Transcript presentation 2í.ppt

Pharmacology of Drugs Affecting
Autonomic Nervous System
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Basic Functions of the
Nervous System



Recognizing changes in
 Internal environment
 External environment
Processing and integrating environmental
changes
Reacting to environmental changes by
producing an action or response
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Two Major Divisions of the
Nervous System

Central Nervous System (CNS)


Brain and spinal cord
Peripheral Nervous System

all nervous tissues outside the CNS, including
sensory and motor neurons
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Divisions of human nervous
system
Human
Nervous
system
Central
Nervous
System
Peripheral
Nervous
System
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Brain
&
Spinal Cord
Nerves
enter or leave
CNS
Carry massage
from CNS to
peripheral tissues
Carry massage
from
peripheral tissues
to CNS
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Divisions of the Peripheral
Nervous System

Somatic nervous system


Voluntary control over skeletal muscles
Autonomic nervous system

Involuntary control over smooth and cardiac
muscle and glands
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Basic anatomy of ANS
Sympathetic NS
Parasympathetic NS
Two main differences
OriginFunction-
Enteric NS
-Collection of nerve fibers that
innervate GIT, pancrease & gall
bladder
-Called “brain of gut”
-They control motility, exocrine
& endocrine secretion, as well as
microcirculation of gut
-Modulated by sympathatic &
Parasympathatic systems
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Autonomic Pharmacology

Autonomic Nervous System
This system is divided into two separate systems.
 These systems are called the parasympathetic
nervous system and the sympathetic nervous
system.
 These systems often produce opposite effects,
but branches do not always produce opposite effects.
 Homeostasis – proper balance of the two
branches achieved by changing one or both
branches

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2
Autonomic Nervous System: Sympathetic and
Parasympathetic Divisions

Drugs in this group are designed to either enhance or
mimic the autonomic nervous system or to block the
effects of the neurotransmitters at their receptor sites.
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Steps of Neurotransmission

Propagation of the nerve impulse in
the preganglionic nerve fiber
+++++++++++
---------------- - - - - - - - - - - - - ++++++++++
Polarized
Resting Membrane Potential
++++----+++
-----++++--------++++---+++----++
Depolarized
Nerve Action Potential
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Synaptic Transmission


Synapse – junction of neurons
Connection of two neurons outside CNS –
ganglionic synapse.
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Efferent neurons




Preganglionic neurons:
Cell body within CNS
Ganglia: aggregation of nerve cell bodies
located in the peripheral nervous system.
Postganglionic neurons: cell body originate in
the ganglia, terminates on effector organ.
Divided
into
sympathatic
and
parasympathatic
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Origin
Symp. NS
Function
Thoracolumbar
outflow
Short pre-ganglionic nerve
Long post-ganglionic nerve
Parasymp. NS
Craniosacral
outflow
Long pre-ganglionic nerve
Short post-ganglionic nerve
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Figure 13.4 Receptors in the autonomic nervous system: (a) sympathetic division; (b) parasympathetic division
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Role of CNS in autonomic control
functions

CNS centers in hypothalamus,
medulla oblongata & spinal
cord


Reflex arc
Emotions
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Organs Supplied by ANS


Heart
Smooth Muscles
-
-

-Bronchi
- Urinary Bladder
Glands
-

Eye
GIT
Blood Vessels
Exocrine Glands: Lacrymal, Salivary, Sweat
Endocrine Glands: Adrenal Medulla
Metabolism



Liver
Adipose Tissue
Kidney
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Sympathetic Nervous System

Sympathetic Nervous System
 This nervous system is designed to
cope with emergency situations.
 This is commonly known as the “fright or
flight” response.
 Its neurotransmitters are epinephrine
and norepinephrine.
 Its receptors are the α and β receptors.
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4
Sympathetic nervous system
Fight or flight response results in:
1.
Increased BP
2.
Increased blood flow to brain, heart and
skeletal muscles
3.
Increased muscle glycogen breakdown for
energy
4.
Increased rate of coagulation
5.
Pupil dilation
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parasympathatic Nervous
System




