Reduced blood perfusion of organs
o Excessive cardiac stimulation (overstimulating beta-1 receptors)
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 Arrhythmias
o Glycogenolysis (overstimulating beta-2 receptors in the liver)
 Hyperglycemia (bad if you have diabetes mellitus)
Noncatecholamines
o Are also direct acting adrenoreceptor agonists
o They do NOT have a catechol moiety, therefore they are not substrates for
COMT and may be resistant to monoamine oxidase
o Therefore they have a higher bioavailability than catecholamines (and thus can
be given orally) and also have a longer duration of action (longer half-life)
o Phenylephrine
 Well absorbed orally/topically; also given IV
 Partially metabolized in liver and intestines by monoamine oxidase
 Activates alpha-1 receptors: causing smooth muscle contraction
 Indications:
 As nasal decongestant or as an ocular decongestant
 In ophthalmologic exams to induce mydriasis (pupil dilation)
 Hypotension/shock due to:
o Excessive vasodilators, drugs, septic/neurogenic shock,
maintenance of blood pressure during surgery
o Midodrine
 Taken orally, rapidly absorbed, and converted to an active metabolite
(desglymidodrine) in the liver and tissues
 Activates alpha-1 receptors, thus causing smooth muscle contraction
 Results in vasoconstriction and increased blood pressure (both systolic
and diastolic) whether patient is standing, sitting or supine
 Used to treat orthostatic hypotension
 Adverse effects include hypertension
Beta-2 agonists: molecules that bind to the beta-2 adrenoreceptor and stimulate its
effects, namely smooth muscle relaxation
o Bioavailabilty of 30-50% b/c of incomplete absorption and 1st pass metabolism
 In other words, not all of the drug that is taken makes it into the
bloodstream
o Metabolized to inactive compounds and excreted renally
o Can be administered orally, IV or inhaled
o Beta-2 agonists cause relaxation of bronchial, uterine and vascular smooth
muscle
o Indications:



Asthma, COPD : you want to induce bronchodilation to improve their
airflow
 Premature labor: with this, the problem is contractions of uterine smooth
muscle, therefore you want to correct this by RELAXING uterine smooth
muscle
o Adverse effects: tachycardia, skeletal muscle tremor, nervousness
o Examples: albuterol, terbutaline, metaproterenol, etc.
Imidazolines
o Can activate:
 Alpha-1 receptors: causing smooth muscle contraction
 Ex. oxymetazoline-nasal and ocular decongestant
 Alpha-2 receptors: indirectly causing smooth muscle relaxation via
feedback inhibition of norepinephrine
 Ex. brimonidine- decreases intraocular pressure w/ocular surgery
o Alpha-2 and imidazoline leads to receptor activation in the CNS
o Clonidine- used to treat HTN
 Alpha-2 receptor agonist in the CNS
 By stimulating alpha-2 receptors in the medulla, clonidine
promotes feedback inhibition of norepinephrine, leading to
decreased effects of norepinephrine
o Specifically a decrease in vasoconstriction (thus promoting
vasodilation) a decrease in heart rate and cardiac output
 Leading to decrease in blood pressure
 Adverse effects: dry mouth, sedation, dizziness
 DO NOT STOP COLD TURKEY
 Can result in rebound HTN
 w/o clonidine, you no longer have the same alpha-2 stimulation,
therefore feedback inhibition of norepinephrine is decreased,
meaning you will have overarching effects of norepinephrine (HTN
via alpha-1 stimulation, tachycardia via beta-1 stimulation and
sweating via sympathetic stimulation of sweat glands)
Indirect-acting adrenoreceptor agonists
o Molecules that increase the concentrations of norepinephrine in the synaptic
cleft, thus potentiating the effects of norepinephrine at adrenoreceptors (still
promoting sympathetic activities)
o Amphetamine: increases the amount of norepinephrine released into the
synapse



