dh206: pharmacology chapter 4: autonomic drugs lisa mayo, rdh, bsdh copyright © 2011, 2007 mosby,...

DH206: PharmacologyChapter 4: Autonomic Drugs

Lisa Mayo, RDH, BSDH

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.


Objectives1. Review of nervous system

2. ANS

3. ANS Anatomy Review

4. ANS Drugs Overview

5. PANS Drugs

6. SANS Drugs


Objective #1 Review of Nervous System


Nervous System Primary function: control & coordinate the activity of all the systems

in the body Elaborate system that functions in both conscious and unconscious

levels 2 subdivisions

1) CNS Brain & spinal cord oReceive information from afferent nervesoInitiates appropriate responses via efferent nerves

2) PNS: Peripheral Nervous System (next slide) 12 pairs cranial nerves, 31 pairs spinal nerves 2 subdivisions: somatic & visceral based on the type of

muscle to which these nerves innervate


PNS Subdivisions PNS

1. Somatic Division Branches of cranial & spinal motor nerves that innervate

skeletal muscle CONSCIOUS CONTROL

2. Visceral Division (ANS): this chapter covers Visceral nerves are the branches of the cranial and spinal

motor nerves that innervate cardiac & smooth muscle (involuntary) internal organs & glands

UNCONSCIOUS CONTROL Nerves regulated by hypothalamus & medulla oblongata Visceral nerves commonly called ANS 2 subdivisions: Parasympathetic & Sympathetic


Objective #2: ANS


ANS Function: regulate organs (either ↑ or ↓ their activity)

ALL organs have PANS & SANS receptors Practice of medicine and dentistry greatly benefitted from the

understanding of the ANS Relies on neurotransmitters (NTs) & receptors to cause a response NT: synthesized in the neuron & stored in axon

When an AP occurs – NT released into synapse – eventually bind to target organs in the body

Results in either excitation or inhibition of the organNT removed: degradation by enzymes, or through “reuptake” NT used in ANS: Norepi, ACHOther NT’s: epi, dopamine, serotonin, GABA

Referred to as catecholamines


ANS Receptors

Receive NTs from axon terminalsLocated on the dendrites of POSTganglionic neurons

or smooth muscle, cardiac muscle, glands


ANS Divisions

1. PANS: parasympathetic autonomic nervous system Also known as the craniosacral division

2. SANS: sympathetic autonomic nervous system Also known as the thoracolumbar division

Most organs receive a nerve from each divisionException: blood vessels do NOT receive PANS

○ Why BP is controlled by SANS drugs & not PANS drugs

○ Decrease stimulation = vasodilation○ Increase stimulation = vasoconstriction


ANS: PANS Active during periods of rest & restoration of body

energy stores Increase body functions (ex: digestion, waste

elimination) When PANS activated: only select nerves can be

stimulated (unlike SANS) and confined to particular body systemsEx: urination


PANS


ANS: SANS Innervates blood vessels (PANS does not) When SANS engaged, the whole body is stimulated (unlike PANS) Fight-or-Flight

Adrenal medulla releases epi, some norepi into blood

↓Catecholamines act as hormones

↓Travel to all sympathetic receptors

↓Produce intense stimulation

↓Increase activity: heart rate, bronchodilationDecrease activity: GI and urinary tracts


SANS


ANS: PANS vs SANSMajority of time: actions produced are opposites

SANS stimulates radial smooth muscles → increase in pupil size (dilation)○ Dilated pupils are termed mydriasis

PANS stimulates circular smooth muscles → decrease in pupil size○ Constricted pupils are termed myosis


ANS

Body Effects in text found p.34, Table 4-1


Objective #3ANS Anatomy Review


ANS: Anatomy ReviewPeripheral motor (efferent) nerves

Branches of nerves that travel from brain/spinal column to organs

Neurons that emerge from the spinal column are called PREGANGLIONIC NERVE FIBERS

Neurons that travel from the ganglion to the organs are called POSTSYNAPTIC NERVE FIBERS

SYNAPSE: space between the preganglionic and postganglionic fibers


Synapse


ANS: Anatomy Review

Main pharmacological difference between PANS & SANS is the NT released from nerve endings

PANS: ACH, ACH SANS: ACH, Norepinephrine

Nerves that release ACH = cholinergic nerveNerves that release Norepi = adrenergic nerve


