PHARMACOLOGY 1

MIDTERM
 PERIPHERAL NERVOUS
SYSTEM (PNS)
o Collection of nerves and ganglia
scattered throughout the brain

o Consists of 12 pairs of cranial

nerves, 31 pairs of spinal
nerves and their branches to
the entire body.
 CRANIAL NERVES
I. Olfactory -sensory
II. Optic - sensory
III. Occulomotor -motor
IV. Trochlear - motor
V. Trigeminal -mixed
VI. Abducens - mixed
VII. Facial -mixed
VIII. Vestibulocochlear -sensory
IX. Glossopharyngeal - mixed
X. Vagus - mixed
XI. Spinal -motor
XII. Hypoglossal -motor

5
 Major subdivisions of the
PNS
1. Autonomic
2. Somatic
3. Enteric nervous system (ENS)
Enteric nervous system

-It includes the myenteric plexus

and the submucous plexus
 Somatic division
– is largely concerned with
consciously controlled functions
such as:
• movement
• Respiration
• posture
 AUTONOMIC
NERVOUS SYSTEM
 AUTONOMIC
NERVOUS SYSTEM
• largely autonomous (independent)
• its activities are not under direct
conscious control.
• concerned primarily with visceral
functions
– cardiac output
– blood flow to various organs
– Digestion
 Autonomic pathway

Preganglionic nerve fiber – terminates and

synapses in an autonomic ganglion

Postganglionic nerve fiber- originates in a

ganglion and terminates in smooth
cardiac muscle or a gland.
 SYMPATHETIC NS PARASYMPATHETIC NS
ORIGIN • thoraco-lumbar • Cranio (III,VII,IX,X)-sacral
(III,IV)
Neurotransmitter
Preganglionic fiber • Acetylcholine • Acetylcholine
Postganglionic fiber
• Norepinephrine • Acetylcholine
Preganglionic fiber

Postganglionic fiber • Short • Long

• Long • Short
Receptors

• Alpha, beta • Muscarinic, nicotinic

 FIGHT!
FLIGHT!
FRIGHT!
ergotropic
activates those organs necessary
during stressful situations such as
exercise, anxiety and fear

SYMPATHETIC ACTIVATION
trophotropic

REST and
DIGEST
PARASYMPATHETIC ACTIVATION
NEUROTRANSMITTERS
 Adenosine triphosphate (ATP)
 May act as a cotransmitter at inhibitory ENS
neuromuscular junctions.
 Inhibits release of ACh and norepinephrine from
ANS nerve endings.
 An excitatory transmitter in sympathetic–smooth
muscle synapses.
NEUROTRANSMITTERS
 Calcitonin gene-related peptide (CGRP)
 Found with substance P in cardiovascular sensory
nerve fibers.
 Present in some secretomotor ENS neurons and
interneurons.
 A cardiac stimulant.
NEUROTRANSMITTERS
 Cholecystokinin (CCK)
 May act as a cotransmitter in some excitatory
neuromuscular ENS neurons.
NEUROTRANSMITTERS
 Dopamine
 A possible postganglionic sympathetic transmitter in
renal blood vessels.
 Probably a modulatory transmitter in some ganglia
and the ENS.
NEUROTRANSMITTERS
 Enkephalin and related opioid peptides
 Present in some secretomotor and interneurons in the
ENS.
 Appear to inhibit ACh release and thereby inhibit
peristalsis.
 May stimulate secretion.
NEUROTRANSMITTERS
 Galanin
 Present in secretomotor neurons
 may play a role in appetite-satiety mechanisms.
 NEUROTRANSMITTERS

 GABA ( gamma- aminobutyric acid)

