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NEUROPHARMACOLOGY OF

AUTONOMIC NERVOUS SYSTEM


INTRODUCTION
Luis Mejia

Introduction to the Autonomic Nervous System


I. Peripheral nervous systems:
A. Somatic: voluntary; movement, breathing, posture
B. Autonomic: involuntary; visceral functions
1. Sympathetic nervous system (SNS): anatomical definition; not determined
by the transmitter released or its effects
2. Parasympathetic nervous system (PNS): anatomical definition
3. Non-adrenergic, noncholinergic (NANC): functional definition
4. Enteric: myenteric plexus (Auerbach plexus) and submucous plexus
C. The SNS and the PNS often subserve opposing physiological actions

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II. General organization: Almost all efferents leaving the CNS are cholinergic.
Figure 1.

Somatic
Various
levels of
spinal
chord

ACh
Skeletal
muscle

Parasympathetic
Varicosity
Craniosacral
spinal
chord

Pre

ACh

Post

Smooth muscle
Heart
Glands

Sympathetic
Thoracolumbar
spinal
chord

ACh

Pre

ACh

Post

NE

Smooth muscle
Heart
Glands
Kidney (DA)

ACh
Adrenal
medulla
Epi and NE

NE is norepinephrine; a.k.a. noradrenaline and levarterenol.


Epi is epinephrine; a.k.a. adrenaline. ACh is acetylcholine.
DA is dopamine.

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Figure 2.

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III. Cholinergic, noradrenergic, dopaminergic and nitrergic neurons


A. Distribution
1. Cholinergic
a. Motor neurons to skeletal muscle
b. Parasympathetic preganglionic neurons
c. Parasympathetic postganglionic neurons
d. Sympathetic preganglionic neurons
e. Sympathetic postganglionic neurons to sweat glands and skeletal vessels
2. Noradrenergic (a.k.a. adrenergic)
a. Most sympathetic postganglionic neurons
3. Dopaminergic
a. Sympathetic postganglionic neurons to renal vasculature smooth muscle
4. Nitrergic
a. Sympathetic(?) and parasympathetic(?) postganglionic

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IV. NANC mediators:


A. A number of other substances are released from nerve endings and act as
primary neurotransmitters, co-transmitters (more than one agent activates the
effector cell) or neuromodulators (the released substance modulates the
transmission process).
B. Released from efferent motor or afferent sensory nerves:
1. ATP, vasoactive intestinal polypeptide (VIP), substance P, neuropeptide Y
(NPY), other neuropeptides
C. NO: released from nitrergic nerves
V. Nerve terminology: based on transmitter released, not anatomical origin
A. Noradrenergic nerves: release NE
B. Cholinergic nerves: release ACh

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VI. Receptors involved in the actions of the neurotransmitters, co-transmitters


and neuromodulators in the peripheral nervous systems
A. Receptor subtypes
1. Based on relative affinities (potencies) for agonists or antagonists
Figure 3.

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B. Adrenoceptors: widespread distribution


1. -Adrenoceptors: mediate the actions of NE and Epi
a. 1: smooth muscle
b. 2: nerve terminals (i.e., prejunctional), smooth muscle, platelets
2. -Adrenoceptors: mediate the actions of NE and Epi
a. 1: heart
b. 2: smooth muscle
c. 3: lipocytes
3. Dopamine receptors: mediate the actions of dopamine
a. D1 - 4: renal vasculature
b. D2: prejunctional (nerve ending); smooth muscle
c. D5: brain
C. Cholinoceptors: mediate the actions of ACh
1. Muscarinic (muscarine): wide distibution
a. M1-5: smooth muscle, heart, glands, endothelium, nerve endings
2. Nicotinic (nicotine)
a. Nn: parasympathetic and sympathetic ganglia (autonomic)
b. Nm: skeletal muscle end plate (somatic)

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D. Purinoceptors: mediate the actions of ATP (P2X and P2Y) and adenosine (A1
A3)
E. Peptide receptors: mediate the actions of VIP, NPY, etc.; neurokinin receptors
F. Autoreceptors (prejunctional)
1. Many of the transmitters, co-transmitters and neuromodulators feed back onto
the nerve ending from which they are released and decrease or increase
transmitter release.
G. Heteroreceptors (prejunctional)
1. Receptors for non-transmitter substances that regulate neurotransmission.
H. NO: no receptors are involved in signalling
1. NO activates guanylate cyclase.
2. It can interact with free radicals and nitrosylate proteins.

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VII. Regulation of the cardiovascular system by sympathetic and


parasympathetic systems
A. Heart
1. Parasympathetic (cholinergic): rate and conduction velocity; innervation
extends to:
a. Sinoatrial (SA) node
b. Atria
c. Atrioventricular (AV) node
d. His-Purkinje system and ventricular myocardium: little effect
2. Sympathetic (noradrenergic): rate, conduction velocity, and contractility;
innervation extends to
a. SA node
b. Atria
c. AV node
d. Purkinje system
e. Ventricular myocardium
B. Blood vessels
1. Sympathetic (noradrenergic; dopaminergic)
a. Nearly all vascular beds
b. Skeletal muscle (dilation; cholinergic)
2. Parasympathetic (cholinergic) restricted to:
a. Facial: blush region
b. Uro-genital organs: sexual function
c. G.I. mucosa: digestion
d. Tongue and pharynx

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VIII. Receptors and innervation


A. Cells receiving innervation will contain receptors for the released transmitters/cotransmitters/neuromodulators.
B. Receptors may be present even though a cell is not innervated
1. Example: vascular endothelium and ventricular myocardium are not
innervated with parasympathetic nerves, but muscarinic receptors are present
and the cells will respond to administered muscarinic agonists.
C. Many drugs are designed to mimic, block or modify the effects of
neurotransmitters.

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IX. Selected effects of sympathetic and parasympathetic activation


A. Fight and flight; rest and digest
B. The SNS and PNS usually produce opposite effects when activated.
Table 1.
Effector

Noradrenergic nerves/
Sympathetic activity

Cholinergic nerves/
Parasympathetic activity

Iris/pupil

Dilate (contract radial dilator)


(Mydriasis)

Constrict (contract circular sphincter)


(Miosis)

Airways

Dilate (Epi)

Constrict

Intestine (enteric
nervous system)

Decrease tone and motility

Increase tone and motility

Blood vessels

Vasoconstriction

Vasodilation (skeletal; sympathetic)

Bladder

Contracts sphincter
Relaxes detrusor

Contract detrusor
Relaxes sphincter

Heart rate

Increase

Decrease

Myocardial
contractility

Increase

Sex organs

Ejaculation

Erection

Liver

Gluconeogenesis
Glycogenolysis

Nerve terminals

Decrease ACh release

Decrease NE release

Gall bladder
smooth muscle

Relaxation

Contraction

Salivary glands

Secretion*

Secretion*

Uterus (pregnant)
*Similar effects

Contracts*

Contracts*
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ANS EYES

Postganglionic
sympathetic neuron

Dilator
(radial smooth muscle)

(noradrenergic)
(adrenoceptors)

Sphincter
(circular smooth muscle)

Postganglionic
parasympathetic neuron

Pupil

(cholinergic)
(muscarinic receptors)

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Cholinergic Pharmacology I & II


Acetylcholine (Ach) release (botulism toxin)
Acetylcholinesterase (AChE) (cholinesterase inhibitors such as
donezepil & pyridostigmine)

Ach receptors
- nicotinic agonists (nicotine)
- nicotinic antagonists (succinylcholine & atracurium) @
skeletal muscle
- muscarinic agonists (bethanechol)
- muscarinic antagonists (atropine, scopolamine, tiatropium &
darifenacin)
bold = generic drug names for exam
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Functional classification based


on
transmitter

NE = nor-adrenergic
ACh = cholinergic

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Endocrine system: blood borne chemically


unique effectors (40+) induce breadth of specific
responses due to tissue-specific expression of
specific receptors
______________________________