Highly lipid soluble, increases levels of norepinephrine in CNS and
peripherally
 Potentiates the effects of norepinephrine:
 Vasoconstriction via alpha-1 stimulation
 Cardiac stimulation via beta-1 stimulation
 Increased blood pressure via alpha-1 and beta-1 effects
 CNS stimulation
o Cocaine
 Blocks the reuptake of norepinephrine by postganglionic neurons,
therefore increasing its concentration and potentiating its effects at the
synapse
 Results in:
 Vasoconstriction, pupillary dilation via alpha-1
 Cardiac stimulation via beta-1
 Increased blood pressure via alpha-1 and beta-1
 CNS stimulation
 Adverse effect: cardiac damage, heart failure due to excessive stimulation
Mixed-acting adrenoreceptor agonists
o Molecules that promote activity at adrenoreceptors by exerting both direct and
indirect effects (i.e. can bind to the receptor or increase the amount of
norepinephrine in the synapse)
o Ephedrine and pseudoephedrine
 Activate the following:
 Alpha-1: causing smooth muscle contraction, leading to
vasoconstriction, increased blood pressure and urinary retention
 Beta-1: cardiac stimulation, leading to tachycardia
 Beta-2: causing smooth muscle relaxation, leading to
bronchodilation
 CNS stimulation leading to insomnia
Adrenoreceptor antagonists
o Molecules that inhibit the activity of adrenoreceptors
 Since adrenoreceptors are involved in sympathetic activities,
adrenoreceptor antagonists result in a decrease in sympathetic activities
(thus promoting parasympathetic activities)
o Benefits of adrenoreceptor antagonists:
 Blocking alpha-1 receptors: prevents smooth muscle contraction
 Perhaps used to treat HTN
 Blocking beta-1 receptors: decrease cardiac stimulation
 Think beta-blockers
o Adverse effects of adrenoreceptor antagonists:
 By blocking alpha-2 receptors, you get dizziness, headache, nasal
congestion
 By blocking beta-2 receptors, you decrease smooth muscle relaxation
 In the lungs this results in bronchoconstriction
 In the liver this results in inhibition of glycogenolysis
o Alpha-1 antagonists:
 Decrease smooth muscle contraction
 Leads to vasodilation (and decreased blood pressure), relaxation of
smooth muscle in urinary tract
 Indications: HTN, urinary symptoms due to benign prostatic hypertrophy
 Adverse effects: hypotension, dizziness, sedation
 Non-selective alpha-adrenergic antagonists
 Molecules that inhibit the activity of alpha-1 and/or alpha-2
receptors
 Phenoxybenzamine
o Non-competitive antagonist of epinephrine and other
adrenoreceptor agonists
o Gradual onset/duration
o Decreases blood pressure
o Used to treat HTN in patients w/pheochromocytoma until
sx
 Phentolamine
o Competitive antagonist (competing w/the substrate or an
agonist for the alpha adrenoreceptor)
o Immediate onset, short duration
o Decreases blood pressure
o Used to treat: HTN caused by alpha-1 agonists, dermal
necrosis/ischemia due to extravasation of epinephrine,
perioperatively for patients w/pheochromocytoma
o Alpha-2 receptor antagonists
 Blocks the activity of alpha-2 receptors
 Meaning they prevent the feedback inhibition of production of
norepinephrine by adrenergic neurons
 You are inhibiting the inhibition, thus you get INCREASED
norepinephrine production
 Example: Yohimbine (Yocon)


Competitive antagonist
Enters CNS where it:
o Increases blood pressure and heart rate (via alpha-1 and
beta-1 stimulation) and motor activity
o Beta-1 receptor antagonists (aka cardioselective beta-blockers)
 Molecules that inhibit the activity at beta-1 adrenoreceptors (responsible
for cardiac simulation)
 Beta-1 receptors primarily found in cardiac tissue
 As you increase the dose of administration of a beta-1 antagonist, it will
also have inhibitory effects at beta-2 receptors (responsible for smooth
muscle relaxation)
 Results in decreased heart rate, force of contraction and electrical
conduction velocity
 Ultimately decreasing cardiac output and blood pressure
 Also decreases secretion of aqueous humor in the eye, thereby
decreasing intraocular pressure
o Nonselective beta adrenoreceptor antagonists
 Block beta-1 receptors in the heart: leading to decreased cardiac
output/stimulation
 Block beta-2 receptors: leading to decreased smooth muscle relaxation
(thus promoting smooth muscle contraction); also results in inhibition of
glycogenolysis (b/c you are blocking beta-2 receptors in the liver)
o Partial agonist
 A molecule that binds to a receptor and promotes the normal activity of
the receptor, but not to the same degree (or strength) as the normal
substrate/agonist would
 Also concurrently functions as an antagonist b/c it prevents the normal
substrate/full agonist from binding and exerting its complete effect(s)
Neuromuscular Blocking Agents