 May have presynaptic effects on excitatory ENS
nerve terminals.
 Has some relaxant effect on the gut.
 Probably not a major transmitter in the ENS.
NEUROTRANSMITTERS
Gastrin-releasing peptide (GRP)
 Extremely potent excitatory transmitter to gastrin
cells.
 Also known as mammalian bombesin
NEUROTRANSMITTERS
Neuropeptide Y (NPY)
 Present in some secretomotor neurons in the ENS and
may inhibit secretion of water and electrolytes by the
gut.
 Causes long-lasting vasoconstriction.
 It is also a cotransmitter in many parasympathetic
postganglionic neurons and sympathetic postganglionic
noradrenergic vascular neurons.
NEUROTRANSMITTERS
 Nitric oxide (NO)
 A cotransmitter at inhibitory ENS neuromuscular
junctions; especially important at sphincters.
 Probable transmitter for parasympathetic
vasodilation.
NEUROTRANSMITTERS
 Serotonin (5-HT)
 A major transmitter at excitatory neuron-to-neuron
junctions in the ENS.
NEUROTRANSMITTERS
 Substance P (and related "tachykinins")
 Substance P is an important sensory neuron transmitter in
the ENS and elsewhere.
 Tachykinins appear to be excitatory cotransmitters with
ACh at ENS neuromuscular junctions.
 Found with CGRP in cardiovascular sensory neurons.
 Substance P is a vasodilator (probably via release of
nitric oxide).
NEUROTRANSMITTERS
 Vasoactive intestinal peptide (VIP)
 Excitatory secretomotor transmitter in the ENS;
may also be an inhibitory ENS neuromuscular
cotransmitter.
 A probable cotransmitter in many cholinergic
neurons.
 A vasodilator (found in many perivascular neurons)
and cardiac stimulant.
NEUROTRANSMITTERS
Norepinephrine (NE)
The primary transmitter at most
sympathetic postganglionic nerve
endings.
 SYMPATHETIC NERVOUS SYSTEM

Aka: ADRENERGIC SYSTEM

• Neurotransmitter: NOREPINEPHRINE

• Adrenergic nerve fibers

- fibers that release Norepinephrine
 SYMPATHETIC NERVOUS SYSTEM

DOPAMINERGIC SYSTEM

• Neurotransmitter: DOPAMINE

• located in the renal, mesenteric, coronary and

cerebral arteries
5 STEPS OF NEUROTRANSMISSION

1 Synthesis
2 Storage
3 Release
4 Receptor binding
5 Removal of the neurotransmitter from the
synaptic gap
Synthesis of epinephrine
SYMPATHETIC NEUROTRANSMITTER BIOSYNTHESIS

34
 Removal of NE

1. Diffusion
2. Metabolism
3. Reuptake
 Removal of NE

2. Metabolism
Enzymes that inactivate NorEpinephrine
**MAO (Monoamine oxidase)
**COMT (Catechol-O-methyl transferase)

Metabolites
– Are excreted in the urine
– Eg. Vanillyl mandelic acid (VMA), metanephrine,
normetanephrine
NOREPINEPHRINE & EPINEPHRINE METABOLISM

Norepinephrine and Epinephrine is metabolized by catechol-O-

methytransferase (COMT) and monoamine oxidase (MAO). The final
product of these pathways is vanillylmandelic acid (VMA). This final
product, along with its precursors normetanephrine and metanephrine, is
measured in urine and plasma in the diagnosis of pheochromocytoma,
which can cause severe hypertension and cardiac arrhythmias. 37
 Removal of NE

3. Reuptake
• recaptured by an uptake system
– Pulls the NE back to the neuron
– Involves Na+/K+ ATPase

uptake 1 or reuptake 1- transport of NE into the

cell cytoplasm
uptake 2 or reuptake 2- transport of NE into
presynaptic glia or smooth muscle cells
 Drugs that affect
neurotransmission
process example site action
Action Local anesthetics, Nerve axons Block sodium
potential tetrodotoxin,1 channels;
propagation saxitoxin2 block
conduction

