NOTRE DAME OF DADIANGAS UNIVERSTY (NDDU)

College of Pharmacy
COURSE TITLE PHARMACOLOGY I COURSE CODE Pharm26
CREDIT UNITS 3 units COURSE Human Physiology and
REQUISITES Pathophysiology
CONTACT HOURS 3 hours/week Contact 6hours/ Week 1 (Online)
54 hours/sem Hours/Date for
this topic ______________
COURSE 2nd Year, Summer SME: Melba M. Roma, RPh, MSPh
PLACEMENT
MODULE 1: Basic Principles of Pharmacology
Content Standards Demonstrate understanding on the basic concepts of Pharmacology
Objectives o Define pharmacology and discuss basic concepts of pharmacokinetics and
pharmacodynamics
o Describe receptor concepts, its interactions, signaling mechanism and drug
action

Flipped vidwatch-

PK- https://www.youtube.com/watch?v=NKV5iaUVBUI&ab_channel=SpeedPharmacology
PD- https://www.youtube.com/watch?v=tobx537kFaI&ab_channel=SpeedPharmacologySpeedPharmacologyVerified
https://www.youtube.com/watch?v=PGzT3cTPah8&ab_channel=ProfessorDaveExplainsProfessorDaveExplainsVerified
https://www.youtube.com/watch?v=t0OEm-cJs40&ab_channel=PharmapediaPharmapedia

PHARMACOLOGY
 The study or science of drugs
 The study of the biochemical and physiologic aspects of drug effects, including (
absorption, distribution, metabolism, excretion, toxicity, and specific mechanism of
drug action (LADMERT)

Two major areas of pharmacology:

1. Pharmacokinetics- refers to the way the body handles absorption, distribution,
metabolism (biotransformation), and excretion of drugs.
2. Pharmacodynamics- refers to the molecular, biochemical, and physiological effects
of drugs, including drug mechanism of action.
Originating in the 19th century, the discipline makes drug development
possible. Pharmacology is one of the cornerstones of the drug discovery process. The
medicinal chemist may create the candidate compound, but the pharmacologist is the one
who tests it for physiologic activity.

Drug  Any chemical that affects the processes of a living organism

- Any substance or product that is used for diagnosis, prevention, treatment/cure of a
disease or is intended to be used to modify or explore physiological systems or
pathological states for the benefit of the patient.

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Drug Nomenclature:
 Chemical name – from the drug’s chemical composition and molecular structure
 Generic name (nonproprietary name) - Name given by the United States Adopted Name
Council
 Trade name (proprietary name) - The drug has a registered trademark; use of the name
restricted by the drug’s owner (usually the manufacturer)

Ex. Chemical name : 2-(p-isobutylphenyl) propionic acid Comment [a1]: Ex. S-CMC, APAP, ASA,

Generic name: ibuprofen

Trade name : Motrin

Pharmaceutics - The study of how various drug forms influence pharmacokinetic and
pharmacodynamic activities

Pharmacokinetics -The study of what the body does to the drug: ADME (from LADMERT)

 Absorption
 Distribution
 Metabolism
 Excretion
Pharmacodynamics -The study of what the drug does to the body: The mechanism of drug
actions in living tissues

Pharmacotherapeutics -The use of drugs and the clinical indications for drugs to prevent and Comment [a2]: Clinical pharmacy

treat diseases

Pharmacognosy -The study of natural (plant, mineral and animal) drug sources

PHARMACOKINETICS

A. General Principles
1. Drug Transport. The movement of drug molecules in the body affects absorption,
distribution, and excretion. Drugs can cross cellular membranes by simple diffusion,
carrier-mediated diffusion, filtration, active transport, or endocytosis. The cell
membrane, being a bimolecular lipid layer, can also act as a barrier to some drugs.
a. Passive diffusion. Most foreign compounds penetrate cells by diffusing as
the un-ionized moiety through the lipid membrane. Factors affecting the
passage of the molecule through a membrane are the molecule’s size and
charge, the lipid-water partition coefficient, and the concentration gradient.

The two types of passive drug transport are simple diffusion and filtration.
1. Simple diffusion
a) Simple diffusion is based on Fick’s Law.

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 dQ/dt = (-D) (A) (dc/dx)

i. The greater the concentration gradient, the greater the

rate of absorption
ii. The larger the absorbing surface, the greater the drug
flux
iii. The diffusion constant, D, is directly proportional to the
temperature and is inversely related to the molecular
size.
iv. The greater the lipid-water partition coefficient, the
greater the drug flux.

b) In simple diffusion, molecules cross the lipid membrane in an

uncharged form. The distribution of the uncharged form is a
function of the pKa of the compound and the pH of the
medium and is expressed by the Henderson-Hasselbalch
equation:
i. If the drug is a weak acid:

pKa = pH + log concentration of unionized acid

concentration of ionized acid

ii. If the drug is a weak base:

pKa = pH + log concentration of ionized base
concentration of unionized base

c) The pH of the medium, therefore, affects the absorption and

excretion of passively diffused drug.
i. Aspirin and other weak acids are best absorbed in the
stomach because of its acidic environment
ii. Alkalinic drugs are best absorbed in small intestine,
which has a higher pH.
iii. Since pH of urine is acidic, a weakly acidic drug can be
extensively reabsorbed into the body from the urine. If
the pH of urine is increased, excretion of the drug can be
increased.

2. Filtration
a) Water, ions, and some polar and nonpolar molecules of low
molecular weight can diffuse through membranes, suggesting
that pores or channels may exist.

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 b) The capillaries of some vacular beds (e.g. in the kidney) have
large pores, which permit the passage of molecules as large as
proteins.

b. Carrier-mediated facilitated diffusion

1) In this type of transport, movement across the membrane is facilitated by

a macromolecule.
2) The properties of carrier-mediated diffusion are as follows:
a) It is a saturable process; that is, external concentrations can be
achieved in which increasing the external/internal concentration
gradient will not increse the rate of influx.
b) It is selective for the chemical structure of a drug; that is, the carrier
mechanism transports only those drugs having a specific molecular
configuration.
c) It requires no energy.
d) It cannot move against a concentration gradient, and, therefore, is
still a diffusion process.

c. Active transport

1) Active transport is similar to carrier-mediated diffusion in several ways:

a) Movement across the membrane is mediated by the macromolecule.
b) It is a saturable process.
c) It is selective for chemical structure.
2) Several important features, however, distinguish active transport from
diffusion processes:
a) It requires metabolic energy; this is often generated by the enzyme
known as Na+-K+-ATPase.
b) It transports molecules against a concentration gradient.
d. Endocytosis is a minor method by which some drugs are transported into cells
1) A vacuolar apparatus in some cells is responsible for the process.

2. BIOAVAILABILITY is the relative rate and extent to which an administered drug

reaches the general circulation; this is especially important when a drug is administered
orally. Factors that influence bioavailability are:

a. Solubility of the drug in the contents of the stomach

b. Dietary patterns
c. Tablet size

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 d. Quality control in manufacturing and formulation

B. Absorption -The rate at which a drug leaves its site of administration and the extent to
which absorption occurs.

 Bioavailability
 Bioequivalent
Bioequivalence. Two related drug preparations are bioequivalent if they show
 Comparable bioavailability
 Similar times to achieve peak blood concentrations.
Therapeutic equivalence. Two similar drug products are therapeutically equal if they
are pharmaceutically equivalent with similar clinical and safety profiles

1. Route of administration is an important determinant of the rate and efficiency of

absorption.

Factors That Affect Absorption:

1. Administration route of the drug

2. Food or fluids administered with the drug
3. Dosage formulation
4. Status of the absorptive surface
5. Rate of blood flow to the small intestine
6. Acidity of the stomach
7. Status of GI motility
Routes -A drug’s route of administration affects the rate and extent of absorption of that
drug.
I. Enteral route (alimentary) - Drug is absorbed into the systemic circulation
through the oral or gastric mucosa, the small intestine, or rectum.
 Oral
 SL
 Buccal
 Rectal
o Advantages:
o Disadvantages:

Drug Absorption of Various Oral Preparations

 Liquids, elixirs, syrups Fastest

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  Suspension solutions ↓
 Powders ↓
 Capsules ↓
 Tablets ↓
 Coated tablets ↓
 Enteric-coated tablets Slowest

Extensive hepatic metabolism may occur before the drug reaches the site of action.
This is known as First-Pass Effect.
o The metabolism of a drug and its passage from the liver into the circulation.
o A drug given via the oral route may be extensively metabolized by the liver before
reaching the systemic circulation (high first-pass effect).
o The same drug—given IV—bypasses the liver, preventing the first-pass effect from
taking place, and more drug reaches the circulation.

Routes that bypass the liver: Sublingual, Transdermal, Buccal, Vaginal, Rectal*,
Intramuscular, Intravenous, Subcutaneous ,Intranasal Inhalation
*Rectal route undergoes a higher degree of first-pass effects than the other routes
listed.

II. Parenteral route- bypass the alimentary tract

 Intravenous - Fastest delivery into the blood circulation
 Intramuscular
 Subcutaneous
 Intradermal
 Intrathecal
 Intraarticular
o Advantages:
o Disadvantages:

III. Miscellaneous route

 Topical - Skin (including transdermal patches), Eyes , Ears , Nose
 Inhalation-lungs
 Vagina

2. Factors affecting drug absorption

a. Solubility of the drug affects absorption
b. Dosage affects the drug’s concentration at its site of action and, thus,
greatly influences the biologic response to the drug. The larger the dose,

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 the greater the effect, until a maximum effect is achieved. This is called
the dose-response relationship.
c. Route of administration affects the area of absorbing surface available
to the drug. Drugs are absorbed more quickly from large surface areas.
1) After any route of administration except intravenous
administration, the absorption of most drugs follows first-order
(exponential) kinetics; thus a constant fraction of drug is
absorbed
2) After IV administration, the absorption of drug follows zero-
order kinetics; thus, a constant amount (i.e.) 100% of drug is
absorbed.

C. Distribution. After absorption or injection, drugs may be distributed into interstitial or

cellular fluids.

1. Once in the circulatory system, some drugs can bind nonspecifically and reversibly
to various plasma proteins; that is to albumins or globulins.
a. In this case, the bound and free drug reach an equilibrium
b. Only the free drug exerts biologic effect; the bound drug stays in the vascular
space, and is not metabolized or eliminated.
2. Some areas of the body (e.g. the brain) are not readily accessible to drug due to
anatomic barriers. The placenta also provides a barrier to some drugs.
3. Some drugs may be sequestered in storage depots; for ex., lipid-soluble drugs in
fatty tissue and in equilibrium with free circulating drug.
4. Eventually, the drug achieves a free state and is excreted either directly or after it
has been metabolized.
5. Factors modifying the distribution of a drug to a particular region of the body:
a. Physical and chemical characteristics of the drug (lipid to water partition
coefficient)
b. Cardiac output
c. Capillary permeability in various tissues
d. Lipid content of the tissue
e. Binding to plasma proteins and tissues

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D. Drug Metabolism (also known as Biotransformation)
It is the biologic transformation of a drug into an inactive metabolite, a more soluble
compound, or a more potent metabolite.
1. Principles:
a. The liver is the major site of metabolism for many drugs or other xenobiotocs,
but other organs, such as the lungs, kidneys, and adrenal glands, can also
metabolize drugs.
b. Many lipid-soluble, weak organic acids or bases are not readily eliminated
from the body and must be conjugated or metabolized to compounds that are
more polar and less lipid-soluble before being excreted.
c. Metabolism often, but not always, results in inactivation of the compound.
d. Some drugs are activated by metabolism. These substances are called
prodrugs.

