Peripheral Nervous System Somatic Sympathetic adrenergic NE,
EPI, Ach Autonomic Parasympathetic cholinergic Ach
Slide 5
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Action Potential Na + Ca 2+ ACH Acetylcholinesterase Na +
Sympathetic Ganglionic Synapse Preganglionic neuronPostganglionic
neuron Nicotinic Receptor
Slide 8
9/10/2015 Action Potential Ca 2+ Na + NE Sympathetic Organ
Synapse G Effector Organ Postganglionic neuron Adrenergic
Receptor
Slide 9
9/10/2015 Action Potential Na + Ca 2+ ACH Acetylcholinesterase
Na + Parasympathetic Ganglionic Synapse Preganglionic
neuronPostganglionic neuron Nicotinic Receptor
Slide 10
9/10/2015 Action Potential Ca 2+ Na + ACH Acetylcholinesterase
Parasympathetic Organ Synapse K+K+ G Effector Organ Postganglionic
neuron Muscarinic Receptor
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Most organs receive dual sympathetic and parasympathetic
innervation However, some organs only receive sympathetic
innervation : Spleen Sweat Glands Piloerector Muscles Most Blood
Vessels Vascular smooth muscle is a prime example of a target organ
that does not have dual innervation Blood pressure and peripheral
resistance are controlled by the sympathetic nervous system
Slide 14
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General Features of Peripheral Autonomic Neurotransmission
Membrane Depolarization of Pre- or Postganglionic Fiber Calcium
Entry into Varicosity Exocytosis of NT Diffusion of NT Across
Neuroeffector Junction or Synapse Activation of NT Receptors
Depolarization of Postganglionic Fiber or Response of Effector Cell
Nerve Impulse
9/10/2015 Signal Transduction by 2 - and - Adrenergic
Receptors
Slide 24
9/10/2015 Nicotinic Receptors (Activated by nicotine from
tobacco) M 2 (Heart & SM) M 3 (Heart & SM) M 4 (SM &
Glands) M 5 (?) N M (Neuromuscular) N Autonomic ganglia, Adrenal
medulla & CNS (Blocked by Trimethaphan) (Blocked by
Tubocurarine) (Defined by Molecular Cloning) Muscarinic Receptors
(Activated by muscarine from Amanita muscaria) Cholinergic
Receptors: Receptors Activated by ACh M 1 (Nerve Cells)
Slide 25
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Slide 26
Formation of IP 3 Formation of DAG Release of Intracellular
Calcium Activation of PKC subunit Inhibition of Adenylyl Cyclase
Opening of Potassium Channels Activation of PLC GqGq Muscarinic
Receptors s ubunit GiGi
Slide 27
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Sympathetic: Contraction of radial muscle produces dilation
(mydriasis) Parasympathetic: Contraction of circular muscle
produces constriction (miosis)
Slide 30
9/10/2015Summary Peripheral NS consists of two types of
efferent nerves (Somatic nerves innervate skeletal muscle and
Autonomic nerves innervate visceral organs) Autonomic nerves are
classified as sympathetic or parasympathetic Autonomic preganlionic
neurons in the CNS and ALL parasympathetic postganglionic neurons
release acetylcholine (cholinergic) Virtually all sympathetic
postganglionic neurons release norepinephrine (adrenergic)
Exceptions: A few populations of sympathetic neurons (i.e. those
that innervate sweat glands) are cholinergic The adrenal medulla is
an endocrine gland that is innervated by sympathetic preganglionic
neurons and releases hormones, epinephrine and norepinephrine into
the blood stream Dual innervation occurs in many, but not all
target organs.