Transmitter a-Methyltyrosine Adrenergic Blocks

synthesis (metyrosine)*** nerve synthesis
terminals
and
adrenal
medulla:
cytoplasm
 Drugs that affect
neurotransmission
process example site action
Transmitter Reserpine Adrenergic Prevents
storage terminals: storage,
vesicles Depletes
 Drugs that affect
neurotransmission
process example site action
Transmitter Tyramine, Adrenergic Promote
release amphetamine nerve transmitter
terminals Release
Bretylium, Adrenergic Inhibit
Guanetidine nerve release
terminals
 Drugs that affect
neurotransmission
process example site action
Transmitter Cocaine, tricyclic Adrenergic Inhibit
uptake antidepressants nerve reuptake;
after terminals increase
release transmitter
effect on
postsynaptic
Receptors
6-Hydroxy- Adrenergic Destroys the
dopamine nerve terminals
terminals
 Distribution of Adrenoceptor
Subtypes
Type Tissue Actions

a1 Most vascular smooth Contraction

muscle (innervated)

Pupillary dilator muscle Contraction

(dilates pupil)
Pilomotor smooth muscle Erects hair
 Distribution of Adrenoceptor
Subtypes
Type Tissue Actions

a1 Penis, seminal vesicles ejaculation

Bladder/sphincter contraction

Sweat glands (apocrine) Increase

stress secretions
 Distribution of Adrenoceptor Subtypes
Type Tissue Actions

a2 Postsynaptic CNS Probably multiple

adrenoceptors
Platelets Aggregation
Adrenergic and Inhibition of
cholinergic nerve transmitter
terminals release
Distribution of Adrenoceptor Subtypes

Type Tissue Actions

a2 Some vascular Contraction

smooth muscle
Fat cells Inhibition of
lipolysis
Distribution of Adrenoceptor Subtypes

Type Tissue Actions

B1  Increases
force and
rate of
contraction
 Distribution of Adrenoceptor Subtypes

Type Tissue Actions

B2 Respiratory, Promotes smooth

uterine, and muscle relaxation
vascular smooth
muscle
Skeletal muscle Promotes
potassium uptake
Human liver Activates
glycogenolysis
Distribution of Adrenoceptor Subtypes

Type Tissue Actions

B3 Fat cells Activates

lipolysis
D1 Smooth muscle Dilates renal
blood vessels
D2 Nerve endings Modulates
transmitter
release
 ADRENERGIC DRUGS

• stimulate the sympathetic NS

• adrenergic agonist, sympathomimetic,
adrenomimetic
• they mimic NE and Epinephrine
• act on one or more receptor sites
 Classification of Sympathomimetic/adrenergic
Drugs According to their effect on organ cells

• Direct – acting
• Indirect – acting
• Mixed – acting
 Classification of Sympathomimetic/adrenergic
Drugs According to their effect on organ cells

1. Direct-acting
– directly stimulate the adrenergic receptors
 Indirect-acting
• stimulate the release of NE from the terminal
nerve ending - amphetamine
 Mixed -acting
• both - ephedrine
 ADRENERGIC agonists

• Derivatives of beta phenylethylamine

• Important features:
– Location of OH substitutions on the benzene ring
– Nature of substituent on an amino nitrogen
 CATECHOLAMINES

• Sympathomimetic amines
– Contain dihydroxybenzene group
• Epinephrine
• NE
• Isoproterenol
• Dopamine
**Catechol
– 1,2-dihydroxybenzene
 Properties of catecholamines

• High potency
– OH groups show highest potency in activating alpha or beta
receptors
• Rapid inactivation
– COMT (POSTSYNAPTICALLY), gut wall
– MAO (intraneurally), liver, gut wall

• Poor penetration into the CNS

– polar
 Non - catecholamines

• Compounds lacking catechol hydroxyl groups

• Have longer half life (not inactivated by COMT)

Examples:
• Phenylephrine
• Ephedrine
• Amphetamine
 Mixed alpha and beta agonists

Epinephrine (adrenaline)
• synthesized from tyrosine in the adrenal medulla
• is a very potent vasoconstrictor and cardiac
stimulant.