Cholinergic nerve

Cholinergic nerve

Cholinergic nerve

Adrenergic nerve


ANS: Anatomy ReviewSummary

Effects of SANS produced by1) Norepi released from adrenergic nerve endings

2) Epi released from the adrenal medulla

○ Both norepi & epi stimulate adrenergic receptorsEffects of PANS produced when ACH which binds to

cholinergic receptors○ 2 main types of cholinergic receptors (both stimulated by

ACH)

1. Muscarinic: Located POSTganglionic junction PANS

2. Nicotinic: Located PREganglionic junction PANS & SANS


ANS: Anatomy Review

Cholinergic Receptors

1. Muscarinic Located on cell membranes of visceral organs and

glands (PANS innervated) – stimulated by ACH released from POSTGANGLIONIC nerve endings

2. Nicotinic: 2 types receptors (nerve & muscle)

1) Nn: on both PANS and SANS ganglion & stimulated from ACH released from PREGANGLIONIC nerve endings to conduct impulses across autonomic ganglion to POSTGANGLIONIC fibers of both divisions (see next slide)

2) Nm: Part of Somatic, not ANS (skeletal muscles)


ANS: Anatomy ReviewAdrenergic Receptors (SANS): divided into alpha(α) & beta (β) receptors

α Receptor Locations Action

Alpha-1 smooth muscles ( GI system, sweat glands, eye)

Vasoconstriction arteries/veinsContract eye muscles

Alpha-2 POSTganglionic neurons

Called autoreceptors

↓ release norepi↓ BP↓ secretion insulin↓ eye secretion


ANS: Anatomy Review

Adrenergic Receptors (SANS): divided into alpha(α) & beta (β) receptors

β Receptor Locations Action

Beta-1 Cardiac tissue Positive chronotrophic effects (↑ heart rate)Positive inotropic effects (↑ contractibility/strength)

Beta-2 Smooth muscle of bronchioles, skeletal muscles, blood vessels of heart/kidney

BronchodilationVasodilation


ANS: General Rules for α & β1. α-receptor activation = generally excitatory or

stimulating (vasoconstriction, uterine contraction) EXCEPT intestinal relaxation

2. β-receptor activation generally inhibitory/relaxing EXCEPT heart which stimulates

3. Epi released by adrenal medulla – activates both α and β but more potent on β-2 (higher affinity for those receptors)

4. Norepi acts on ALL α and only some β. Chiefly a vasoconstrictor.

5. β-1 predominate in the heart & blood vessels


NBQ

Which of the following neurotransmitters is released from sympathetic postganglionic neurons?

a. Dopamine

b. Serotonin

c. Acetylcholine

d. Norepinephrine


NBQ

Which of the following neurotransmitters is released from sympathetic and parasympathetic preganglionic neurons?

a. Dopamine

b. Serotonin

c. Acetylcholine

d. Norepinephrine


Objective #4ANS Drugs Overview


Autonomic Drugs

All drugs are either agonist or antagonist @ cholinergic & adrenergic receptors

AGONISTSympathomimetic / Parasympathomimetic

ANTAGONISTSympatholytic / Parasympatholytic

Certain ANS drugs are used in dentistryVasoconstrictors added to local anesthetic Drugs used to ↑ or ↓ salivary flow


AUTONOMIC DRUGS

PANSCholinergic (Parasympathomimetic) Agents P+Anticholinergic (Parasympatholytic/Cholinergic P-

blockers) Agents SANS

Adrenergic (Sympathomimetic) Agents S+

Adrenergic Blocking (Sympatholytic/ S- Sympathetic blockers) Agents


Autonomic Drugs: p.36-384 drug groups of the ANS

1. A drug that stimulates the PANS is called P+ (cholinergic or parasympathomimetic)

2. A drug that blocks the PANS is called P– (anticholinergic, parasympatholytic, or cholinergic blockers)

3. A drug that stimulates the SANS is called S+ (sympathomimetic or adrenergic)

4. A drug that blocks the SANS is called S– (adrenergic blockers, sympathetic blockers, or sympatholytic)


Objective #5PANS Drugs


PANS DRUGS: p.38-43

1. Cholinergic (parasympathomimetic) agents○ Produce the effects of PANS (see handout)

2. Anticholinergic (parasympatholytic) agents○ Produce effects opposite the PANS (see handout)


PANS: General Inactivation of ACH

Achieved through hydrolysis by certain enzymes (this occurs quickly so the effects of ACH last only a few seconds)