Slide 31
9/10/2015 SYMPATHOMIMETICS: Drugs that facilitate or mimic some
or all of the actions of the sympathetic nervous system Direct
Acting Indirect Acting Drugs that facilitate NE release Drugs that
block NE uptake -adrenergic agonists -adrenergic agonists
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9/10/2015
Slide 33
Adrenergic Agonists Direct-Acting: E and NE activate both and
receptors NE has a relatively low affinity for receptors
Phenylephrine (1 agonist) Clonidine (2 agonist) Dobutamine (1
agonist) Isoproterenol (1 = 2 agonist) Terbutaline (2 agonist)
9/10/2015 Dopamine
Indirect-Acting:EphedrinePhenylpropanolamineAmphetamine
Slide 34
Epinephrine (Adrenaline) 1 = 2 ; 1 = 2 Catecholamine
Synthesized in the Adrenal Medulla and released in the blood stream
Pharmacological effects - acts as an agonist at both alpha and beta
receptors Vascular effect - Dose specific - Low dose beta
stimulated vasodilation and high dose yields alpha stimulated
vasoconstriction 9/10/2015
Slide 35
Cardiac effects - beta1 - increased contractility (inotropic)
and rate (chronotropic) Increased systolic blood pressure and
decrease diastolic due to decreased peripheral resistance caused by
low dose beta 2 effect Respiratory - Bronchodilation due to beta 2
response Will relieve allergic or histamine induced constriction
Hyperglycemia - due to glycogenolysis in liver and increase release
of glucagon (Beta 2) and decrease release of insulin (alpha 2)
Slide 36
9/10/2015 Indications - Broncospasm, glaucoma (side effect is
mydriasis), anaphylactic shock, prolong local anesthetics due to
vasoconstriction, cardiac arrest Pharmacokinetics - Rapid onset,
brief duration, destroyed by COMT/MOA and metabolites excreted in
urine
Slide 37
9/10/2015 Adverse reactions CNS - anxiety, tension, headache
and tremor Increased blood pressure and possible cerebral
hemorrhage Cardiac arrhythmias Pulmonary edema - Causes peripheral
constriction and cardiac stimulation
Slide 38
9/10/2015 Norepinephrine (Levarterenol , Levophed ) 1 = 2 ; 1
>> 2 Pharmacological Effects - Mainly alpha effects when
given therapeutically which is contrary to the expected outcome
since it is the endogenous adrenergic neurotransmitter
Pharmacological Effects - Mainly alpha effects when given
therapeutically which is contrary to the expected outcome since it
is the endogenous adrenergic neurotransmitter Peripheral
Vasoconstriction, Increase in systolic and diastolic BP Peripheral
Vasoconstriction, Increase in systolic and diastolic BP Reflex
bradycardia Reflex bradycardia Indications - Some hypotensive
states such as shock but because it restricts blood flow to the
kidney, other medications like dopamine are better first line
agents Indications - Some hypotensive states such as shock but
because it restricts blood flow to the kidney, other medications
like dopamine are better first line agents
Slide 39
9/10/2015 Isoproterenol (Isuprel ) 1 = 2 >>> Synthetic
Catecholamine which is nonselective for beta receptors but little
alpha effects Synthetic Catecholamine which is nonselective for
beta receptors but little alpha effects Cardiac - increase rate and
contraction Cardiac - increase rate and contraction Decrease
peripheral resistance Decrease peripheral resistance Result is
decreased diastolic and little effect on systolic pressure Result
is decreased diastolic and little effect on systolic pressure
Bronchodilation Bronchodilation Indications Indications Heart
stimulation to increase rate and force in emergency situations
Heart stimulation to increase rate and force in emergency
situations Pharmacokinetics Pharmacokinetics Stable against MAO and
only a marginal substrate for COMT Stable against MAO and only a
marginal substrate for COMT
Slide 40
9/10/2015 Dopamine (Intropin ) Natural precursor to
Norepinephrine Natural precursor to Norepinephrine Can activate
alpha and beta adrenergic receptors and D1 and D2 dopaminergic
receptors (beta and dopamine effects at normal doses; alpha effects
at higher doses) Can activate alpha and beta adrenergic receptors
and D1 and D2 dopaminergic receptors (beta and dopamine effects at
normal doses; alpha effects at higher doses) Dopamine causes
vasodilatation in the renal vascular beds increasing blood flow to
the kidney Dopamine causes vasodilatation in the renal vascular
beds increasing blood flow to the kidney Pharmacological Actions
are dose dependent Pharmacological Actions are dose dependent alpha
1 alpha 2 B1 B2 DA alpha 1 alpha 2 B1 B2 DA 1-3mcg/kg/min - - 1 - 4
3-10mcg/kg/min 0/1 0 4 2 4 >10-20mcg/kg/min 3 0 4 1 0
Slide 41
9/10/2015 Cardiovascular Positive inotropic and chronotropic
effects due to Beta 1 activation (except at high doses where it