• a1= a2 : ß1 = ß2
 Mixed alpha and beta agonists

• Epinephrine (adrenaline)

USES:
1. is the agent of choice for Anaphylactic shock
– (0.3–0.5 mg (0.3–0.5 mL of 1:1000 epinephrine
solution)
 Mixed alpha and beta agonists

• Epinephrine (adrenaline)
USES:
2. treat bronchospasm and hypersensitivity
reactions
– rapidly acting bronchodilator when injected
subcutaneously (0.4 mL of 1:1000 solution) or inhaled
as a microaerosol from a pressurized canister (320 g
per puff)
 Mixed alpha and beta agonists

• Epinephrine (adrenaline)
USES:
3. It is also used to prolong the activity of local
anesthetic solutions (1:100,000)
 Mixed alpha and beta agonists

• Epinephrine (adrenaline)
USES:
4. to restore cardiac activity in cardiac arrest.
• Epinephrine (adrenaline)
USES:
5. It is also used topically in the treatment of
glaucoma (2% soln)
• Epinephrine (adrenaline)
USES:
6. Local application of epinephrine is used to arrest
blood flow in epistaxis and gingival surgery.
 Mixed alpha and beta agonists

Norepinephrine (levarterenol, noradrenaline)

• have similar effects w/ Epi on beta 1 receptors

• similar potency at alpha receptors

a1= a2 : ß1 >> ß2
 Alpha agonists

USES:
A. Systemically in certain types of hypotension

B. Locally for nasal or conjunctival decongestion

or as adjuncts in infiltration anesthesia
 Alpha-1 agonists

• A.1 Methoxamine
– direct-acting a1-receptor agonist.

– For hypotension (parenteral)

 Alpha-1 agonists

• A.2 Midodrine
– MOA:
Activates phospholipase C, resulting in increase
intracellular calcium and vasoconstriction
– Effects:
Vascular smooth muscle contraction --- increasing BP
– Used in the treatment of postural hypotension, typically
due to impaired autonomic nervous system function
– prodrug that is hydrolyzed to desglymidodrine
 Alpha-1 agonists

B. Decongestants
B.1. Phenylephrine
B.2. Phenylpropanolamine
B.3. Xylometazoline & oxymetazoline (topical)
 Alpha-1 agonists

• B.1 Phenylephrine
– Has longer duration of action than the catecholamines.
Because it is not a catechol derivative
it is not inactivated by COMT
a1 > a2 >>>> ß
• mydriatic (used to facilitate examination of the retina)
and decongestant for minor allergic hyperemia and
itching of the conjunctival membranes.
 Alpha-1 agonists

B. 2 Phenylpropanolamine (PPA)
• over the-counter agent combined in numerous weight
reduction and cold medications.

 It has been withdrawn from over-the-counter use in

the USA because of concerns regarding an association
with hemorrhagic stroke.
 Alpha-1 agonists

B.3. Xylometazoline & oxymetazoline

(topical)
****When taken in large doses, oxymetazoline
may cause hypotension, presumably because
of a central clonidine-like effect
 Alpha-1 agonists

• Sympathomimetics administered as ophthalmic

drops are also useful in localizing the lesion in
Horner's syndrome
 Alpha-1 agonists

What is Horner's syndrome?

a condition, usually unilateral that results from

interruption of the sympathetic nerves to the face.
The effects include vasodilation, ptosis, miosis, and
loss of sweating on the side affected.
caused by either a preganglionic or a postganglionic
lesion, such as a tumor .
 Alpha-1 agonists

postganglionic lesion
indirectly acting sympathomimetics will not dilate the pupil

Phenylephrine – direct acting will dilate the pupil

Preganglionic lesion will show a normal

response to both drugs
 Alpha agonists

Dipivefrin
• Non selective alpha AGONIST
• Prodrug of epinephrine
• Topical drops ---used in Open-Angle
Glaucoma
 Alpha 2 SELECTIVE agonists

 Clonidine
 Methyldopa
 Guanfacine
 Guanabenz

 USE: for the treatment of hypertension

 ADR: sedation
 Alpha 2 agonists
MECHANISM OF ACTION:
 Inhibits adenylyl cyclase thereby
inhibiting the release of norepinephrine from
sympathetic nerve endings
 Alpha 2 SELECTIVE agonists