Cholinergic nervous system:

One transmitter: Ach


tissue specificity due primarily to sitespecific release
Systemic drugs affecting the cholinergic
nervous system:
analogous to hormones (via blood no
site specific release)
development of Ach receptor selective
agonists & antagonists for
pharmacological therapy only
partially selective
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Cholinergic Pharmacology I & II


Acetylcholine (Ach) release (botulism toxin)
Acetylcholinesterase (AChE) (cholinesterase inhibitors
such as donezepil & pyridostigmine)

Ach receptors
- nicotinic agonists (nicotine)
- nicotinic antagonists (succinylcholine &
atracurium)
- muscarinic agonists (bethanechol)
- muscarinic antagonists (atropine,
scopolamine & darifenacin)

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ACh release
ACh:

Synthesized in nerve terminals & stored


in synaptic vesicles

Released into synaptic cleft by proteincoupled (SNARE) fusion of vesicles


with the pre-synaptic membrane
Released ACh is rapidly hydrolyzed by
acetylcholinesterase (AChE)
Choline released by the hydrolysis of
AChE is recycled by an active uptake
process in the pre-synaptic
membrane (no re-uptake of Ach)
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Formation of SNARE complex


(synaptobrevin, SNAP-25 &
syntaxin)
required for fusion of ACh granules
with membrane
botulism toxins degrade SNARE
protein(s) & prevent transmitter
release (not specific for
cholinergic nerves)

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different serotypes of botulism


(AG) cleave different SNARE
components
prevents adrenergic &
cholinergic (parasymp. &
somatic) transmitter release
Serotype A commonly
injected
(B also available)
Effects last ~3 months
regeneration dependent on
nerve re-sprouting
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FDA approved uses for botulism toxin A (Bo-Tox)


excessive underarm sweating (hyperhidrosis)
loss of control of neck muscles (cervical dystonia)
upper limb stiffness/spasticity
facial skin wrinkles
urinary incontinence due to overactive bladder (multiple site injections into
detrusor of bladder with visualization using cystoscopy)
un-coordinated eye alignment (strasbismus)
uncontrolled blinking of eyelids (blepharospasm)
__________________________________________
chronic migraine headaches (total of 31-39 i.m. injections
@ 7 sites on head & back of neck)
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botulism serotype A (Bo-Tox) toxicity:


-inappropriate skeletal muscle paralysis
- ex. uneven smile or eyelid control, difficulty swallowing,
urinary retention
-allergic reactions & possible decreased sensitivity with repetitious
therapy due to immune response
-reduced emotional sensitivity & cognition
(via impaired facial muscle signaling to brain?)

-honey contraindicated in infants 1 year of age


- insufficient C. botulinum inhibitory intestinal
flora in infants
- low concentration of C. botulinum inhibitory
bile salts
Therapy of systemic (Bo-Tox) toxicity: anti-toxin + respiratory
support
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Fate of Ach release: acetylcholinesterase


(AChE)

Released ACh is rapidly hydrolyzed(0.15m sec) by


acetylcholinesterase (AChE)

Motor neurons: AChE concentrated at post-synaptic end


plate

CNS, sensory & parasympathetic neurons: diffuse


distribution of AChE (pre- & post-synaptic membranes)

AChE inhibitors used therapeutically for Alzheimer's,


glaucoma, myasthenia gravis, GI & bladder motility,
insecticides & as chemical warfare agents

butyryl AChE (pseudocholinesterase) absent from


neurons, synthesized in liver & found in blood.
Sensitive to AChE inhibitors & used as a parameter
to assess poisoning by AChE inhibitors
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Hydrolysis of ACh by acetylcholinesterase (AChE)

Step 1

(CH 3 )3 N+ CH 2CH 2 OCCH 3

Step 2
(CH 3 )3 N+ CH 2CH 2 OH +

OH

an ioni c site esteratic si te

Step 3

O
CCH 3

OH2

O
CH 3 COH

an ioni c site esteratic si te

OH

an ioni c site esteratic si te

AChE consists of two sites: (1) an anionic site that attracts the positively-charged quaternary ammonium
group of ACh and (2) an esteratic site where the ester linkage is hydrolyzed.

Different classes of AChE inhibitors bind with different affinities to AChE


Specific congeners within a class can differ with respect to CNS penetration
CNS penetrating for Alzheimers
CNS excluded for myasthenia gravis, GI tract & urinary tract
dysfunctions

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Three classes of AChE inhibitors, based on duration


of interaction with AChE:
- 5-15 minutes, reversible, non-covalent
(edrophonium & donezepil)
- 30 min-6 hrs, covalent/reversible (neostigmine,
physostigmine & pyridostigmine &
carbaryl/Sevin**)
- 100 hours, covalent (ecothiophate*, malathion**,
sarin***)
* occular anti-hypertensive (open angle
glaucoma)
** insecticide
***chemical warfare

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Therapeutic uses of cholinesterase inhibitors

Alzheimers Disease

myasthenia gravis

GI atony & urinary retention

open angle glaucoma (local application)

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Why a cholinesterase inhibitor (donezepil or tacrine)


for Alzheimers Disease?
- early signs of memory & cognition associated with
loss of cholinergic fibers in cortex, hippocampus
and nucleus basalis
- characteristic side effects of CNS penetrating
anti-cholinergic drugs in otherwise normal individuals
are: memory & cognition

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AChE inhibitors for Alzheimers Disease


donezepil (Aricept) & tacrine (Cognex)
reversible (short acting, i.e. 5-15 min) AChE inhibitors
daily oral dosing; CNS penetration preferentially
inhibits CNS AChE
palliative therapy for mild Alzheimers Disease
- improved cognition & delayed symptomatic
progression for 2 years individual variation
- side effects
(N/V/D)
tacrine hepatotoxic monitor liver function
(donezepil preferred therapy)

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Rationale for AChE inhibitor use in myasthenia gravis:


disease is due to auto-immunity @ the nicotinic
ACh receptor on skeletal muscle
decreased post-junctional receptor concentration
results in diminished signaling
therapy with AChE inhibitors increase duration of ACh
in synapse greater response
however, excessive AChE inhibition flaccid paralysis
recommendation: individualize using single dose
increments to establish optimum
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AChE inhibitor use in myasthenia gravis:


Edrophonium:
reversible (short acting, i.e. 5-15 min) AChE inhibitor
excluded from CNS
given i.v. as a provocative test in differential
diagnosis of myasthenia gravis
diagnostic if skeletal muscle function improved

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pre- vs. post edrophonium if Myasthenia


Gravis

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Intermediate acting (30 min-6 hrs) covalent/reversible


inhibitors in myasthenia gravis
neostigmine:
orally active & excluded from CNS
- administered 2-4 hr intervals for myasthenia gravis
- also used to treat paralytic ileus & post-op
urinary retention
pyridostigmine:
orally active & excluded from CNS
- preferred to neostigmine for myasthenia gravis;
less potent, longer duration (6 hrs) ,
steadier benefit with less side effects

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AChE inhibitors for glaucoma

open angle glaucoma


- reduction in intra-ocular pressure by contraction of ciliary muscle & aqueous humor out-flow
- topical (conjunctiva) ecothiophate (long acting) daily
- potential for systemic effects
narrow angle glaucoma
- short-term drug induced constriction of pupil stretching iris relieved
blockage of sponge-like trabecular meshwork
- However, ecothiophate & other long acting AChE inhibitors may exacerbate angle closure; surgical therapy is preferred

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Other uses for organophosphate AChE (irreversible


inhibitors):
malathion: used for head lice & as an insecticide; selective toxicity to insects vs.