2. Biochemical reactions involved in drug metabolism occur in two phases.

Phase I Reactions (Non synthetic) alter chemical reactivity and increase
aqueous solubility. Ex. Oxidation, reduction, hydrolysis
Phase II Reactions (synthetic) further increase the solubility, promoting
elimination. Ex. Conjugation
a. Oxidation, (removal of H+) the most common metabolic reaction, involves
the addition of oxygen or the removal of hydrogen from the drug.
1) Microsomal Oxidation
a) The smooth endoplasmic reticulum of cells in many organs,
especially the liver, contains membrane-associated enzymes,
which are responsible for drug oxidation. This enzyme system has
been termed a mixed-function oxygenase. The subcellular
components of the endoplasmic reticulum, called microsomes, can
be isolated by centrifugation of organ homogenates.
b) The primary components of this enzyme system are cytochrome
P-450.
c) Types of microsomal oxidation reactions are:
i. Carbon oxidation-hydroxylation of aliphatic or aromatic
groups (e.g. pentobarbital and phenytoin)
ii. N- or O-dealkylation (e.g. diazepam and codeine)
iii. N-oxidation or N-hydroxylation (e.g. 2-acetylaminofluorene)
iv. Sulfoxide formulation (e.g.chlorpromazine)
v. Deamination (e.g. amphetamine)
vi. Desulfuration (e.g. thiobarbital)

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 2) Nonmicrosomal oxidation
a) Soluble enzymes found in the cytosol or mitochondria of cells are
responsible for the metabolism of relatively few compounds. These
enzyme activities are, however, important.
i. Alcohol dehydrogenase and aldehyde dehydrogenase,
which oxidize ethanol to acetaldehyde and acetate,
respectively, in reactions requiring oxidized nicotinamode
adenine dinucleotide (NAD+)
ii. Xanthine oxidase, which converts hypoxanthine to xanthine
and xanthine to uric acid
iii. Tyrosine hydroxykase, which is important to the metabolism
of catecholamines and serotonin
b. Reduction (addition of H+) occurs in both the microsomal and
nonmicrosomal metabolizing systems, it is less common than oxidation.
i. Ex. Of microsomal reduction include nitro (chloramphenicol)
and azo (prontosil)
ii. Ex. Of nonmicrosomal reduction include aldehyde (chloral
hydrate), ketone (naloxone), and quinone (menadione)
c. Hydrolysis
1) Nonmicrosomal hydrolases exist in a variety of body systems,
including the plasma. Examples.
a) Nonspecific esterases for drugs, such as acetylcholine,
succinylcholine, and procaine
b) Peptidases (e.g. proinsulin)
c) Amidases for drugs, such as procainamide and indomethacin
d. Conjugation involves coupling of a drug or its metabolite with an
endogenous substrate, usually inorganic sulfate, a methyl group, acetic acid,
an amino acid, or a carbohydrate. Usually, a conjugate is a readily excreted
polar substance.
1) Glucuronide conjugation is the most common conjugation reaction
which occurs frequently with phenols, alcohols, and carboxylic acids.
Glucuronides ae generally inactive and are rapidly excreted in urine or
bile by anionic transport systems.
2) Other conjugation reactions. All conjugatins except glucuronide
formation are catalyzed by nonmicrosomal enzymes. These include
a) Sulfate formation, in which phenols, alcohols, and aromatic
amines are converted to sulfates and sulfanilates, (e.g. steroids)
b) O-, S-, and N-methylation (e.g. norepinephrine)
c) N-acetylation (e.g. isoniazid)

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 d) Lycine and glutamine conjugation with acids (e.g. salicylic acid)
e) Glutathione conjugation (e.g. ethacrynic acid)

3. Factors affecting drug metabolism

a. Genetics. The most important factor is genetically determined
polymorphisms.(water-soluble)ex. Acetylation of INH and hydrolysis of
succinylcholine are genetically controlled.
b. Chemical properties of the drug. Certain drugs may stimulate or inhibit
the metabolism of other drugs (e.g. phenobarbital stimulates the
metabolism of diphenylhydantoin)
c. Route of administration. The oral route , for example, can result in
extensive hepatic metabolism of some drugs (the first-pass effect).
d. Diet . Starvation can deplete glycine stores and alter glycine conjugation
e. Dosage. Toxic doses can deplete enzymes needed for detoxification
reactions.
f. Age. The liver cannot detoxify drugs, such as chloramphenicol, as well in
neonates as it can in adults.
g. Gender. Young males are more prone to sedation from barbiturates than
in females.
h. Disease. Liver disease decreases the ability to metabolize drugs, while
kidney disease hampers the excretion of drugs.
i. Species difference. Experimental findings in animals do not necessarily
translate to humans.
j. Circadian rhythm. The rate of hepatic metabolism of some drugs follows
a diurnal rhythm.

Factors that decrease metabolism:

 Cardiovascular dysfunction
 Renal insufficiency
 Starvation
 Obstructive jaundice
 Slow acetylator
 Erythromycin or ketoconazole drug therapy

Factors that increase metabolism:

 Fast acetylator
 Barbiturates
 Rifampin therapy

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 Delayed drug metabolism results in:
 Accumulation of drugs
 Prolonged action of the effects of the drugs
Stimulating drug metabolism causes:
 Diminished pharmacologic effects

E. Drug Excretion – The elimination of drugs or metabolite from the body

1. Rate of elimination
a. For most drugs, elimination from the blood (liquid soluble) follows
exponential (first-order) kinetics. The fractional change in the amount of
drug in the plasma or blood per unit of time is expressed by the half-life
(t ½ )- or by the elimination rate constant (k), which is equal to
0.693/ t ½
2. Routes of elimination
a. The kidney is the most important organ for excretion of drugs and their
metabolites which involves the three processes:
i. Glomerular filtration
ii. Passive tubular reabsorption
iii. Active tubular secretion
b. The biliary tract and the feces are important routes of excretion for
some drugs that are metabolized in the liver.
c. Other routes. Drugs and their metabolites can also be eliminated in
expired air, sweat, saliva, tears, and breast milk. And they tend to be lipid-
soluble and nonionized.

Half-Life

 The time it takes for one half of the original amount of a drug in the body to be
removed.
 A measure of the rate at which drugs are removed from the body. Comment [a3]: Ex.250mg/hr

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 F. Effect of repeated doses

A drug accumulates in the body if the time interval between doses is less than four of its
half-lives, in which case the total body stores if the drug increases exponentially to a
plateau and is known as steady-state concentration.

PHARMACODYNAMICS
Action of drugs in the body; the cellular processes involved in the drug and cell
interaction

A. Mechanism of drug action

1. Most drugs interact with macromolecular components, called receptors, of a cell or
an organism to begin biochemical and physiologic changes that produce the drug’s
observed effects or response.
a. Receptors bind ligands and transduce signals.
b. Drug receptors are identified primarily by the effect or lack of effect of
antagonists and the relative strength of agonists.

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 1) A drug is called an agonist if it produces some of the effects of
endogenous compounds when it interacts with the receptor. The
agonist, acetylcholine, has intrinsic activity.
2) An antagonist is a drug that has no intrinsic activity yet can reduce
or abolish the effect of an agonist.
a) Examples of pure antagonists are atropine and curare, which
inhibit the effect of acetylcholine.
b) Atropine and curare occupy cholinergic receptor sites,
preventing the further binding of acetylcholine to these
receptors
3) Some drugs (e.g. nalorphine) are partial agonists; that is, they
possess some intrinsic activity.
2. Other drugs may not cause a response by interacting with receptors. These drugs may
combine with small molecules or ions found in the body (e.g., chelating agent).

B. RECEPTORS Comment [a4]: A receptor are protein that

binds to an extracellular ligand , and then
undergoes a conformational or biochemical shift
The term receptor is used in pharmacology to denote a class of cellular macromolecules that in such a way that it initiates a chain of
intracellular events by which the cell reacts to
are concerned specifically and directly with chemical signaling between and within cells. Thru the extracellular signal .
the MOA: Comment [a5]: mostly proteins

• Affinity: The capability of a drug to form the complex (Drug Receptor Complex)
with its receptor.
• Intrinsic activity: The ability of a drug to trigger the pharmacological response
after making the drug-receptor complex.
D + R  DR
Where
 D: Drug or endogenous ligand
 R: Receptor
 DR: Drug-Receptor Complex

Chemistry of Drug-Receptor Interactions: Most drug-receptor interactions

 are reversible
 weak chemical bonds

Irreversible drug-receptor interactions Comment [a6]: gives undesirable effects

 not common
 strong chemical bonds (covalent)
 e.g. aspirin, anti-tumor drugs
 usually undesirable
o reversal of effects/toxicity
o mutagenicity/carcinogenicity

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 Agonist: These are the drugs which have both high affinity as well as high intrinsic
activity.
Antagonist: – These are the drugs which have only the affinity but no intrinsic activity. Comment [a7]: in their mechanism to receptors
Vidwatch https://www.youtube.com/watch?v=nqmLitfBrz4&t=832s

Types of receptors
1. Ligand-gated ion channels
2. G protein coupled receptors
3. Enzyme-linked receptors
4. Intracellular receptors

Ligand-gated ion channels Comment [a8]: in chem, a ligand is an ion or

molecule (functional group) that binds to a
 The first receptor family comprises ligand-gated central metal atom to form a coordination
ion channels that are responsible for regulation complex.
of the flow of ions across cell membranes
 The activity of these channels is regulated by
the binding of a ligand to the channel.
 Response to these receptors is very rapid, having durations of a few
milliseconds.
 The nicotinic receptor and the gamma-aminobutyric acid (GABA)
receptor are important examples of ligand-gated receptors, the functions of
which are modified by numerous drugs
 Agonist opens the channel.
 Antagonists prevents agonist from opening the channel
 Inverse agonist closes an open channel

G protein coupled receptors

 A second family of receptors consists of
G protein coupled receptors.
 These receptors are comprised of a
single peptide that has seven
membrane-spanning regions, and these
receptors are linked to a G protein (Gs
and others) having three subunits.
 Binding of the appropriate ligand to the
extracellular region of the receptor
activates the G protein so that GTP
replaces guanosine diphosphate (GDP)
on the subunit.
 Stimulation of these receptors results in
responses that last several seconds to minutes.

Enzyme-linked receptors

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  A third major family of receptors
consists of those having cytosolic
enzyme activity as an integral
component of their structure or
function.
 Binding of a ligand to an extracellular
domain activates or inhibits this
cytosolic enzyme activity.
 Duration of responses to stimulation
of these receptors is on the order of
minutes to hours.
 The most common enzyme-linked
receptors (epidermal growth factor,
platelet-derived growth factor, atrial
natriuretic peptide, insulin, and
others) are those that have a tyrosine
kinase activity as part of their structure Comment [a9]: tyrosine kinase is an enzyme
that can transfer a phosphate group from ATP to
 Typically, upon binding of the ligand to receptor subunits, the receptor undergoes the tyrosine residues of specific proteins inside a
conformational changes, converting from its inactive form to an active kinase cell. It functions as an "on" or "off" switch in many
cellular functions.

Intracellular receptors
 The fourth family of receptors differs considerably
from the other three in that the receptor is entirely
intracellular and, therefore, the ligand must
diffuse into the cell to interact with the receptor.
 This places constraints on the physical and
chemical properties of the ligand in that it must
have sufficient lipid solubility to be able to move
across the target cell membrane.
 Because these receptor ligands are lipid soluble,
they are transported in the body attached to plasma
proteins, such as albumin.
 For example, steroid hormones exert their action on
target cells via this receptor mechanism.

Receptor Regulation

Overview

 Intrinsic Regulation • receptors initiate regulation of a variety of events and are themselves
subject to regulatory and homeostatic controls.
 Disease States • disease states can alter the number, function, and/or activity of receptors.

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 Comment [a10]: a group of substances that bind
 Drugs • drugs can act as agonist, antagonists and allosteric modulators all of which can alter to a receptor to change that receptor's response to
receptor function and number. stimulus.
Allostery-capable to change or being changed

Intrinsic Regulation • receptors are subject to regulation and

homeostatic control. Left unregulated, receptors may be over
stimulated, which may lead to pathological changes, including
apoptosis. Therefore, regulation helps protect cells. There are
times when an increased response is needed and others when a
decreased response is preferred.

Cellular mechanisms of Increased Response

 Super/Hyper Sensitivity
 Synergism
 Upregulation Comment [a11]: Sensitive response

Super/Hypersensitivity • Super or hypersensitivity refers to an

enhanced response to an agonist. Hypersensitivity may occur as
a result of unmasking of receptors or accentuation of signal
amplification.

 Unmasking of Receptors • some receptors have a masking protein covering the intracellular
portion of a receptor, like the GPCR seen below for example. This masking protein prevents
signal transduction and leads to decreased activity. When a masking protein in removed,
activity increases.

 Accentuation of Signal Amplification • this may occur with an increase in receptor

phosphorylation or increased enzymatic activity. As was discussed earlier, phosphorylation Comment [a12]: A biochemical process that
involves the addition of phosphate to an organic
can lead to the activation of a chain of second messengers and signal amplification. Therefore, compound. Examples include the addition of
as phosphorylation increases, so does signal transduction and amplification. Likewise, there phosphate to glucose to produce glucose
are enzymes that catalyze components in a signal transduction pathway leading to increased monophosphate and the addition of phosphate to
adenosine diphosphate (ADP) to form adenosine
signal transduction and amplification as well. triphosphate (ATP).
It regulates protein function and cell signaling by
causing conformationl changes in the phosphate
Synergism • when two receptors produce a combined effect that is greater than the sum of group.
their individual effect.

