Pharmacology of the

Autonomic Nervous System

Ana B. Mendoza
Department of Basic Sciences
College of Veterinary Medicine
Benguet State University
La Trinidad, Benguet
Objectives:
1. Correctly identify the different classes of drugs affecting
the autonomic nervous system(autonomic drugs)

2. Discuss the effects and therapeutic uses of various drugs

acting on the autonomic nervous system.

3. Identify side effects and contraindications of commonly

used autonomic drugs.

4. Rationally prescribe autonomic drugs in clinical practice

Introduction
The CNS receives diverse internal and external
stimuli.

These are integrated and expressed

subconsciously through the autonomic nervous
system to modulate the involuntary functions of
the body.
The autonomic nervous system
Aka:
Visceral
vegetative
involuntary nervous system
is distributed widely throughout the body and regulates autonomic
functions that occur without conscious control.
In the periphery, it consists of nerves, ganglia, and plexuses that
innervate the:
Heart
blood vessels
glands
other visceral organs, and
smooth muscle in various tissues.
The autonomic nervous system
Controls the vegetative functions of the body.
These include functions like
Circulation
Respiration
Digestion
Maintenance of body temperature
 Autonomic Nervous System
2 divisions:
Sympathetic
“Fight or flight”
“E” division
Exercise, excitement,
emergency, and
embarrassment
Parasympathetic
“Rest and digest”
“D” division
Digestion, defecation,
and diuresis
Note:

The efferent autonomic nerves do not travel directly

from the CNS to the structures they innervate, but relay
first in synapses (autonomic ganglia) outside the CNS.

Thus, each autonomic nerve consists of a

preganglionic fibre and a postganglionic one.
1. Sympathetic division (thoracolumbar outflow)
Origin

lateral horn cells of all thoracic and upper three

lumbar segments of the spinal cord.

The sympathetic fibres

characterized by having a short preganglionic fibre, and

a long post ganglionic fibre
2. Parasympathetic division (craniosacral outflow)
which consists of:
Cranial outflow
Origin
Cranial nuclei - namely III, VII, IX and X.
Sacral outflow
Origin
cells in the 2nd, 3rd and 4th sacral segments of the spinal cord.
The parasympathetic fibres
characterized by having a long preganglionic fibre, and a
short post ganglionic fibre.
The Parasympathetic Nervous System
 Comparison of sympathetic & Parasympathetic Nervous System
Point of comparison Sympathetic Parasympa-
thetic
Length of preganglionic axon Short long
Length of postganglionic axon Long short
Location of sympathetic or Far from target Near or in the
parasympathetic ganglia organs wall of target
organs
Ganglionic Synapse Diffuse Discrete
Neurotransmitter released by Acetylcholine Acetylcholine
preganglionic axons in ganglia
Neurotransmitter released by Norepine-phrine Acetylcholine
preganglionic axons in target sites (Ach)

Function Expenditure of Conserve &

energy Produce energy
Sympathetic and parasympathetic divisions typically function in opposition
to each other.
But this opposition is better termed complementary in nature rather
than antagonistic.
For an analogy:
The sympathetic division as the accelerator
The parasympathetic division as the brake.
The sympathetic division typically functions in actions requiring quick
responses.
The parasympathetic division functions with actions that do not require
immediate reaction.
Consider sympathetic as "fight or flight" and parasympathetic as "rest and
digest".
The Major body functions that are regulated
by the ANS
1. Contraction and relaxation of smooth muscles

2. All exocrine and certain endocrine secretions

3. The heart beat

4. Certain steps in intermediary metabolism

Sympathetic and Parasympathetic Tones:
A state of tonus is the predominance of one
division over the other
e.g. :

Sympathetic tone in the arterioles maintains

systemic blood pressure while parasympathetic tone
in intestinal smooth muscles maintains in gut motility
Predominance of Sympathetic or parasympathetic tone at
effector sites: Effect of autonomic ganglionic blockade
Site Predominant Tone Primary Effects of Ganglionic Blockade

Arterioles Sympathetic Vasodilation, increased peripheral

( adrenergic) blood flow, hypotension
Veins Sympathetic Dilation, pooling of blood,
( adrenergic) decreased venous return,
decreased cardiac output
Heart Parasympathetic
(Cholinergic) Tachycardia

Iris Parasympathetic
(Cholinergic) Mydriasis

Ciliary Muscle Parasympathetic Cycloplegia

(Cholinergic) (focus to far vision)
 Predominance of Sympathetic or parasympathetic tone
at effector sites: Effect of autonomic ganglionic blockade
Site Predominant Tone Primary Effects of Ganglionic Blockade