humans/animals due to little ( 10%) skin absorption & rapid rate of


detoxification (plasma carboxyesterases)
sarin: chemical warfare nerve gas; volatile absorbed through skin and
alveolar membranes; SLUDGE or DUMBBELLS response &
respiratory paralysis**
SLUDGE = salivation (S), lacrimation (L), urination (U), diaphoresis (D), GI motility (G) &
emesis (E)
DUMBBELLS = diarrhea (D), urination (U), miosis (M), bradycardia (B), bronchoconstriction (B),
excitation of skeletal muscles* (E); lacrimation (L), salivation (S) & sweating (S)

** skeletal muscle:
- modest AChE inhibition excitation and fibrillation
- excessive AChE inhibition leads to depolarization block &
flaccid paralysis

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Why flaccid paralysis (rather than tetany) with sustained


depolarized skeletal muscle membrane?
- after initial EPP muscle action potentials, muscle
sequesters Ca++ (relaxation)
- subsequent release of Ca++ (contraction) requires:
- dissociation of Ach from receptor,
- re-polarization of membrane,
- re-binding of Ach to receptor
- new action potential
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Toxicities of Acetylcholinesterase (AChE)


Inhibitors
eye: miosis, block of accommodation (near vs.
far)
salivation & lacrimation
GI tract: increased tone, motility (diarrhea) &
secretions.
urinary tract: incontinence
cardiovascular: bradycardia.
respiratory: bronchoconstriction & secretion
skin: sweating.
CNS: tremor, anxiety, confusion, convulsions &
coma

________________________________
skeletal muscles: loss of synchrony of
transmission, fasciculations, paralysis
(including diaphragm) by depolarizing block
cause of death

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Prevention/reversal of organophosphate effects


Pyridostigmine (same drug used in myasthenia gravis)
prevention (oral, q. 8 hrs)
as a weak AChE inhibitor, competes for irreversible binding by
war gas organophosphates
does not enter the CNS**
used as prophylaxis in 1990 during Persian Gulf War

linked to Persian Gulf War Syndrome of impaired cognition, ataxia,


weakness & incontinence. Possible synergism with insect
repellants & combusted organophosphates. Also, difficult to
distinguish from Post-Traumatic Stress Disorder.
(** conflicting evidence for increased CNS penetration with
stress in animal models)
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Prevention/reversal of organophosphate effects:


Pralidoxime (2-PAM) reversal:

binds to AChE and reactivates the organophosphate bound enzyme by


donating electrons (attacking) to the phosphate, cause inhibitor
to dissociate
doesnt enter CNS
must be given i.v. within 5 min; may be repeated in 20-60 min
early administration is necessary to prevent organophosphate from forming
more stable & different bond (aging)
post-aging , 2-PAM is ineffective

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Acetylcholine (Ach) release (botulism toxin)

Acetylcholinesterase (AChE) (cholinesterase


inhibitors such as donezepil & pyridostigmine)
Ach receptors
- nicotinic agonists (nicotine)
- nicotinic antagonists @ skeletal
muscle (succinylcholine &
atracurium)
- muscarinic agonists (bethanechol)
- muscarinic antagonists (atropine,
scopolamine & tiotropium)

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Cholinergic (ACh) Receptors in


Autonomic Nervous
System:
Pre-ganglionic synapse
nicotinic receptors @
ganglia
- agonist = nicotine
- antagonist =
hexamethonium
Post-ganglionic synapse:
muscarinic receptors
- agonist = muscarine
- antagonist = atropine
Cholinergic (ACh) Receptors in Somatic Nervous System:
nicotinic receptors @ skeletal muscle
- agonist = nicotine
- antagonist = curare

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ACh Receptors: Nicotinic Receptors

receptor is a Na ion channel with two


binding sites for Ach

Activation requires simultaneous


so for muscarinic)

Na ions enter and depolarize

Nicotinic receptors located on nerve (NN)


and skeletal muscle (NM)

Site of inhibitory action of many natural


toxins from plants (curare) &
animals (snake venoms)

Selective pharmacological antagonists


developed for nerve (NN) and
skeletal muscle (NM)

occupation (not

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Cholinergic antagonist at autonomic ganglia

Cholinergic agonist for ganglia & skeletal muscle

Cholinergic antagonist at skeletal muscle


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Nicotine
well absorbed from oral cavity (chewing tobacco) &
lungs (smoking)
CNS:
- stimulatory with activation of pleasure/reward
(dopamine)
- increased respiration (lethal effects via respiration)
- nausea/vomiting (chemo-receptor trigger zone
& vagal afferents)
CVS:
- increased HR & BP (sympathetic ganglia & adrenal
medulla)
GI:
- increased motility with N/V/D (parasympathetic activation)

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while there are many casual users of alcohol & cocaine,


few individuals who smoke cigarettes, smoke a small enough
quantity ( 5/day) to avoid dependence
(Goodman & Gilmans Pharmacological Basis of Therapeutics)

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Pharmacological therapy of nicotine dependence:


-nicotine containing gum or transdermal patch
-constant CNS ACh receptor stimulation to reduce high &
minimize withdrawal symptoms
- varenicline (Chantix)
- partial agonist @ ACh receptor (sub-optimal nicotine effects alone
& antagonism of exogenous nicotine)
- bupropion (Zyban & Wellbutrin)

- anti-depressant that dopamine & norepinephrine by blocking


neuronal re-uptake
Note: all avoid toxic effects of smoke & result in dopamine to alleviate craving

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Skeletal muscle endplate


(nicotinic receptor)
blocking drugs
- non-depolarizing (competitive)
- depolarizing

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Nicotinic Receptors & Neuromuscular Blocking Drugs:


Non-depolarizing (competition for Ach @ nicotinic receptor on skeletal muscle)
(note: effects can be reversed by AChE inhibitors)
isoquinolines
tubocurarine, atracurium, cisatracurium & doxacurium
steroid derivatives
pancuronium, vecuronium, pipecuronium & rocuronium
Depolarizing
succinylcholine
___________________________________________________
General points for both classes:
- neither significant CNS penetration nor effects on autonomic ganglia
- neither anesthetics nor analgesics; thus contraindicated in conscious
patient for surgery
- effects enhanced by anesthetics & Ca++ channel blockers
- administered i.v. for skeletal muscle relaxation
(surgery, electroconvulsive therapy or to facilitate intubation)

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Non-depolarizing (competition for Ach @ nicotinic receptor on skeletal


muscle)
Tubocurarine was prototype
- samples of poison darts used by S. Americans studied in
16th century
- mechanism discovered in 1850
- not orally active (eat meat from poison dart-killed meat)
- no CNS penetration
Newer drugs in this class (ex. atracurium) advantages vs. curare:
- rapid onset/shorter duration (3 min/45 min)
- less blockade of autonomic ganglia (BP & reflex
tachycardia) & muscarinic receptors (tachycardia)
- less histamine release (bronchospasm & secretion, BP)
- metabolized no significant renal clearance

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Cholinergic pharmacology

Succinylcholine:
- dimer of ACh
-more stable interaction with receptor (high affinity
& resistant to AChE)
- generates Phase I & possibly Phase II blocks
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Succinylcholine Phase I vs. Phase II block:


Phase I:
Initial transient muscle fasciculation (depolarization), then flaccid
paralysis in 1-2 min.
Single dose (i.v) effect @ 1-2 min. then dissipates within 10 min.
(dissociation & diffusion)

Phase II:
With multiple or high doses may progress to re-polarization with
characteristics of receptor sensitivity
(diagnosed in OR with nerve stimulation)
Duration of recovery from 12-30 min
Patients with myasthenia gravis more resistant to succinylcholine &
may progress directly to Phase II with single dose

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Succinylcholine plasma half-life depends on degradation


by plasma & hepatic pseudocholinesterase
(pAChE)
heterozygous atypical deficiency in pAChE duration of
recovery to ~ 30 min

1/2800 have homozygous atypical enzyme that is


inactive against succinlycholine
duration of recovery 4-8 hours
support respiration

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Life threatening risks of succinylcholine:


Hyperkalemia
- effects of prolonged depolarization lead to transient increased K efflux
- in patients predisposed to hyperkalemia, single dose can lead to cardiac arrest
Thus avoid use in severe trauma, burns, acidosis, patients taking
cardiac glycosides & K-sparing diuretics.
Malignant hyperthermia
-uncontrolled Ca++ release, contracture, rigidity, excessive heat, increase in skeletal
muscle oxidative metabolism, acidosis & tachycardia pharmacological therapy:
dantroline (blocks Ca++ release)

- genetic susceptibility (autosomal dominant) that is unmasked with


combination of anesthesia & succinylcholine
- masseter muscle rigidity may precede generalized phenomenon

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Succinylcholine
Other side effects
Cardiovascular (hyperkalemia or ganglionic effects can result in &
bradycardia or arrythmia children more susceptible)
Muscle pain
Increase intraocular pressure
Increase intragastric pressure
Increase intracranial pressure

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depolarizing vs. competitive antagonists @ skeletal


muscle nicotinic receptor:
Competitive antagonist (atracurium):
AChE inhibitors (ex. neostigmine, pyridostigmine or edrophonium) used by
anesthesiologists to reverse effect @ termination of surgery
Depolarizing blocker (succinylcholine):
Never combine with AChE inhibitor enhanced effect!
Avoid in hyper-reflexia of upper motor neuron injury
Myasthenia gravis:
- more sensitive to competitive antagonists
(atracurium)
- less sensitive to succinylcholine

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Cholinergic Pharmacology
Acetylcholine (Ach) release (botulism toxin)

Acetylcholinesterase (AChE) (cholinesterase inhibitors


such as donezepil & pyridostigmine)
Ach receptors
- nicotinic agonists (nicotine)
- nicotinic antagonists
(succinylcholine & atracurium)
- muscarinic agonists (bethanechol)
- muscarinic antagonists (atropine,
scopolamine & tiotropium)

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ACh Receptors: Muscarinic Receptors

5 subtypes (7-transmembrane-domain class of


receptors)

Stimulatory (M1,M3 & M5) in peripheral nerve,


gland/smooth muscle & CNS, resp:

ACh
PLC PI

M1, M3, M5
Gq
Ca ++

IP3

via G protein, hydrolysis of


phosphatidyl-inositol (PI), the release of
inositol triphosphate (IP3) and
diacylglycerol (DAG). IP3 triggers the
release of Ca from intracellular Ca stores and
DAG activates protein kinase

DAG
PKC

ACh

Inhibitory (M2 & M4) in heart & CNS, resp:


activation of M2 & M4 receptors inhibits
adenylyl cyclase and can
activate K channels
(hyperpolarize) in the heart.

A-C

M2, M4
Gi
Gbg

K+

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1st cholinomimetic studied


determined to be selective agonist
@ post-ganglionic sites in ANS
Found as natural (potentially lethal) product
in certain mushrooms & resistant
to AChE(s)

Selective muscarinic antagonist from the


shrub Atropa belladonna*
Italian for beautiful woman secondary to
dilated pupils

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Autonomic control at rest: Significance of


cholinergic innervation

No change in BP. Why?

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No cholinergic innervation to
arterioles
However, functional mucarinic
receptors on endothelium
Administration of ACh causes
dilation

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Although no cholinergic innervation to arterioles, ACh or other muscarinic agonists


cause dilation via endothelial derived relaxing factor (EDRF)

From Furchgott et al

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Nobel Prize in 1998 to Furchgott, Ignaro & Murad


for discovery of NO
Furchgotts discovery: EDRF (nitric oxide/NO)

Endothelial NO now known to be auto-regulator of vascular


resistance: shear stress dilation
Exogenous muscarinic agonists can stimulate NO synthesis
Smooth Muscle
Smooth muscle layer
Endothelium
NO
Lumen

M3

Endothelial cell layer

Nitroglycerin (NO donor) used since 1879 to alleviate angina


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Systemic administration of a muscarinic agonist acts on all of parasympathetic


systems to mimic/enhance above effects & in addition, causes vasodilation (BP) via
release of NO.
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Note: administer systemic muscarinic agonist ..have atropine present!Mejia

Core knowledge:
Drugs affecting endogenous cholinergic tone have potential effects on
systems (parasympathetic) below. No effect on vascular resistance.
Cholinergic agonists effect systems (parasympathetic) below and, in
addition, vascular resistance.

63
Mejia

Direct-acting Cholinomimetic Drugs:


ACh and Synthetic Choline Esters
Comparision of ACh and Synthetic Choline Esters
Acetylcholine

Methacholine

Carbachol

Structure

O
(CH3)3N+CH2CH2OCCH3

(CH3)3N+CH2CHOCCH 3
CH3

Bethanechol*
O

O
(CH3)3N+CH2CH2OCNH2

(CH 3 )3 N+ CH 2CHOCNH 2
CH 3

Degraded by both
cholinesterases

very rapidly

slowly

no

no

Nicotinic Agonist

++

+++

Muscarinic Agonist:
Cardiovascular
Gastrointestinal
Urinary bladder
Eye (topical)

++
++
++
+

++
++
++
+

+
+++
+++
++

insignificant CNS penetration of cholinomimetics listed above


* most commonly used

+
+++
+++
++

64

Bethanechol:
most commonly used muscarinic agonist
resistant to AChE
following oral or s.c., affects primarily GI & urinary tract
durations ~ 1 hr
the metabolic fate & mode of elimination of bethanechol
has net been elucidated

65
Mejia

Systemic exposure to a Muscarinic


agonist (bethanechol)
Cardiovascular system:

widespread vasodilation due to release of nitric oxide from the


vascular endothelium.
low-dose: reflex HR due to sympathetic reflex in
response to dilation of vasculature.
high-dose: direct muscarinic effects on heart to HR &
force of atrial contraction.
Gastrointestinal System (GI):

peristaltic activity of the stomach and intestines.


enhanced secretory activity
may produce nausea, belching, vomiting, intestinal cramps and
defecation.
66

Systemic exposure to a Muscarinic


agonist (bethanechol)
Respiratory System:

bronchoconstriction and increased tracheobronchial secretion

Skin:

increased sweating (due to activation of muscarinic receptors at sympathetic


synapses).

Urinary Tract:

increased ureteral peristalsis

promotes voiding of the bladder.

Eye:

iris: contraction of the pupillary muscle constricts the size of the pupil (miosis).

lens: contraction of the cilliary muscle produces accomodation to near focus.

67

Therapeutic uses of muscarinic agonists:


Note that due to lack of organ specificity
a specific therapeutic use may be contraindicated due
to a disease in another muscarinic-sensitive system
ex:
therapeutic use of bethanechol to stimulate micturition may
may be precluded if:
GI ulcers
asthma
cardiac arrhythmias
68
Mejia

Therapeutic uses of cholinomimetics (muscarinic agonists)


GI disorders (post-op abdominal distension, gastric atony):

- administer bethanechol orally before each meal


Urinary bladder disorders (post-op retention, dysfunctional detrusor/sphincer):
- acute therapy for retention: bethanechol s.c on empty stomach
- chronic use: bethanechol orally 2-4 times/day
Dry mouth (xerostomia):
- oral bethanechol
- cevimeline (Evoxac) orally selective M3 agonist (lacks CNS & cardiac effects,
but potential for N/V/D, sweating, blurred vision & headache)
Opthalomology (open angle glaucoma)
- occular instillation of pilocarpine (cholinomimetic similar to bethanechol)
69
Mejia

Outline: Cholinergic Pharmacology


Acetylcholine (Ach) release (botulism toxin)

Acetylcholinesterase (AChE) (cholinesterase


inhibitors such as donezepil & pyridostigmine)
Ach receptors
- nicotinic agonists (nicotine)
- nicotinic antagonists
(succinylcholine & atracurium)
- muscarinic agonists (bethanechol)
- muscarinic antagonists (atropine,
scopolamine & tiotropium)

