NCM 205 - PHARMACOLOGY LABORATORY

GO, K.F.L. – N01

BSN 2
TERMS - It is concerned primarily with visceral
 GANGLIA - Are group of nerve cell bodies, functions such as
usually located outside the brain and spinal •Cardiac Output
cord. •Blood flow to various organs
- It function as RELAY STATIONS •Digestion
between preganglionic and second - Which are necessary for life
nerve cell, the postganglionic neurons (Homeostatic functions)
 NEUROTRANSMITTERS - Are chemical
mediators that transmit nerve impulses
across junctions such as synapse.
- Chemicals by which neurons
communicate.
- The substance release by a neuron.
- Has a specific shape to fit into a
receptor site and cause pharmacological
response such as nerve impulse.
 SYNAPSE - The region of communication
between neuronsQ
- Locus or site of communication between
neurons
 RECEPTOR - Portion of a sensory neuron
that responds to the external stimuli
- Drug molecules or hormones.
- Site of biophase to which drug
molecules can be bound.

DIVISION
> SYMPHATHETIC (thoracolumbar)
> PARASYMPATHETIC (craniosacral)
- Neurons in both divisions originate in nuclei within
the CNS and give rise to preganglionic efferent
SOMATIC DIVISION fibers that exit from the brain stem or spinal cord
- Largely concerned with consciously and terminate in motor ganglia.
controlled functions such as SYMPATHETIC NERVOUS SYSTEM
•Respiration - The sympathetic preganglionic fibers
•Posture •leave the CNS through the thoracic and lumbar
•Movement spinal nerves. (T1 –T12, L1 –L5)
AUTONOMIC NERVOUS SYSTEM •are short and
- Largely autonomous (independent) in  terminate in ganglia located
that its activities are not under direct  in the paravertebral chains that lie on either
conscious control side of the spinal column.
NCM 205 - PHARMACOLOGY LABORATORY
GO, K.F.L. – N01
BSN 2
- The remaining sympathetic
preganglionic fibers are somewhat
longer and terminate in prevertebral
ganglia, which lie in front of the
vertebrae, usually on the ventral surface
of the aorta.
- From the ganglia, postganglionic
sympathetic fibers run to the tissues
innervated.
Location of preganglionic neurons
 T1-T12; L1-3
Location of ganglia
 Principally in the paravertebral and
prevertebral ganglia
Preganglionic fibers –short, myelinated
Postganglionic fibers –long, nonmyelinated
Types of activation
 synchronized
Types of receptors
 Alpha, beta, dopamine
Branching of preganglionic fibers
 Extensive
PARASYMPATHETIC NERVOUS SYSTEM
 The parasympathetic preganglionic fibers
- leave the CNS through the cranial
nerves (especially the 3RD, 7TH,9TH,
10TH) 10973
- 3RD& 4thsacral spinal nerve roots
- Some preganglionic parasympathetic
fibers
- terminate in parasympathetic ganglia
located outside the organs innervated:
• ciliary
• pterygopalatine
• submandibular
• otic and
• several pelvic ganglia.
- majority of parasympathetic
preganglionic fibers terminate on
ganglion cells
Distributed diffusely or in networks in the
walls of the innervated organs.
Location of preganglionic neurons
- CN 10973•S2-4
Location of ganglia
- Principally distributed diffusely in the
wall of the innervated tissue
Preganglionic fibers –long, myelinated
Postganglionic fibers –short, nonmyelinated
Types of activation
- Localized
Types of receptors
- Muscarinic and nicotinic
Branching of preganglionic fibers
- Limited
SYMPATHETIC VS PARASYMPATHETIC
-By using drugs that mimic or block the
actions of chemical transmitter, we can
selectively modify many autonomic
functions
- These autonomic functions involve a
variety of effector tissues
• Cardiac muscle
• Smooth muscle
• Vascular endothelium
• Exocrine glands
• Presynaptic nerve terminal
- A very large number of drugs used for
other purposes have unwanted effects
on autonomic function
NT CHEMISTRY OF THE ANS
- An important traditional classification of
autonomic nerves is based on the
primary transmitter molecules
• acetylcholine
• norepinephrine
- released from their terminal boutons and
varicosities.
- Large number of peripheral ANS fibers
synthesize and release acetylcholine;
they are cholinergic fibers which release
Ach
PARASYMPATHETIC NT
- Most parasympathetic postganglionic
and a few sympathetic postganglionic
fibers are cholinergic
- A significant number of parasympathetic
postganglionic neurons utilize
• nitric oxide or
• Peptides
- as the primary transmitter or
cotransmitters.
NCM 205 - PHARMACOLOGY LABORATORY
GO, K.F.L. – N01
BSN 2
SYMPATHETIC NT
- Most postganglionic sympathetic fibers
release norepinephrine (also known as
noradrenaline);
- they are noradrenergic (often called
simply “adrenergic”) fibers;
- that is, they work by releasing
norepinephrine (noradrenaline).