Gastrointesti Parasympathetic Reduced tone and motility of

nal Tract (Cholinergic) smooth muscle, constipation,
decreased gastric and
pancreatic secretions
Urinary Parasympathetic
Urinary retention
Bladder (Cholinergic)
Salivary Parasympathetic
Xerostomia
glands (Cholinergic)
Sweat Sympathetic (
Anhidrosis
Glands adrenergic)
Neurotransmitters of the Autonomic Nervous
System
Transmission of nerve impulses from one nerve fibre to
another, or from a nerve fibre to an effector organ is
mediated through the release of chemical substances
(transmitters) from the stimulated nerve ending.
Two main chemical transmitters have been identified in
autonomic nerves:
acetylcholine (Ach)
Noradrenaline (NE)
Nerve fibres which release acetylcholine are called
cholinergic fibres and the released acetylcholine
acts on cholinergic receptors in the target cells,

nerve fibres which release noradrenaline are called

adrenergic (more appropriate noradrenergic) fibres
and the released noradrenaline acts on adrenergic
receptors
1. Adrenergic fibers
Norepinephrine (noreadrenaline) is the major
neurotransmitter release at the terminals of the
postganglionic fibers in the neuroeffector junction
The postganglionic fibers are called Adrenergic nerve
fibers
2. Cholinergic fibers
The nerves are Cholinergic nerve fibers
Releases acetylcholine (Ach) which include:
(next slide)
1. Postganglionic parasympathetic fibers at the neuro-
effector junction
2. Preganglionic parasympathetic fibers
3. Preganglionic sympathetic fibers
4. Splanchnic nerve terminal in the adrenal medulla
5. Anatomically sympathetic postganglionic neurons
which innervate sweat glands and blood vessels in
skeletal muscles
6. Somatic nerve terminals at the neuromuscular
junctions
Key features of neurotransmitter function which
may provide potential targets for pharmacologic
therapy:
synthesis
Storage
release
termination of action of the transmitter
Activation/inactivation of receptors
 Storage and Release of Catecholamines
1. Catecholamines are concentrated in storage vesicles
that are present at high density within nerve
terminals
2. The concentration of catecholamines within nerve
terminals remains relatively constant
3. Monoamine oxidase and Catechol-o-
methyltransferase are primarily responsible for the
inactivation of catecholamines
4. The action of catecholamines released at the synapse
is terminated by diffusion and reuptake into
presynaptic nerve terminals.
Biosynthesis of Catecholamines
Essential amino acid
transported across the BBB
TH requires tetrahydrobiopterin/Tyrosine
hydroxylase

Localized to dopamine neurons (formerly dopamine

decarboxylase)
fast-acting enzyme
requires pyridoxal phosphate (from vitamin B6) as a
cofactor

Localized to norepi neurons (of brain and

sympathetic nervous system) -requires vitamin C as
a cofactor

Localized to adrenergic neurons and adrenal

medulla
Biosynthesis of catecholamines.
The rate-limiting step, conversion
of tyrosine to dopa, can be
inhibited by metyrosine (α-
methyltyrosine).
The alternative pathway shown
by the dashed arrows has not
been found to be of physiologic
significant. However, tyramine
and octopamine may accumulate
in patients treated with
monoamine oxidase inhibitors.
(Reproduced, with permission, from
Greenspan FS, Gardner DG [editors]:
Basic and Clinical Endocrinology, 7th ed.
McGraw-Hill, 2003.)
 Catecholamine Storage
Vesicular and nonvesicular
Storage
Formation of vesicle mediated by
clathrin, pinched off from
membrane by dynamin
H+ ATP-ase and VMAT mediate
vesicular packaging
VMAT can be blocked by
reserpine
causes temporary increase in
cytosolic neurotransmitter
levels followed by a depletion in
stores
Catecholamine release
from classical synapses
can be measured by a # of methods
microdialysis
voltammetry/amperometry
capacitance measurements

dendritic release in cell body regions

leaching out by reversal of the NET or DAT
regulated by autoreceptors on presynaptic terminals
↓ ICa2+ ;↑ IK+; inhibit release process
Breakdown of Catecholamines
1. Synaptic breakdown:
Chiefly in the presynaptic cell by monoamine
oxidase (MAO)
2. Systemic breakdown:
MAO and catechol-O-methyltransferase
(COMT), mainly in the liver
High first-pass effect of any catecholamines
ingested
Rapid inactivation of circulating
catecholamines
Two isoenzymes of MAO
MAO A and B
occur in different locations
selective inhibitors exist
MAO responsible for degradation not
only of catecholamines but also of
serotonin and histamine
Three processes for terminating catecholamine
actions:

1. Diffusion into the general circulation (~15%)

2. Enzymatic degradation (~20%)

Involving the action of MAO and COMT

3. Re-uptake into the neuronal and non-neuronal

tissues (~65%)
Cartoon of generic catecholaminergic neuron

synthesis of catecholamine from tyrosine

taken into vesicles by VMATs (vesicular monoamine transporters)
released - act on postsynaptic and presynaptic (release-modulating,
synthesis-modulating, impulse-modulating) receptors
taken up by NET and DAT (transporters) or broken down by
COMT/MAO
Catecholamine receptors

All are metabotropic receptors

Epinephrine and norepinephrine
α receptors
α1A, α1B, α1D (coupled via Gq to PLC)
α2A , α2B, α2C (negatively coupled to cyclase via Gi)
β receptors – β1A , β1B, β1C (positively coupled to cyclase via Gs)

Dopamine
D1, D5
positively coupled to cyclase via Gs (or Golf, in striatum)
D2 short, D2long, D3, D4
negatively coupled to cyclase via Gi
many antipsychotic drugs are D2 antagonists (e.g. haloperidol)
Adrenergic (Catecholamines) Receptors
Adrenergic receptors are the sites where
adrenergic drugs bind and produce their effects.
Adrenergic receptors are divided into alpha-
adrenergic and beta-adrenergic receptors
depending on whether they respond to
norepinephrine or epinephrine.
Both alpha- and beta-adrenergic receptors have
subtypes designated 1 and 2.
Alpha Receptors

Alpha1-adrenergic receptors are located

on the postsynaptic effector cells.

Alpha2-adrenergic receptors are located

on the presynaptic nerve terminals.
Beta Receptors
Both beta-adrenergic receptors are located on
the postsynaptic effector cells.

Beta1-adrenergic receptors are primarily

located in the heart.

Beta2-adrenergic receptors are primarily

located in the smooth muscle of bronchioles,
arterioles, and visceral organs.
Dopaminergic Receptors

Dopaminergic receptors are only

stimulated by dopamine which causes
the vessels of renal, mesenteric,
coronary, and cerebral arteries to dilate
and the flow of blood to increase.
 Adrenergic Receptor Specificity
Drug α1 α2 β1 β2 Dopaminergic

Epinephrine
Ephedrine
Norepinephrine
Phenylephrine
Isoproterenol
Dopamine
Dobutamine
terbutaline
Major adrenergic receptor types
Location Result of Ligand Binding
Distribution of Adrenoreceptor subtypes and their actions
Type Tissue Actions
Alpha 1 Most vascular smooth muscels Contraction
Pupillary dilator muscle Mydriasis
Heart Increase Force of
contraction
Alpha 2 Adrenergic nerve terminals Inhibition of transmitter
release
Platelets Aggregation
Beta 1 Heart Increased rate and force
of contraction
Beta 2 Respiratory, uterine, and Relaxation
vascular smooth muscle
Human Liver Glycogenolysis
Beta 3 Fat cells Lipolysis
 Synthesis, Storage and release of Acetylcholine
1. Acetylcholine is synthesized from its two
immediate precursors, choline and acetyl
coenzyme A.
2. Acetylcholine formation is limited by the
intracellular concentration of choline, which is
determined by uptake of choline into the nerve
ending
3. A second transport system concentrates
acetylcholine in the synaptic vesicle
4. Choline is supplied to the neuron either from plasma
or by metabolism of choline-containing compounds
5. A slow release of acetylcholine from neurons at rest
probably occurs at all cholinergic synapses
6. The relationship between the amount of acetylcholine
in the vesicle and the quanta of acetylcholine
released can only be estimated.
7. Depolarization of the nerve terminal by the action
potential increases the number of quanta released
per unit of time.
8. All acetylcholine contained within the cholinergic
neuron does not behave as if in a single
compartment.
 Biosynthesis of Acetylcholine
Acetylcholine is
synthesized from its
two immediate
precursors :
1.Choline
2. Acetyl-coenzyme A
 Acetylcholinesterase and the Termination of
Acetylcholine Action
1. Cholinesterases are widely distributed throughout
the body in both neuronal and non-neuronal tissue
2. Acetyl cholinesterases exists in several molecular
forms
3. The primary and tertiary structures of the
cholinesterases are known
4. The catalytic mechanism for acetylcholine hydrolysis
involves formation of an acyl enzyme, followed by
deacylation
5. Inhibition of acetylcholinesterase occurs by several
distinct mechanisms
6. Consequences of acetylcholinesterase inhibition
differ between synapses.
Generalized
cholinergic
junction
Cartoon of cholinergic neurons