produces vasculature vasoconstriction due to Alpha stimulation
Cardiovascular Positive inotropic and chronotropic effects due to
Beta 1 activation (except at high doses where it produces
vasculature vasoconstriction due to Alpha stimulation Indications -
Shock Indications - Shock Adverse Effects Sympathetic stimulation
Adverse Effects Sympathetic stimulation
Slide 42
9/10/2015 Dobutamine (Dobutrex ) 1 > 2 >>>
Mechanism of Action Primarily a beta 1 agonist. Increases heart
rate and output with few vascular effects Mechanism of Action
Primarily a beta 1 agonist. Increases heart rate and output with
few vascular effects Considered a Beta 1 selective agent Considered
a Beta 1 selective agent Less likely to cause tachycardia than a
nonselective agent like isoproterenol (because of vasodilation)
Less likely to cause tachycardia than a nonselective agent like
isoproterenol (because of vasodilation) Indication Decompensated HF
by increasing output without increasing oxygen demand Indication
Decompensated HF by increasing output without increasing oxygen
demand
Slide 43
9/10/2015 Phenylephrine (Neo-Synephrine ) 1 > 2 >>>
Non-Catecholamine - so not destroyed by COMT Non-Catecholamine - so
not destroyed by COMT Mechanism of Action direct acting alpha
adrenergic that favors alpha 1 over alpha 2 Mechanism of Action
direct acting alpha adrenergic that favors alpha 1 over alpha 2
Effect Vasoconstrictor that increases systolic and diastolic
pressure, causes reflex bradycardia Effect Vasoconstrictor that
increases systolic and diastolic pressure, causes reflex
bradycardia Indication - Nasal decongestant, vasopressor for
hypotension, mydriatic, and systemically to raise BP Indication -
Nasal decongestant, vasopressor for hypotension, mydriatic, and
systemically to raise BP Available as Available as Nasal drop and
spray for use as a decongestant Nasal drop and spray for use as a
decongestant Systemic injection used to increase blood pressure
Systemic injection used to increase blood pressure
Slide 44
9/10/2015 Oxymetazoline (Afrin ) A direct alpha agonist A
direct alpha agonist Used as a topical decongestant Used as a
topical decongestant Available as nasal spray Available as nasal
spray Indicated for the short term (no longer than 3 days)
treatment of nasal congestion Indicated for the short term (no
longer than 3 days) treatment of nasal congestion
9/10/2015 Beta 2 Selective Drugs Beta 2 selective agents are
used in the treatment of asthma Beta 2 selective agents are used in
the treatment of asthma Used to relax broncho smooth muscle Used to
relax broncho smooth muscle Why are Beta 2 selective drugs now used
over epinephrine, ephedrine and isoproterenol? Why are Beta 2
selective drugs now used over epinephrine, ephedrine and
isoproterenol?
Slide 47
9/10/2015 Albuterol (Proventil , Ventolin ) Action - B2
selectivity Action - B2 selectivity Indication - Bronchodilator
Indication - Bronchodilator The inhaled versions produce the
greatest local effect on airway smooth muscle with the least
systemic toxicity. The inhaled versions produce the greatest local
effect on airway smooth muscle with the least systemic toxicity.
Place in therapy This is the fast acting bronchodilator of choice
in asthmatics Place in therapy This is the fast acting
bronchodilator of choice in asthmatics Pirbuterol (Maxair);
Bitolterol (Tornalate) Pirbuterol (Maxair); Bitolterol
(Tornalate)
Slide 48
9/10/2015 Salmeterol (Serevent ) Action - B2 Selectivity Action
- B2 Selectivity Long acting agent without a rapid onset Long
acting agent without a rapid onset Drug is not used as a rescue
inhaler like albuterol or pirbuterol. Used as a maintenance inhaler
to reduce the occurrence of bronchospasms Drug is not used as a
rescue inhaler like albuterol or pirbuterol. Used as a maintenance
inhaler to reduce the occurrence of bronchospasms Formoterol
(Foradil) Formoterol (Foradil)
Slide 49
9/10/2015 Terbutaline (Brethine , Bricanyl ) Action - B2
Selectivity Action - B2 Selectivity Available as an inhaler,
tablets and injection Available as an inhaler, tablets and
injection Uses Uses Bronchodilator (rarely) Bronchodilator (rarely)
Reduces uterine contractions in premature labor by relaxing uterine
smooth muscle Reduces uterine contractions in premature labor by
relaxing uterine smooth muscle
Slide 50
9/10/2015 Indirect-Acting Adrenergic Agonists MOA - Cause
norepinephrine release from presynaptic terminals MOA - Cause
norepinephrine release from presynaptic terminals Does not bind
directly to the postsynaptic receptors - work by releasing the
stores of natural neurotransmitters. Does not bind directly to the
postsynaptic receptors - work by releasing the stores of natural
neurotransmitters.