Clonidine
Additional uses:
• Used in the treatment of diarrhea in diabetics with
autonomic neuropathy
• diminishes craving for narcotics and alcohol during
withdrawal and may facilitate cessation of cigarette
smoking
• used to diminish menopausal hot flushes and is
being used experimentally to reduce hemodynamic
instability during general anesthesia
 Alpha 2 SELECTIVE agonists

Dexmedetomidine
• centrally acting ALPHA 2-selective agonist
• indicated for sedation of initially intubated
and mechanically ventilated patients during
treatment in an intensive care setting.
 Alpha 2 SELECTIVE agonists

Apraclonidine and Brimonidine

• also lower intraocular pressure and are
approved for use in glaucoma.
• With direct neuroprotective effects
 Alpha 2 SELECTIVE agonists

Tizanidine
• Central muscle relaxant
 beta agonists

• Isoproterenol (isoprenaline)
ß1= ß2 >>>> a
EFFECTS:
1. positive chronotropic and inotropic actions

2. Bronchodilatation 3. peripheral vasodilatation

 Beta2 agonists

• Albuterol
• Terbutaline
• Metaproterenol ANTI-ASTHMA
• Pirbuterol DRUGS
• salmeterol
• Formoterol

ß2>>> ß1 >>>> a
 Beta2 agonists
• Albuterol
• Terbutaline
• Metaproterenol
• Pirbuterol
• salmeterol
• Formoterol
 Beta2 agonists

• salmeterol
long-acting agents
• Formoterol DOA: > 12 hours
as a result of high lipid solubility
 Beta2 agonists

What are the different routes of administration of

adrenoceptor agonists used in asthma?

inhalation
oral route
Parenteral route
Which has the greatest local effect on airway
smooth muscle with the least systemic toxicity
 Beta2 agonists

• Terbutaline
TOCOLYTIC
• Ritodrine DRUGS

Used to achieve uterine relaxation in premature

labor
 Beta 1 selective agonist

• Dobutamine

• used as a pharmacologic cardiac

stress test
 Beta 1 selective agonist

Two isomers of Dobutamine

• (+) isomer
– is a potent beta 1 agonist and an alpha1
receptor antagonist.
• (–) isomer
– is a potent alpha 1 agonist, capable of causing
significant vasoconstriction when given alone
– This action tends to reduce vasodilation and may also
contribute to the positive inotropic action caused by
the isomer with predominantly beta-receptor activity.
 Dobutamine

Major limitation
• Tolerance – prolong use
• Chronic cardiac stimulation in patients with
heart failure may worsen long-term outcome
 Beta 1 selective agonist

PRENALTEROL
– Partial agonist
 Dopamine agonist

• Dopamine
– the immediate metabolic precursor of
norepinephrine
– activates D1 receptors in several vascular beds, which
leads to vasodilation

At low doses= decrease peripheral resistance

(vasodilatation)
 At higher rates of infusion=vasoconstriction
 Dopamine agonist

• Dopamine
Consequently, high rates of infusion of dopamine
may mimic the actions of epinephrine

 D1= D2 >>> ß >>>a

Dobutamine and Dopamine
– Sympathomimetic amines

• USES:
– For heart failure
• produces an increase in cardiac output
• May have a role in cardiogenic shock
 Dopamine 1 agonist

• Fenoldopam
• peripheral vasodilation in some vascular beds.

• for the treatment of severe hypertension (IV)

• D1 >> D2
 Dopamine 2 agonist

• Bromocriptine
• MOA:
Inhibits adenylyl cyclase and interacts with
other intracellular pathways
• Effects:
Mimics dopamine actions in the CNS
• Uses:
Parkinson’s disease, prolactinemia
 Other Sympathomimetics

CNS stimulants
– Ephedrine
– Amphetamine
 Other Sympathomimetics

Ephedrine
 the first orally active sympathomimetic drug.
 It is found in Ma-huang, a popular herbal
medication
 noncatechol phenylisopropylamine
 Its ability to activate B receptors probably accounted
for its earlier use in asthma.
 occasionally useful in the treatment of stress
incontinence.
 Other Sympathomimetics