choline acetyltransferase is the synthesizing enzyme

stored in vesicles by a transporter that is VMAT
release inhibited by muscarinic autoreceptors
inactivation largely by acetylcholinesterase
found at very high concentrations in synaptic cleft
extremely fast enzyme (10,000-100,000/s)
 Acetylcholine Receptors
Two Receptors:
1. nicotinic receptor – uses ionotropic receptor
Fast
Muscle fibers
2. muscarinic receptor – uses metabotropic
receptor
Slow
Dominant in CNS
Degradation is through enzyme:
acetylcholinesterase inhibitor
Classification of cholinergic receptors
Cholinergic Receptors
receptors that bind the acetylcholine and mediate
its actions
These receptors consist of nicotinic receptors and
muscarinic receptors.
Nicotinic receptors are located in the ganglia of the PNS
and SNS and are stimulated by nicotine.
Muscarinic receptors are located postsynaptically in the
smooth muscle, cardiac muscle, and glands.
These receptors are stimulated by muscarine.
Acetylcholine
(ACh) interacts M2 & M4
with a
muscarinic
receptor of the
subtypes
indicated to
induce various M1, M3 and M5 mAChRs
responses

M2 & M4
Structure of
compounds
important to
the
classification of
receptor
subtypes at
cholinergic
synapses.
Major Acetylcholine Receptors
Receptor Typical Location Result of Ligand Binding

CNS neurons, sympathetic Formation of IP3 and

Muscarinic
postganglionic neurons, DAG, increased
M1
some presynaptic sites intracellular calcium
Myocardium, smooth Opening of potassium
Muscarinic
muscle, some presynaptic channels, inhibition of
M2
sites, CNS neurons adenyl cyclase
Exocrine gands, vessels,
Muscarinic Smooth muscle and Similar to M1 receptor-
M3 endothelium), CNS ligand binding
neurons
Muscarinic CNS neurons, possibly Similar to M2 receptor-
M4 vagal nerve endings ligand binding
Major Acetylcholine Receptors
Receptor Typical Location Result of Ligand
Binding
Muscarinic Vascular endothelium especially Similar to M1 receptor-
M5 cerebral vessels, CNS neurons ligand binding
Postganglionic neurons, some
presynaptic cholinergic Opening of Na+, K+,
Nicotinic terminals, receptors typically depolarization
NN contain 2 α3 and one β4 types
subunits in addition to γ and δ
subunits
Skeletal muscle neuromuscular
end plates, receptors typically
Nicotinic Opening of Na+, K+,
contain two α1 and β1 type
NM depolarization
subunits in addition to γ and δ
subunits
 Autonomic Drugs
There are several drugs affecting the ANS which for a
better understanding are classified into groups:
A. Drugs acting on the Sympathetic Nervous system
1. Sympathomimetics or adrenergic drugs are
drugs that mimic the effects of sympathetic nerve
stimulation
2. Sympatholytics are drugs that inhibit activity of
sympathetic nerve or that of sympathomimetics
B. Drugs acting on the parasympathetic nervous system
1. Parasympathomimetics or cholinergic drugs

Are drugs which mimic acethylcholine or the effects of

parasympathetic nerve stimulation

2. Parasympatholytics

Are drugs that inhibit parasympathetic nervous system

activity or that of cholinergic drugs
Sympathomimetic and
Sympatholytic drugs
Sympathomimetic (Adrenergic) Drugs
produce effects similar to those produced by the
sympathetic nervous system.
Classified into two groups:
catecholamines
noncatecholamines

Also classified according to their action:

direct-acting
indirect-acting
dual-acting.
Adrenergic drugs can be grouped by mode of action and
by the spectrum of receptors that they affect.
a. Direct mode of action:
directly interact with and activate adrenoreceptors
e.g., adrenaline and noradrenaline

b. Indirect mode of action:

their actions are dependent on the release of
endogenous catecholamines.
This may be :
1. Displacement of stored catecholamies from the
adrenergic nerve endings
e.g., amphetamine, tyramine
2. Inhibition of reuptake of catecholamines already
released
e.g. cocaine, tricyclic antidepressants
Both types of sympathomimetics, direct and indirect,
ultimately cause activation of adrenoreceptors leading to
some or all characteristic effects of the catecholamines
Therapeutic uses depend on which receptors they stimulate
and to what degree
alpha-adrenergic

beta-adrenergic

dopamine receptors

Most adrenergic drugs stimulate alpha and beta receptors

mimicking the action of norepinephrine and epinephrine.