- some sympathetic fibers release
acetylcholine.
- Dopamine is a very important
transmitter in the CNS, and there is
evidence that it may be released by
some peripheral sympathetic fibers.
- Adrenal medullary cells, which are
embryologically analogous to
postganglionic sympathetic neurons,
release a mixture of epinephrine and
norepinephrine.
NEUROTRANSMITTERS
WAYS OF STOPPING NTs
 Diffusion
 Enzymatic degradation
 Reuptake
Five key features of neurotransmitter function
provide potential targets for pharmacologic therapy:
 synthesis,
 storage,
 release,
 termination of action of the transmitter, and
receptor effects.
CHOLINERGIC TRANSMISSION
- The terminals and varicosities of
cholinergic neurons contain large
numbers of small membrane-bound
vesicles concentrated near the synaptic
portion of the cell membrane as well as
a smaller number of large dense-cored
vesicles located farther from the
synaptic membrane.
-The large vesicles contain a high
concentration of peptide co-transmitters
whereas the smaller clear vesicles
contain most of the acetylcholine.
NEURONAL TRANSMISSION
- Vesicles are initially synthesized in the
neuron cell body and carried to the
terminal by axonal transport. They may
also be recycled several times within the
terminal.
- Vesicles are provided with vesicle-
associated membrane proteins
(VAMPs),
- which serve to align them with
release sites on the inner neuronal cell
membrane and participate in triggering
the release of transmitter.
- The release site on the inner surface of
the nerve terminal membrane contains
synaptosomal nerve-associated
proteins (SNAPs), which interact with
VAMPs.
- Acetylcholine is synthesized in the
cytoplasm from acetyl-CoA and choline
through the catalytic action of the
enzyme choline acetyltransferase
(ChAT).
- Acetyl-CoA is synthesized in
mitochondria, which are present in
large numbers in the nerve ending.
- Choline is transported from the
extracellular fluid into the neuron
- terminal by a sodium-dependent
membrane choline transporter(CHT)
NCM 205 - PHARMACOLOGY LABORATORY
GO, K.F.L. – N01
BSN 2
- After release from the presynaptic
terminal, acetylcholine molecules may
bind to and activate an acetylcholine
receptor ( cholinoceptor).
- Eventually (and usually very rapidly),
all of the acetylcholine released diffuses
within range of an acetylcholinesterase
(AChE) molecule.
- AChEvery efficiently splits
acetylcholine into choline and acetate,
neither of which has significant
transmitter effect, and thereby
terminates the action of the transmitter
- Most cholinergic synapses are richly
supplied with acetylcholinesterase; the
half-life of acetylcholine molecules in the
synapse is therefore very short (a
fraction of a second).
- Acetylcholinesterase is also found in
other tissues, eg, red blood cells. (Other
cholinesterases with a lower specificity
for acetylcholine, including
butyrylcholinesterase
[pseudocholinesterase], are found in
blood plasma, liver, glia, and many other
tissues.)
ADRENERGIC TRANSMISSION
- Adrenergic neuronstransporta precursor
amino acid (tyrosine) into the nerve
ending,
- then synthesize the catecholamine
transmitter, and finally store it in
membrane-bound vesicles.
- In most sympathetic postganglionic
neurons, norepinephrine is the final
product.
In the adrenal medulla and certain areas
of the brain,
>some norepinephrine is further
converted to epinephrine.
- In dopaminergic neurons, synthesis
terminates with DA
- The conversion of tyrosine to dopa, is
the rate-limiting step in catecholamine
transmitter synthesis.
- It can be inhibited by the tyrosine analog
metyrosine
A high-affinity antiporter for
catecholamines located in the wall of the
storage vesicle (vesicular monoamine
transporter, VMAT) can be inhibited by
the reserpine alkaloids.
>Reserpine causes depletion of
transmitter stores.
- Another transporter (norepinephrine
transporter, NET) carries
norepinephrine and similar molecules
back into the cell cytoplasm from the
synaptic cleft
- NET
>commonly called uptake 1 or reuptake
1
>is partially responsible for the
termination of synaptic activity.
>NET can be inhibited by cocaine and
tricyclic antidepressant drugs,
resulting in an increase of transmitter
activity in the synaptic cleft
- In addition to the primary transmitter
>(norepinephrine)
>adenosine triphosphate (ATP),
>dopamine-β-hydroxylase,
>peptide cotransmitters
- released into the synaptic cleft.
Indirectly acting and mixed
sympathomimetics,
>eg, tyramine, amphetamines, and
ephedrine,
>are capable of releasingstored
transmitter from noradrenergic nerve
endings by a calcium-independent
process.