Slide 51
9/10/2015 Amphetamine Actions - CNS stimulant and
cardiovascular stimulant (increased BP and heart rate and
contraction) Actions - CNS stimulant and cardiovascular stimulant
(increased BP and heart rate and contraction) Mechanism of action
Releases catecholamines from presynaptic storage vesicles.
Mechanism of action Releases catecholamines from presynaptic
storage vesicles. Indications - narcolepsy, appetite control
Indications - narcolepsy, appetite control Adverse effects
Restlessness, tremor, irritability, insomnia, tachycardia,
hypertension Adverse effects Restlessness, tremor, irritability,
insomnia, tachycardia, hypertension
Slide 52
9/10/2015 Mixed Action Adrenergic Agonist MOA - Stimulate the
release of norepinephrine and directly activate adrenergic
receptors MOA - Stimulate the release of norepinephrine and
directly activate adrenergic receptors
Slide 53
9/10/2015 Ephedrine Nonselective agent (Similar to epinephrine
but less potent) Nonselective agent (Similar to epinephrine but
less potent) Long duration (not destroyed by COMT and resistant to
MAO) and orally available Long duration (not destroyed by COMT and
resistant to MAO) and orally available Actions - Increases blood
pressure, bronchodilation, enhances muscle contractility, CNS
stimulation (increased alertness, decreased fatigue and prevent
sleep) Actions - Increases blood pressure, bronchodilation,
enhances muscle contractility, CNS stimulation (increased
alertness, decreased fatigue and prevent sleep) Indications -
Asthma (rare), nasal decongestant (rare), hypotension, Indications
- Asthma (rare), nasal decongestant (rare), hypotension, Found in
the herbal medication Ma-huang Found in the herbal medication
Ma-huang
Slide 54
9/10/2015 Pseudoephedrine (Sudafed , Novafed ) A stereoisomer
of ephedrine A stereoisomer of ephedrine Actions decongestant
action due to stimulation of alpha receptors of the vascular smooth
muscle causing vasoconstriction Actions decongestant action due to
stimulation of alpha receptors of the vascular smooth muscle
causing vasoconstriction Indications - Nasal congestion Indications
- Nasal congestion Adverse effects Increased blood pressure and
heart rate and contraction Adverse effects Increased blood pressure
and heart rate and contraction
Slide 55
Adrenergic Antagonists (Blockers) These drugs inhibit to
adrenergic receptors Alpha Blockers Beta Blockers 9/10/2015
Slide 56
Alpha Adrenergic Blocking Agents Reduce blood pressure by
reducing sympathetic tone of blood vessels resulting in decreased
peripheral vascular resistance Will cause reflex tachycardia and
postural hypotension Decrease tone in smooth muscle of bladder neck
resulting in improved urine flow in benign prostatic hyperplasia
(BPH) Diagnosis and treatment of pheochromocytoma 9/10/2015
Slide 57
Alpha 1 Blockers Adverse Reactions First Dose Effect -
Exaggerated hypotensive effect that can lead to syncope especially
when patient stands after sitting or lying down (orthostatic or
postural hypotension) Suggest the first dose be taken at night or
reduce the amount of the first dose Nasal congestion, headache, and
drowsiness 9/10/2015
Slide 58
Prazosin (Minipress ) Actions Selective alpha 1 competitive
blocker Effects - Decreased peripheral vascular resistance to lower
BP and relax bladder neck smooth muscle Indications Hypertension
and BPH (not FDA approved) 9/10/2015
Slide 59
Terazosin (Hytrin ) and Doxazosin (Cardura ) Similar actions
and effects to prazosin but they have a longer duration of action
9/10/2015
Slide 60
Tamsulosin (Flomax ) Treatment of BPH - Alpha1(1A selectivity)
blocker that has specific action on bladder sphincter and less on
the vasculature Indicated for BPH not for the treatment of
hypertension 9/10/2015
Slide 61
Phenoxybenzamine (Dibenzyline ) Actions - Non-selective alpha
blocker that binds irreversibly and non-competitively to alpha 1
and alpha 2 presynaptic receptors Effects - Reduces blood pressure
by inhibiting vasoconstriction Not good for maintenance therapy due
to reflex tachycardia and increased cardiac output Indication -
Treatment of Pheochromocytoma 9/10/2015
Slide 62
Pheochromocytoma A tumor usually in the adrenal medulla that
releases large amounts of epinephrine and norepinephrine Signs
include hypertension, tachycardia and arrhythmias Diagnosed usually