1. Enzyme located in the area of the cholinergic receptor – ACETYLCHOLINESTERASE (yields metabolites of choline & acetic acid)

2. Enzyme PSEUDOCHOLINESTERASE is located in liver & plasma that can hydrolyze ACH

Ex: Botox: inhibits the release of ACH from the cholinergic nerve ending to produce paralysis of skeletal muscle – only lasts 3mo


ACETYLCHOLINESTERASE choline & acetic acid metabolites

PSEUDOCHOLINESTERASEIn plasma/liver


PANS 1. Cholinergic Agents

Cholinergic agents are classified 2 ways:

1. Direct acting Bind to muscarinic/cholinergic receptor to produce

effects similar to those of ACH

2. Indirect acting (cholinesterase inhibitors) Inhibit enzyme acetylcholinesterase to produce effects

similar to those of ACH

p.36-38



1. Direct acting Not useful drugs because of its extremely short duration of

action Actions: see handout for heart, kidney, GI, eye effects Ex: Pilocarpine (stimulate saliva, decrease intraocular

pressure)

2. Indirect actingWhen cholinesterase enzyme deactivates in the synaptic gap

– then ACH can build up because the enzyme is not there to destroy it = ↑ concentrations of ACH at the receptor site

Subdivisions (based on duration of action)

1) Reversible inhibitors: NOT tightly bound to receptors

2) Irreversible inhibitors: bind irreversibly to receptors


p.36, Table 4-3USE THESE TABLES FOR REFERENCE, NOT BOOK

Myasthenia gravis

NEED TO KNOW WHOLE GRAPH: USES, DRUG NAMES, CLASSIFICATION!

CHOLINERGIC PARASYMPATHOMIMETIC DRUGSTYPE DRUG USES

Direct Acting Bethanechol(Urecholine)

Pilocarpine (Salagen)

Urinary retention

Glaucoma, Xerostomia

TYPE CLASS DRUG USES

Indirect Acting Irreversible

Reversible

Chemical Warfare (sarin)

Physostigmine(Antilirium)Neostigimine(Prostigmin)Pyridostigmine(Mestinon)Donepezil(Aricept)Tacrine(Cognex)

GlaucomaMGMGAlzheimer'sAlzheimer's



Adverse reactions (excessive stimulation of PANS)SLUD (salivation, lacrimation, urination, defecation)Tx adverse rxns with pralidoxime or atropine

Tx reactions caused by several drugs: Physostigmine Pharmacologic Effects (see handout)


Contraindications1) Bronchial asthma: may cause asthma attack2) Hyperthyroidism: may cause atrial fibrillation3) Severe cardiac disease: reflex tachycardia may

exacerbate a severe cardiac condition4) Peptic ulcer: cholinergic agents stimulate gastric

acid secretion and increase gastric motility



Prevent the action of ACH at POSTganglionic endingsRelease of ACH is not blocked, but the receptor site is

competitively blocked by the anticholinergic

PANS 2. Anticholinergic Agents

p.38-40


Atropine, scopolamineLipid solubleLow doses: cause dry mouth, inhibit sweating



Pharmacological Effects

1. CNS effects ○ Drowsiness & sedation○ OTC doses: limited amts scopolamine & used as sleep aids○ Used in tx Parkinson’s disease & motion sickness

2. Exocrine Glands↓ sweatingDentistry: ↓salivation & create a dry field

3. Eye: mydriasis (dilation of the pupil) used during eye exams

4. RespiratoryRelax smooth muscle Ipratropium is an anticholinergic inhaler used to treat asthma

PANS 2. Anticholinergic (parasympatholytic) agents


Contraindications (see handout)Glaucoma (Only ANS class drug that is not safe to use

for pt’s with glaucoma)



Drug Interactions: Avoid using in drugs that also cause same adverse effects

SEE HANDOUT

Adverse effects important to dentistry Xerostomia: provide education


If pt using anticholinergic inhaler to tx asthma – need education on dry mouth


Which of the following receptors is stimulated when pilocarpine is taken?