Neuromuscular junction
o Synapse formed between the presynaptic somatic motor neuron and the
postsynaptic muscle fibers
o ACh is released into the synaptic cleft, where it binds to receptors (either
nicotinic or muscarinic) on the muscle fibers, ultimately leading to muscle
contraction
 Nicotinic: ion-channel coupled receptor
 Muscarinic: G-protein coupled receptor


o Acetylcholinesterase is the enzyme within the synaptic cleft responsible for the
breakdown of ACh that lingers in the synapse
Nicotinic ACh receptors
o Can be Nm or Nn
 Nm: the nicotinic receptor found on the muscle fibers
 Nn: the nicotinic receptor found at the synapse between pre and
postganglionic neurons in either the sympathetic or parasympathetic
neuronal pathways
o Ligand-gated ion channels; requires 2 ACh molecules to bind before it opens
o Each nicotinic receptor is composed of five subunits (pentamer structure)
 There are 5 different types of subunits that can come together to form
the pentamer
 Alpha, beta, gamma, delta, epsilon
o 10 different alpha types and 4 different beta types
Neuromuscular blocking agents
o Work by binding to the nicotinic ACh receptors at the muscle fibers of the
neuromuscular junction
 Since the blocking agent is binding to the nicotinic receptor, that means
ACh cannot bind and exert its effects on muscle (i.e. contraction of
skeletal muscle)
 Therefore the patient will experience muscle weakness and paralysis
o These drugs do NOT cross the blood-brain barrier, therefore CNS effects
probably won’t occur, meaning the patient will be paralyzed but still cognitively
intact
o These drugs are classified as depolarizing or nondepolarizing
 Depolarizing neuromuscular blocking agent:
 These drugs act as AGONISTS of the nicotinic ACh receptor
 It stimulates the activity of the receptor over a PROLONGED
period of time, essentially “burning out” the activity of the
receptor, which leads to the eventual muscle weakness and
paralysis
 Think of it as “over-stimulation”
 Nondepolarizing neuromuscular blocking agent:
 These drugs act as COMPETITIVE ANTAGONISTS of the nicotinic
ACh receptor
o Meaning they bind to the receptor, thereby preventing
ACh from binding and exerting its effects
 Leading to muscle weakness and paralysis



 Many of the neuromuscular blocking agents are of this type
Neuromuscular blocking agents can have other pharmacologic effects
o They can stimulate the release of histamine
 Histamine release results in bronchospasm (airways close down) and
hypotension (decrease in blood pressure)
 Example: tubocurarine, mivacurium, atracurium
o Block the activities of nicotinic ACh receptors at the synapse between pre and
postganglionic neurons (in the sympathetic and parasympathetic pathways)
 Can lead to hypotension and tachycardia (elevated heart rate)
o Block cardiac muscarinic receptors (remember muscarinic receptors facilitate
parasympathetic activity)
 Leads to tachycardia
Pharmacokinetics of neuromuscular blocking agents
o Pharmacokinetics: what the body does to the drug
o These drugs are poorly absorbed from the GI tract; therefore they are given IV
(to get improved bioavailability)
o They do NOT cross the blood-brain barrier or enter cells
 Distribution and blood volume are similar
 Meaning that the amount of drug that enters the circulation
essentially stays in circulation
o Eliminated via urine (by way of kidneys) and bile (by way of liver) essentially
unchanged
o Two specific drugs: atracurium and cisatracurium
 Undergo spontaneous nonenzymatic degradation to lighten the burden
on the kidneys and liver as far as elimination
 Used in patients w/poor liver and kidney function
Succinylcholine
o A DEPOLARIZING neuromuscular blocking agent
o Drug binds to the nicotinic ACh receptor at the motor end plate, causing
prolonged depolarization (since it can’t be degraded by acetylcholinesterase);
ultimately leads to over-stimulation of the receptor, causing it to be desensitized
o Effects of the drug occur in two phases
 Phase I block: initial muscle fasciculation (twitching beneath the skin)
over the chest and abdomen; this is followed by flaccid paralysis in the
order of: eye/face, arms/legs/neck, intercostal muscles/diaphragm
 Phase II block: the plasma membrane of the muscle fiber repolarizes but
has become desensitized due to prolonged stimulation
o The patient’s recovery occurs in the reverse order of presentation