confirmed by discovering an excessive amount of catecholamine
metabolites in the urine Surgical removal of the tumor is the best
treatment Drug therapy with alpha blocker (phenoxybenzamine) and
beta blockers may be required before surgery to control
hypertension 9/10/2015
Slide 63
Phentolamine (Regitine ) Actions - Competitive alpha 1 and
alpha 2 blocker that also blocks serotonin and acts as an agonists
at muscarinic and histamine receptors. Indications Historically
used to diagnose Pheochromocytoma Extravasation of vasoconstrictive
agents 9/10/2015
Slide 64
Beta Adrenergic Blockers Competitive antagonists that block the
effects of catecholamines at beta receptors Nonselective - B1 and
B2 effects B1 selective Cardioselective Lower blood pressure
without causing orthostatic hypotension because they do not affect
the vasculature. Uses Hypertension, angina, cardiac arrhythmias,
MI, CHF, glaucoma, and migraine prevention, essential tremor
9/10/2015
Slide 65
Beta Blockers Cardiovascular Reduce blood pressure by combined
effects on the heart (negative inotropic and chronotropic effects)
Reduction in the effect of the renin-angiotensin system Peripheral
vasoconstriction - reflex response because of decreased cardiac
output. Overall result still a decrease in systolic and diastolic
pressure (probably due to renin release) Bronchoconstriction -
Result of B2 receptor blockade (Beta blockers are contraindicated
in asthma) 9/10/2015
Slide 66
Beta Blockers Eye Reduce intraocular pressure by reducing
production of aqueous humor Metabolic and endocrine effects Beta
blockers (especially Beta 2 blockers) inhibit the bodys ability to
recover from hypoglycemia by inhibiting lipolysis and
glycogenolysis They mask signs of hypoglycemia Use with caution in
diabetics 9/10/2015
Slide 67
Propranolol (Inderal ) A non selective beta blocker Available
in various oral forms and as a parenteral injection Uses Migraine
prophylaxis Various cardiac uses however Beta 1 selective agents
are now used to a greater extent. Pheochromocytoma - used in
conjunction with alpha blockers Hyperthyroidism Essential tremor
9/10/2015
Slide 68
Beta 1 Blockers used for their cardiac function Beta 1
selective agents primary beta blockers used for treatment of
hypertension Safer than non-selective agents in patients with
asthma, diabetes or peripheral vascular disease but still must
consider benefits vs. risks Atenolol (Tenormin) Oral tablets 25, 50
and 100mg tablets & inj; once a day dosing Metoprolol
(Lopressor) Oral tablets 50, 100mg tabs, extended release 50, 100
and 200mg Toprol XL tabs & injection 1mg/ml - The extended
release tablets have indication for CHF 9/10/2015
Slide 69
Other Beta Blockers Nadolol (Corgard) Non selective beta
blocker with a long half life (long duration of action). Esmolol
(Brevibloc) Beta 1 selective agent that is noteworthy due to its
short half-life (10 minutes). Used in situations such as surgery or
the treatment of critically ill patients where quick dose changes
may be needed. Available only as an injection. 9/10/2015
Slide 70
Beta Blockers with ISA ISA is Intrinsic Sympathomimetic
Activity - another term for partial agonist Bind to a receptor and
cause a weak response (less than that produced by endogenous
neurotransmitters). May be useful in patients who can not tolerate
the other beta blockers because of bradycardia, inability to
recover from hypoglycemia or bronchoconstriction Acebutolol
(Sectral) is a B1 selective agent with ISA Pindolol (Visken) is a
non-selective agent with ISA 9/10/2015
Slide 71
Drugs for Glaucoma Multiple medication classes used to treat
glaucoma- several are autonomic drugs Alpha 2 adrenergic agonists
(Apraclonidine) [Iopidine]; (Bromonidine) [AlphaganP] Topical
carbonic anhydrase inhibitors (Dorzolamide) [Trusopt] Beta blockers
(Betaxolol, Timolol) Prostaglandin analogs (Latanoprost) [Xalatan]
Cholinergic agonists - Direct (Pilocarpine) Sympathomimetics
(Dipivefrin) 9/10/2015
Slide 72
PARASYMPATHOMIMETICS (CHOLINOMIMETICS): Drugs that facilitate
or mimic some or all of the actions of the parasympathetic nervous
system Muscarinic receptor agonists Anticholinesterases
Slide 73
9/10/2015 Direct Cholinergic Agonists
EstersMethacholineCarbacholBethanecholAlkaloidsMuscarinePilocarpine
Alkaloids are not metabolized by cholinesterases
Slide 74
9/10/2015