a. Cholinergic nicotinic

b. Cholinergic muscarinic

c. Adrenergic alpha

d. Adrenergic beta

NBQ


Which of the following drugs may cause xerostomia?a. Epinephrine

b. Dopamine

c. Cevimeline

d. Atropine

NBQ


A patient has an extensive history. All of the following drugs can cause xerostomia as an adverse effect EXCEPT which one?

a. Scopolamine

b. Pilocarpine

c. Homatropine

d. Atropine

NBQ


A patients has an extensive history. All of the following drugs can cause xerostomia as an adverse effect EXCEPT which one?

a. Scopolamine

b. Pilocarpine

c. Homatropine

d. Atropine

NBQ


Objective #6SANS Drugs


SANS DRUGS: p.40-45

1. Adrenergic (sympathomimetic) agents2. Adrenergic blocking agents3. Neuromuscular blocking drugs

Cholinergic nerveAdrenergic nerve


SANS: General

NTs in SANS: norepi(NE) and epinephrineNE: released at terminal nerve endings of the

SANSEpinephrine: released from adrenal medulla &

distributed via the bloodBoth NTs stimulate many internal organs to ↑

sympathetic activityEpi will relax smooth muscle, NE does not

○ Ex: epi used for bronchodilation, NE is not


SANS: General Adrenergic nerve ending takes up the amino acid tyrosine

↓

Then forms DOPA (dihdroxyphenylalanine) & dopamine

↓

Then converted to Norepi

↓

Norepi then stored within vesicles inside nerve endings

↓

When nerves are stimulated – NE released – travel to smooth & cardiac muscle – attach to their receptors – produce sympathetic response

↓

Then NE will reuptake back into nerve ending or destroyed by MONOAMINE OXIDASE enzyme

p.40


SANS: Generalα-Receptors

Alpha-1 adrenergic receptorsWhen stimulated by NE or Epi = cause

vasoconstriction○ Remember: PANS drugs have NO direct action

on arteries Alpha-2 adrenergic receptors

Drugs used in this category tx hypertension


Cholinergic nerve Adrenergic nerveα-2

α-1

HBP

Vasoconstriction

↓ NE


SANS: General-Receptors

Beta-1 receptors (memory trick - 1 heart)When stimulated = ↑ heart rate & force of contractionMetabolic effects on glycogen formation

(glycogenolysis) (NBQ) Beta-2 receptors (memory – 2 lungs)

When stimulated = produce vasodilation (mainly skeletal & cardiac) and bronchodilation

Drugs used in tx asthma


SANS: GeneralAlpha & Beta Receptors

2 divisions of drugs

1. Sympathomimetics/Adrenergic S+

Alpha & beta-agonists

2. Sympatholytics/Adrenergic Blocking S- Alpha, beta-blockersAntagonize or ↓ sympathetic activity


SANS: SympathomimeticSympathomimetic/Agonist drugs divided by their mechanism of action (just like PANS drugs)

1) Direct acting Bind to & activate α or β receptorsEx: catecholamines (Epi, NE, Dopamine,

Isoproterenol)2) Indirect acting

Not bind to receptorCause release NE from nerve endingsEx: Amphetamines (Adderall) & Cocaine

3) Mixed-ActingEphedrine & Pseudoephedrine(Sudafed) activate α1

& β2 receptors by direct & indirect methods


SANS: Sympathomimetic

Direct-Acting Agonists (next slides)1) α-adrenergic agonists2) β-adrenergic agonists


SANS: SympathomimeticAlpha-1 Agonist Drugs

α1 receptor drugs (cause contraction of smooth muscle)

Vasoconstrict blood vessels (can cause xerostomia)

Stimulate submax/subling salivary glands = thick, viscous saliva produced

Contract ocular muscles that cause dilation of the pupil (mydriasis)

Next slide for clinical indications


Clinical Indications α1 receptor drugsIV in hypotensive statesDilate pupils for eye exams Ocular decongestantsOpen nasal passages = ↑breathing

○ Used as nose drops & nasal sprays for their decongestant effect

○ Ex: phenylephrine(Neo-Synephrine), oxymetazoline(Afrin)○ Should not use more than 3-5 days due to re-bound

swelling & congestion that will occur



α1-agonist Clinical Use

phenylephrine(Neo-Synephrine) Nasal decongestant

oxymetazoline(Afrin) Nasal decongestant

Tetrahydrozoline(Visine) Ocular decongestant

Dipivefrin(Propine) Glaucoma

Norepinephrine(Levarterenol, Levophed) Hypotension, Shock

Epinephrine Prolong action local anesthetics

Levonordefrin Prolong action local anesthetics (not as potent as epi)