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 Upregulation • Upregulation refers to an increase in the number of receptors due to prolonged
deprivation of receptors of interacting with their physiological neurotransmitter (e.g. by
denervation of chronic use of a receptor antagonist). By expressing more receptors, there is a
greater probability that a hormone will bump into and stimulate its receptor.

Cellular mechanisms of Decreased Response

 Desensitization
 Downregulation Comment [a13]: Lead to tolerance
 Tachyphylaxis
 Tolerance

Desensitization • Desensitization refers to a reduced response to an agonist drug due to over

activation of a receptor (high doses, prolonged exposure to agonist). There is a number of
mechanisms of desensitization including: loss of receptor function through a decrease in
receptor-coupled signaling components (e.g., G-proteins). Receptor desensitization may occur
in the absence of significant changes in the number of receptors.

This example here demonstrates loss of receptor function; one of several types of
desensitization. As you can see on the far right, the agonist is bound to
the receptor, however, this does not result in the channel opening.

Downregulation • Downregulation specifically refers to a reduction in

the total number of receptors available to be stimulated due to
prolonged receptor activation (e.g. by chronic treatment with a
pharmacological agonist drug or prolonged inhibition of metabolism of a
neurotransmitter). This reduction in receptors in turn will decrease the
cell’s sensitivity to an agonist or drug. Downregulation occurs through
endocytosis. Internalized receptors may either be degraded in the
lysosomes or recycled back to the membrane surface later.

As the image shows, endocytosis involved the internalization of a

receptor preventing it from carrying out signal transduction. A receptor
may either go to the endosome then lysosome to be degraded or
recycled back to the membrane surface to once again carry out signal
transduction.

Tachyphylaxis • Tachyphylaxis is a rapid decrease in response to an agonist drug following

repeated administration within a brief period; an acute form of desensitization. This can occur
without a change in the number of receptors or the ability of a receptor to affect the

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downstream signaling molecules. Increasing the dose of the drug will not improve the
response.

Tolerance • Tolerance refers to a gradual decreased response to a drug, requiring a higher

dose of drug to achieve the same initial response. Tolerance is different from tachyphylaxis
because it develops over a long period of time, whereas, tachyphylaxis is an acute event. In
addition, tolerance can be overcome by increasing the dose, unlike tachyphylaxis.

Changes in receptor response by disease states

Disease states may alter the number of available receptors, which can alter the sensitivity
and response of a given cell or tissue. Disease states may therefore alter the actual function
or activity of those receptors; either through loss or gain of function.
Example • Loss of Receptors

Myasthenia Gravis is an autoimmune disorder in which antibodies destroy nicotinic

acetylcholine receptors [nAChR] located in skeletal muscle. nAChRs help communicate
signals resulting in muscle contraction. Thus, Myasthenia Gravis causes muscle weakness,
droopy eyes and even difficulty in swallowing.

Myasthenia Gravis is treated with immunosuppressants to decrease the production of

antibodies that destroy nAChRs as well as with acetylcholine esterase inhibitors [AChEIs] that
prevent the breakdown of acetylcholine, a nAChR agonist, to increase its level in the synapse.

Example • Loss of Function • Androgen Receptors [AR]

Page 18 of 21
Androgen receptors have variants caused by genetic mutations. These variants have varied
levels of function, ranging from partial to complete loss of function. Individuals who have
complete AR insensitivity exhibit Complete Androgen Insensitivity Syndrome [CAIS], and
those who have partial AR insensitivity suffer from Partial Androgen Insensitivity
Syndrome [PAIS]. Both syndromes cause a loss of receptor function.

Treatment for these syndromes includes hormone therapy; testosterone and/or

dihydrotestosterone [DHT]. One great advantage of DHT over testosterone is that cannot be
aromatized to estrogen, eliminating possible side effects associated with estrogen exposure.

Example • Gain-of-Function •A number of endocrine diseases are caused by gain-of-function

mutations of GPCRs.

Type 2 Diabetes Mellitus [DM2] • DM2 can be associated with a gain-of-function mutation,
resulting in increased expression of the α2 (A-adrenergic receptor 2); a GPCR that
prevents or suppresses the secretion of insulin. As you can imagine, a patient with this gain-of-
function mutation will have elevated blood glucose, potentially leading to type II diabetes
mellitus.

Familial Hypocalcemia Hypocalciuria • This disease involves a gain-of-function mutation of

the calcium-sensing receptor [CaSR]; a GPCR that allows the body to monitor and regulate
the amount of calcium in the blood. This gain-of-function leads to increased sensitivity to
calcium. Because CaSR maintains calcium homeostasis, its exaggerated response to calcium
tells the body to excrete more calcium. This leads to decreased calcium levels in the blood
(hypocalcemia) by suppressing the secretion of parathyroid hormone and increased renal
excretion of calcium (hypercalciuria).

The synapse

How neurons communicate with each other at synapses. Chemical vs. electrical synapses.
A single neuron, or nerve cell, can do a lot! It can maintain a resting potential—voltage
across the membrane. It can fire nerve impulses, or action potentials. And it can carry out the
metabolic processes required to stay alive.
A neuron’s signaling, however, is much more exciting when we consider its interactions with
other neurons. Individual neurons make connections to target neurons and stimulate or inhibit
their activity, forming circuits that can process incoming information and carry out a response.

Page 19 of 21
How do neurons "talk" to one another? The action happens at the synapse, the point of
communication between two neurons or between a neuron and a target cell, like a muscle or a
gland. At the synapse, the firing of an
action potential in one neuron—
the presynaptic, or sending, neuron—
causes the transmission of a signal to
another neuron—the postsynaptic, or
receiving, neuron—making the
postsynaptic neuron either more or less
likely to fire its own action potential.

Chemical transmission involves release of chemical messengers known

as neurotransmitters. Neurotransmitters carry information from the pre-synaptic—sending—
neuron to the post-synaptic—receiving—cell.
As you may remember from the article on neuron structure and function, synapses are usually
formed between nerve terminals—axon terminals—on the sending neuron and the cell body or
dendrites of the receiving neuron.

A single axon can have multiple branches, allowing it to make synapses on various
postsynaptic cells. Similarly, a single neuron can receive thousands of synaptic inputs from
many different presynaptic—sending—neurons.
Inside the axon terminal of a sending cell are many synaptic vesicles. These are membrane-
bound spheres filled with neurotransmitter molecules. There is a small gap between the axon
terminal of the presynaptic neuron and the membrane of the postsynaptic cell, and this gap is
called the synaptic cleft.

Page 20 of 21
When an action potential, or nerve impulse, arrives at the axon terminal, it activates voltage -
gated calcium channels in the cell membrane. Ca2+, which is present at a much higher
concentration outside the neuron than inside, rushes into the cell. The Ca2+ allows synaptic
vesicles to fuse with the axon terminal membrane, releasing neurotransmitter into the synaptic
cleft.

The molecules of neurotransmitter diffuse across the synaptic cleft and bind to receptor
proteins on the postsynaptic cell. Activation of postsynaptic receptors leads to the opening or
closing of ion channels in the cell membrane. This may be depolarizing—make the inside of
the cell more positive—or hyperpolarizing—make the inside of the cell more negative—
depending on the ions involved.
References:
https://www.slideshare.net/rajud521/pharmacological-principles
https://www.slideshare.net/harshit172/receptor-pharmacology-115226744
https://open.lib.umn.edu/pharmacology/chapter/receptor-regulation/
https://www.khanacademy.org/science/biology/human-biology/neuron-nervous-system/a/the-synapse
Refer to the video https://www.neuroscientificallychallenged.com/glossary/g-protein-coupled-receptor

Page 21 of 21
 NOTRE DAME OF DADIANGAS UNIVERSTY (NDDU)
College of Pharmacy
COURSE TITLE PHARMACOLOGY I COURSE CODE Pharm26
CREDIT UNITS 3 units COURSE Human Physiology and
REQUISITES Pathophysiology
CONTACT HOURS 3 hours/week Contact Hours/Date 6 hours
54 hours/sem for this topic
COURSE 2nd Year, Summer SME: Melba M. Roma, RPh, MSPh
PLACEMENT
MODULE 2 : Autocoids & Eicosanoids
Content Standards Demonstrate knowledge and understanding of the pharmacology of autacoids and
eicosanoids.
Declarative I. Pharmacology of the Autacoids and Eicosanoids
Knowledge a. Histamine receptors and effects
b. Serotonin receptors and effects
c. Biological responses of eicosanoids
d. Drugs modifying Autacoids and Eicosanoids
Functional o Discuss the effects of Histamine, Serotonin and Eicosanoids.
Knowledge o Describe pharmacokinetic properties, mechanisms of action, clinical application,
pharmacologic and toxic effects of:
- Histamine and Serotonin modifiers
- Eicosanoidal analogues

Flipped vidwatch
Autocoids: https://www.youtube.com/watch?v=zWjOfrtZN6c&ab_channel=Zeus-TerraDentalAcademyZeus-
TerraDentalAcademy
Eicosanoids: https://www.youtube.com/watch?v=2Mzr5eos2EE&ab_channel=MedMadeSirius-
lyeasy%21MedMadeSirius-lyeasy%21
Comment [a1]: Vasodilators-paracrine
hormones/local hormones
The hormones act locally by diffusing from its
AUTACOIDS AND THEIR PHARMACOLOGICAL MODULATORS source to target cells in the neighborhood.

I. INTRODUCTION

A. Definitions
1. Autacoids are chemical mediators that are synthesized and function in a localized tissue or
area and participate in physiologic or pathophysiologic responses to injury. They act only
locally and therefore also termed “local hormone.” Autacoids normally do not function as the
classical blood-borne hormones. Typically, autacoids are short-lived and rapidly degraded.
2. Autacoid modulators interfere with the synthesis; inhibit the release (antagonists) or the
receptors upon which they act.

Page 1 of 18
B. Physiologic function
1. Autacoids modulate blood flow in specific tissues. Comment [a2]: In the skin during
exercise/facilitate heat loss
2. Some autacoids modulate secretory processes, for example, histamine on gastric acid
formation.
3. Autacoids modulate smooth muscle function.
4. Autacoids play a key role in allergy, inflammation, smooth muscle function, pain, and certain
types of drug reactions (Anaphylaxis). Comment [a3]: Life threatening allergic
reactions (dec pulse, heart,respi system shock)

C. Major classes. The autacoids can be divided into three categories based on their chemical
structure.

1. Biogenic amines: Histamine, serotonin (5-hydroxytryptamine/tryptophan)

2. Polypeptides: Bradykinin, angiotensin Comment [a4]: Causes
bronchoconstriction/action is similar to histamine
3. Lipid-derived autacoids
a. Eicosanoids. Prostaglandins (Pg), leukotrienes (LT) interleukins(IL) , thromboxane
(TXA)
b. Platelet activating factor

II. BIOGENIC AMINES

Vidwatch: Histamines
https://www.youtube.com/watch?v=D5PHANcdA_E&ab_channel=Zeus-
TerraDentalAcademyZeus-TerraDentalAcademy

A. Histamine
1. Biosynthesis. Derived chiefly form dietary histidine, it is decarboxylated by l-histidine
decarboxylase to form histamine

Comment [a5]: Inactive metabolites

2. Metabolism. Two pathways are involved in the degradation of histamine. The major
degradation pathway (>50% histamine degradation) involves conversion of histamine to an
inactive metabolite 1-methylhistamine by imidazole-N-methyltransferase. The minor pathway
(25% histamine degradation) involves breakdown of histamine by diamine oxidase
(histaminase) to form imidazole acetic acid.

Page 2 of 18
3. Distribution and storage sites. Histamine is widely distributed in tissues and its
concentration and rate of synthesis varies greatly from tissue to tissue.

a. The primary tissue sites storing histamine are the lungs, skin, mucosal layer of Comment [a6]: Site for mast cells
the stomach and basophils. Comment [a7]: A WBC, If your basophil level
(1) Food and vagal stimulation can release histamine from the stomach mucosal is low, it may be due to a severe allergic
reaction.
enterochromaffin-like (ECL) cells. The released histamine then initiates gastric acid Basophils are non-mast site
secretion Comment [a8]: Vagus nerve-one of the cranial
nerves that connect the brain to the body
(2) Allergic responses in the skin and lungs are due in part to histamine release from
mast cells.

b. Mast cells are the primary cells that store histamine where it exists in a complex with Comment [a9]: AKA masctocyte cells –a migrant
cell that contains granules rich in histamine and
heparin sulfate and chondroitin sulfate E in storage granules. The rate of histamine synthesis heparin.
and turnover in mast cells is low. It regulates allergic responses, innate & adaptive
immunity & inflammation

c. Histamine is also found in CNS where it may act as a neurotransmitter. Non-mast cell sites: basophils, CNS

d. Many venoms and insect stings contain histamine, as well as other biologically active
substances.

e. Histamine is found in the digesta where it is formed in large part by bacterial action. This
histamine normally does not reach the systemic circulation since it is metabolized by enzymes
in the gut wall and liver.