- These drugs are poor agonists (some
are inactive) at adrenoceptors, but they
are excellent substrates for monoamine
transporters.
- Termination of noradrenergic
transmission results from two
processes:
>simple diffusion - away from the
receptor site (with eventual metabolism
in the plasma or liver) and
>reuptake into the nerve terminal by
NET - or into perisynaptic glia or other
cells.
AUTONOMIC RECEPTORS
- Different autonomic receptor subtypes,
>Muscarinic
>nicotinic cholinoceptors,
>α, β, and dopamine adrenoceptors
- The primary acetylcholine receptor
subtypes were named after the alkaloids
originally used in their identification:
>muscarine
>nicotine,
NCM 205 - PHARMACOLOGY LABORATORY
GO, K.F.L. – N01
BSN 2
>-thusmuscarinic and nicotinic  Nicotinic receptors
receptors. •Located on Na+-K+ ion channels •Respond
ADRENOCEPTOR to Ach and nicotine
- is widely used to describe receptors that 2 major nicotinic subtypes located in ganglia
respond to catecholamines such as and skeletal muscle end plate
norepinephrine >Nn -ANS ganglia
- The general class of adrenoceptors can >Nm –neuromusclar end plate
be further subdivided into
>-adrenoceptor,
>a -adrenoceptor, and
>dopaminereceptor
- types on the basis ofboth agonist and
antagonist selectivity and on genomic
grounds.
Alpha receptors
- Located on vascular smoothemuscle,
presynaptic nerve terminals, blood platelets,
fat cells and neurons in the brain
2 major types NON-ADRENERGIC, NON-CHOLINERGIC
Alpha 1 (NANC) NEURONS
Alpha 2 Autonomic effector tissues
Beta receptors - Gut, airways, bladder
- Located on most types of smooth - Contain nerve fibers that do not show
muscle, cardiac muscle, some the histochemical characteristics of
presynaptic nerve terminals and either cholinergic or adrenergic fibers
lipocytes Peptides
3 major types - Most common transmitter substances
Beta 1 found in these nerve endings, other
Beta 2 substances such as NO synthase and
Beta 3 purines
Dopamine receptors - Present in many nerve terminals
- Subclass of adrenoceptors but with Capsaicin
rather different distribution and functions - Neurotoxin derived from chili peppers
- Important in the renal and splanchnic - Can cause the release of transmitter
vessels and in the brain (substance P) from such neurons
5 major types The enteric system in the gut wall:
Dopamine 1 – most important DA receptor - Is the extensively studied system
on peripheral effector cells containing NANC neurons in addition to
D2 – found on presynaptic nerve terminals cholinergic and adrenergic fibers
D3 - Examples
D4, D5 >NO synthase
CHOLINOCEPTOR >calcitonin gene-related peptide
- denotes receptors (both muscarinic and >Cholecystokinin
nicotinic) that respond to acetylcholine. >Dynorphin•Enkephalins
 Muscarinic receptors >Gastrin-releasing peptide
•Respond to muscarine as well as to Ach >5-hydroxytryptamine
•The effects of activation of these receptors >Neuropeptide Y
resemble those of postganglionic >Somastatin
parasympathetic nerve stimulation >Substance P
•Located primairly on autonomic effector >VIP
cells FUNCTIONAL ORGANIZATION OF AUTONOMIC
ACTIVITY
PARASYMPATHETIC SYSTEM
- Trophotropic (leading to growth)
NCM 205 - PHARMACOLOGY LABORATORY
GO, K.F.L. – N01
BSN 2
- Rest or digest CARDIOVASCULAR EFFECTS
SYMPATHETIC SYSTEM - D1 -dilate renal, celiac, hepatic &
- Ergotropic (leading to energy mesenteric vasculature
expenditure) - Fenoldopam - Dec BP, Inc renal blood
- Fight or flight flow
ADRENERGIC AGONISTS OTHER EFFECTS
RECEPTORS: - Nausea & Vomiting
ALPHA - Alpha 1, Alpha 2 Stimulate medullary chemoreceptor
BETA – Beta 1, Beta 2, Beta 3 trigger zone
CLASSIFICATION OF ADRENERGIC DRUGS - D2 -Dopamine binds to lactotropecells in
 Direct Acting – drugs that bind directly to the the anterior pituitary gland
adrenergic receptors and produce effects Inhibits the release of prolactin
 Indirect Acting - drugs that increase the ENDOGENOUS CATECHOLAMINES: DOPAMINE
amount of norepinephrine to stimulate the BROMOCRIPTINE
adrenergic receptors - Dopaminergic agonist
 Mixed - Treatment for female infertility
ENDOGENOUS CATECHOLAMINES: - Control excessive secretion of growth