DIRECT ACTING α1-agonists



α2 receptor drugsUsed to tx hypertension by decreasing heart rateProtype drug = CatapresAdverse effects

○ Xerostomia○ Orthostatic hypotension


α2-agonist Clinical Use

Clonidine(Catapres) HypertensionWithdrawal from alcohol

Methydopa(Aldomet) Hypertension

DIRECT ACTING α2-agonists


SANS: Sympathomimetic

Direct-Acting Agonists (next slides)1) α-adrenergic agonists2) β-adrenergic agonists


SANS: SympathomimeticBeta Drugs

Most beta drugs have VERY FEW alpha effects (EXCEPT EPI)

Isoproterenol: Protype drugNon-selective drugProduce effects on heart (↑BP) & lungs

(bronchodilation) @ same timeNew drugs are selective – now can cause an

effect on the lungs & not the heart


Non-Selective β-agonist Clinical Use

Isoproterenol(Isuprel) Asthma

Isoetharine(Bronkosol) Asthma

Epinephrine(Adrenaline) Anaphylactic shockBronchodilatorVasoconstrictorIncrease BP

DIRECT ACTING Non-Selective β-agonists


SANS: SympathomimeticBeta Drugs

β1 selective drugsDobutamine (Dobutrex): ↑ myocardial contractility,

main use is in heart failure (IV) β2 selective drugs

Tx asthma through bronchodilationVasodilation of skeletal muscleCan inhibit uterine contractions (how preterm labor is

stopped) Terbutaline


β1-agonist Clinical Use

Dobutamine (Dobutrex) Stimulates heart

DIRECT ACTING Selective β1-agonists


β2-agonist Clinical Use

Albuterol(Ventolin, Proventil) Asthma

Terbutaline(Brethine) Asthma, Pre-term labor

Metaproterenol(Alupent, Metaprel) Asthma

Salmeterol(Serevent) Asthma

DIRECT ACTING Selective β2-agonists


Possess alpha & beta effects (β effects greater than α) Cannot give orally: enzymes would destroy it too quickly Alpha effects: vasoconstriction

Mydriasis, ↑BP, ↑heart rate, palpitations Beta effects

β1 stimulation: Tachycardia, cardiac arrhythmiasβ2 stimulation: Bronchodilator

○ Why is the drug of choice for anaphylaxis (bronchoconstriction)

Increases glycogenolysis (β-receptor)○ ↑ glucose production, release insulin = hyperglycemia

SANS: SympathomimeticEpinephrine


Epi in dental local anesthetic typically causes β2 responses

If use over 3-4 carpules = α1 responses will begin to occurEx: increase systolic BP (not diastolic, just systolic)

SANS: SympathomimeticEpinephrine


Which of the following receptors does epi in low dose primarily stimulate?

a. Alpha-1

b. Alpha-2

c. Beta-1

d. Beta-2

NBQ


NBQ

Epinephrine goes through biphasic response concerning BP. After the initial increase in BP, there is a decrease. This decrease in blood pressure is due to stimulation of which of the following receptors?

a. α1

b. α2

c. β1

d. β2


NBQ

In high doses that are used in anaphylactic shock, which of the following receptors does epi primarily stimulate?

a. α1

b. α2

c. β1

d. β2


SANS: GeneralAlpha & Beta Receptors

2 divisions of drugs

1. Sympathomimetics/Adrenergic S+

Alpha & beta-agonists

2. Sympatholytics/Adrenergic Blocking S- Alpha, beta-blockers Antagonize or ↓ sympathetic activity


SANS: Sympatholytics

Used in tx of:HBPUrinary retentionMigraine headachesGlaucoma

Therapeutic effects & adverse effects due to the blocking of alpha or beta receptors

Most all drugs are SELECTIVE – eliminate potential adverse effects


SANS: SympatholyticsAlpha-Blockers

Bind to alpha receptors to block actions of NE and Epi Pharmacological effects

1) Relaxation of smooth muscle bladder & prostate

2) Vasodilation

3) Decrease BP: can ↑ risk orthostatic hypotension Clinical Indications

1) Hypertension

2) Raynaud’s disease (poor blood flow to skin & extremities)