4. Release (factors mediating release of Hormones)

a. Immune release. When sensitized mast cells or basophils are coupled to IgE antibodies Comment [a10]: Antibodies produced during
allergy,thus allergic reaction
and then exposed to the proper antigen; the mast cell degranulates, thereby releasing
histamine and other autacoids. This is also referred to type I IgE-mediated hypersensitivity
reaction.
b. Drug-induced release. Drugs, usually strong bases (morphine, polymyxin, tubocurarine, Comment [a11]: Drugs compete w/ histamine
for the binding sites of heparin. Heparin can
codeine, lidocaine, penicillin), and/or their vehicles are capable of releasing histamine but this modulate inflammatory processes, inhibit mast cell
release does not involve degranulation or mast cell injury. These drugs displace or compete degranulation
with histamine for the binding sites with heparin.
c. Plant and animal stings are capable of releasing histamine, which is an important
component of the physiologic reaction (erythema, pain, itch) to these stings.
d. Physical injury such as heat, cold, or trauma can disrupt the mast cells thereby releasing
histamine.

Page 3 of 18
5. Receptor pharmacology (for Histamine)

Four classes of receptors (H1, H2, H3, and H4) mediate the action of histamine.

a. H1-receptors are coupled to Gq protein–phospholipase C and mediate the following

effects:
(1) Contraction of smooth muscle and neuronal actions are due to increases in [Ca 2+]i and
activation of protein kinase C
(2) Relaxation of vascular smooth muscle involves Ca 2+-induced formation of nitric oxide (NO). Comment [a12]: Maintains the duration of Ca
++ wave
(3) H1-receptors mediate contraction of bronchiolar and intestinal smooth muscle, vasodilation
of small arteries and veins, increased capillary permeability and pruritus.

b. H2-receptors are coupled to Gs protein-adenylyl cyclase

Stimulation of Gs-coupled H2 receptors activate adenylyl cyclase and increase tissue cAMP Comment [a13]: Cyclic adenosine
monophosphate (a second messenger), a derivative
levels. This is the mechanism by which vascular smooth muscle relaxes, and gastric acid of ATP
secretion is stimulated.
H2-receptor primarily mediates gastric acid secretion and vasodilatation.
(1) Agonists include 4-methylhistamine and dimaprit.
(2) H2-Antihistaminic include: cimetidine, ranitidine, famotidine, and nizatidine. Recent
evidence suggests, just like H 1-antihistamines, these drugs are inverse agonists. Comment [a14]: Drug binds to the same
receptor as an agonist but induces a pharmaceutical
response opposite to that of agonist
c. H3-receptors are coupled to Gi/o protein. Inhibition of the release of histamine and other
neurotransmitters involves inhibition of cAMP synthesis, opening of K + channels to increase
K+ efflux, and closure of Ca2+ channels to block Ca2+ entry into the nerve.
H3-receptors are located presynaptically on neurons and inhibit neurotransmitter release.

d. H4-receptors are coupled to Gi/o protein.These receptors are selectively expressed in mast
cells, basophils, and eosinophils. Activation of H 4-receptors mediates histamine-induced mast
cell chemotaxis and leukotriene B4 production.
H4-receptor antagonists are being developed as anti-inflammatory drugs that involve mast
cells and eosinophils.

6. Physiologic and pathologic roles Comment [a15]: How it affects body & generate
certain conditions.

a. Gastric acid secretion. Histamine is the most important regulator of gastric acid secretion
and it stimulates secretion via H2 receptors
b. Allergic reactions and anaphylactic shock. The binding of antigenic substances to IgE
molecules on mast cells causes the release of histamine. Other biologically active substances
such as prostaglandin D2 and leukotrienes (LTC4 and LTD4) are also released. Comment [a16]: A potent mediator of allergic
inflammation (PGD2)
c. Inflammation. Histamine may be involved in the vasodilation observed in the inflammatory
process.
d. Neurotransmission. Histamine is a neurotransmitter in various brain areas and is involved
in activating sensory nerves resulting in pain and itch sensations.
e. Microcirculation. Histamine relaxes arterioles and increases capillary permeability. Comment [a17]: vasodilateion

Page 4 of 18
7. Pharmacologic effects

a. Cardiovascular system
(1) Histamine dilates arterioles, capillaries, and venules, increases cardiac contractility and
heart rate by activating both H1– and H2-receptors. The cardiovascular effects are complex.
There is a decrease in peripheral resistance (vasodilatation), resulting in hypotension. The
stimulation of cardiac activity involves a direct action and reflex activation of the sympathetic
nervous system, which is activated by the low blood pressure.
(2) There is an increase in capillary permeability brought about by contracting the endothelial
cells, which exposes the basement membrane. Fluid and protein pass across the basement Comment [a18]: thin fibrous extracellular
matrix that separates the lining of an internal or
membrane to produce edema. external body surface from underlying connective
tissue

b. Respiratory system. Respiratory smooth muscle is contracted in most species via H 1-

receptor. There is also stimulation of glandular secretion and prostaglandin formation.

c. Glandular tissue. Histamine can stimulate glandular tissues to increase secretion. A most
important action of histamine is its ability to increase gastric acid and pepsin secretion from the
gastric mucosa via H2-receptors

(1) Regulation of gastric acid production is quite complex. Acid secretion by parietal cells is
regulated by histamine, acetylcholine (ACh), gastrin, and prostaglandin E 2 (PGE2).
(2) Gastrin has both a direct and indirect action. Gastrin directly activates CCK2-receptors on Comment [a19]: cholecystokinin
parietal cells to increase gastric acid secretion and indirectly increases gastric acid secretion
by activating the release of histamine from ECL cells, which again in turn activates H2- Comment [a20]: enterochromaffin-like cells
found in acid- secreting regions of stomach
receptors on the parietal cells. Thus, histamine release is a major factor in the stimulation
of acid production by both ACh and gastrin.
(3) Histamine can increase the release of catecholamines from the adrenal medulla and Comment [a21]: muscarinic effect
stimulate salivary secretion. Comment [a22]: antihistamine s/e is dryness of
mouth

.
B. Antihistamines. Therapeutically useful antihistamine drugs are H 1-antihistamines and H2-
antihistamines. At present there are no clinically useful H 3 or H4-antihistamines.

1. H1-antihistamines were the first type of antihistaminic drugs discovered and are sometimes
referred to as the classical antihistaminics.

a. Mechanism of action. Traditionally, it was thought that H 1-antihistamines act as

competitive antagonists of histamine receptors. However, recently it has been
demonstrated that most, if not all, of H 1-antihistamines act as inverse
agonists rather than the receptor antagonists. Comment [a23]: the drug binds to the same
b. Classification of H1–antihistamines. Histamine can be broadly classified into two receptor as an agonist but induces opposite
response
groups based on usage: (1) first-generation H1-antihistamines and (2) second
generation H1-antihistamines.

Page 5 of 18
 Most frequently used first-generation H1-antihistamines are diphenhydramine,
dimenhydrinate, hydroxyzyline, chlorpheniramine, meclizine,
promethazine, and cyproheptadine. These drugs are unionized drugs at physiological pH Comment [a24]: lipophilic
and easily cross the blood–brain barrier (BBB). Therefore, they produce CNS side effects, in
particular, sedation.
Commonly used second-generation drugs are loratadine (Claritin®), cetirizine (Zyrtec®),
and fexofenadine (Allegra®). This class of drugs is ionized at physiological pH and is Comment [a25]: hydrophilic
difficult to cross BBB. 1st Gen-lipophilic-cross BBB (+) sedation – Kd
c. Pharmacologic effects of H1-antihistamines excretion. Only lipophilic can cross BBB
nd
2 Gen-hydrophilic-not cross BBB-non sedating-
1) Relaxation of contracted bronchiolar smooth muscle. fecal excretion
2) Relaxation of contracted intestinal smooth muscle.
3) Inhibition of histamine-induced vasodilation and increased capillary permeability
and thereby blocking formation of edema and wheals. Comment [a26]: “pantal”
4) Inhibition of itch sensation by prevention of stimulation of sensory nerves. Many
H1-antihistamines have a potent local anesthetic action that may contribute to
their inhibition of itching and pain.
Note: H1-antihistamines alone are not effective for treatment of systemic anaphylaxis
because large amount of other autacoids are released during anaphylaxis. Comment [a27]: Administer steroids, IV
antihistamines

d. Other pharmacologic effects of H 1-antihistamines

1) Sedation is a common effect of first-generation H1 -antihistamines but sedation
does not correlate with their potency for inhibiting H 1-receptors. Sedation may be
a desirable/undesirable effect and can be expected to be additive to other CNS
depressants.
2) Antimuscarinic effects are prominent for some H1-antihistamines, for Comment [a28]: Anticholinergic effects –
dryness!
example, diphenhydramine and promethazine, which decrease secretions and
relax smooth muscles.
3) Antimotion sickness (antiemetic) effects. This effect is due to the inhibition of
histaminergic signals from the vestibular nucleus to the vomiting center in the
medulla. All H1-antihistamine have this effect, but some of them
(diphenhydramine, dimenhydrinate, and meclizine) have more potent antimotion
sickness effect than others in the group.
e. Therapeutic uses. H1-antihistamines are administered orally, parenterally, or
topically for the following conditions.
1) Treatment of patients with allergic conditions and to reduce or ameliorate the
effects due to histamine. Conditions benefited from H1-antihistamines include:
i. Urticaria and pruritus
ii. Allergic reactions to drugs
iii. Anaphylaxis
2) Prevention of motion sickness. Diphenhydramine, dimenhydrinate, and meclizine
are more effective in preventing motion sickness than other H1-antihistamines.
3) Sedation induction. Promethazine and diphenhydramine are the most potent for
inducing sedation.

Page 6 of 18
 f. Pharmacokinetics
1) All H1-antihistamines are effectively absorbed following oral administration
and Tmax = 1–3 hours. Comment [a29]: Time at which Cmax attained
2) All H1-anithistamines that have been studied for pharmacokinetics are well
distributed and are bound by plasma proteins (≥60%).
3) All H1-antihistamines are metabolized by cytochrome P450 enzymes, and these
metabolites further undergo conjugation.
4) The first-generation antihistamines are excreted primarily by the kidneys as Comment [a30]: Cross BBB thus sedation
metabolites.
5) The second-generation antihistamines that cause least or no sedation are Comment [a31]: Ionized form
excreted more into feces when compared with the first-generation drugs:
cetirizine (70% in urine, 30% in feces); loratadine (40% in urine, 40% in feces as
metabolites); fexofenadine (11% in urine, 80% in feces).

g. Adverse effects
1) CNS depression (lethargy, somnolence, ataxia) are the most common but they Comment [a32]: sleepiness
may diminish with time. Comment [a33]: lack of voluntary coordination
2) Antimuscarinic effects (dry mouth, urinary retention) occur with many H 1- of muscle movement

antihistamines. They should be used with caution in patients with angle closure
glaucoma. Comment [a34]: increased likelihood of
producing complete obstruction and outflow of
3) In high doses CNS stimulation is possible aqueous humor resulting in increased intraoccular
4) Some individuals could develop allergy to the use of H 1-antihsitamines. pressure (IOP) due to relaxed ciliary muscle(dilates)
5) Drug tolerance. The decrease in efficacy and sedation (also called subsensitivity)
can develop during the use of H1-antihistamines for days or weeks.