Dopaminergic drugs act primarily on SNS receptors

stimulated by dopamine.
 Organ-system Effects of Activation of the
Adrenergic System
1. CVS:
a. Heart:
increased rate and force of contraction, increased cardiac output,
myocardial demand, and AV conduction
b. Blood Vessels and Blood pressure:
constriction of blood vessels in the skin and mucous membranes
Dilation of skeletal muscle vessels
Adrenaline increases systolic and decreases diastolic blood
pressure at low doses but increases both at higher doses
Noradrenaline increases both systolic and diastolic blood pressure
2. Smooth Muscle:
a. Bronchi:
relaxation
b. Uterus:
relaxation of the pregnant uterus
c. GIT:
relaxation of wall muscles and contraction of sphincters
d. Bladder:
relaxation of detrusor muscle; contraction of sphincter and
trigone muscle
3. Eye:
mydriasis; reduction of intraocular pressure in normal and
glaucomatous eyes
4. Respiration:
Bronchodilation; relief of congestion; mild stimulation of respiration
5. Metabolic:
Increased hepatic glycogenolysis; decreased peripheral glucose
intake; increased free fatty acids in the blood (lipolysis)
6. CNS:
excitement, vomiting, restlessness
7. Skeletal muscle:
facilitation of neuromuscular transmission and vasodilation
 Drugs Acting on the Adrenergic Receptor
Subtypes
α1 α2 β1 β2

Clonidine Dobutamine Salbutamol

Phenylephrine
Agonist Oxymetazo Isoproterenol Terbutaline
Methoxamine
line Terbutaline Isoetharine

Yohimbine Propranolol
Prazosin Propranolol
Phentolamin Pindolol
Phentolamine Pindolol
Antagonist e Atenolol
Phenoxybenza Phenoxybe Butoxamine
Metoprolol
mine Timolol
nzamine Timolol
Catecholamines-these are compounds which have the
catechol nucleus
Stimulate the nervous system
constrict peripheral blood vessels
increase heart rate
dilate the bronchi
Can be natural or synthetic and include:
Dobutamine
Dopamine
Epinephrine
Norepinephrine
isoproterenol
Pharmacokinetics:
Not administered orally

when administered sublingually are absorbed rapidly

through the mucous membranes

when administered SC absorption is slowed due to

vasoconstriction around the injection site

when administered IM absorption is more rapid.

 Widely distributed throughout the body

predominantly metabolized by the liver

excreted primarily in the urine.

Pharmacodynamics:

Are primarily direct-acting

Activation of alpha receptors generates an excitatory

response except for intestinal relaxation.
Activation of the beta receptors mostly produces an
inhibitory response except in the heart cells where
norepinephrine produces excitatory effects.

The clinical effects of catecholamines depend on the

dosage and route of administration.
Positive ionotropic effects

heart contracts more forcefully.

Positive chronotropic effects

heart beats faster

Positive dromotropic effects

increased conduction through the AV node.

Catecholamine that stimulates α receptors are used to treat
hypotension caused by a loss of vasomotor tone or
hemorrhage.
Catecholamines that stimulate beta1-receptors are used to treat
bradycardia
heart block
low cardiac output
paroxysmal atrial or junctional Tachycardia
ventricular fibrillation
Asystole
cardiac arrest
Catecholamines that stimulate β2-receptors are used
to treat:
acute and chronic bronchial asthma

Emphysema

Bronchitis

acute hypersensitivity reactions to drugs

Dopamine that stimulates dopaminergic receptors is

used to improve blood flow to kidneys.
Synthetic catecholamines have a short duration of
action which can limit their therapeutic usefulness.

Drug interactions/adverse reactions:

hyper and hypotension

arrhythmias

seizures

hyperglycemia
Non-catecholamines - lack the catechol nucleus.
Uses include:
local or systemic constriction of blood vessels
phenylephrine

nasal and eye decongestion and dilation of bronchioles

albuterol (Ventolin)

smooth muscle relaxation

terbutaline sulfate
Pharmacokinetics:
have different routes of administration

Variable absorption and distribution

can be administered orally

metabolized primarily by the liver

excreted primarily in the urine

Pharmacodynamics:
1. Direct-acting noncatecholamines that stimulate
alpha activity include
phenylephrine

2. Direct-acting noncatecholamines that stimulate

beta2 activity include:
albuterol (Ventolin)

Terbutaline
3. Indirect-acting
phenylpropanolamine

4. Dual-acting

ephedrine
Pharmacotherapeutics:
Stimulate the sympathetic nervous system and
produce a variety of effects in the body.
Example: ritodrine

used to stop pre-term labor

Drug interactions/adverse reactions:

Taken with monoamine oxidase inhibitors can cause
severe hypertension and death
Adrenergic Stimulants:
Group 1 : Directly stimulating adrenergic receptors
Endogenous catecholamines
Epinephrine
Norepinephrine
dopamine
Synthetic agonists:
Alpha agonists – phenylephrine, methoxamine,
phenylpropanolamine
Alpha-2 agonist – xylazine, clonidine
Beta agonist – isoproterenol, methoxyphenamine
Beta-2 agonist – clenbuterol, salbutamol
Beta-1 agonist – dobutamine, dopamine
Group 2: Indirectly acting on receptors, replace and release
NE from the secretory vesicles on nerve terminals

the release of NE then stimulates the receptors.

Examples:

Amphetamine

Hydroxyamphetamine

metamphetamine
Group 3: Dual acting (directly and indirectly stimulate
receptors)

replace NE from secretory vesicles and at the same

time can stimulate the receptor directly

Examples:

Ephedrine

Pseudoephedrine

metaraminol
Group 4: Blocking the re-uptake of NE back to the
nerve terminal

NE stays longer in the synapse to cause prolonged

receptor stimulation

Examples

Imipramine

cocaine
Sympatholytic drugs/
Adrenergic Blocking Drugs
Used to disrupt SNS function by blocking impulse
transmission at adrenergic receptor sites

Interference with NE release from terminal vesicles

Examples:
Bretylium

Guanethidine
Classified according to their site of action:
alpha-adrenergic blockers - inhibits peripheral
vasoconstriction
Phenoxybenzamine
Phentolamine
Prazosin
Ergot alkaloids
Phenothiazine tranquilizers
yohimbine
beta-adrenergic blockers
Propanolol
Metoprolol
butoxamine
Alpha-Adrenergic Blockers
Work by interrupting the actions of the catecholamines
norepinephrine and epinephrine at the alpha receptors
resulting in:
relaxation of the smooth muscle in the blood vessels increased
dilation of blood vessels
decreased blood pressure.

Prototype drug
prazosin
Pharmacokinetics:
The action of alpha blockers in the body is not well
understood.

Pharmacodynamics:
Block the synthesis, storage, release, and uptake of
norepinephrine by neurons.

Antagonize epinephrine and norepinephrine at alpha

receptor sites.
Alpha-Adrenergic Blockers do not discriminate alpha1 and alpha2
receptors.
Occupy alpha receptor sites on the smooth muscle of blood vessels
resulting in:
vasodilation
decreased peripheral vascular resistance
decreased blood pressure
Used to treat:
Hypertension
peripheral vascular disorders
pheochromocytoma
(a catecholamine-secreting tumor causing severe hypertension).
Drug interactions/adverse reactions:
orthostatic hypotension

severe hypotension

vascular collapse
Beta Antagonists (β Blockers)
Frequently used to Lower Blood Pressure
Negative chronotropes and ionotropes

Beta1 Selective Blockade Nonselective

atenolol propranolol

esmolol labetalol

metoprolol sotalol
Prevent stimulation of the sympathetic nervous
system by inhibiting the action of catecholamines at
the beta-adrenergic receptors (beta-blockers).

Are selective or nonselective.

Nonselective beta-blockers affect beta1 receptor

sites located mainly in the heart and beta2 receptor
sites located in the bronchi, blood vessels, and
uterus.
Pharmacokinetics:

Absorbed rapidly and are protein-bound

the onset of action is primarily dose and drug-

dependent

distributed widely with the highest concentrations in

the heart, lungs, and liver; metabolized primarily in the
liver

excreted primarily in the urine.

Pharmacodynamics:
Effect adrenergic nerve endings as well as the adrenal
medulla
Effects on the heart include:
decreased peripheral vascular resistance
decreased blood pressure
decreased force of heart contractions
decreased oxygen consumption
slowed impulse conduction
decreased cardiac output
Selective beta1-blockers reduce stimulation of the heart
also called cardio selective beta-adrenergic blockers

Nonselective beta1 and beta2-blockers not only reduce

stimulation of the heart but can also cause the
bronchioles of the lungs to constrict.
Pharmacotherapeutics:
Clinical usefulness is based largely upon how they affect
the heart

Used to treat :
heart attacks

Angina

Hypertension

hypertrophic cardiomyopathy

supraventricular arrhythmias
 Also used to treat
anxiety
cardiovascular symptoms associated with thyrotoxicosis,
essential tremor
migraine headaches
open-angle glaucoma
pheochromocytoma