Parasympathetic Nervous System
 This system is concerned with the
conservation of the body processes.
Activated under non stressful conditions
Rest-and-digest response
Digestive processes promoted, heart rate
and blood pressure decline
 Its
main
neurotransmitter
is
acetylcholine.
 Its receptors are muscarinic, nicotinic.
3
Figure 13.2 Effects of the sympathetic and parasympathetic nervous systems. Source: Biology Guide to the Natural
World, 2nd ed (p. 558) by David Krogh, 2002 Upper Saddle River, NJ, Prentice Hall. Reprinted by permission.
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Single
Innervations
Symp. NS
Parasymp. NS
Dilator pupilae muscle
Adrenal Medulla
Ventricles
BV
Sweat Gland
Kidney
Constrictor pupillae
muscle
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Figure 13.1
Functional divisions of the peripheral nervous system.
Primary Neurotransmitters of
Autonomic Nervous System


Norepinephrine (NE)…………..adrenergic
neurotransmission
Acetylcholine (Ach)…………….cholinergic
neurotransmission
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Acetylcholine

1.
2.
3.
4.
5.
6.
Released by
All preganglionic nerve fibers
Preganglionic sympathatic nerves to adrenal
medulla
All postganglionic parasympathatic nerves
Postganglionic sympathatic nerve to sweat
glands
All somatic nerves.
CNS
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Cholinergic Transmission (Cont.)
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Rate limiting
step
ATP &
proteoglycan
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Cholinergic Receptors
Muscarinic Receptors
Nicotinic Receptors
(Peripheral Cholinergic )
(Central Cholinergic) R.)
Strong affinity to muscarine
Weak affinity to nicotine
Weak affinity to muscarine
Strong affinity to nicotine
-Parasympathetic supplying
effector organs
-Sweat gland
- CNS
-Autonomic ganglia (Nn)
- Adrenal Medulla (Nn)
- Neuromuscular junction (Nm)
-CNS (Nn)
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Nicotinic receptors

Composed of 5-subunits and functions as ligand-gated channel

Binding of two Ach molecules elicits a conformational change that
allows the entry of sodium ions, resulting in depolarization of the
effector cell

Nm (blocked by
hexomethonium)
tubocurarine)
differs
from
Nn
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(blocked
by
Muscarinic Receptors
M1 (Neural)
- CNS
- Gastric parietal cells
M2 (Cardiac)
-CNS Presynaptically
- Atria and conducting
tissue
↑ Phospholipase C
↓ Adenylate cyclase
Atropine & Pirenzepine
Atropine & Gallamine
M3 (Glandular)
-Exocrine gland
-Smooth muscles
-Vascular endothelium
↑ Phospholipase C
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Atropine
Sympathatic neurotransmission




Norepinephrine is released by most
postganglionic sympathatic nerves
Dopamine is released by postganglionic
nerves stimulating the kidney.
ACH
is
released
by
Postganglionic
sympathatic nerve to sweat glands
Adrenal medulla acts as ganglia releasing
epinephrine and NE.
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Adrenergic Transmission

Neurotransmitter: Two catecholamines NA
& Ad

Sites of Release:
Post ganglionic sympathetic nerve ending (80% NA &
20% Ad)
- Adrenal Medulla (80% Ad & 20% NA)
- CNS
-
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Adrenergic receptors



Alpha—A1 and A2
Beta—B1, B2, B3
Dopamine—subsets D1-5
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Adrenergic
Adrenergic
Adrenergic
AdrenergicReceptors
Receptors
Receptors
Receptors
αα Subtype
Subtype
α1
ββSubtype
Subtype
α2
↑ Phospholipase C
smooth muscles
β1, β2 & β3
↓ Adenylate cyclase
↑ Adenylate cyclase
- Presynaptic adrenergic
nerve terminal
CNS-
β1 (heart)
β2 (smooth muscles)
β3 (lipocytes)
β cells of pancreas-
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Alpha1-adrenergic Receptors