 Diaphragm, limb and trunk muscles, small muscles of eye and face
o Adverse effects:
 Genetic variations in butyrylcholinesterase
 Succinylcholine can cause decreased levels of
butyrylcholinesterase or can create abnormal forms of the
enzyme that result in prolonged activity and apnea
 Increased intraocular and intragastric pressure
 Hyperkalemia (increased K+ levels)
 Patient who experience: burns, neuromuscular disease, nerve
damage, closed head injury, trauma, etc. release excess K+ into
the blood
o Could potentially result in cardiac arrest
When to use neuromuscular blockers
o Endotracheal intubation
o Those patients on mechanical ventilators
 Done to decrease O2 consumption
o Prevent bone fractures during electroconvulsive therapy
o To decrease the depth (amount) of anesthesia required for surgery
Drug interactions with neuromuscular blocking agents
o INHALED ANAESTHETICS POTENTIATE THE EFFECTS OF NEUROMUSCLAR
BLOCKERS!
o Therefore when you use both of these together, the dosage must be reduced
o Malignant hyperthermia can result when succinylcholine is used alongside an
inhaled anesthetic (rare)
 Anesthetic potentiates (increases) the effect of succinylcholine
 You get abnormal release of calcium from skeletal muscle
 Increases the initial muscle contraction and rigidity, leading to
increased heat production which causes the hyperthermia
(increased body temp)
o These drug interactions can also cause metabolic acidosis and tachycardia
o ANTIBIOTICS POTENTIATE THE EFFECTS OF NEUROMUSCULAR BLOCKERS
 Aminoglycosides: decrease the release of ACh at the neuromuscular
junction; with decreased levels of ACh in the synapse, the nicotinic ACh
receptors on the muscle becomes less sensitive
 Tetracyclines: chelate Ca++, decreasing the release of ACh at the synaptic
cleft
 Clindamycin: blocks nicotinic ACh receptors, preventing the effects of
ACh at the neuromuscular junction



When administering antibiotics alongside neuromuscular blocking agents,
the dosage must be reduced
o Local anesthetics and neuromuscular blockers
 Local anesthetics, like inhaled anesthetics, potentiates the effects of
neuromuscular blockers
 Either blocks neuromuscular transmission (blocking the release of ACh) or
prolongs the activity of the blocker
Drug-disease considerations
o Avoid prolonged duration of neuromuscular blocking agents with the elderly and
those with kidney or liver disease
 Since they are older, their kidneys and liver are probably not the greatest,
therefore they may have decreased clearance of these drugs; with
decreased clearance, the drugs will therefore have a longer duration of
activity
 Remember NM blocking agents are cleared via urine and bile
o Hyperkalemia: potentiates the effects of depolarizing agents but counteracts the
effects of non-depolarizing agents
o Hypokalemia: potentiates the effects of non-depolarizing agents and counteracts
the effects of depolarizing agents
Drug selection: How do you choose which NM blocker to administer to your patient?
o Onset of action: how long does it take for the drug to kick in
o Duration of action: how long does the drug work for
o Adverse effects
o The patient’s renal and hepatic function
o Potential for reversal
 Non-depolarizing neuromuscular blocking agents (those that act as
competitive antagonists) can have their effects reversed by
cholinesterase inhibitors
 Reasoning: if you inhibit acetylcholinesterase, you increase the
levels of ACh in the synapse, meaning it can outcompete with the
blocker for the nicotinic ACh binding site on the muscle
Skeletal Muscle Relaxants


Skeletal muscle relaxants = spasmolytics
Two broad classes
o Antispasticity drugs:
 Decrease muscle cramping/tightness due to neurological disorders (MS,
CP, spinal cord injury, etc.)