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Slide 76
Cholinesterase Inhibitors Slow or prevent degradation of ACh
released into synapse Reversible inhibitors (water soluble)
EdrophoniumNeostigminePhysotigminePydridostigmine Irreversible
inhibitors Organophosphates (lipid soluble/cross BBB)
ParathionSomanSarin Atropine in treatment of organophosphate
poisoning
Slide 77
9/10/2015 Direct Cholinergic Agonists (Cholinomimetic)
Bethanechol (Urecholine ) Resistant to acetylcholinesterase MOA
stimulate cholinergic receptors causing contraction of bladder
detrusor and sphincter relaxation Indication Urinary retention
after surgery or postpartum Adverse affects sweating, salivation,
flushing, decreased blood pressure, nausea, abdominal pain,
diarrhea and bronchospasm Contraindications Physical obstruction
and asthma Oral tablets and injection for subcutaneous use
Slide 78
9/10/2015 Glaucoma (Current page 161-163) A condition of
increased intraocular pressure (IOP) 2% of individuals over 40 have
glaucoma Open Angle Glaucoma Aqueous humor outflow is constantly
subnormal, Gradual and asymptomatic onset Angle-Closure Glaucoma
Results from closure of the anterior chamber angle causing severe
pain and vision loss. No abnormal resistance to aqueous humor
outflow, Medical emergency with acute onset
Slide 79
9/10/2015 Pilocarpine (Isopto Carpine, Ocusert) MOA -
Contraction of ciliary muscle attached to the trabecular meshwork
to enhance aqueous humor outflow IOP decreases in 1 hour Adverse
reactions Miosis (reduced night vision), decreased far vision and
brow aches Products Ophthalmic: 0.25 10% drops, 4% ointment and
Oral pilocarpine (Salagen ) is used to treat xerostomia (dry mouth)
Ophthalmic: 0.25 10% drops, 4% ointment and Oral pilocarpine
(Salagen ) is used to treat xerostomia (dry mouth) Place in therapy
Historically an initial treatment of choice for glaucoma but has
been replaced by newer agents Indicated for both angle-closure and
open-angle glaucoma
Slide 80
9/10/2015 Cholinesterase Inhibitors Indirect Cholinergic agents
Acetylcholinesterase cleaves acetylcholine to acetate and choline
both in the pre and post synaptic cleft. Inhibiting enzyme prolongs
the duration of endogenous acetylcholine Agents divided into two
categories Reversible Inhibitors that compete with cholinomimetic
substrates for acetylcholinesterase binding sites Reversible
Inhibitors that compete with cholinomimetic substrates for
acetylcholinesterase binding sites Most of the agents that have
therapeutic applicationsMost of the agents that have therapeutic
applications Irreversible Inhibitors that permanently bind with
acetylcholinesterase Irreversible Inhibitors that permanently bind
with acetylcholinesterase Most of these agents are used as
Insecticides or nerve agentsMost of these agents are used as
Insecticides or nerve agents
Slide 81
9/10/2015 Physostigmine (Antilirium ) Mechanism of action -
binds with acetylcholinesterase and prevents it from destroying
acetylcholine prolongs action of Ach Indications Treatment for
anticholinergic overdose (atropine, tricyclics and phenothiazines)
Adverse reactions - Can enter CNS and cause convulsions in high
doses Can enter CNS and cause convulsions in high doses Vomiting,
salivation, and bradycardia from systemic use Vomiting, salivation,
and bradycardia from systemic use Miosis and allergic irritation
from ophthalmic use Miosis and allergic irritation from ophthalmic
use Injection
Slide 82
9/10/2015 Neostigmine (Prostigmin ) Mechanism of action
Anticholinesterase agent that does not enter CNS Clinical
Indication antidote for neuromuscular blockers, myasthenia gravis
and GI and urinary tract retention Adverse reactions salivation,
flushing, decreased BP, diarrhea Available systemic injection
Slide 83
9/10/2015 Pyridostigmine (Mestinon, NAPP) MOA: Reversible
anticholinesterase Used for myasthenia gravis treatment more often
than neostigmine due to its longer duration of action Fewer side
effects than neostigmine in myasthenia gravis Available as oral
tablets & syrup; injection
Slide 84
9/10/2015 Edrophonium (Tensilon ) Clinical indication diagnosis
of myasthenia gravis More rapidly absorbed and shorter duration of
action than neostigmine
Slide 85
9/10/2015 Irreversible Anticholinesterases (Cholinesterase
Inhibitors) Toxins, Poisons, Nerve agents, Insecticides Permanently