Drug interactions/adverse reactions:

Many causing cardiac and respiratory depression
arrhythmia
severe bronchospasm
severe hypotension
Epinephrine Reversal effect

Refers to the condition of severe hypotension

following administration of epinephrine in the
presence of alpha adrenergic blocking drugs.
Epinephrine acts both on alpha and beta adrenergic
receptors causing vasoconstriction and vasodilation.
Since alpha adrenergic stimulation is greater than beta
stimulation, the net effect of epinephrine is
vasoconstriction and increased blood pressure. So,
when epinephrine is administered while alpha receptors
are blocked, the net effect is due to dominantly beta-
stimulation; and the usual effect of epinephrine is
reversed.
Parasympathomimetic/Cholinomimetic
Cholinolytic drugs
Parasympathomimetic/Cholinergic Drugs
Promote the action of the neurotransmitter acetylcholine.

Also called parasympathomimetic drugs because they

produce the effects that mimic parasympathetic nerve
stimulation.

Two major classes of cholinergic drugs:

cholinergic agonists

anticholinesterase drugs
There are two groups of cholinergic drugs:
1. Direct-acting:
bind to and activate muscarinic or nicotinic receptors
(mostly both) and include the following subgroups:
a. Esters of choline:
Methacholine
Carbachol
betanechol
b. Cholinergic alkaloids:
Pilocarpine
Muscarine
Arecoline
nicotine
2. Indirect-acting:
inhibit the action of acetylcholinesterase enzyme
a. Reversible:
Neostigmine
Physostigmine
edrophonium
b. Irreversible:
Organophosphate compounds
echothiophate
The actions of acetylcholine may be divided into two
main groups:
1. Nicotinic actions
those produced by stimulation of all autonomic ganglia
and the neuromuscular junction
2. Muscarinic actions
those produced at postganglionic cholinergic nerve
endings
Cholinergic Agonists
aka cholinergic stimulants, parasympathomimetics,
parasympathetic stimulants
Includes drugs that stimulate cholinergic functions and
therefore mimic the action of acetylcholine
Direct-acting cholinomimetics
Have a direct action on the receptor for acetylcholine
Indirect-acting cholinomimetics
Act by blocking the metabolism of acetylcholine by cholinesterase.
These drugs effectively increased the concentration of
acetylcholine at all cholinergic synapse.
Categories:
Choline esters
Derivatives of acetylcholine
Binds directly to muscarinic receptors
Examples:
Methacholine
Carbachol
Bethanechol – used clinically to treat neurogenic urinary paralysis and
esophageal achalasia
Natural alkaloids
Of plant origin
Muscarine – of toxicological importance only
Pilocarpine – used as pupillary constrcition
Arecholine- once used as purgatives to remove intestinal
worms
Pharmacokinetics:
Administered topically (eye), orally, and subcutaneously
metabolized by cholinesterases
excreted by the kidneys
Pharmacodynamics:
Mimic the action of acetylcholine on the neurons of target organs
producing:
Salivation
bradycardia
Vasodilation
constriction of bronchioles
increased GI activity
increased tone
contraction of the bladder muscles
constriction of pupils.
Anticholinesterase Drugs
Block the action of the enzyme
acetylcholinesterase, which breaks down
acetylcholine, at the cholinergic receptor sites.

Divided into two categories:

reversible and irreversible
Reversible have a short duration and include: donepezil
and edrophonium
Anticholinesterase Drugs/cholinesterase
inhibitors ( Indirect cholinergic stimulants)
Irreversible anticholinesterase drugs have long-lasting
effects.

Used primarily as toxic insecticides and pesticides or

as a nerve gas in chemical warfare.
Note:
Acetylcholine is not used as a drug because:
1. The effects of Acetylcholine are too generalized
2. It is readily hydrolyzed by acetylcholinesterase
Myasthenia gravis is a condition in which the
number of cholinergic receptors in the skeletal
muscle end plate is reduced
May be caused by a congenital defect or an
autoimmune disease.
There are three types categories:
1. Carbamates
used as insecticides
Examples:
carbaryl (sevin)
Propuxur (Baygon)
In carbamate poisoning, the antidote is atropine
A competitive blocker of muscarinic cholinergic
receptors
2. Organophosphates (OPs)
Used as pesticides and as anthelmintics
Some deadly gases are: OPs, DFF, TOCP and Sarin
Examples of OPs are:
Malathion, dichlorvos
Coumaphous (Asuntol)
Trichlorfon (neguvon)
OP poisoning is counteracted by atropine
Early stages of poisoning may be counteracted
by pralidoxime also known as 2-PAM (2-Pyridine
aldoxime methiodide) by dephosphorylation of
cholinergic receptors
However, in prolonged OP poisoning, the
condition may be irreversible, and the use of 2-
PAM may be useless.
3. Short acting cholinesterase inhibitors

a. Physostigmine (or eserine)