o Antispasmodic agents:
 What people typically think of as muscle relaxants
 Designed to prevent use-related minor muscle spasms; used to treat
lower back pain (patient comes to you saying they threw their back out)
Antispasticity Drugs
o Note: these are the kinds used to treat muscle cramping/tightness due to
NEUROLOGICAL disorders
o Spasticity:
 Hyperexcitability of alpha motor neurons in the spinal cord
 Can be due to:
 Loss of normal inhibition
 Imbalance of excitatory and inhibitory neurotransmitters
 Antispasticity drugs work by altering neurotransmitter activity both in the
CNS and at neuromuscular junctions
o Antispasticity drugs are designed for SYMPTOMATIC treatment
 Meaning they are meant to improve the patient’s quality of life and allow
them to perform basic activities and functions
 They are NOT designed to treat the underlying disease/condition
o How to manage spasticity (order of progression):
 Remove or treat the noxious stimuli
 Physical/occupational therapies including proper positioning and regular
stretching
 Oral drug therapy
 Injection of botulinum toxin type A
 Intrathecal baclofen
 Surgical intervention
o Spasticity is associated with the muscle stretch reflex arc
 A muscle fiber in the periphery undergoes stretching, which activates
stretch receptors in the muscle fiber
 These stretch receptors send sensory information via afferent fibers to
the spinal cord (specifically the dorsal horn of the gray matter)
 Within the gray matter of the spinal cord are numerous interneurons
 These interneurons receive the sensory information from the stretch
receptors, integrate and process the information, deciding the
appropriate response
 The interneurons can then release glutamate (an excitatory
neurotransmitter) that in turn acts on the motor (efferent) neuron in the
ventral horn, placing it in an excited state

The motor neuron, being excited, causes muscle contraction at the
effector muscle, resulting in the spasticity characteristic of the patient
o Baclofen:
 MOA:
 binds to GABA-B receptors on the presynaptic terminal of
interneurons in the spinal cord; GABA-B is a metabotropic
receptor (coupled to a G-protein)
 causes hyperpolarization of the membrane, meaning it is now
more difficult to reach threshold and fire an action potential
 no action potential means no Ca++ influx, which means no
neurotransmitter release; therefore the motor neuron is not
excited
 Widely distributed, crosses the blood-brain barrier
 1ST LINE MEDICATION USED TO TREAT SPASTICITY!
 Adverse Effects:
 Drowsiness
 DO NOT ABRUPTLY WITHDRAW (as it can cause hallucinations,
seizures)
 Use with caution in patients with seizures or renal impairment, as
it lowers the threshold for seizures (making it easier to have one)
 Can be given orally or through an intrathecal pump
 Intrathecal administration: pump is placed between muscle/skin
of abdomen w/catheter running into subarachnoid space
 Allows direct drug access to CNS
o Diazepam
 MOA:
 Binds to GABA-A receptors (Cl- channels) at both the pre and
postsynaptic neurons in the spinal cord and brain
o Specifically binds at the benzodiazepine site, keeping the
Cl- channel open longer
 Cl- influx into the neurons, causing hyperpolarization, leading to
decreased chance of generating an action potential and
decreased neurotransmitter releases
 Has quick onset of action (15-30min)
 Is metabolized by CYP450 in the liver
 Three of its metabolites are active!
 Has numerous drug interactions
 Has long elimination half-life (48hrs)

Adverse effects:
 Sedation, impaired mental/psychomotor function
 Anterograde amnesia: you have trouble forming new memories
 Physical dependence and withdrawal (high abuse potential)
 Crosses the placenta (don’t give to pregnant women)
o Tizanidine
 MOA:
 Binds to alpha-2 adrenergic receptors on the presynaptic neuron
(interneuron) to inhibit spinal motor neurons
 Has a LOW bioavailability due to extensive hepatic first pass metabolism
 Metabolized in the liver by CYP1A2
 Avoid taking w/ciprofloxacin as this is an inhibitor of CYP1A2,
meaning tizanidine will hang around in the patient’s system
longer
 Use with caution in patients with renal insufficiency as clearance of the
drug will be reduced by 50%
 i.e. the drug will remain in their system longer
 Adverse effects:
 Dose-related hypotension, sedation, dry mouth
 Avoid abrupt withdrawal as it can cause rebound hypertension
o Dantrolene
 MOA:
 Acts WITHIN the skeletal muscle
 Binds to receptors on the sarcoplasmic reticulum, preventing
release of Ca++ from the SR in response to increased intracellular
Ca++ concentrations
 w/o release of Ca++ from the SR, no muscle contraction takes
place
 Well absorbed, metabolized in liver via CYP450
 DRUG OF CHOICE FOR TREATING MALIGNANT HYPERTHERMIA
 Characterized by: high fever, tachycardia, hypertension, rigidity
 Adverse effects:
 Hepatotoxicity w/chronic use
o Dalfampridine
 MOA:
 Broad-spectrum K+ channel blocker that increases action
potential conduction through a demyelinated axon
 Excreted via urine essentially unchanged