2. H2-antihistamines. These drugs are inhibitors of gastric acid secretion. They have little
action on H1-receptors.

a. Chemistry. H2-antihistamines contain imidazole ring with uncharged side chains and
are smaller than H1-antihistamines..

b. Pharmacologic effects. H2-antihistamines competitively inhibits histamine (H2-

receptors) in parietal cell and thereby decreases gastric acid production during basal
conditions and when stimulated by food, vagal activity, pentagastrin, gastrin, or
histamine. H2-antihistamines have been reported to act as inverse agonists, but further
validation of this observation is needed.

c. Therapeutic uses. H2-antihistamines are administered orally to treat gastric, abomasal

and duodenal ulcers, drug-induced erosive gastritis, duodenal gastric reflux, and
esophageal reflux. Cimetidine is least potent among the four H 2-antihistamines. Comment [a35]: but increased in C/I & ADR-
potent inhibitor thus decr metabolism,incr toxicity

Page 7 of 18
 d. Pharmacokinetics
1) All four drugs are well absorbed when administered orally. T max is 2–3 hours for all four
drugs. The bioavailability for cimetidine, ranitidine, nizatidine, and famotidine is 95%,
81%, >70%, and 40–50%, respectively.
2) All four drugs are well distributed in the body, with 10–20% bound by plasma proteins.
3) Cimetidine, ranitidine, and famotidine are metabolized by cytochrome P450 enzymes.
Only < 10% of nizatidine is metabolized by CYP450 enzymes.
4) All four drugs are excreted by the kidneys as the primary route. The majority of
cimetidine, ranitidine, and famotidine is excreted as metabolites and 30– 50% is
excreted as the unchanged drug. A total of ≥60% of nizatidine is excreted as the
unchanged drug.

e. Adverse effects are uncommon when recommended dosages are used. Cimetidine
possesses weak antiandrogenic activity and can cause gynecomastia and decreased Comment [a36]: incr amount of breast gland
tissue
libido in humans. The antiandrogenic effect is, in part, due to decreased testosterone
synthesis.
Ranitidine, famotidine, and nizatidine seem to be very well tolerated. Rarely, agranulocytosis Comment [a37]: severe decr of WBC
(neutrophils)
has been seen with the use of ranitidine and famotidine.

f. Drug interactions. Cimetidine can inhibit the hepatic cytochrome P450 enzymes. It
may reduce the metabolism of other drugs, which undergo hepatic metabolism, thereby
elevating and prolonging their concentration in the plasma.

3. Inhibitors of histamine release. The one drug in this category, cromolyn sodium, differs in
mechanism of action from the H1– and H2-antihistamines discussed above.
a. Cromolyn sodium inhibits the release of histamine and other autacoids from mast cells. Comment [a38]: mast cell stabilizer, available as
It does not inhibit H1– and H2-receptors, but opens chloride channel to hyperpolarize the cells. nasal spray ,OTC for nasal allergies

1) It is primarily used to treat pulmonary and nasal allergic reactions.

2) It is not well absorbed from the gut and has no clinical use when given orally.
3) It is used in a prophylactic manner. Comment [a39]: used before exposure to
allergenic food
4) It has been used in the horse where it is nebulized and delivered via a face mask.
5) The 4% eye drop is used to control allergic conjunctivitis.

Histamine receptors
Recep Location &function/ Effect Treatment Agonists antagonists
tor
H1  Smooth muscle(GIT,airway,uterus): Allergies, 2-methyl Diphenhydramine,
contraction nausea, histamine cetirizine,
 Endothelium-VD sleep chlorphenamine,
 Smooth muscle-VC disorders 2-pyridyl buclizine Comment [a40]: as appetite stimulant-H1 have
 Brain-transmitter ethylamine meclizine poor selectivity & as a result it is capable of
occupying other receptors such as cholinergic, a-
 Adrenal –release of CAs(catecholamines) adrenergic, & serotonin receptors. Blockade of
serotonin receptors may cause incr in appetite.
H2  Gastric(parietal cells) -acid secretion Stomach 4methyl Cimetidine, ranitidine Buclizine induces a state of mild hypoglycemia
 BV(smooth muscle)-dilation ulcers histamine, Famotidine, nizatidine or decrease in blood glucose level. This sends
 Heart:A-+ve chrono & V-+ve ionotrpy dimaprit, signal to the brain that the body is in a state of
hunger thus, ordering it to eat by stimulating
 Brain-transmitter appetite

Page 8 of 18
 H3  Presynaptic-inhib of release-sedation (brain) α- methyl Thioperamide
 Ileum- decr in Ach release histamine Impromidine
 BV-decr in NA release-VD ciproxifan
H4  Immune system- (spleen,thymus) Mediate Autoimmune N-methyl Thioperamide
mast cell chemotaxis diseases histamine

Serotonin receptors

Serotonin receptors or 5- Hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Comment [a41]: Monoamines are produced in
the brain & function to regulate mood, appetite,
Serotonin is found in: sleep & cognitive
 GIT
 Platelets
 CNS
 Approximately 90% of the human body's total serotonin is located in the enterochromaffin
cells (ECL) in the alimentary canal (gut), where it is used to regulate intestinal movements.

 The remainder is synthesized in serotonergic neurons of the CNS, where it has various
functions. These include the regulation of mood, appetite, and sleep.

 Serotonin secreted from the ECL eventually finds its way out of tissues into the blood.
There, it is actively taken up by blood platelets, which store it. When the platelets bind to a
clot, they release serotonin, where it serves as a vasoconstrictor and helps to regulate
hemostasis and blood clotting. Comment [a42]: Stop bleeding

Biosynthesis

Biosynthesis of serotonin begins with

hydroxylation of an essential amino
acid L- Tryptophan. L-Tryptophan is
transported through the BBB into the
brain using the neutral amino acid
transmitter on which it competes with
other amino acids- phenylalanine,
leucine and methionine.
Tryptophanhydoxylase is the 1st step
and speed limiting factor of 5-HT
synthesis.
This enzyme was found in the brain
only in serotonergic neuron. It enable Comment [a43]: nerve ending that releases and
is stimulated by serotonin.
the conversion of tryptophan into 5-
hydroxy tryptophan, followed by the
decarboxylation mediated by L- amino
acid decarboxylase onto 5-
hydroxytryptamine (serotonin).

Page 9 of 18
 Receptors Types

This group consists of 5 receptor subtypes: 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1E, 5-HT1F

5-HT1A Receptors
 This is the most extensively distributed of all 5-HT receptors. In CNS, these receptors
are present in high density in cerebral cortex, hippocampus, septum, amygdala, but
they are proven in small amounts in basal ganglia and thalamus as well.
 They are involved in the inhibition of discharge of neurons, regulation of production of
behavior and eating.
 They play an important role in the emergence of anxiety.
 They also exert some effects on CV system.

Receptors Effects & functions Agonist Antagonist

CNS:Agression,anxiety,appetite,memor Buspirone Alprenolol
5HT1A y,mood Ergotamine Pindolol
CVS: VC,BP,HR Yohimbine Propranolol
5HT1B CNS: Agression, Anxiety, Learning, Ergotamine Yohimbine
Locomotion, Memory, Mood Dihydroergotamine Propranolol
Vessels: Pulmonary VC Sumatriptan Pindolol
Zolmitriptan
5HT1D CNS: Locomotion, anxiety Sumatriptan Methiotepin
Ergotamine
Yohimbine
5-HT1E CNS: memory
5-HT1F BV: VC

Page 10 of 18
5-HT1B Receptors
 They are present in CNS where they induce presynaptic inhibition and behavioural
effects. They exhibit vascular effects as well, such as pulmonary vasoconstriction. o
Discovery of antimigraine properties of Sumatriptan (non-selective 5-HT1D/1B agonist)
increased intrest in this sub type of receptors.
 Expression of 5-HT1D receptor is very low as compared to 5-HT1B and their clinical
significance still largely unknown.
 The function of 5-HT1E receptor is unknown but it is hypothesized that they are involved
in regulation of memory.
 5-HT1F receptor has possible role in vascular contraction. Distribution in brain appears
limited.

5-HT2 Receptors
This class has 3 sub types: 5-HT2A, 5-HT2B, 5-HT2C

 5-HT2A Receptors This receptor type is expressed in many central and peripheral
tissues. This subtype show increased platelet aggregation and increased capillary
permeability following exposure to serotonin. In CNS, these receptors are mainly
present in basal ganglia. 5-HT2A antagonist are being developed for the treatment of
schizophrenia.

 5-HT2B Receptors Activation of 5-HT2B receptors leads to the contraction of smooth

muscle of fundus. Direct injection of selective agonist BW723C86 in amygdala have
anxiolytic effects in rats. Antagonist of these receptors are relatively new and may find
clinical application in the treatment and prevention of Migraine.

 5-HT2C Receptors These receptors may found in hippocampus and substantia nigra.
Due to lack of selective ligands for 5HT2C receptors the knowledge of its action remains
unclear.

Receptors Effects & Functions Agonist Antagonist

5-HT2A CNS: Anxiety, Imagination, Yohimbine Aripiprazole
learning, Perception Clozapine
SM: Contraction Olanzapine
Platelet: Aggregation Trazodone

5-HT2B CNS: Anxiety Norfenfluramine Agomelatine

GIT: GI Motility
5-HT2C CNS: Mood, Sleep , Anxiety - Clozapine
Olanzapine

5-HT3 Receptors With the exception of the 5-HT receptor, a ligand- gated ion channel, all
other serotonin receptors are G protein-coupled receptors that activate an intracellular second
messenger cascade to produce an excitatory or inhibitory response. The 5-HT receptor
antagonist suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT receptors.

Page 11 of 18
5-HT4 Receptors These receptors are found on CNS and Myenteric neurons. Prucalopride
(brand name Resolor, developed by Johnson & Johnson) is a drug acting as a selective, high
affinity 5-HT receptor agonist which targets the impaired motility associated with chronic
constipation, thus normalising bowel movements.

5-HT5 Receptors Rodents have been shown to possess two functional 5-HT5 receptor
subtype, 5-HT5A and 5-HT5B. Pharmacological function of these receptors is unknown. Based
on their localization, it has been speculated that they may be involved in motor control, anxiety,
learning, adaptive behaviour and brain development.

5-HT6 Receptors The exact clinical significance of these receptors remain still unclear.
Selective antagonist of this type of serotonin receptor has an impact on behaviour and seem to
improve the spatial memory of laboratory animal.

5-HT7 Receptors 5-HT7 receptors are expressed abundantly in the vessels and are
responsible for persistant vasodilation of anesthesized experimental animal. 5-HT7 receptors
are also expressed in CNS and in smooth muscles (in GIT tract).

Future Aspects
Serotonin is unique among the monoamines in that its effects are subserved by distinct G-
protein-coupled receptors and one ligand- gated ion channel. In the last two decades, a vast
amount of new information has become available concerning the various 5-HT receptor types
and subtypes, and their characteristics. It still remains to be seen which functions some of the
many subtypes play in health or disease.

The challenge for the next years of serotonin research is to clear to what extent diversity in
receptors fulfills specific physiological or pathophysiological roles. The research may then
assist in designing drugs with an adequate profile at the target organ and specific disease.
https://www.slideshare.net/FarazaJaved/serotonin-receptors

III. Polypeptides

A. Angiotensins

Angiotensin is a hormone that has constitutive effects throughout the body that serve the
global system. The precursor for all angiotensins is angiotensinogen, a plasma α-globulin.
Angiotensin is produced within the liver and excreted into the blood in its inactive form. Renin
converts hepatic angiotensinogen to Angiotensin I and is hydrolyzed by a peptidyl dipeptidase
called angiotensin-converting enzyme (ACE) found in large quantities on capillary
endothelial cells and converts in the lungs to Angiotensin II.

Of all corticotropic hormones, Angiotensin II plays the most constitutive and comprehensive
role in directly and indirectly regulating the hemodynamic. It is one of the most potent
vasoconstrictors known, being 40 times more potent than norepinephrine. Its direct effects

Page 12 of 18
include an augmentation of sympathetic activity, which improves cardiac output. It produces
positive inotropic and chronotropic effects, which are due to central and peripheral
sympathetic stimulation. It vasoconstricts, improving perfusion pressure. It augments tubular
reabsorption of sodium, chloride, and water and the excretion of potassium, which improves
intravascular volume. Within the CNS, it stimulates thirst and a craving for salt. It also
augments lipogenesis.

Its indirect effects complement its direct effects. It stimulates the excretion of aldosterone. It
stimulates vasopressin, which has three roles: increased vascular tone, antidiuresis (prevents
the loss of free water), and relaunching of the adrenal cortex activity by stimulating ACTH in
the presence of CRH. Together with vasopressin, angiotensin aids in myocardiac repair.

B. Kinins

Like angiotensin, the kinins are vasodilating polypeptides. Two enzymes called kallikreins,
catalyze the formation of the plasma kinins bradykinin, a nonpeptide, and kallidin (lysyl-
bradykinin, a decapeptide, from α-globulin precursors called kininogens. High-molecular-
weight (HMW) kininogen is the precursor of bradykinin. Low-molecular-weight (LMW)
kininogen is the precursor of kallidin. Bradykinin is inactivated by ACE.
Kinins are powerful algesic agents, where the algesic action is mediated by a direct stimulation
of nerve endings. Kinins are potent vasodilators. They act directly on smooth muscles of fine
resistance vessels and also cause the classic triple response seen with histamine.