Ephedrine
• Compared with epinephrine , ephedrine has:
– Longer duration
– Orally active
– More pronounced central effects
• (gains access to the central nervous system)
– Lower potency
 Other Sympathomimetics

Amphetamine
• Phenylisopropylamine

 Its peripheral actions are mediated primarily

through the release of catecholamines.
 Other Sympathomimetics

Amphetamine
• penetrate the blood–brain barrier
• it has marked stimulant effects on mood and
alertness and a depressant effect on
appetite.
 Other Sympathomimetics

Amphetamine
USES: ADVERSE effects:
• CNS stimulant – insomnia
• For narcolepsy – Restlessness
• For exogenous – Tremor
obesity – Anxiety
(appetite-suppressing effect) – high doses: induces
paranoid state
 Other Sympathomimetics

Amphetamine
• misused results to “doping” effect
– there is a risk of dangerous physical overexertion.
– Because of the absence of a sense of fatigue, a drugged
athlete may be able to mobilize ultimate energy reserves. In
extreme situations, cardiovascular failure may result
 Other Sympathomimetics

Methamphetamine
• (N-methylamphetamine)
• is very similar to amphetamine with an even
higher ratio of central to peripheral
actions.
 Other Sympathomimetics

Phenmetrazine
• a variant phenylisopropylamine with
amphetamine-like effects.
• anorexiant
• also a popular drug of abuse
 Other Sympathomimetics

• for ADHD
– Methylphenidate and pemoline
 Other Sympathomimetics

Methylphenidate and pemoline

are amphetamine variants whose
major pharmacologic effects and abuse
potential are similar to those of
amphetamine.

 Used in some children with attention

deficit hyperactivity disorder
 Other Sympathomimetics

Pemoline

• ADR: life-threatening hepatic failure

 Other Sympathomimetics

Modafinil
• new drug with both similarities to and
differences from amphetamine.
• has significant effects on central 1B receptors
but in addition appears to affect GABAergic,
glutaminergic, and serotonergic synapses

• approved for use in narcolepsy

Tyramine
• normal by-product of tyrosine metabolism
• metabolized by MAO
• inactive when taken orally because of a very
high first-pass effect
 Tyramine containing foods

• Beer
• Broad beans, fava beans
• Cheese, natural or aged
• Chicken liver
• Chocolate
• Sausage, fermented (eg, salami, pepperoni,
summer sausage)
• Smoked or pickled fish (eg, pickled herring)
• Snails, red wine, Yeast
Tyramine + MAO inhibitors= Hypertensive crisis


Norepinephrine
levels
CATECHOLAMINE REUPTAKE
INHIBITORS

Atomoxetine
Reboxetine
Duloxetine
Milnacipran
Sibutramine
Cocaine
 Other Sympathomimetics

Atomoxetine
• selective inhibitor of NE reuptake transporter
• For ADHD
• Cause orthostatic tachycardia
 Other Sympathomimetics

Duloxetine
• with balance serotonin and NE reuptake
inhibitory effects
• antidepressant
• Cause orthostatic tachycardia
 Other Sympathomimetics

Milnacipran
• Serotonin and NE reuptake inhibitor
• For the treatment of pain in fibromyalgia
 Other Sympathomimetics

Sibutramine
• inhibits neuronal reuptake of NE and serotonin

• It diminishes appetite and is classified as an

antiobesity agent
 Other Sympathomimetics

Cocaine
• with a peripheral sympathomimetic action
• readily enters the central nervous system and
produces an amphetamine-like effect that is
shorter lasting and more intense
 Other Sympathomimetics

Cocaine
• MOA : inhibition of transmitter reuptake at
noradrenergic synapses

• Major action in CNS:

– to inhibit dopamine reuptake into neurons
in the "pleasure centers" of the
brain.
 Other Sympathomimetics

Cocaine
– Methods of admin:
• smoked, "snorted" into the nose, or
injected for rapid onset of effect
 Other Sympathomimetics

Cocaine
ADR’s:
• Precipitate convulsions
• Cerebral hemorrhage
• Arrhythmias
• Myocardial infarction