70
Mejia

Therapeutic uses of muscarinic antagonists


Selective muscarinic antagonist from
the shrub Atropa belladonna

S. Europe & N. Africa


2-5 berries, can be lethal due to CNS effects
(respiratory & cardiac depression & coma)
71
Mejia

Therapeutic uses of muscarinic antagonists (competitive)


(all orally active except tiotropium; none are entirely organ system selective):
atropine: oral, s.c, i.m. or i.v. (hyperhidrosis, mydriasis, bradycardia during
resuscitation, certain heart blocks, enhanced imaging of GI tract,
inhalation for bronchospasm, therapy of organophosphate
poisoning)
scopolamine (greater CNS penetration than atropine; used as
transdermal patch as prophylaxis for motion sickness best ofthe antimuscarinics for motion sickness)
tiotropium (no CNS, not orally active; used as inhalation for asthma &
chronic obstructive lung disease; relative to atropine less accumulation of airway
secretions due to ciliary-dependent mucous clearance; few peripheral & CNS effects due to
restricted distribution)

72
Mejia

Therapeutic uses of muscarinic antagonists (competitive)


darifenacin* (& tolterodine, solifenacin & oxybutinin) - used
for urinary incontinence
* (relative to others in class, low CNS penetration - thus less
cognitive impairment, dizziness, anxiety)
pirenzepine (partial selectivity for intestinal ganglia; used for GI
ulcers to decrease proteolytic enzyme secretion)
trihexyphenidyl, benztropine & diphenhydramine used for antimuscarinic effects in the therapy of early Parkinsons
- orally active
- CNS therapeutic effect on substantia nigra
(greater effect on bradykinesia & tremor than
rigidity)
- CNS side effects of sedation & confusion as well as
peripheral manifestations

73
Mejia

Atropine (muacarinic receptor antagonist): rank order of


sensitivity:
salivary & sweat glands & bronchioles eye & heart urinary bladder & gut stomach
(sensitivity differences due to degree of functional cholinergic tone)

Site

Predominant Tone

Effect of Ganglionic Blockade

arterioles

sympathetic (adrenergic)

vasodilation; postural hypotension

veins

sympathetic (adrenergic)

vasodilation; decreased venous return

heart (SA node)

parasympathetic (cholinergic)

tachycardia

iris

parasympathetic (cholinergic)

mydriasis

ciliary muscle

parasympathetic (cholinergic)

cycloplegia

GI tract

parasympathetic (cholinergic)

reduced tone & motility; constipation;


abdominal discomfort; nausea

urinary bladder

parasympathetic (cholinergic)

urinary retention

salivary glands

parasympathetic (cholinergic)

dry mouth

sweat glands

sympathetic (cholinergic)

decreased sweating

ex: common side effects of scopolamine patch dry mouth, blurred


vision, drowsiness - no heart, urinary or GI problems
74

Atropine (anti-muscarinic) toxicity:


dry as a bone, hot as a hare, red as a beet, blind as a bat,
mad as a hatter & full as a flask
or
hot, dry, red & mad

high doses of atropine can enter the CNS & initially cause excitation
(restlessness, hallucinations, delirium), then progress to depression
(cardiac, respiration, coma, death)

75
Mejia

Cautions / Contraindications with anti-muscarinics (issue of lack of organ


specificity)
- Narrow angle glaucoma due to increased intra-ocular pressure & may
precipitate
attacks in predisposed use is OK in open angle
- External heat or fever
- Cardiac arrhythmias
- Reflux esophagitis ( relax esophageal sphincter & motility)
-Diarrhea due to infection
-Ulcerative colitis or other obstructive diseases ( motility may precipitate
toxic megacolon: dehydration, electrolyte loss & potential for shock)
- Obstructive uropathy (benign prostatic hypertrophy)

76
Mejia

Pharmacology of Noradrenergic Transmission


I. Characteristics of noradrenergic transmission
A. Architecture
B. Synthesis of neurotransmitter
C. Storage of neurotransmitter
D. Release of neurotransmitter
E. Activation of the effector cell
F. Termination of the response
1. Destruction (metabolism) of transmitter
2. Removal of transmitter

77
Mejia

II. Architecture, synthesis, storage, release and effector cell activation


Figure 1.

78
Mejia

Figure 2.

VMAT
VMAT = vesicular monoamine
transporter

79
Mejia

Norepinephrine, epinephrine and dopamine


are catecholamines:

HO

NH 2

HO

Figure 3.

80
Mejia

Figure 4.

VAMPS

SNAPS = synaptosomeassociated proteins


VAMPS = vesicle-associated
membrane proteins

SNAPS

81
Mejia

Figure 5.

VMAT = vesicular monamine


transporter

VMAT
NET

NET = norepinephrine
transporter

82
Mejia

III. Destruction/metabolism of transmitter


A. Catechol-O-methyl transferase (COMT)
1. Specific for catechols (phenolic rings with 2 adjacent hydroxyls)
2. O-methylates the meta hydroxyl in catecholamines
3. Locations (widespread):
a. Liver: most important site for metabolism by COMT
b. Metabolism of circulating catecholamines
4. Reduces potency by approximately 100-fold.
5. Chemistry
Figure 6.

OH
HO

COMT

HO

OCH 3

B. Monoamine oxidase (MAO)


1. Not very specific; metabolizes many types of amines (e.g., 5-HT)
2. Removes the amine from the -carbon, which abolishes agonist activity
3. Locations (widespread):
a. Noradrenergic nerve endings
i) Controls level of free catecholamines
b. Liver
i) Deaminates foreign amines, such as occur in food
ii) Metabolism of circulating catecholamines
4. Two isoforms: A and B
5. Chemistry
Figure 7.

O
N
H

CH3

MAO

OH
83
Mejia

C. COMT and MAO pathways


Figure 8.

OH

OH

HO

HO

OH

N
H

CH 3
OH

Nore pinephrine

Epine phrine

COMT
HO

MAO

OCH 3

OH

COMT

MAO
OH

OCH 3

HO
N
H

Meta nephrine

NH 2

HO

CH 3

OH

OH

OH
3,4 D ihydroxym andelic Ac id

COMT

MAO

NH 2

Norm etanephrine

MAO
HO

OCH 3
O
OH
OH

Vanillylma ndelic Ac id
84
Mejia

Figure 9.

HO
HO

NH 2
Dopamine

COMT

MAO
OH
HO

OCH 3
HO

NH 2

OH
Dihydroxyphenylacetic Acid

COMT

HO

3-Methoxytyramine

MAO
OCH 3
O
OH

Homovanillic Acid

85
Mejia

IV. Effects of pharmacological agents on noradrenergic neurotransmission


Table 1.
Agent

Step

Effect

Mechanism

Synthesis

Depletion of NE

Blocks tyrosine hydroxylase

Methyldopa

Synthesis

Depletion of NE

False transmitter; 2-selective

Cocaine, tricyclic
antidepressants

Termination

Potentiates NE

Blocks NET

Reserpine

Storage

Depletes NE (and
dopamine)

Blocks vesicular active


transport (VMAT)

Bretylium, guanethidine

Release

Inhibits NE release

Selective local anesthetic


effect (?)

Tyramine, amphetamine

Release

Causes NE release

Indirect-acting

MAO inhibitors
(phenylzine)

Termination

Little, but potentiates


tyramine

Enzyme inhibitor

COMT inhibitors
(Tolcapone)

Termination

Slight (affects
circulating CAs)

Enzyme inhibitor

- and -Adrenoceptor
agonists

Receptor

Elicit cell responses

Stimulate signal transduction

- and -Adrenoceptor
antagonists

Receptor

Inhibit agonist effects

Receptor blockade

Termination

Potentiate Epi

Inhibit extraneuronal uptake

-Methyltyrosine

Glucocorticoids

86
Mejia

Figure 10.

87
Mejia

Figure 11.