EPINEPRHINE AND NOREPINEPHRINE hormones which are associated with
 Vascular Effects adenomas
 Cardiac Effects - Stimulates growth hormone release
 Non Vascular Smooth Muscle ALPHA ADRENERGIC RECEPTOR AGONIST
 Salivary Glands PHENYLEPHRINE AND METHOXAMINE
 Metabolic Response - Selective action on Alpha-1 Adrenergic
 CNS Effects receptor
VASCULAR EFFECTS - Contraction of vascular smooth muscle
- NE to Alpha receptors --> inc BP, - Inc BP; bradycardia
bradycardia PHENYLPROPANOLAMINE
- Vasoconstriction - OTC cold remedy
CARDIAC EFFECTS - Inc risk for hemorrhagic stroke in women
- NE & EPI stimulate Beta 1 receptors MIDODRINE
- inc in heart rate - synthethic; selective alpha 1 adrenergic
- inc rate of force development & agonist
subsequent relaxation is accentuated - vasoconstriction
NON VASCULAR SMOOTH MUSCLE - treatment for postural hypotension
- Alpha 1 -smooth muscle contraction CLONIDINE, GUANABENZ, GUANFACINE,
- Beta 2 -smooth muscle relaxation METHYLDOPA
SALIVARY GLANDS - enters CNS
- NE & EPI bind to secretory cells (a & B) - stimulates selectively Alpha 2 adrenergic
- Alpha 1 stimulation on myoepithelial receptors
cells - contract secretory acinar units - centrally acting in the nucleustractus
- water & electrolyte secretion solitarius of the brainstem
- Beta receptors stimulate production of - moderate decrease in BP,
amylase - reduce venous return, heart rate,
METABOLIC RESPONSE cardiac output
- Glycogenolysis METHYLDOPA
- Inc glucagon secretion - vasoconstrictor in local anesthetics
- Beta 3 - lipolysis; Inc free fatty acids CLONIDINE
CNS EFFECTS - first used as a nasal decongestant
- Ephedrine, Amphetamine - Dec blood pressure
- Stimulate Alpha 1 receptors in the brain - Xerostomia
- *when given to addicts in withdrawal:
blocks N&V, sweating, diarrhea
NCM 205 - PHARMACOLOGY LABORATORY
GO, K.F.L. – N01
BSN 2
OXYMETAZOLINE, TETRAHYDROZOLINE, RITODRINE
XYOMETAZOLINE - Uterine relaxant (tocolytic)
- stimulates alpha2 adrenergic receptors - short-term management for labor
- contraction of smooth muscles in blood - withdrawn from the market
vessels MIXED ACTING ADRENERGIC AGONIST
- Used as nasal decongestant EPHEDRINE
BROMONIDINE AND APRACLONIDINE - causes the release of NT -Epi & NE
- newer alpha 2 agonists - directly stimulates alpha & beta
- decrease intra-ocular pressure in receptors
patients with glaucoma AMPHETAMINE, DEXTROAMPHETAMINE,
BETA ADRENERGIC RECEPTOR AGONISTS METHAMPHETAMINE
 Cardiac and Vascular Effects - CNS active, indirect
 Effects on Bronchial smooth muscles - causes alertness, relief of fatigue,
 Metabolic effects enhanced athletic performance,
ISOPROTERENOL euphoria
 Cardiac and Vascular Effects GENERAL THERAPEUTIC USES
- decreases diastolic BP by Beta 2 - Local vasoconstriction
receptor-mediated vasodilation - Treatment of hypotension & shock
- Increase in systolic BP from Inc CO - Bronchodilation
caused by stimulation of Beta 1 - Uterine relaxation
receptors - Ophthalmic uses
- Inc in heart rate due to stimulation of - Treat allergic states
Beta 1 receptors in the pace maker cells - CNS stimulation
 Effects on Bronchial Smooth Muscle - Treat hypertension
- relaxes bronchioles, prevents ADVERSE EFFECTS
bronchoconstriction - Cardiac disturbances
- non selective MI, heart attack, arrhytmias, ventricular
- development of tolerance fibrillation, hypertensive crisis, rebound
 Metabolic and Other Effects hypertension
- Stimulates glycogenolysis and - CNS reactions
gluconeogenesis in the liver nervousness, excitability, insomnia,
- not as effective as epinephrine dizziness, tremors, xerostomia, sexual
- causes CNS excitation dysfunction
DOBUTAMINE
- Synthetic dopamine
- no effect on dopamine receptors
- Alpha 1 receptor inhibition
- Increase myocardial contractility, CO,
heart rate
- Inotropic effect by stimulation of beta 1
receptors
- for short-term treatment of acute
myocardial insufficiency from CHF, MI,
surgery
SELECTIVE BETA2 ADRENERGIC RECEPTOR
AGONIST
- Metaproterenol, terbutaline, albuterol,
levalbuterol, pirbuterol, salmeterol•Relax
bronchial and uterine muscles
- Dec airway resistance
- Inhaled drugs