inactivates acetylcholinesterase enzymes requiring the synthesis of
new enzyme molecules Antidote = Pralidoxime / 2 PAM Chloride
(Protopam) will reactivate cholinesterase most reactivation occurs
at neuromuscular junction (prolonged use results in paralysis) most
reactivation occurs at neuromuscular junction (prolonged use
results in paralysis) Atropine (an anticholinergic agent) in
conjunction with Pralidoxime for muscarinic effects Atropine (an
anticholinergic agent) in conjunction with Pralidoxime for
muscarinic effects
Slide 86
9/10/2015 Echothiophate (Phospholine) Irreversible
anticholinesterase used to treat glaucoma Side effects are similar
to pilocarpine
Slide 87
9/10/2015 Other Agents Use in Alzheimers not ANS drugs;
cholinesterase inhibitors that work on the CNS to treat mild to
moderate Alzheimers Mechanism of action Increase cerebral
concentrations of acetylcholine by inhibiting acetylcholinesterase
Tacrine (Cognex)- First agent approved Donepezil (Aricept)
Galantamine (Reminyl) Rivastigmine (Exelon)
Slide 88
9/10/2015 General Toxic Effects Direct acting cholinergic
agonists Muscarinic symptoms - Vasodilation (flushing), sweating,
bradycardia, bronchoconstriction, GI distress, belching, nausea and
vomiting, diarrhea, salivation Muscarinic symptoms - Vasodilation
(flushing), sweating, bradycardia, bronchoconstriction, GI
distress, belching, nausea and vomiting, diarrhea, salivation
Nicotinic symptoms All the above and convulsions, coma, respiratory
arrest, hypertension and cardiac arrhythmias Nicotinic symptoms All
the above and convulsions, coma, respiratory arrest, hypertension
and cardiac arrhythmias Anticholinesterase Agents
(Organophosphates) Signs of acute intoxication Signs of acute
intoxication Same as the symptoms above but miosis (reduction in
pupil size) also occurs as wellSame as the symptoms above but
miosis (reduction in pupil size) also occurs as well
Slide 89
9/10/2015 Cholinergic Antagonists (Ch 9) May be referred to as
cholinergic blockers, cholinoceptor-blocking drugs, anticholinergic
drugs, antimuscarinic Antinicotinic Ganglionic Blockers, little
therapeutic use Ganglionic Blockers, little therapeutic use
Neuromuscular Blockers, used as muscle relaxants Neuromuscular
Blockers, used as muscle relaxants
Slide 90
9/10/2015 Antimuscarinic Agents Block muscarinic receptors on
the effector organs parasympathetic nervous system and on sweat
glands (exception from sympathetic system) Specificity for
muscarinic receptors is key reason behind their usefulness because
they have little effect at skeletal neuromuscular junction or
autonomic ganglia
Slide 91
9/10/2015 Atropine Sulfate General Pharmacological Effects - A
belladonna alkaloid competitively blocks muscarinic receptors from
acetylcholine - ability to cross the CNS Indications Eye -
Diagnostic use only - Causes mydriasis (pupil dilation) and
cycloplegia (inability to focus). Increases intraocular pressure in
patients with glaucoma Eye - Diagnostic use only - Causes mydriasis
(pupil dilation) and cycloplegia (inability to focus). Increases
intraocular pressure in patients with glaucoma GI - Antispasmodic
agent for GI tract and bladder - Reduces motility and slightly
reduces hydrochloric acid secretion. GI - Antispasmodic agent for
GI tract and bladder - Reduces motility and slightly reduces
hydrochloric acid secretion. Antidote for cholinergic agonists -
organophosphate overdoses Antidote for cholinergic agonists -
organophosphate overdoses Cardiovascular applications
Cardiovascular applications Adverse Reactions - (autonomic)- dry
mouth, blurred vision, dry eyes, tachycardia, and constipation;
(CNS) - confusion, and hallucinations
Slide 92
9/10/2015 Belladonna Alkaloid Belladonna alkaloid means the
drug is derived form plant (Atropa belladonna)
Slide 93
9/10/2015 Atropine Cardiovascular Effects Atropine is used in
Bradycardia First drug used for symptomatic sinus bradycardia
Bradycardia First drug used for symptomatic sinus bradycardia
Improves sinus node and atrioventricular node conduction by
inhibiting vagal activity Cardiovascular effects vary depending on
dose both tachycardia and bradycardia (low dose) are possible. both
tachycardia and bradycardia (low dose) are possible. At normal
doses it blocks vagal slowing resulting in tachycardia. At normal
doses it blocks vagal slowing resulting in tachycardia.