88
Mejia

Figure 12.

89
Mejia

Figure 13.

90
Mejia

Figure 14.

91
Mejia

Figure 15.

92
Mejia

IV. Effects of pharmacological agents on noradrenergic neurotransmission


Table 1.
Agent

Step

Effect

Mechanism

Synthesis

Depletion of NE

Blocks tyrosine hydroxylase

Methyldopa

Synthesis

Depletion of NE

False transmitter; 2-selective

Cocaine, tricyclic
antidepressants

Termination

Potentiates NE

Blocks NET

Reserpine

Storage

Depletes NE (and DA)

Blocks vesicular active


transport (VMAT)

Bretylium, guanethidine

Release

Inhibits NE release

Selective local anesthetic


effect (?)

Tyramine, amphetamine

Release

Causes NE release

Indirect-acting

MAO inhibitors
(Phenylzine)

Termination

Little, but potentiates


tyramine

Enzyme inhibitor

COMT inhibitors
(Talcapone)

Termination

Slight (affects
circulating CAs)

Enzyme inhibitor

- and -Adrenoceptor
agonists

Receptor

Elicit cell responses

Stimulate signal transduction

- and -Adrenoceptor
antagonists

Receptor

Inhibit agonist effects

Receptor blockade

Termination

Potentiate Epi

Inhibit extraneuronal uptake

-Methyltyrosine

Glucocorticoids

93
Mejia

Pharmacology of Adrenoceptors
I. Adrenoceptors
A. Receptors which are activated by sympathomimetic amines and catecholamines
1. Sympathomimetic amines (endogenous)
a. Epinephrine (Epi)
b. Norepinephrine (NE)
c. Dopamine (DA)
2. Catecholamines
a. Chemical designation
b. Compounds containing a catechol moiety
B. Adrenoceptors are large, 7-transmembrane spanning receptors
1. G-protein coupled receptors (GPCR)
a. Interact with endogenous agonists: Epi, NE and DA
2. Adrenoceptor agonist drugs mimic the actions of these substances on their
receptors
3. Antagonist drugs block the actions of the endogenous agonists

94

C. Types of adrenoceptors and subtypes


1. Alpha ( ) receptors
a. Epi NE >> Iso (Iso is isoproterenol, a synthetic catecholamine)
b. There are 2 major subtypes of -receptors
i.
1
ii. 2
c. There are 3 subtypes of 1-receptors (A, B, and D)
d. There are 3 subtypes of 2-receptors (A, B, and C)
2. Beta ( ) receptors
a. Iso > Epi NE
b. There are 3 major subtypes of -receptors
i.
1: Epi = NE
ii. 2: Epi > NE
iii. 3: Iso = NE > Epi
3. DA receptors
a. There are 5 subtypes of DA receptors (D1 - D5)
b. DA also stimulates 1-receptors

95
Mejia

II. Effects of activation of peripheral adrenoceptors


A. Actions of catecholamines and sympathomimetic amines
1. Cardiac: excitation
2. Smooth muscle: excitation
3. Smooth muscle: inhibition
4. Metabolic effects
5. Endocrine effects
6. CNS effects through peripheral reflexes
7. Presynaptic effects

96
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Table 1. Effects of activation of peripheral adrenoceptors by agonists


Primary
Response resulting from activation of the primary receptor
receptor
Cardiac
Increase contractility (+ inotropic)
1

Smooth
muscle

Increase heart rate (+ chronotropic)

Arrhythmias

Increased conduction velocity

Vasoconstriction (arterioles, pre-capillary sphincter,


veins)
Vasodilation (skeletal and visceral beds)
Intestinal relaxation

Presynaptic decrease ACh release


Relaxation of smooth muscle

Endocrine

Eye

Nerve
endings

some

B. Generalizations (Table 1 shows exceptions)


1. Most cardiac effects: 1
2. Most smooth muscle contractile effects:

2
2

G.I. sphincter contraction

Uterus:

Contraction
Relaxation
Urinary bladder: Contraction of sphincter
Relaxation of detrusor

Metabolic

1,

2
1
2

Sex organs: Ejaculation and detumescence

Pupillary dilation (constriction of radial muscle; mydriasis)

Contraction of ureter

Contraction of spleen

Pilomotor erection

Airway smooth muscle relaxation

Liver and muscle glycogenolysis

Lipolysis: Activation
Inhibition

Fat cells (activation of glycolysis)

Pancreas

(and ATP)

3.
4.
5.
6.

Most smooth muscle relaxant effects:


Most metabolic effects: 2
Most prejunctional effects: 2
Many inhibitory effects: 2

Stimulation of insulin secretion


Inhibition of insulin secretion

Renin release: Stimulation


Inhibition

Intraocular pressure :

Increase aqueous humor outflow


Decrease aqueous humor secretion
Increase aqueous humor secretion

Inhibit transmitter release


Facilitate transmitter release

2
2

97
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C. Prejunctional (presynaptic) receptors:

2,

, and D2

Figure 1.

98
Mejia

III. Effects of sympathomimetics and catecholamines in the cardiovascular system


A. Direct effects on the heart
1. Pacemaker and latent pacemakers
a. Increase phase 4 (diastolic) depolarization
b. Increase phase 0 depolarization
Figure 2.

2. Other cardiac cells


a. Shorten effective refractory period (ERP)
b. Shorten action potential duration (APD)
c. Increase [Ca2+]i contractility
3. Consequences:
a. HR
b. Conduction velocity
c. Contractility
d. Possible toxicity
i. Activation of latent (ectopic) pacemakers
ii. Shortened ERP
iii. Both can lead to arrhythmias
99
Mejia

B. Direct effects on vascular beds


1. NE: 1, 2, 1
2. Epi: 1, 2, 1, 2
3. Iso: 1, 2

Vascular bed

Table 2. Responses of vascular beds


Receptors
Epi
NE

Skin

1,

Splanchnic

1,

2,

Skeletal

1,

2,

Renal, coronary,
cerebral

D1

some
2

Iso

DA

Constriction

Constriction

None

Constriction

Constriction

Weak dilation -

Dilation*

Constriction

Dilation

Dilation

*Dose-dependent

Mejia

100

IV.

Determinants of mean arterial pressure: Hydraulic equation


Figure 3.

Mean arterial blood pressure

BP = CO X TPR
Cardiac
output

Heart
rate

Stroke
volume

Total
peripheral
resistance

Arteriolar
radius

Blood
Viscosity

Mejia

101

V. Influence of the sympathetic and parasympathetic nervous systems on blood


pressure
Figure 4.

Mejia

102

VI. Role of the baroreceptor reflex in homeostatic regulation of blood pressure


A. Stretch receptors
1. Carotid sinus and aortic arch
2. BP stretches the receptors
3. Firing of afferents to the CNS
4. Sympathetic neurons in the NTS are tonically active
Figure 5.

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103

VII. Vascular responses to sympathomimetic amines and catecholamines


A. Responses to i.v. bolus injection (1 g/kg)

Norepinephrine (an
Phenylephrine (PE; an

Isoproterenol (a

1,

and

agonist)

agonist)

agonist)
Epinephrine (an

(From the University of Washington, Seattle, WA with permission)

agonist)

Mejia

104

B. Responses to i.v. infusion

Norepinephrine

Isoproterenol

Epinephrine

(From the University of Washington, Seattle, WA with permission)

Mejia

105

C. Summary of infusion effects


Table 3. Cardiovascular effects of infusion of the four adrenoceptor agonists
Vascular Resistance
Agonist

Skin

Visceral Skeletal

Blood Pressure

Heart

TPR

Diastol

Systol

HR

Str. Vol.

CO

Iso

0,,

NE

0, ,

Epi

PE

0,,

0,,

*Dose-dependent

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106

VIII. Signal transduction pathways associated with - and -adrenoceptors


A. -Adrenoceptors

Figure 6.

Mejia

107

Figure 7.