Adverse effects:
 Contraindicated in patients with renal dysfunction (creatinine
clearance of less than 50ml/min) and in patients with history of
seizures
o Lowers seizure threshold
o Botulinum toxin type A
 MOA:
 Works at the neuromuscular junction, blocking the release of ACh
from the presynaptic neuron into the synaptic cleft
o Specifically functions by degrading the protein SNAP-25,
needed for the presynaptic vesicle containing the ACh to
fuse with the presynaptic membrane
 No ACh release means no muscle contraction
 Given intramuscularly for spasticity, such as that seen with cerebral palsy
 Takes about 1 week for effect to start (b/c you have to degrade the
SNAP-25 proteins) but lasts for about 3 months
Antispasmodic agents
o Used to prevent minor muscle spasms related to use/activity; also used to treat
lower back pain
o Typically what most patients think of when they hear the term “muscle relaxant”
o Big indications for usage: low back pain, tension headaches
 However, they are NOT 1ST LINE THERAPY CHOICES
 Instead, BEGIN WITH ACETAMINOPHEN AND NSAIDS!!!
o Pharmacology is UNKNOWN (is why they shouldn’t be used right off the bat)
 They do NOT act on motor neurons or the muscle
 However, they are known to be CNS depressants and therefore cause
sedation
o Chlorzoxazone
 Undergoes extensive phase II metabolism in the liver
 Serves as a substrate for numerous CYP450 enzymes and is also an
inhibitor of certain CYP450 enzymes
 As such it has NUMEROUS DRUG INTERACTIONS
 Adverse effects:
 RED OR ORANGE URINE
 Contraindicated in patients w/hepatic dysfunction
o Reasoning: since chlorzoxazone undergoes extensive
hepatic metabolism, if the patient’s liver function is
impaired, the drug won’t be adequately metabolized,
therefore it will have a prolonged effect
o Cyclobenzaprine
 Undergoes complete oral absorption
 A majority binds to proteins
 Serves as a substrate for certain CYP450 enzymes
 Be on the lookout for drug interactions
 Eliminated via urine and bile
 Reveals the most evidence for efficacy
 Adverse effects:
 Tachycardia, hypotension, drowsiness
 Dry mouth, urinary retention (anticholinergic effects)
 Avoid w/serotonergic agents
 Incidences of QT prolongation and possible torsade de pointes
have been seen alongside fluoxetine (a CYP450 2D6, 3A4
inhibitor)
o Cyclobenzaprine is a substrate for CYP450 2D6 and 3A4
o Therefore if you take cyclobenzaprine alongside
fluoxetine, the fluoxetine inhibits the enzymes responsible
for metabolism of cyclobenzaprine, leading to longer
duration of activity of cyclobenzaprine
o Metaxalone
 Undergoes hepatic metabolism
 Is a CYP450 substrate for certain forms and an inhibitor of others
o Look for drug interactions!
 Eliminated via kidney
 Adverse effects:
 Leukopenia (decreased WBC); hemolytic anemia (rare; decreased
RBC)
 Contraindicated in those with impaired renal/hepatic function
o Methocarbamol
 Widely distributed throughout the body
 Undergoes first pass metabolism in the liver
 Eliminated renally 3 days after the first dose
 Adverse effects:
 Black/brown/green urine
 Avoid in pregnancy as fetal abnormalities have been found
o Orphenadrine





Readily absorbed via GI tract
Widely distributed throughout the body
Hepatic metabolism; renal elimination
Elimination half-life of 14-16 hours (long)
Adverse effects:
 Drowsiness
 Dry mouth, urinary retention, increased intraocular pressure
o Anticholinergic effects
 Contraindicated in glaucoma, myasthenia gravis
o Carisoprodol
 Aka Soma
 Is metabolized to meprobamate, a controlled substance w/physical and
psychological dependence
 No better than any other skeletal muscle relaxants
 DO NOT USE!!!!!
o Be aware with all antispasmodic agents of SEDATION
 Advice your patients to use caution when driving or operating heavy
machinery
o Evidence of effectiveness of antispasmodic agents
 They are effective in acute low-back pain and roughly equivalent to
NSAIDS (which is why you should administer NSAIDS first)
 We are not sure whether the pain relief effects are due to muscle
relaxation or simply the sedation caused by the drug
 Using a skeletal muscle relaxant ALONGSIDE an NSAID is better than
using either one alone