Slide 94
9/10/2015 Anticholinergic Contraindications Contraindications -
Narrow angle glaucoma, Tachycardia, GI or GU Obstructive disease,
Myasthenia gravis, Asthma (Atropine only) Myasthenia gravis -
Anticholinergics contraindicated however (Atropine and
propantheline) may be used in conjunction with Anticholinesterase
medications to reduce GI side effects Atropine in asthma - Systemic
absorption and CNS penetration results in side effects and
toxicity
Slide 95
9/10/2015 Scopolamine Belladonna alkaloid with similar
peripheral effects and greater CNS effects compared to atropine
Indications Motion Sickness Motion Sickness Surgery; block
short-term memory, reduce the flow of saliva (antisialagogue).
Atropine also used for this purpose but does not cause the amnesia
effect Surgery; block short-term memory, reduce the flow of saliva
(antisialagogue). Atropine also used for this purpose but does not
cause the amnesia effect Adverse Reactions - Similar to atropine:
drowsiness (17%), dry mouth (67%), blurred vision, pupil dilation.
Wash hands after handling patch.
Slide 96
9/10/2015 Ipratropium (Atrovent ) Indication Bronchospasm
Available as an inhaler, solution for nebulization, and nasal spray
(for rhinorrhea) Bronchodilation - caused by inhibiting cyclic
guanosine monophosphate in the lungs
Slide 97
9/10/2015 Ganglionic Blockers No selectivity - block receptors
on both the parasympathetic and sympathetic ganglia Rarely used
therapeutically Nicotine can act as a ganglionic blocker at high
doses Low doses ganglionic stimulation causing euphoria and
arousal. It also causes relaxation, and improves attention Low
doses ganglionic stimulation causing euphoria and arousal. It also
causes relaxation, and improves attention High doses ganglionic
blockade (depolarization blockade) causing respiratory paralysis
and hypotension High doses ganglionic blockade (depolarization
blockade) causing respiratory paralysis and hypotension
Slide 98
9/10/2015 Neuromuscular Blocking Drugs Nicotinic receptors on
the neuromuscular skeletal muscle junctions Antagonists
(nondepolarizing) Antagonists (nondepolarizing) Agonists
(depolarizing) Agonists (depolarizing) Indication Surgery to
produce complete muscle relaxation
Slide 99
9/10/2015 Nondepolarizing blockers Tubocurarine - Developed
from Curare - used to by Amazon hunters to paralyze game.
Competitive blocker - action reversed by increasing concentration
of acetylcholine with cholinesterase inhibitors (neostigmine,
edrophonium and pyridostigmine) MOA Low dose - Combine with
receptor and prevent ACh binding. Overcome by increasing
concentration of acetylcholine (ie. Physostigmine) Low dose -
Combine with receptor and prevent ACh binding. Overcome by
increasing concentration of acetylcholine (ie. Physostigmine) High
doses- the ability of acetylcholine reversal is reduced due to the
blockage of the end plates High doses- the ability of acetylcholine
reversal is reduced due to the blockage of the end plates
Nondepolarizing agents - pancuronium and vecuronium
Slide 100
9/10/2015 Depolarizing Agents Attaches to nicotinic receptor
and depolarizes Succinylcholine duration of action is short
Indication - Rapid Intubation Adverse Effects Malignant
hyperthermia
Slide 101
9/10/2015Review Cholinergic agents Direct (act like ACh) Direct
(act like ACh) Bethanechol (urinary retention)Bethanechol (urinary
retention) Pilocarpine (glaucoma)Pilocarpine (glaucoma) Indirect
(take out AChe) Indirect (take out AChe) Reversible Physostigmine,
Neostigmine, Pyridostigmine, EdrophoniumReversible Physostigmine,
Neostigmine, Pyridostigmine, Edrophonium Diagnosis/tx of MG;
reversal of NMBs; anticholinergic OD Diagnosis/tx of MG; reversal
of NMBs; anticholinergic OD Irreversible Nerve agents,
Echothiophate (glaucoma)Irreversible Nerve agents, Echothiophate
(glaucoma)