In all sympathetic target organs except heart
Response


Constriction of blood vessels
Dilation of pupils
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Alpha2-adrenergic Receptors


At presynaptic adrenergic neuron terminals
Activation inhibits release of norepinephrine
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Beta1-adrenergic Receptors


In heart and kidneys
Response


Activation increases heart rate and force of
contraction of heart.
Increases release of renin
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Beta2-adrenergic Receptors


In all sympathetic target organs except the
heart
Inhibit smooth muscle
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Organ
Sympathetic
R
Parasympathetic
R
Heart
Stimulant
β1
Depressant of atria
M2
Constriction
Dilation
(BV Sk. M.)
α
β2
No innervation
(dilation by EDRF)
M3
Kidney Vasculature
D
No innervation
β2
Constriction
↑ Secretion
M3
M3
↓ motility
Constriction
-----
β2
α1
↑ motility
Dilation
↑ Secretion
↑Gastric acid
Enteric system
M3
M3
M3
M1
M1
Smooth Muscles
a- BV
b- Bronchi
c- GIT
Smooth muscle
Sphincter
Glands
d- Urinary Bladder
Smooth muscle
Relaxation
β2
Contraction
Sphincter
Constriction
α1 Inc., an affiliate ofDilation
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M3
M3
Organ
Sympathetic
R
e- Eye:
* Iris
-Radial muscle
-Circular muscle
*Ciliary Muscle
Contraction
α1
Glands:
Salivary Glands
Lacrimal Glands
Sweat Glands:
Thermoregulatory
Apocrine (stress)
Parasympathetic
R
M3
M3
M3
M3
Relaxation
(slight)
β2
Constriction
Contraction
↑ Secretion
No effect
α1, β2
--------
↑ Secretion
↑ Secretion
↑ Secretion
↑ Secretion
M3
α1
Metabolic Functions:
Liver
Gluconeogenesis
Glycogenolysis
Adipose tissue
Lipolysis
Kidney
Renin release
β2
β2
β3
β1
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Five Mechanisms by Which
Drugs Can Affect Synaptic
Transmission
1.
2.
3.
Affect the synthesis of the neurotransmitter
in the presynaptic nerve.
Prevent storage of the neurotransmitter in
vesicles within the presynaptic nerve.
Influence release of the neurotransmitter
from the presynaptic nerve.
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Five Mechanisms by Which Drugs Can
Affect Synaptic Transmission (cont'd)
4.
Prevent the normal destruction or reuptake
of the neurotransmitter.
5.
Bind to the receptor site on the postsynaptic
target tissue
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Drugs Not Given to Correct
Autonomic Nervous System


System is relatively free of disease
Drugs used to stimulate or inhibit target
organs of the autonomic nervous system
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Classification and Naming of
Autonomic Drugs

1.
Based on four possible actions of sympathetic
and parasympathetic nervous systems
Stimulate sympathetic nervous system

2.
Adrenergic agents or sympathomimetics
Inhibit sympathetic nervous system

Adrenergic-blocking
agents,
antagonists, or sympatholytics
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adrenergic
Classification and Naming of
Autonomic Drugs (cont'd)
3.
Stimulate parasympathetic nervous system

4.
Cholinergic agents or parasympathomimetics
Inhibit parasympathetic nervous system

Cholinergic-blocking agents, anticholinergics,
parasympatholytics, or muscarinic blockers
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Cholinergic Agonists

They act:

Directly → Receptor (choline receptors)

Indirectly → Drugs that inhibit destruction
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of ACh
Direct-Acting Cholinergic Agonist


These agents are:







Synthetic ester of choline e.g. carbachol & bethanichol
Naturally occurring alkaloids e.g. pilocarpine
They are called “Muscarinic Agonists”
ACh has NO therapeutic value
The key features of Ach molecule:
The quaternary ammonium group
The ester group
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Muscarinic Agonists
 Substitution of acetyl
gp by carbamyl gp →
Carbachol

Addition of methyl gp
on β carbon →
Methacholine

Combining these two
modification →
Bethanichol

Pilocarpine: Tertiary
amine
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Effects of Muscarinic Agonists








Cardiovascular effect:
Heart: Slowing the heart
BV: Dilation
BP: ↓
Exocrine Glands:
Sweating
Lacrymation
Salivation
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Effects of Muscarinic Agonists
Smooth Muscles:

Bronchi: Bronchoconstriction & ↑ secretion

GIT: ↑ motility, sphincter dilation, ↑ gastric secretion

Urinary Bladder: ↑ motility of detrusor urinae muscle,
sphincter dilation (bladder emptying)

Eye: - Contraction of pupillae sphincter muscles → miosis and
widening of filtration angel
- Contraction of ciliary muscles → accommodation
vision and opening of canal of schlemm
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to
near
Clinical Uses of Muscarinic Agonists
Glaucoma: Pilocarpine

(action lasts for 1 day), the most
effective as being a tertiary amine, it can cross the conjunctival
membrane.

Bladder emptying in case of neurological disease or
surgery: Carbachol & Bethanichol

Hair preparation: Pilocarpine, it promotes hair growth by
dilation of scalp blood vessels.

Atropine Poisoning: Pilocarpine
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Adverse Effects of Muscarinic Agonists






Hypotension
Sweating & Salivation
Bronchospasm
Nausea, abdominal pain & diarrhea
Urinary urgency
Miosis
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Indirect-acting
cholinergic agonist
 Inhibition of ChE is
either reversibly or
irreversibly
 Accumulation of Ach
in
the
synaptic
spaces which can
stimulate:



Both M & N of ANS
Nm
In brain
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Reversible Anticholinesterase

Quaternary amines:

Neostigmine
Pyridostigmine
Edrophonium

Tertiary amines:



Physostigmine (eserine)
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Effects of Reversible antiChE




An enhancement of cholinergic transmission at
cholinergic
autonomic
synapses
&
the
neuromuscular junction
Physostigmine → Eye, GIT, Urinary bladder & CNS
Neostigmine → GIT, Urinary bladder & Sk. M.
Pyridostigmine & Edrophonium → Sk. M.
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Clinical Uses of Reversible antiChE

In glaucoma: Physostigmine (eye drops)

In intestinal & bladder atony: Physostigmine & Neostigmine

In anesthesia: Neostigmine (IV), it reverses the action of nondepolarizing neuromuscular blocking drugs.


In overdose of drugs with anticholinergic actions such as
atropine, phenothiazines & TCA
In treatment of Myasthenia gravis
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Dental choliergic

1- encourage patients to use good oral
hygiene.

2- Raise the patient from the dental chair
slowly to avoid hypotension
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Cholinergic Antagonists

They include 3 classes:
1. Muscarinic Antagonist
2. Ganglion Blockers (Nn)
3. Neuromuscular Blockers (Nm)
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1. Muscarinic Antagonists

They block muscarinic receptors competitively,
causing inhibition of all muscarinic functions

They are effective in several clinical situations
unlike cholinergic agonists
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Muscarinic Antagonists (cont.)