Pharmacological effects Physiological and pathophysiological

Role
Vasodilation + ↑ capillary permeability Renal and Cardiovascular Regulation
Extravascular smooth muscle contraction Inflammatory Response and Pain
(bronchioles, GI slow rhythmic contraction)
Stimulation of nerve endings – pain
Increase in Na excretion in kidney

IV. EICOSANOIDS

The eicosanoids consist of the prostaglandins (PG), thromboxanes (TX), leukotrienes (LT)
and lipoxins (LX). The PGs and TXs are collectively identified as prostanoids. The
nomenclature of the prostanoids includes a subscript number which refers to the number of
carbon-carbon double bonds that exist in the molecule. The majority of the biologically active
prostaglandins and thromboxanes are referred to as series 2 molecules due to the presence
of two carbon-carbon double bonds. The predominant leukotrienes are series 4 molecules due
to the presence of four carbon-carbon double bonds..

Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes

from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their
Page 13 of 18
names. The lipoxins are inflammation resolving eicosanoids synthesized through
lipoxygenase interactions (hence the derivation of the name). Lipoxins are potent
inflammation modulating eicosanoid derivatives and their synthesis can be increased in
response to ingestion of aspirin.

The eicosanoids produce a wide range of biological effects on inflammatory responses

(predominantly those of the joints, skin and eyes), on the intensity and duration of pain and
fever, and on reproductive function (including the induction of labor). They also play important
roles in inhibiting gastric acid secretion, regulating blood pressure through vasodilation or
constriction, and inhibiting or activating platelet aggregation and thrombosis.

The principal eicosanoids of biological significance to humans are a group of molecules

derived from the 20:4 (20 carbons: 4 sites of unsaturation) fatty acid, arachidonic acid. Other
important eicosanoids are derived from the omega-3 fatty acids eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA) which are derived from the essential fatty acid, α-linolenic
acid (ALA), or obtained in the diet.

The major source of arachidonic acid is through its release from phospholipids of
membranes of the body’s cells, and is abundant in the brain, muscles, and liver. Within cell
membranes, arachidonic acid resides predominantly at the C–2 position of phospholipids and
is released from there upon the activation of the lipid hydrolase phospholipase A2, PLA2.

The immediate dietary precursor of arachidonic acid is the 18-carbon essential fatty acid,
linoleic acid. Linoleic acid is converted to arachidonic acid.

Eicosanoid Synthesis Comment [a44]: Greek means “20”

All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are
extremely potent, able to cause profound physiological effects at very dilute concentrations.
All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein
linked signaling pathways.

Two main pathways are involved in the biosynthesis of eicosanoids, the cyclic and the linear
pathways. The prostaglandins and thromboxanes are synthesized by the cyclic pathway,
the leukotrienes are synthesized by the linear pathway.

Prostaglandin and Thromboxane Synthesis

The cyclic pathway is initiated through the action of prostaglandin G/H synthase, PGS (also Comment [a45]: AKA cyclooxygenase

called prostaglandin-endoperoxide synthetase). This enzyme possesses two activities,

cyclooxygenase (COX) and peroxidase. There are two forms of the COX activity in humans, Comment [a46]: Functions to convert PGG2 to
PGH2 (peroxidative reduction)
COX-1 and COX-2. COX-1 (PGS-1) is expressed constitutively in gastric mucosa, kidney,
platelets, and vascular endothelial cells. COX-2 (PGS-2) is inducible and is expressed in
macrophages and monocytes in response to inflammation. The primary triggers for COX-2

Page 14 of 18
induction in monocytes and macrophages are platelet-activating factor, PAF and interleukin-1,
IL-1. Both COX-1 and COX-2 catalyze the 2-step conversion of arachidonic acid to PGG2 and
then to PGH2.

Comment [a47]: PGs Series of 2 molecules due

to presence of 2 c=c,
LTs series of 4 molecules, 4 c=c

Refer also for tutorial video https://www.youtube.com/watch?v=018PxnH702k

Leukotriene Synthesis Comment [a48]: Involve in asthmatic & allergic

reactions & acts to sustain inflam.rxns
The linear pathway is initiated through the action of arachidonate lipoxygenases (LOXs)
of which there are three forms, 5-LOX, 12-LOX and 15-LOX. The official names for these
three enzymes are arachidonate 5-lipoxygenase, arachidonate 12-lipoxygenase, and
arachidonate 15-lipoxygenase. The 5-LOX enzyme is encoded by the ALOX5 gene which is
located on chromosome 10q11.21. It is 5-LOX that gives rise to the leukotrienes. The
leukotrienes are synthesized by several different cell types including white blood cells
(leukocytes, hence the derivation of the name of the compounds), mast cells, lung, spleen,
brain and heart. The activities of 12-LOX and 15-LOX are involved in the synthesis of the
lipoxins.

Eicosanoid Receptors

Each of the eicosanoids functions via interactions with cell-surface receptors that are
members of the G-protein coupled receptor (GPCR) family. There are at least ten
characterized prostaglandin receptors. Receptors that bind the prostaglandin D family of
lipids are called the DP receptors, those that bind E family prostaglandins are called the EP
receptors, those that bind F family prostaglandins are called the FP receptors, those that

Page 15 of 18
bind prostacyclin (PGI2) are called the IP receptors, and those that bind the thromboxanes
are called the TP receptors. There are at least four leukotriene receptors.

Eicosanoids and Inflammatory Responses

As indicated in the Table below, the major actions of the series-2 prostaglandins and
thromboxanes (predominantly PGE2 and TXA2) are pro-inflammatory as are the series-4
leukotrienes (predominantly LTB4). Thus, it makes sense that drugs that reduce the
production of these compounds would be beneficial at reducing inflammation and the
associated vascular pathologies. A widely used class of drugs, the non-steroidal anti-
inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, and
phenylbutazone all act upon the cyclooxygenase activity, inhibiting both COX-1 and COX-2.
Aspirin is unique among the class of NSAIDs in that its actions on relief from pain
(analgesia) and as an anti-inflammatory as well as a heart protective drug are not solely due
to its ability to inhibit COX activity.
Due to the vasodilating action of PGE1 it is used pharmaceutically as alprostadil for the Comment [a49]: PGE1 agonist analog

treatment of erectile dysfunction (ED). This drug makes the blood vessels expand. That
boosts blood flow throughout the body, including the penis, so it helps men with ED have an
erection. The ED applications of PGE1 are sold as MUSE® and Caverject®. MUSE is a
urethral suppository and Caverject is an injectable version. Alprostadil is also used clinically
to treat newborn infants with ductal-dependent congenital heart disease. The administration
of alprostadil in these infants maintains a patent ductus arteriosus until surgery can carried
out to correct the underlying heart defect
Because inhibition of COX-1 activity in the gut is associated with NSAID-induced
ulcerations, pharmaceutical companies have developed drugs targeted exclusively against
the inducible COX-2 activity [e.g. Celebrex® (celecoxib), Prexige® (lumiracoxib) and the
recently removed Vioxx® (rofecoxib) and Bextra® (valdecoxib)]. Unlike the effects of aspirin
on the action and synthesis activities of COX-2, this latter class of drug does not induce the
synthesis of anti-inflammatory lipids. In fact the cardiac benefits of low-dose aspirin are
negated when taken along with COX-2 specific inhibitors such as Celebrex.
Another class of anti-inflammatory drug, the corticosteroidal drugs, act to inhibit PLA 2,
thereby inhibits the release of arachidonate from membrane phospholipids and the
subsequent synthesis of eicosanoids.

Page 16 of 18
 Major site(s) of synthesis
Eicosanoid
platelets, endothelial cells,
mucosal epithelial cells
LXA4
and other leukocytes via
inteactions with PMNs
platelets, endothelial cells,
mucosal epithelial cells
LXB4
and other leukocytes via
inteactions with PMNs
mast cells, eosinophils,
PGD2
brain
PGE1
PGE2 kidney, spleen, heart
PGF2α kidney, spleen, heart
PGH2
heart, vascular endothelial
PGI2
cells
Major biological activities
reduce PMN and eosinophil infiltration to sites of
inflammation, stimulate nonphlogistic (non-inflammatory-
inducing) monocyte recruitment, stimulate macrophage
phagocytosis of apoptotic PMNs, block IL-8 (chemokine)
expression, block TNF-α release and actions, stimulate
TGF-β action
same as for LXA4
induces inflammatory responses principally by recruiting
eosinophils and basophils; induces bronchoconstriction;
involved in androgenetic alopecia, inhibitors of PGD 2
being studied to treat male pattern baldness
induces vasodilation and inhibits platelet aggregation
increases vasodilation and cAMP production,
enhancement of the effects of bradykinin and histamine,
induction of uterine contractions and of platelet
aggregation, maintaining the open passageway of the
fetal ductus arteriosus; decreases T-cell proliferation
and lymphocyte migration and secretion of IL-1α and IL-
2
increases vasoconstriction, bronchoconstriction and
smooth muscle contraction
precursor to thromboxanes A2 and B2, induction of
platelet aggregation and vasoconstriction
inhibits platelet and leukocyte aggregation, decreases T-
cell proliferation and lymphocyte migration and secretion
of IL-1α and IL-2; induces vasodilation and production of
cAMP
Page 17 of 18
TXA1 induces vasodilation and inhibits platelet aggregation

induces platelet aggregation, vasoconstriction,

TXA2 platelets
lymphocyte proliferation and bronchoconstriction

TXB2 platelets induces vasoconstriction

monocytes, basophils, powerful inducer of leukocyte chemotaxis and

LTB4 neutrophils, eosinophils, aggregation, vascular permeability, T-cell proliferation
mast cells, epithelial cells and secretion of INF-γ, IL-1 and IL-2

component of SRS-A, microvascular vasoconstrictor,

monocytes and alveolar
vascular permeability and bronchoconstriction and
macrophages, basophils,
LTC4 secretion of INF-γ, recruitment of leukocytes to sites of
eosinophils, mast cells,
inflammation, enhance mucus secretions in gut and
epithelial cells
airway

monocytes and alveolar

LTD4 macrophages, eosinophils, same as LTC4
mast cells, epithelial cells

LTE4 mast cells and basophils same as LTC4

 https://veteriankey.com/autacoids-and-their-pharmacological-modulators/
 https://themedicalbiochemistrypage.org/eicosanoids.php
 https://www.slideshare.net/SivaYarasi/autacoids-pharmacological-actions-and-drugs-related-to-them
 https://www.youtube.com/watch?v=018PxnH702k

Page 18 of 18
 NOTRE DAME OF DADIANGAS UNIVERSTY (NDDU)
College of Pharmacy
COURSE TITLE PHARMACOLOGY I COURSE CODE Pharm26
CREDIT UNITS 3 units COURSE Human Physiology and
REQUISITES Pathophysiology
CONTACT 3 hours/week Contact Hours/Date Week 2
HOURS 54 hours/sem for this topic 2020 June 16
nd
COURSE 2 Year, Summer SME: Melba M. Roma, RPh, MSPh
PLACEMENT
MODULE 3: Autonomic Nervous System
Drugs Affecting Peripheral Neurohumoral Transmission
Objectives o Identify the origin of parasympathetic/ sympathetic nerves, the
parasympathetic/sympathetic neurotransmitters and receptors
o Identify the parts of the synapse and the steps involved in synaptic
neurotransmission
o Describe actions mediated by autonomic nervous system
o Describe parasympathetic/ sympathetic effects in different organs and
identify direct-acting, indirect-acting and mixed-acting
parasympathetic/sympathetic drugs and parasympatholytic/
sympatholytic drugs
o Describe the mechanisms of action of direct-acting, indirect-acting and
mixed-acting parasympathetic/ sympathetic drugs and
parasympatholytic/ sympatholytic drugs
o Identify the effects, clinical applications, toxicities and interactions of
parasympathetic/ sympathetic drugs and parasympatholytic/
sympatholytic drugs tissues and receptors responsible

Ref: Jacob, Leonard S. Pharmacology, 3rd ed. 1992, Williams& Wilkins

Vidwatch: NS
https://www.youtube.com/watch?v=QBLqs-2ryZ0&ab_channel=DrMatt%26DrMikeDrMatt%26DrMike

I. PERIPHERAL EFFERENT NERVOUS SYSTEM

The peripheral efferent nervous system consists of the somatic and the autonomic nervous
system.
A. The somatic NS innervates and controls the motor function of the body. Axons from the
spinal cord innervate skeletal muscle; the neurotransmitter is acetylcholine.
B. Autonomic NS. Axons from preganglionic neurons within the spinal cord connect to
neurons in ganglia outside the spinal cord. Postganglionic axons from the ganglia
innervate smooth and cardiac muscle and exocrine glands. The ANS has two parts: the
parasympathetic and sympathetic NS. These two divisions control homeostatic
functions that are primarily involuntary.