B.

1-Adrenoceptors

Mejia

108

C.

2-Adrenoceptors

Figure 8.

Cell inhibition

Cell activation

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109

Pharmacology of Alpha-Adrenoceptor Antagonists


I.

Control of major peripheral systems by adrenoceptors


Figure 1.

TPR

TPR

Vasoconstriction

NE
Re le ase

1
M ydriasis

Adrenoceptors

1
Cardiac Effe cts

GI
M otility

Vasoconstriction

Inhibition
of
Lipolysis

3
2

Lipolysis

Vasodilation
TPR

A. The pharmacological effects of the - and -adrenoceptor antagonists can be


explained largely from knowledge of the responses elicited by - and -adrenoceptor
agonists in the different tissues and the effects of stimulation of the adrenergic nerves
innervating those tissues.
B. The antagonists inhibit responses to agonists and activation of adrenergic nerves.
C. The effects of receptor activation in the various tissues are reviewed next.

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110

Table 1. Effects of activation of peripheral adrenoceptors by agonists


Response resulting from activation of the primary receptor
Cardiac

Smooth
muscle

Metabolic

Endocrine

Eye

Increase contractility (+ inotropic)


Increase heart rate (+ chronotropic)
Arrhythmias
Increased conduction velocity
Vasoconstriction (arterioles, pre-capillary sphincter, veins)
Vasodilation (skeletal and visceral beds)
Intestinal relaxation: Presynaptic decrease ACh release
Relaxation of smooth muscle
G.I. sphincter contraction
Uterus: Contraction
Relaxation
Urinary bladder: Contraction of sphincter
Relaxation of detrusor
Sex organs: Ejaculation and detumescence
Pupillary dilation (constriction of radial muscle; mydriasis)
Contraction of ureter
Contraction of spleen
Pilomotor erection
Airway smooth muscle relaxation
Liver and muscle glycogenolysis
Lipolysis: Activation
Inhibition
Fat cells (activation of glycolysis)
Pancreas:
Stimulation of insulin secretion
Inhibition of insulin secretion
Renin release: Stimulation
Inhibition
Intraocular pressure: Increase aqueous humor outflow
Decrease aqueous humor secretion
Increase aqueous humor secretion

Nerve endings Inhibit transmitter release


Facilitate transmitter release

Primary receptor
1
1
1
1

1,

some

2
2
2
1
1
2
1
2
1

(and ATP)

1
1
1
1
2
2
1
2
3
2
2
1

2
2
2

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111

II.

Affinities of -Adrenoceptor Antagonists for Adrenoceptors


Table 2
Antagonist

Selectivity

Phentolamine

High

High

Very low

Very low

Phenoxybenzamine

High

High

Very low

Very low

Prazosin

High

Low

Very low

Very low

Yohimbine

Moderate

High

Very low

Very low

Propranolol

Very low

Very low

High

High

Metoprolol

Very low

Very low

High

Moderate

Butoxamine*

Very low

Very low

Moderate

High

High

Low

High

Moderate

Labetalol
* no real clinical role

Blue cells = -adrenoceptor-selective antagonists; yellow cells = -adrenoceptor-selective antagonists

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112

Antagonism
Duration of
action
Selectivity

Table 3. Effects of -adrenoceptor antagonists


Imidazolines
Quinazolines*
-haloalkyamines
Phentolamine
Prazosin (Minipres)
Phenoxybenzamine
(Regitine)
Terazosin (Hytrin)
(Dibenzyline)
Doxazosin (Cardura)
Alfuzosin (UroXatral)
Nonequilibrium
Equilibrium competitive
Equilibrium competitive
competitive
Long (days)
Moderate (hrs)
Moderate (hrs)
1

>

Other actions

1. Inhibits ACh, 5-HT and


histamine receptors
2. Blocks NET and
extraneuronal uptake

Hemodynamic
effects

1. TPR and BP
2. Venodilation
3. Cardiac stimulation:
a. Baroreceptor reflex:
increase in HR and
contractility
b. Increase in NE
release

Adverse
reactions

1. Orthostatic
hypotension
2. Tachycardia
a. BR reflex
b. 2 block: NE rel.
3. Miosis
4. Nasal stuffiness
a. 1 on veins
5. Inhibited ejaculation
1. Pheochromocytoma
2. Peripheral vascular
disease (Reynauds)

Indications

>>>

III.

-Adrenoceptor antagonists

1. Inhibits 5-HT and


1. Direct vasodilator in
histamine receptors
high doses (cyclic
2. Releases histamine
nucleotide PDE
inhibition; prazosin)
3. Some efficacy
4. Some cholino-mimetic
efficacy
1. Similar to
1. First dose syncope
phenoxybenzamine
2. Veins less susceptible
to antagonism than
arteries; orthostatic
hypotension eventually
is not a problem
3. Less reflex cardiac
stimulation; no block
of presynaptic 2receptors
1. Similar to phenoxy1. Residual orthostatic
benzamine
hypotension
2. G.I. disturbances
(histamine release)

1. Same as phenoxybenzamine

1. Mild to moderate
hypertension
2. BPH: urine flow in
urethra

*Names end in osin. Quinazolines in red font are non-selective at all 1-adrenoceptors.

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113

A. Tamsulosin (Flomax)
1. Newer drug for BPH
a. Selective for 1A-receptors in prostate smooth muscle
b. 1B- and 1D-receptors are important in vascular smooth muscle; therefore,
this drug is more tissue-specific
2. Inhibits contraction of the urinary bladder base and prostate smooth muscle
3. Smaller incidence of vascular side effects, i.e., hypotension
4. Ineffective is pathological changes in prostate have occurred
B. Yohimbine
1. For male impotence; doubtful efficacy
2. Blocks central 2-adrenoceptors and increases NE release in noradrenergic
nuclei
3. Results in an increase in blood flow in the penis
4. Its effects are opposite those of clonidine, the 2-adrenoceptor agonist
a. Increases blood pressure and heart rate
b. Blockade of prejunctional 2-adrenoceptors
5. There are few other examples of a need to block 2-adrenoceptors in therapy

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114

V.

Presynaptic vs. postsynaptic effects of -adrenoceptor antagonists

Normal
Adrenergic
neuron

2
NE

-receptor

1-receptor

NE

Phentolamine Blockade
2 PH
NE

PH

NE

-receptor

-receptor

Tachycardia

Prazosin Blockade
PR

2
NE

NE

-receptor

-receptor

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115

V. Cardiovascular effects of phentolamine on epinephrine-induced responses:


epinephrine reversal
Heart Rate

160

200

Blood
pressure

135/85

128/50

Phentolamine
Heart Rate

180

210

Blood
pressure

135/90

190/124

160/82

175/110

Epinephrine before phentolamine


Heart Rate

190

210

Blood
pressure

125/85
100/35
Epinephrine after phentolamine

Adapted from Hoffman, B.B. in Katzung, Basic and Clinical Pharmacology, p.140.

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116

VI. Pharmacological properties of ergot alkaloids


A. Agents
1. Ergotamine and dihydroergotamine (migraine)
2. Ergonovine (post-partum hemorrhage; angina provocation test for coronary artery
vasospasm [off label])
B. Effects
1. This group of alkaloids has complex pharmacology and a range of effects
2. The agents differ in their potency in causing these effects.
a. -Adrenoceptor antagonism
b. Interaction with 5-HT and DA receptors (migraine)
c. Vasoconstriction (post-partum hemorrhage; partial agonist activity)
d. Oxytocic (post-partum hemorrhage)

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Pharmacology of Beta-Adrenoceptor Antagonists


I. Control of major peripheral systems by adrenoceptors
Figure 1.

TPR

TPR

Vasoconstriction

NE
Release

1
Mydriasis

Adrenoceptors

1
Cardiac Effects

GI
Motility

Vasoconstriction

Inhibition
of
Lipolysis

3
2

Lipolysis

Vasodilation
TPR
A. The pharmacological effects of the - and -adrenoceptor antagonists can be
explained largely from knowledge of the responses elicited by - and -adrenoceptors
in the different tissues and the effects of stimulation of the adrenergic nerves
innervating those tissues.
B. The effects of receptor activation in the various tissues is reviewed next.