Drugs belong to this group
a- Atropine & Hyoscine (scopolamine)
(natural
alkaloids)
b- Homatropine (synthetic comp.)
c- Atropine methonitrate (quaternary comp.)
d- Ipratropium (quaternary comp.)
e- Pirenzepine (selective M1 antagonist)
f- Cyclopentolate and tropicamide (tertiary
developed for ophthalmic use)
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amines
Effects of Muscarinic Antagonists

Cardiovascular effect:
• Heart: Small dose (bradycardia, CIC)
Larger dose (block M2 at SA node, tachycardia 8090 beat/min)
• BV: No effect
• BP: No effect

Exocrine glands:
• At low dose, it inhibits salivary, lachrymal, bronchial & sweat
glands
• Inhibition of secretions by sweat glands can cause elevated
body temp
• It produces uncomfortable dry mouth & skin
• Gastric secretion is only slightly reduced
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Effects of Muscarinic Antagonists (cont.)

Smooth Muscles:
• Eye:
- Iris: Passive mydriasis & becomes unresponsive to light
- Ciliary Muscle: Paralysis of accommodation (cycloplegia)
- In patient with narrow angel glaucoma, IOP may rise dangerously, so
short acting antimuscarinic tropicamide or α agonist phenylephrine are
more preferred in ophthalmic examination

CNS:
• Excitatory, at low dose (restlessness) & at high dose (agitation &
disorientation)
• In poisoning, rise in body temp. & hypereactivity
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Clinical Uses of Muscarinic Antagonists

Cardiovascular:
• Treatment of heart block (atropine)

Ophthalmic:
• Mydriatic

Neurological:
• Prevention of motion sickness (scopolamine)
• Reduce
involuntary movement & rigidity
Parkinsonism (benztropine)
• Nocturnal enuresis (TCA is more preferred)
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in
case
of
Clinical Uses of Muscarinic Antagonists (cont.)

Respiratory:
• Treatment of asthma & COPD (ipratropium)
• To dry secretions & prevent reflex bronchconstriction during
anesthesia (atropine or hyoscine)

GIT:
• Antispasmodic action & suppress gastric acid secretion
• Hyoscine is used in case of endoscopy & pirenzepine in case of
peptic ulcer (H2 antagonists are more preferred)
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Clinical Uses of Muscarinic Antagonists (cont.)

Antidote for cholinergic agonists:
• Atropine
is used for the treatment of overdoses of
cholinesterase inhibitors such as:
• physostigmine & organophosphate insecticides
• Mushrooms (muscarine)
• The ability of atropine to enter CNS is of particularly
importance
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Adverse Effects of Muscarinic Antagonists

Dry mouth & blurred vision

Tachycardia

Restlessness, confusion, hallucination & delirium

Flushing & fever
In elderly:


Glaucoma
Prostatic enlargement
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2. Ganglion Blockers (Nn)

They block nicotinic receptors of autonomic
ganglia, therefore they are rarely used
therapeutically
(experimental
tools
in
pharmacology)
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3. Neuromuscular Blockers

Drugs can block neuromuscular transmission in three
main ways:
1.
By inhibiting Ach synthesis
e.g. hemicholinum & triethylcholine
2.
By inhibiting Ach release
e.g. botulinum toxins, excess Mg, aminoglycosides
antibiotics
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By interfering with the
postsynaptic action of Ach:
a- Depolarizing Blocking Agents (DNMB)
3.
•
•
Produce initial stimulation followed by failure of transmission
e.g. succinylcholine & decamethonium
b- Competitive Blocking Agents (CNMB)
•
They are pure antagonists
•
e.g. curare & gallamine
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Dental antichloinergic
These drugs are used to create a dry, oral
field.
SIDE EFFECT.
xerostomia:
 1-you have to direct the patient for meticulous
oral hygine including floss and brushing
 2- plenty of water
 3instruct the patient to avoid alcohol
containing
preparations,
as
well
as
caffeinated beverages as they increase
xerostomia
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

4- instruct the patient not to use fruit juice and
soda as they contain sugar and increase risk
of caries
5- recommend to chew sugarless candy to
minimize dry mouth.
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Adrenergic Drugs

These drugs stimulate α and β receptors
throughout the body.