Page 1 of 28
1. Parasympathetic NS
a. Location of preganglionic neurons. In the parasympathetic (craniosacral) NS,
preganglionic neurons are located in cranial and sacral portion of the spinal cord.
b. Location of the ganglia. In the parasympathetic NS, the ganglia are close to the
innervated organ, so that the preganglionic axons are long and the postganglionic
axons are short.
c. Innervation of organs
i. The p-sympathetic NS innervates the heart, bronchial smooth muscle, iris,
salivary glands, and urinary bladder.
ii. Under normal conditions, the heart, eye, GIT, urinary bladder, bronchi, and
salivary glands are under p-sympathetic control.

2. Sympathetic NS
Vidwatch:
https://www.youtube.com/watch?v=D96mSg2_h0c&ab_channel=AlilaMedicalMediaAlilaMedicalMediaVerified

a. Location of preganglionic neurons. In the sympathetic (thoracolumbar) NS, the

neurons are located in lumbar and thoracic portions of the spinal cord.

Page 2 of 28
 b. Location of the ganglia. In the sympathetic NS, the ganglia are close to the spinal
cord, so that the preganglionic axons are short and the postganglionic axons are
long.

C. Neurotransmitters. These are chemical mediators that transmit nerve impulses across
junctions such as synapses

1. At the ganglionic synapse in both the sympathetic and the parasympathetic NS,
the neurotransmitter is acetylcholine.
2. At the postganglionic synapse, the two systems differ.
a. The parasympathetic neurotransmitter is acetylcholine.
b. The sympathetic transmitter is usually norepinephrine, but at sweat glands
and at some blood vessels, it is acetylcholine.

Page 3 of 28
 Receptors of the NS. More than one type of receptor exists for each neurotransmitter.
The receptors are distinguished in part on the basis of their affinity for various agonists
and antagonists.

Cholinergic receptors (for acetylcholine) are broadly subdivided into muscarinic and
nicotinic receptors.

a. Muscarinic receptors
1) Muscarinic receptors are further subdivided into M1 and M2 receptors.
Muscarinic receptors of both types are found in Central Nervous System
(CNS). In addition, M1 receptors are also found at autonomic ganglia; M2
receptors at end-organ effector sites.
2) Muscarine is the classic agonist for muscarinic receptors, and atropine is an
antagonist.
b. Nicotinic receptors are found in the CNS, in autonomic ganglia, and in striated
muscle.
1) Nicotine, the classic agonist, first stimulates and then blocks the autonomic
ganglia and skeletal muscle end-plates.
2) d-Tubocurarine blocks nicotinic receptors in striated muscle and in
autonomic ganglia, especially the former, while hexamethonium
preferentially blocks ganglionic nicotinic receptors.
c. The various cholinergic receptors and their sites are summarized in Table 3-1.

Table 3-1. Sites of Cholinergic Receptors

Site Receptors
Muscarinic Nicotinic
M1 M2
Skeletal muscle - - +
Autonomic ganglia + - +
CNS + + +
End organ innervation - + -

2. The adrenergic system also has two classes of receptors, named the alpha (α)-
adrenergic receptor and beta (β)-adrenergic receptor. Unlike cholinergic receptors, these
receptor types are not classified by which drugs can bind to them. All of them are G protein–
coupled receptors. There are two types of α-adrenergic receptors, termed α1 and α2, and
there are three types of β-adrenergic receptors, termed β1, β2 and β3, but we will look at
only β1 and β2.

a. α-Adrenergic receptors. Agonists, in decreasing order of potency, are epinephrine

> norepinephrine > isoproterenol. Antagonists are phentolamine and
phenoxybenzamine. Some α-adrenergic receptors precede the synapse between
nerve terminal and effector organ; others are postsynaptic.

Page 4 of 28
 1) α1-Adrenergic receptors are postsynaptic receptors. They are found on blood
vessels, on the radial muscle of the eye, in the gastrointestinal tract, and on the
splenic capsule.
2) α2-Adrenergic receptors are presynaptic or postsynaptic; all seem to serve
an inhibitory function. Isoproterenol is ineffective on α 2 receptors.
i. Presynaptic α2 receptors are found at adrenergic and cholinergic nerve
terminals. Presynaptic α2 receptors, when activated, inhibit the release of
further neurotransmitter.
ii. Postsynaptic α2 receptors are found in blood vessels and in CNS.
b. β-Adrenergic receptors. Agonists for β receptors are isoproterenol, epinephrine,
and norepinephrine. Propranolol is an antagonist. The β receptors are also
subdivided on the basis of their relative response to agonists and antagonists.
1) β1-Adrenergic receptors are found predominantly on cells in the heart and
intestine. The relative potency of agonists is isoproterenol > epinephrine and
norepinephrine.
2) β2-Adrenergic receptors are found at other sites, most importantly, on bronchial
and vascular smooth muscle. The relative potency of agonists is isoproterenol >
epinephrine > > norepinephrine.

D. Direct effects of autonomic stimulation on various organs. Stimulation of effector

organs may be either direct or indirect. A direct effect occurs when the nerve innervating
an organ is stimulated. Indirect responses are mediated by changes caused in other
organs.

1. Direct effects of p-sympathetic and sympathetic stimulation on various organs

a. Heart
i. Sympathetic stimulation increases the heart rate (chronotropic effect) and
the contractile force (inotropic effect)
ii. P-sympathetic stimulation decreases the heart rate but has little effect on
contractile force because there is no p-sympathetic innervation of the
ventricles.
b. Blood vessels
i. Sympathetic stimulation
a) Stimulation of α-receptors causes constriction of the arteries,
arterioles, and veins.
b) Stimulation of β receptors causes dilation of skeletal muscle arteries.
ii. Parasympathetic stimulation has no effect on blood vessels because most
have no parasympathetic innervation.
c. GIT. Sympathetic stimulation decreases the activity of the GIT, while p-
sympathetic stimulation increases it.

Page 5 of 28
 d. Eye
i. Sympathetic stimulation contracts the radial muscle, causing dilation of the
pupil.
ii. P-sympathetic stimulation produces contraction of the circular and ciliary
muscles, causing pupillary constriction and changes in accommodation.
e. Bronchial smooth muscle is relaxed by sympathetic stimulation and contracted by
p-sympathetic stimulation.
f. Glycogenolysis is increased in liver and muscle by sympathetic stimulation.

Table 3-2. Receptor-End Organ Response

Organ Receptor Type End Organ Effect

Heart β1 Increased inotropism and chronotropism
M2 Decreased inotropism & chronotropism
Coronary & Pulmonary β2(predominant type) Dilation
arterioles, BV to skeletal α constriction
muscles M2 Dilation
Other arterioles α Constriction
β Dilation
M2 Dilation
Veins α Constriction
β2 Dilation
Bronchi β2 Relaxation
M2 Constriction
GIT α, β Decreased motility and secretion
M2 Increased motility and secretion
Bladder α, β Retention
M2 Evacuation
Eye α1 Mydriasis
β Relaxation of ciliary muscle
M2 Miosis, constriction of ciliary muscle
II. SYMPATHOMIMETIC (ADRENERGIC) AGENTS.
These are drugs (adrenergic amines) that mimic the actions of the sympathetic nervous
system.

A. Catecholamines: norepinephrine and epinephrine

1. Chemistry
a. Tyrosine is hydroxylated on the aromatic ring by tyrosine hydroxylase, yielding
dopa (dihydroxyphenylalanine); this step is the rate-limiting step in the
biosynthesis of adrenergic transmitters.

Page 6 of 28
 b. Dopa is decarboxylated to give dopamine.
c. Dopamine is hydroxylated on the β-carbon to give norepinephrine.
d. Epinephrine is formed in the adrenal medulla by the methylation of
norepinephrine. The medulla releases 85% epinephrine and 15%
norepinephrine.

2. Pharmacokinetics of epinephrine and norepinephrine

a. Absorption is poor with oral administration because the drugs are rapidly conjugated
and oxidized.
b. Absorption is slow with subcutaneous administration because the drugs cause local
vasoconstriction.
c. Nebulized and inhaled solutions are usually used for their actions on the respiratory
tract
d. The drugs can be given IV, but this route must be used with caution so that the heart
does not fibrillate.
e. The liver is important in the degradation of epinephrine and NE. The majority of the
dose is metabolized by catechol-O-methyltransferase (COMT) and monoamine
oxidase (MAO), and the metabolites are excreted in the urine.

3. Pharmacologic effects of epinephrine. Epinephrine interacts strongly with both β

and α receptors. Its effects on some body systems depend on the concentration of
epinephrine as well as well as the type of receptor. At low concentrationss, β effects
predominate, and at high concentraitons, α effects predominate.

Page 7 of 28
a. Effects on blood pressure
1) A large dose of epinephrine IV, causes an increase in BP, the systolic
pressure increasing more than the diastolic. Subsequently, the mean
pressure falls below normal before returning to the control value. The rise in
pressure is due to:
i. Vasoconstriction through activation of α receptors
ii. Increased ventricular contraction through activation of β receptors
iii. An initial increase in heart rate, which, at the height of vasopressor
response, will be slowed by a compensatory vagal discharge.
2) Low doses, cause a fall in blood pressure because the β2 (vasodilator)
receptors are more sensitive to epinephrine than are the α (vasoconstrictors)
receptors.
b. Vascular effects. Epinephrine exerts its action on small arterioles and
precapillary sphincters. Its vascular effects include:
i. Decreased cutaneous blood flow
ii. Increased blood flow to skeletal muscle at low concentrations and
decreased flow at higher concentrations
iii. Increased hepatic blood flow with increased splanchnic vascular
resistance
iv. Increases renal vascular resistance, producing decreased renal blood
flow
v. Increased arterial and venous pulmonary pressure
vi. \increased coronary blood flow, caused indirectly by an increase in the
work of the heart, and mediated by local effectors
c. Effects on the heart produced by epinephrine inlcude:
i. A direct effect on β1 receptors, producing a slight initial increase in the
heart rate, which is slowed by a compensatory vagal discharge
ii. Increased stroke volume
iii. Increased cardiac output
iv. A propensity toward arrhythmias
d. Effects on smooth muscle depend on the predominant type of adrenergic
receptor in the muscle.
i. Epinephrine relaxes GI smooth muscle (α1 and βreceptors
stimulation), while it usually increases sphincter contraction α-
stimulation).
ii. Uterine contractions may be inhibited (β) or stimulated (α), depending
on menstrual phaseor state of gestation.
iii. In the bladder, the detrusor muscle relaxes (β) , while the trigone and
sphincter contratc (α).
iv. Bronchiolar smooty muscle relaxes (β2)

Page 8 of 28
 e. Metabolic effects of epinephrine also depend on the type of adrenergic
receptor. These effects include:
i. An increase in glucose and lactate production via liver and muscle
glycogenolysis (β2)
ii. Inhibition of insulin secretion (α)
iii. An increase in free fatty acids, mediated by cyclic adenosine 3’5’-
monophosphate [cyclic AMP] (β1)
iv. An increase in oxygen consumption

4. Pharmacologic effects of norepinephrine. NE is equipotent to epinephrine in its

reaction on β1 receptors, and slightly less potent on α receptors. It has very little
effect on β2 receptors.
5. Termination of action
a. Transport or uptake into the cells, is an important mechanism for
terminating the action of many neurotransmitters. There are two active amine
transport systems:
i. A system in the plasma membrane transports amines from the ECF to
the cytosol
ii. A system in the secretory granular membrane transports amines into
granules.
b. Deactivation by conversion to inactive metabolites is also a way of
terminating action. Two enzymes are involved:
i. COMT adds a methyl group to the hydroxyl of the catechol ring.
ii. MAO removes the amine group. When metabolic breakdown or
transports is prevented (as in patients taking MAO inhibitors or tricyclic
antidepressants), then the dosage of sympathomimetic agents must be
reduced.
6. Therapeutic uses
a. Epinephrine is used
i. To treat bronchospasm
ii. For relief of hypersensitivty reactions; it is the primary treatment for
anaphylactic shock
iii. To prolong the duration of infiltrate anesthesia
iv. To restore cardiac activity in cardiac arrest
v. To facilitate aqueous drainage in chronic open-angle glaucoma
b. Norepinephrine is used for treating hypotension during anesthesia when
tissue perfusion is good
7. Adverse effects. Both epinephrine and NE can cause:
a. Anxiety
b. Headache

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 c. Cerebral hemorrhage from the vasopressor effects
d. Cardiac arrhythmias, esp in the presence of digitalis and certain anesthetic
agents
e. Pulmonary edema from pulmonary hypotension

B. Isoproterenol
1. Pharmacokinetics
a. it is readily absorbed when given parenterally or as inhaled aerosol.
b. It is principally metabolized by COMT; MAO plays a much smaller role than in
epinephrine or NE metabolism

2. Pharmacologic effects
a. isoproterenol has an N;alkyl substitution, which makes it act almost entirely on β
receptors and have very little effect on α receptors.
b. IV infusion produces a reduction of peripheral vascular resistance in skeletal
muscles and in renal and mesenteric vascular beds.
c. Renal blood flow decreases in normotensive individuals, but it increases in
patients with nonhemorrhagic shock.
d. Relaxation of both bronchial and gastrointestinal smooth muscle occurs.
e. Pancreatic islet cells are activated, stimulating insulin secretion.
3. Therapeutic uses. Isoproterenol is used as a bronchodilator and as a cardiac
stimulant.
4. Adverse effects
a. Similar to the A/E of epinephrine
b. Overdosage by inhalation can induce fatal ventricular arrhythmias
c. Tolerance to the desired effects occurs with overuse in the asthmatic.