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Table 1. Effects of activation of peripheral adrenoceptors by agonists


Primary
Response resulting from activation of the primary receptor
receptor
Cardiac
Increase contractility (+ inotropic)
1

Smooth
muscle

Increase heart rate (+ chronotropic)

Arrhythmias

Increased conduction velocity

Vasoconstriction (arterioles, pre-capillary sphincter,


veins)
Vasodilation (skeletal and visceral beds)
Intestinal relaxation:

Presynaptic decrease ACh release


Relaxation of smooth muscle

G.I. sphincter contraction


Uterus:

Contraction
Relaxation
Urinary bladder:
Contraction of sphincter
Relaxation of detrusor

Metabolic

Endocrine

Nerve
endings

2
2
1
1
2
1
2
1

Pupillary dilation (constriction of radial muscle; mydriasis)

Contraction of ureter

Contraction of spleen

Pilomotor erection

Airway smooth muscle relaxation

Liver and muscle glycogenolysis

Lipolysis: Activation
Inhibition

Fat cells (activation of glycolysis)

Pancreas:

(and ATP)

Stimulation of insulin secretion


Inhibition of insulin secretion
Stimulation
Inhibition

Intraocular pressure:

some

Sex organs: Ejaculation and detumescence

Renin release:
Eye

1,

Increase aqueous humor outflow


Decrease aqueous humor secretion
Increase aqueous humor secretion

Inhibit transmitter release


Facilitate transmitter release

2
1
2
2
2

2
2

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II. Affinity of -adrenoceptor antagonists for adrenoceptors


Table 2
Antagonist

Phentolamine

High

High

Very low

Very low

Phenoxybenzamine

High

High

Very low

Very low

Prazosin

High

Low

Very low

Very low

Yohimbine

Moderate

High

Very low

Very low

Propranolol

Very low

Very low

High

High

Metoprolol

Very low

Very low

High

Moderate

Butoxamine*

Very low

Very low

Moderate

High

High

Low

High

Moderate

Labetalol

Selectivity
,

* No real clinical role


Blue cells= -adrenoceptor-selective antagonists; yellow cells = -adrenoceptor selective
antagonists
Many drugs end in lol or olol.

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III. Diverse actions of -adrenoceptor antagonists


A. The members of this class of drugs show a diversity of actions. All block
-adrenoceptors, but, in addition, individual drugs may also
1. Stimulate -receptors as partial agonists
2. Exhibit slight positive agonist activity
3. Exhibit inverse agonist activity
4. Elicit NO release from endothelium
5. Be antioxidants
6. Block Ca2+ channels
7. Block -receptors
B. Generations of -adrenoceptor agonists
1. First: classical non-selective blockers
2. Second: 1-selective blockers
3. Third: non-selective blockers with other actions
4. Third: 1-selective blockers with other actions
C.

-Adrenoceptor antagonists find wide usage in a number of cardiovascular diseases.

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IV. Non-selective -adrenoceptor antagonists


A. Isoproterenol (shown for comparison; it is an agonist)
Figure 2.

OH
HO

OH

CH3
H
N
CH3
H

B. Propranolol (Inderal)
1. Bulk on the amine favors -receptors
2. 3-Carbon chain on the amine favors antagonist properties
3. Note the presence of the ester linkage in propranolol and some -blockers
3. Neutral antagonist
4. Stabilizes cardiac membranes in high doses
Figure 3.

O
OH

CH 3
H
N
CH 3
H

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C. Nadolol (Corgard)
1. Long-acting
2. Inverse agonist activity
3. Indications: hypertension and myocardial ischemia(angina)
Figure 4.

O
HO

OH
H

CH 3
CH 3
N
CH 3
H

OH

D. Pindolol (Viskin)
1. Slight positive agonist activity
2. Indications: hypertension and myocardial ischemia
Figure 5.

HN

O
OH

CH 3
H
N
CH 3
H

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E. Timolol (Blocadren)
1. Primary use: open-angle glaucoma
2. Receptor selectivity here is unknown
Figure 6.

CH 3
CH 3
N
CH 3
H

S N
N

O
N

OH

O
F. Labetalol (Normodyne): third generation
1. Racemic formulation
a. SR isomer: 1-blocker
b. RR isomer: 1 + 2 blocker
2. Some 2-agonist activity
3. Selectivity for
is 3:1
4. End result: TPR and vasodilation
a. Hypotension caused by -receptor blockade causes less reflex tachycardia than
other -receptors by themselves
5. Indication: hypertension
Figure 7.

HO

CH 3

H2 N
O

OH

N
H

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G. Carvedilol (Coreg): third generation


1. Similar to labetalol
2. Selectivity for
is 10:1
3. A powerful antioxidant and free radical scavenger
4. May inhibit VDCC in higher concentration than needed to block -receptors
a. A poitential antiarrhythmic effect
5. Indication: CHF

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V.

1-Adrenoceptor-selective

antagonists PREFERABLE IN THE ASTHMATIC PATIENT

A. Metoprolol (Lopressor, Toprol)


1. Inverse agonist
2. Indications: CHF, hypertension, myocardial ischemia
Figure 8.

O
OH

CH 3
H
N
CH 3
H

B. Acebutolol (Sectral)
1. Indication: Hypertension
Figure 9.

H
N
O

O
H3 COC

OH

CH 3
H
N
CH 3
H

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C. Esmolol (Brevibloc)
1. Fast-acting
2. Short duration: metabolized by esterases
3. Allows fine control of effects
4. Used in urgent settings where rapid -blockade is needed
Figure 10.

O
CH3O
O
OH

CH3
H
N
CH3
H

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VI. Agonist Activities of Selected -Adrenoceptor Antagonists


Table 3
Propranolol
-Receptor antagonist selectivity
Agonist activity
Membrane stabilizing activity
(Interfere with Na channels)

None
None
Yes
(High doses)

Metoprolol
1

Inverse
Slight

Labetalol

Pindolol

None

None

Slight
Slight

Slight
Slight

-Adrenoceptor antagonists that are partial agonists may cause a lesser decrease in heart
rate and blood pressure than those which are not partial agonists.

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VII. Major

-adrenoceptor antagonist effects


Table 4

Effects of

1-receptor

antagonism*

Cardiovascular system
Heart

Effects of

2-receptor

antagonism*

Cardiovascular
Vasoconstriction in skeletal beds

Electrophysiological changes
HR
Slowed A-V conduction
Phase 4 depolarization
Contractility changes
Stroke volume
Residual volume

Pulmonary
Bronchoconstriction
Metabolic
Glycogenolysis
Recognition of hypoglycemia
Endocrine
Insulin release

Velocity of contraction (dP/dT)


CO
Oxygen consumption
Peripheral vascular changes
BP
CO
GFR
Renin release
Angiotensin II in blood
Na retention and edema from above
Other effects
Lipolysis
*Non-selective

-receptor antagonists have effects shown in both columns.

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VIII. Pharmacology of -Adrenoceptor Antagonists


A. Primary uses
1. Myocardial ischemia
2. Myocardial infarction
3. Arrhythmias
4. Hypertension
a. CNS
b. Renin release
c. CO
5. Glaucoma: aqueous humor secretion
B. Other uses
1. Congestive heart failure (mild)
2. Hyperthyroidism
3. Performance anxiety
C. Contraindications
1. Congestive heart failure
2. Asthma
3. Atrioventricular node conduction disturbances
4. Hypoglycemia
D. Side effects
1. Rebound ischemia
2. Tiredness
3. Vivid dreams
4. Insomnia
5. Hallucinations
6. Exercise intolerance

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