Adrenergic drugs can be classified as having
direct action, indirect action, or mixed action.
1.
Drugs with direct action (epinephrine,
norepinephrine, isoproterenol) produce their
effect by directly stimulating the receptor site.
Drugs with indirect action:
aStimulate
release
of
endogenous
norepinephrine which then stimulates the
receptor; amphetamine.
2.
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20
b- Inhibition of the membrane reuptake of
catecholamines by drugs such as cocaine
and
tricyclic
antidepressants.
c. Inhibition of monoamine oxidase by drugs
such as Tranylcypromine.
3.
Drugs with mixed action (ephedrine) either
directly stimulate the receptor or release
endogenous norepinephrine.
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Adrenergic Drugs

Pharmacology
 Central Nervous System (CNS)
• These drugs produce CNS excitation or
alertness.
• Higher doses produce anxiety, apprehension,
restlessness, and tremors.
 Eye
• These drugs can cause mydriasis.
 Respiratory System
• These drugs cause a relaxation of bronchiole
smooth muscles.
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21
Effects of Adrenergic Agonists

Cardiovascular:
 Heart: ↑HR, contractility » ↑CO + O2
consumption
↑Conductivity (atria, AV node & ventricles)
↑Excitability » arrhythmia
 BV: VD or VC depending on the selective activity
of drug and the anatomic site of vessels
e.g. Skin, Splanchnic, Sk.M., renal BV
 BP: Depends on effect on heart, PR & venous
return
The effect of α-agonist is different from β-agonist
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Adrenergic Drugs
1.
2.
 Metabolic Effects
Hyperglycemia:
 Increase liver glycogenolysis (β2)
 Increase glucagon release (β2)
 Decrease insulin release (α2)
Lipolysis:
 Increase hydrolysis of TG into free fatty acids &
glycerol (β3)
 Salivary Glands
• These drugs produce vasoconstriction of the
salivary glands which leads to decreased salivary
flow which results in xerostomia.
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22
Adrenergic Agents (Sympathomimetics)

Primary use: depends on receptors activated
 Alpha1-receptors:
phenylephrine.
nasal
congestion, hypotension, dilation of pupils for
eye examination
 Alpha2-receptors: clonidine. Hypertension ?
 Beta1-receptors: dobutamine and isoprenaline.
cardiac arrest, heart failure, shock
 Beta2-receptors: sulbutamol and terbutaline.
asthma and premature-labor contractions as
they relax uterine smooth muscle (tocolytics)
 Dopaminergic receptors : dopamine. shock
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
Anaphylactic reactions:
Adrenaline is the first line of treatment for
bronchoconstriction & CV collapse
Haemostatic: adrenaline and ephedrine
Mydriatic: Ephedrine
Glaucoma: Adrenaline decrease IOP in
open angel glaucoma & decrease aqueous
humor production by VC of ciliary body BV
With local anesthetics: Ad & NA
Depression: Amphetamine
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Dopamine


Immediate precursor of NE
Occurs in




CNS (act as neurotransmitter)
Adrenergic nerve ending
Adrenal medulla
Activates:




α1(at high doses)
β1 (at small doses)
D1(occurs in renal vascular bed)
D2 (occurs in presynaptic adrenergic neurons)
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Pharmacological Effects of
Dopamine

CVS:



+ve chronotropic & inotropic effects
At high doses: VC of BV
Renal & visceral:


VD of renal and splanchnic arterioles
Effective in treatment of shock (the drug of choice
taken by continuous infusion)
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Dental Use