Used for iatrogenic atropine overdoses at muscarinic
receptors

An alkaloid derived from plant-effects are mainly

muscarinic, almost exclusively used in ophthalmology
b. Neostigmine
Analogue of physostigmine
Can reverse nondepolarizing neuromuscular blockade
It directly stimulate cholinergic receptors (dual action) used in
treating myasthenia gravis
It increases the available acetylcholine in the motor end plate to
increase the chances of stimulating (maximally) whatever
normal receptors are left
In addition neostigmine and the others also directly stimulat
cholinergic receptors.
Pharmacokinetics:
Most are readily absorbed from the GI tract, SC, and
mucous membranes

distribution varies among drugs

metabolized by enzymes in the plasma

excreted in the urine.

Pharmacodynamics:
Depending on the site, dosage, and duration of action,
stimulant or depressant effects can be produced.
Pharmacotherapeutics:
Therapeutic uses include:
reduce eye pressure
increase bladder tone
improve GI tone and peristalsis
promote muscular contraction
diagnose myasthenia gravis
an antidote to cholinergic blocking drugs
treat dementia due to Alzheimer’s
Drug interactions/adverse reactions:

Taken with other cholinergic drugs can increase

the risk of toxicity manifested by:
Nausea

Vomiting

Diarrhea

respiratory distress

seizures
 Assignment: Complete the Table
Description Pharmacokin Pharmacody Indications Adverse
etics namics effects

Anticholinest
erase Drugs

1. Physostig
mine
2.
Neostigmine
3. OP
Cholinergic Blocking
Drugs/antimuscarinic/parasympathetic antagonists
Interrupt parasympathetic nerve impulses in the central
and autonomic nervous systems.
Also referred to as anticholinergic drugs because
they prevent acetylcholine from stimulating the
muscarinic cholinergic receptors.
Drugs include the belladonna alkaloids
the prototype is atropine
 Anticholinergics block the effects of acetylcholine and
other cholinergic drugs at cholinergic receptors of
effector cells.
Anticholinergics fall into two major families:
1. Antinicotinics which include ganglion blockers such as
hexamethonium, trimethaphan, etc., and neuromuscular
blockers such as gallamine, tubocurarine, pancuronium,
etc.
2. Antimuscarinics include tertiary amines such as
atropine, scopolamine, tropicamide, etc, andquaternary
amines such as propantheline, ipratropium, benztropine,
etc.
Pharmacokinetics:

Absorbed from the eyes, GI tract, mucous membranes,

and skin

when given IV atropine works immediately, distributed

widely, cross the BBB, moderate protein-binding,
metabolized by the liver, excreted by the kidneys.
Pharmacodynamics:

Can produce a stimulating or depressing effects

depending on the target organ.

In the brain low drug levels stimulate and high drug

levels depress.
Clinical uses of Atropine

Preanesthetic medication to reduce a salivary and

respiratory secretions, and to prevent heart block
associated with induction of general anesthesia

In ophthalmology – used to produce mydriasis

For treatment of OP or carbamate poisoning

Other uses include

treatment of motion sickness

Parkinson’s disease

Bradycardia

Arrhythmias

pupil dilation

organophosphate pesticide poisoning

Synthetic atropine derivatives
There are a number of synthetic atropine derivatives,
which are used in the treatment of various conditions,
their actions are similar to that of atropine but have
fewer side effects.
These groups of drugs include:
1. Mydriatic atropine substitutes, this group of drugs have
shorter duration of action than atropine and are used
locally in the eye
drugs included:
Homatropine, Eucatropine etc.
2. Antiseccretory antispasmodic atropine substitutes:
Effective more localized to the GlT
Drugs include: propantheline and hyoscine
3. Antiparkinsonian atropine substitute:
drugs like Benztropine, Trihexyphenidyl
4. Atropine substitutes which decrease urinary bladder
activity like oxybutynin
5. Atropine substitutes used in bronchial asthma drugs like
ipratropium
Atropine-like drugs include
Scopolamine
Tropicamide
Aminopentamide
Ipatropium bromide
Homatropine
Hyocine
Has greater CNS effect
Has a unique antiemetic effect in dogs
Glycopyrrolate
Used as a preanesthetic medication
Propantheline
Uses as a gastrointestinal antispasmodic drug
Eucatropine
Used in ophthalmology as a mydriatic