3) Prostate hyperplasia (enlarged prostate which interferes w/urinary flow through ureter)

4) Penile erectile dysfunction (α2)


α1-antagonist Clinical Use

prazosin (Minipress) Hypertension

doxazosin (Cardura) Hypertension

terazosin (Hytrin) Hypertension, prostate hypertrophy, urinary retention

Tamsulosin(Flomax) Prostate hypertrophy

phenoxybenzamine, phentolamine Raynaud's

DIRECT ACTING Selective α1-antagonists

α2-antaonist Clinical Use

Yohimbine(Aphrodyne) Penile erectile dysfunction

DIRECT ACTING Selective α2-antagonists


Adverse Effects: complete opposite of alpha effects Instead of pupil dilation, will see constriction (miosis) Nasal congestion instead of decongestion Increase GI activity Reflex tachycardia will occur if the BP is lowered too

much Orthostatic hypotension

SANS: SympatholyticsAlpha-Blockers


There are no therapeutic uses for blocking beta-2 receptors General names end in olol so it is easy to recognize them β1 blockers = most widely prescribed autonomic drugs! Clinical Indications

1) Hypertension

2) Angina

3) Heart arrhythmias

4) Panic attacks

5) Migraine headaches

6) Glaucoma

SANS: SympatholyticsBeta-Blockers



Antagonize the beta actions of NE and Epi Patients with HBP, angina, arrhythmias have

increased sympathetic activity

↓

If you can block the beta receptors with these drugs

↓

Then you reduce the effects Epi & NE

↓

Thus improve the patient’s heart issues by decreasing heart activity


1. Selective β-1 (best choice for asthmatic patients who have heart conditions) (NBQ) Protype drug: Atenolol (Tenormin) Fewer side effects, only affect heart, not lungs =

lower chance of drug interactions

2. Non-Selective (will block beta-1&2)

NEXT SLIDE



1. Selective Beta-1

2. Non-Selective (will block beta-1&2) Protype drug: Propranolol (Inderal) Block β1 & β2 (NBQ-never give to asthmatic!)

Block β1

Effect on heart: Reduce cardiac output & BP Effect on eye: Reduce secretions & intraocular pressure

Block β2

Effect on lungs: Bronchoconstriction in asthmatics Effect on liver: inhibit glycogenolysis, may cause

hypoglycemia in diabetics Contraindicated: asthma, diabetes



β1-antagonist/blocker Clinical Use

Metoprolol(Lopressor) Hypertension

Atenolol(Tenormin) Hypertension

Esmolol(Brevibloc) Hypertension

Bisoprolol fumerate(Zebeta) Hypertension

DIRECT ACTING Selective β1-antagonists

All end in ~olol


Non-selective β-antagonist/blocker Clinical Use

Naldolol(Corgard) Hypertension

Propranolol(Inderal) Hypertension

Timolol(Blocadren) Hypertension, migraines, MVP, tremors

DIRECT ACTING Non-Selective β-antagonists

All end in ~olol


MetabolismAtenolol is NOT lipid-soluble

○ Does NOT pass blood-brain barrier ○ Excreted unmetabolized by kidney

Propranolol is the most lipid-soluble β -blocker ○ Passes into the brain easily where it can exert pharmacological

effects

○ CNS sedation, mental depression, decreased central sympathetic activity which may contribute to the lowering of BP in tx of hypertension

○ Can tx secondary tachycardia associated w/ hyperthyroidism



NBQ

What is the best choice medication to use for a patient with angina pectoris and asthma?

a. Proanolol

b. Timolol

c. Labectalol

d. Atenolol


NBQ

Which of the following types of drugs is used in the treatment of nasal congestion?

a. B1-agonist

b. Selective B2-antagonist

c. Alpha-1-agonist

d. Alpha-2-agonist


NBQ

Which of the following pathways is activated in a “fight-or-flight” situation?

a. Adrenergic

b. Cholinergic

c. Adrenergic antagonist

d. Somatic nervous system

dh206: pharmacology chapter 4: autonomic drugs lisa mayo, rdh, bsdh copyright © 2011, 2007 mosby,...

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