Vasoconstriction
• These drugs are used in dentistry because of their
vasoconstrictive actions on blood vessels. They
are added to local anesthetics because they
prolong the action of the local anesthetic, reduce
the risk for systemic toxicity, and help to create a
dry field.
• Act as homeostatic agent aids in control
bleeding
• Cocaine has limited use as a local anesthesic
and vasoconstrictor in surgical procedures
involving oral, laryngeal or nasal cavities.
• But close monitoring regard to cardiac effects
• These drugs raise blood pressure .
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24
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Cautions Relevant to Dentistry
1)
2)
Cocaine and amphetamine-like agents (tricyclic
antidepressants as well) could potentiate the
effects of direct acting agonists such as
epinephrine.
epinephrine can be absorbed systemically after
intraoral administration. This epinephrine can
be taken up by nerve terminals and this uptake
contributes to the termination of the actions of
epinephrine. Thus, the risk of hypertension and
other problems associated with systemic
absorption of epinephrine will be greater in
patients taking cocaine or amphetamine-like
drugs.
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Adrenergic Drugs

Adverse Reactions
 The adverse reactions associated with
these drugs are an extension of the drugs’
pharmacologic effects.
 They include:
• Anxiety
• Tremors
• Tachycardia
• Increased blood pressure
• Arrhythmias
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23
Contraindications to use of
adrenergics






Cardiac dysrhythmias, angina pectoris
Hypertension
Hyperthyroidism
Cerebrovascular disease
Distal areas with a single blood supply such
as fingers, toes, nose and ears
Renal impairment use caution
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epinephrine



Affects both alpha and beta receptors
Usual doses, beta adenergic effects on heart
and
vascular
smooth
muscle
will
predominate, high doses, alpha adrenergic
effects will predominate
Drug of choice for bronchospasm and
laryngeal edema of anaphylaxis
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epinephrine




Excellent
for
cardiac
stimulant
and
vasoconstrictive effects in cardiac arrest
Added to local anesthetic
May be given IV, inhalation, topically
Not PO
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Clonidine


ALPHA2 AGONISTS
Actions
and
Therapeutic
Uses
1. This drug stimulates alpha2 receptors in the
nucleus tractus solitarius (NTS) to decrease
sympathetic outflow to the heart and blood
vessels.
2. The decrease in sympathetic tone results in a
decrease
in
blood
pressure.
3. Clonidine is used in dental practice in the
management of chronic pain. It can be given
orally
or
in
patch
form.
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Inhibits NE
release
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Clonidine is a second-line antihypertensive
that has many other uses including opiate
withdrawal, nicotine withdrawal, vascular
headaches, diabetic diarrhea, glaucoma,
ulcerative colitis.
 Side Effects
The use of clonidine may result in clinical
symptoms related to dry mouth, such as
difficulty in swallowing and speech. Chronic
use of xerostomia-producing drugs is
associated with a higher incidence of oral
candidiasis and dental caries.

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Monoamine Oxidase Inhibitors


These drugs inhibit monoamine oxidase and
are used as antidepressants in psychiatric
practice.
Can precipitate a hypertensive crisis. Patients
taking MAO inhibitors must not be given
drugs that have indirect sympathomimetic
activity or are inactivated by MAO.
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


Occasionally, the dentist may find reason to
use the vasoconstrictor phenylephrine.
Because
it
causes
even
a minor release of norepinephrine from
adrenergic nerves and is subject to
metabolism by MAO.
phenylephrine must be avoided in patients
taking MAO inhibitors.
Epinephrine and levonordefrin, which are
most commonly found in local anesthetic
solutions, are not contraindicated, since they
are direct agonists and are largely inactivated
by catechol-O-methyltransferase.
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

Nonetheless, the avoidance of hemostatic
preparations containing high concentrations
of
epinephrine
is
recommended.
Opioids and other CNS depressants should
be used cautiously and usually at lower
doses
in
patients who are taking MAO inhibitors.
Meperidine is absolutely contraindicated.
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Adrenergic Receptor Antagonist
 α-Blockers:
- Non selective: Phenoxybenzamine & Phentolamine
- α1-Blocker: Prazosin, Terazosin, Doxazosin &
Tamsulosin
- α2-Blocker: Yohimbine (Sympatholytic ?)
 β-Blockers:
- Non selective: Propranolol, Timolol & Nadolol
- β1-Blocker: Atenolol, Metoprolol & Esmolol
 α & β Blocker: Labetalol & carvedilol
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Effects of α-adrenoceptor
Antagonists





The most important effect is CVS effect
They block α1 receptors causing decrease in
peripheral resistance and consequently BP
The resultant hypotension provokes reflex
tachycardia
pupillary constriction
increased motility of GI tract

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Alpha 1 antagonists





Used in Benign Prostatic Hyperplasia.
Produces smooth muscle relaxation of
prostate gland and bladder neck.
Pulmonary hypertension in newborns. Can be
given SC , IM or IV.
May be useful in treating pheochromocytoma
May be used in Raynaud’s disease.
Side Effect : orthostatic hypotension
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Orthostatic hypotension in
dentistry



Orthostatic hypotension is a problem with prazosin
analogs and to a lesser extent tamsulosin.
Significantly, orthostatsis is a problem that can be
seen with any vasodilator that affects the tone on
venous smooth muscle.
This would include, organic nitrates, hydralazine,
clonidine, minixodil and the many drugs.
Orthostatic hypotension or postural hypotension
occurs when systemic arterial blood pressure falls by
more than 20 mmHg upon standing.
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

In this situation, cerebral perfusion falls and
an individual may become light headed, dizzy
or fatality may occur.
In changing from the supine to the standing
position, gravity tends to cause blood to pool
in the lower extremities. However, several
reflexes, including sympathetically mediated
venoconstriction minimize this pooling and
maintain cerebral perfusion. If these reflex
actions do not occur, then orthostatic
hypotension could result.
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


By blocking the alpha1-receptors associated
with venous smooth muscle, prazosin-like
drugs, inhibit the sympathetically mediated
vasoconstriction associated with postural
changes. Hence, orthostatic hypotension can
occur.
Drugs like clonidine cause orthostasis due to
its CNS actions that block the sympathetic
reflexes.
Vasodilators such as nitrates, minoxidil,
hydralazine or impotence medications cause
orthostasis because of their actions directly
on the vasculature.
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
A consideration for patients being treated with
some sympatholytics is the patient's position
during and after dental procedures.
Suddenly standing upright after being in a
supine position in the dental chair is very
probable to cause syncope.
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beta blocking drugs









Decreased heart rate
Decreased force of contraction
Decreased Cardiac Output
Slow cardiac conduction
Decreased automaticity of ectopic pacemakers
Decreased renin secretion from kidneys
Decreased BP
Bronchoconstriction
Less effective metabolism of glucose. May result
in more pronounced hypoglycemia and early s/s of
hypoglycemia may be blocked (tachycardia).
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Uses of Beta blocking
medications





Inderal (propranolol) is prototype
Mainly for cardiovascular disorders (angina,
dysrhythmias,
hypertension,
Myocardial
Infarction and glaucoma.
In angina, beta blockers decrease myocardial
oxygen consumption by decreasing rate, BP and
contractility. Slow conduction both in SA node
and AV node.
Useful in pheochromocytoma in conjunction with
alpha blockers (counter catecholamine release)
migraines
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Combination selectivity




Labetalol and carvedilol (Coreg) block alpha
1 receptors to cause vasodilation and beta 1
and beta 2 receptors which affect heart and
lungs
Both alpha and beta properties contribute to
antihypertensive effects
May cause less bradycardia but more
postural hypotension
Less reflex tachycardia
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Application to dentistry


Because nonselective β-blockers block β2receptor mediated vasodilation, there is a
risk of a hypertensive episode following
administration of local anesthetic agents that
contain epinephrine.
In this situation, the vasoconstrictor actions of
epinephrine at α1 -receptors are not opposed
by the vasodilatory actions of β2-receptors
resulting in an exaggerated blood pressure
response that could be deleterious in patients
with hypertension or ischemic heart disease.
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