C. Dopamine
1. Chemistry. Dopamine is an intermediate in the synthesis of NE
2. Pharmacokinetics. Dopamine resembles epinephrine and NE in its Pk
3. Central dopamine receptors (D1, D2, D3)
a. The central D1 receptor site is excitatory and directly activates the adenylate
cyclase system
b. The D2 receptor site is inhibitory in some brain tissues and uses cAMP as its
intracellular messenger. Pituitary-related side effects of neuroleptics are
thought to be mediated through D2 receptors in the pituitary.
c. The D3 receptor is localized in the limbic system and is not found in the
pituitary. It is principally associated with emotional and cognitive behavior.
4. Pharmacologic effects

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 a. Dopamine is an important neurotransmitter in the CNS. It is a direct agonist,
acting on β1 receptors and also releases NE from nerve terminals. The result
is a positive inotropic effect on the myocardium.
b. Low or intermediate uses of dopamine reduce arterial resistance in the
mesentery and kidney; this raises the glomerular filtration rate. The effect is
mediated by a receptor for dopamine.
c. Dopamine increases systolic pressure but has little effect on diastolic
pressure.
d. At higher doses, it acts on α receptors and causes vasoconstriction with a
consequent reduction in renal function.
5. Therapeutic uses. Dopamine is used in the treatment of cardiogenic and septic
shock and in chronic refractory congestive heart failure.
6. Adverse effects. Overdosage results in excessive sympathomimetic activity.
Anginal pain, arrhythmias, nausea, and hypertension can occur, but these effects
are short-lived because of dopamine’s rapid metabolism.

D. Dobutamine
1. Pharmacokinetics . Dobutamine is not absorbed orally. It has a half-life of 2
minutes when given by IV.
2. Pharmacologic effects. Though it resembles dopamine chemically, it is a direct
β1-receptor agonist. It has a greater inotropic than chronotropic effect. It does
not act on dopaminergic receptors.
3. Therapeutic uses. It is used to improve myocardial function in CHF. Oxygen
demand is less than with other sympathetic agonists because dobutamine
causes minimal changes in heart rate and systolic pressure.
4. Adverse effects. Dobutamine increases atrioventricular conduction and must,
therefore, be used with caution in atrial fibrillation. Other a/e are similar to those
of other catecholamines.

E. Phenylephrine
1. Pharmacologic effects.
a. It is a direct-acting sympathomimetic agent. Its effects are similar to those of
NE, but it is less potent and has a longer duration of action.
b. Vasoconstriction, increased atrial pressure, and reflex bradycardia occur with
parenteral administration.
2. Therapeutic uses.
a. Nasal decongestant and pressor agent
b. To provide local vasoconstriction as a 10% ophthalmic solution and an
adjunct for use with local anesthetics
c. For relief paroxysmal atrial tachycardia

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 3. Adverse effects
a. Large doses cause cardiac irregularities
b. Ophthalmic solution, like intranasal solutions, can be systematically absorbed.
Their use in patients taking BB increases the risk of cardiac irregularities,
myocardial infarction, and intracranial hemorrhage.
c. Rebound nasal congestion can occur with chronic use of nasal decongestant.

F. Ephedrine
1. Pharmacokinetics. Ephedrine is absorbed orally. It is resistant to COMT and
MAO, so that its action is prolonged.
2. Pharmacologic effects.
a. Ephedrine is a mixed-acting sympathomimetic agent; that is, it has both
direct and indirect action.
i. Its primary action is indirect: It causes the release of NE from
storage in nerve terminals, apparently by competing with NE for
transport into the granules.
ii. It also produces direct stimulation of adrenergic receptors.
b. When administered IV it action is similar to that of epinephrine. However,
i. Its pressor response occurs more slowly and lasts 10x longer
ii. Its potency is 1/250 that of epinephrine in producing an equivalent
pressor response.
c. Ephedrine increases arterial pressure by causing peripheral VC and cardiac
stimulation
d. Its effects on bronchi and other smooth muscle are qualitatively similar to
those of epinephrine.
e. It causes CNS stimulation, which can result in effects such as insomnia,
nervousness, nausea, and agitation.
f. Tachyphylaxis occurs with repeated administration (rapidly diminishing
response to successive doses of a drug, rendering it less effective, common to NS
drugs)
3. Therapeutic uses. Ephedrine is used in the treatment of bronchial asthma, as
a nasal decongestant, as a pressor in spinal anesthesia , and as a mydriatic.
4. Adverse effects. A/E is similar as seen with epinephrine. CNS effects may
occur. It must be used with caution in patients with CV diseases or
hyperthyroidism because it is a powerful heart stimulator.
5.

G. Amphetamine
1. Pharmacologic effects
a. Amphetamine acts indirectly by releasing NE.

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 b. It is also a CNS stimulant
c. The dextrorotatory (d-) form is more active in the CNS than the levo (l-) form
d. It depresses the appetite , decreasing food intake, by affecting the feeding
center in the lateral hypothalamus.
e. It increases metabolism to a small extent.
2. Therapeutic uses
a. Amphetamine is used in the treatment of narcolepsy and the hyperkinetic
syndrome in children
b. The control of obesity is not a recommended use because abuse of
amphetamine is not rare and because tolerance to the anorexic effects
develops within a few weeks.
3. Adverse effects
a. Tolerance to amphetamine can occur within several weeks
b. Psychic and physical dependence can occur
c. Toxic psychosis can result from large doses
d. Prolonged use can lead to mental depression and fatigue
e. Reactions attributable to CNS stimulation can occur, such as restlessness or
insomnia.
f. Cardiovascular stimulationcan result in tachycardia and hypertension
g. Mydriasis and dry mouth can occur
h. It is contraindicated in patients with CVD, because it stimulates the heart, and
also in those receiving MAO inhibitors or guanithidine, as these compounds
increase NE concentrations outside the cells, as amphetamine does.
i. Treatment of acute intoxication should include:
i. Acidification of the urine by ammonium chloride administration
ii. Administering chlorpromazine, which is effective for treating both the CNS
symptoms and the elevated BP because of its α-blocking activity.

H. Methamphetamine and hydroxyamphetamine

1. Methamphetamine is related chemically to both amphetamine and ephedrine
a. It is a mixed-acting sympathomimetic agent, it is equal to amphetamine and
ephedrine.
b. Therapeutic indications are limited to those that make use of its CNS effects,
such as narcolepsy.
2. Hydroxyamphetamine has an action resembling that of ephedrine but without
CNS effects. It is used as mydriatic, decongestant, and pressor agent.

I. Β2-Stimulating bronchodilators

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 1. Pharmacologic effects. The adrenergic agents that are primarily β2 agonists
have a relaxing effect on bronchial smooth muscle and show little effect on
cardiac β1 receptors.
2. Therapeutic uses. These agents are used therapeutically for the treatment of
bronchial asthma or bronchospasm where their lack of cardiac stimulation is a
decided advantage. They are used chiefly as aerosol inhalants; oral and
injectable forms are also available.
3. Adverse effects of the β2 agonists are similar to those seen with the
sympathomimetic drugs. Even though their effects are primarily bronchial, they
should be used with caution in patients with cardiovascular disease or
hyperthyroidism because they can still stimulate (though minimally) β1 receptors
of the heart.

4. Specific agents.
a. Metaproterenol has a more rapid onset of bronchodilating action is
asthma than either albuterol or terbutaline.
b. Albuterol is somewhat more bronchoselective than isoproterenol when
given as an inhalation. In asthma, the effcts of albuterol are apparent with
15 minutes, are maximal at about 60-90 minutes, and last about 3-4
hours.
c. Terbutaline , when used in the treatment of bronchial asthma, has a
longer duration of action than metaproterenol. It may have more side
effects than other sympathomimetic agents.

III. SYMPATHETIC ANTAGONISTS

Synonyms:
 Sympatholytics
 antiadrenergic agents
 adrenergic blocking agents

A. α-Adrenergic blocking agents (α-blockers)

 Alpha-blockers work by blocking the transmission of certain nerve impulses. The ends
of some nerves release a chemical (neurotransmitter) called noradrenaline
(norepinephrine) when the nerve is stimulated. This chemical then stimulates alpha-
adrenergic receptors. These receptors are tiny structures which occur on cells in

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 various parts of the body, including the heart, involuntary (smooth) muscles and blood
vessels. When these receptors are stimulated, they cause various effects.
 The alpha-blocker medicine attaches to alpha-adrenergic receptors and stops (blocks)
the receptor from being stimulated. This can have various effects in the body:
a. For high blood pressure (hypertension): alpha-blockers work by relaxing
blood vessels. This allows blood and oxygen to circulate more freely around
your body, lowering blood pressure and reducing strain on your heart.
b. For prostate gland enlargement: alpha-blockers work by relaxing the muscles
of your bladder and around your prostate gland so that you can pass urine more
easily.

Indications. Alpha blockers are considered second line therapy in the treatment of
hypertension, and thus are only used if first line therapy fails. Alpha blockers are also used to
treat the urinary symptoms of benign prostatic hypertrophy (BPH) since they relax the urinary
sphincter.

Side effects. Some alpha blockers might have a "first-dose effect." When you start taking an
alpha blocker, you might develop pronounced low blood pressure and dizziness, which can
make you faint when you rise from a sitting or lying position (postural hypotension). As a
result, the first dose is often taken at bedtime.

Other side effects might include:

 Dizziness
 Headache
 Pounding heartbeat
 Weakness

Common drugs

Page 15 of 28
 Ergot alkaloids
a. Mechanism of action. These agents are weak α-adrenergic blockers as well as
being serotonin antagonists. They are also partial agonist at α-adrenergic receptors,
and agonists at tryptaminergic and dopaminergic receptors.
b. Pharmacologic effects
1. Ergot alkaloids are CNS stimulants and, therefore, may cause effects such
as confusion, irregular respiration, and anxiety.
2. They directly stimulate smooth muscle.
3. They cause significant elevation of BP via peripheral vasoconstriction.
c. Therapeutic uses
1. Ergotamine tartrate, by virtue of its vasoconstricting effects, is used in the
treatment of migraine headaches.
2. Ergonovine maleate is a powerful oxytocic but lacks the adrenergic blocking
activity of ergotamine. It causes direct contraction of uterine smooth muscle
and is used to decrease postpartum bleeding.
3. Methylergonovine maleate is also used to decrease postpartum uterine
bleeding.

Ergotamine Ergometrine

Peptide alkaloid Amine alkaloid

Polypeptide chain present Polypeptide chain absent

Powerful antagonist on alpha receptor Mild agonist on alpha receptor

and partial agonist

No effect on dopamine receptor Mild effect on dopamine receptor

Partial agonist on serotonin receptor Partial agonist and antagonist on

serotonin receptors

Less effect on uterus More effect on uterus

B. β-ADRENERGIC BLOCKING AGENTS (BB)”olol”

1. Propranolol is a nonselective β-antagonist: it competes with both β1 and β2 receptors.
a. Pharmacokinetics
i. Although propranolol is completely absorbed from the GIT, a large portion of the
drug is extracted by the liver before it enters the systemic circulation.
ii. Wide variation in the hepatic metabolism of the drug among individuals causes
significant differences in the plasma concentration attained.

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iii. Propranolol is approx. 90% bound to plasma proteins.
iv. The elimination t ½ is approx. 3 hrs for small doses but it is prolonged with larger
doses and significantly prolonged in the presence of cirrhosis.
v. A metabolic product, 4-hydroxypropranolol, is active but has a short t ½.

b. Pharmacologic effects
i. Propranolol decreases the heart rate and cardiac output and prolongs systole.
ii. It decr total coronary blood flow and oxygen consumption.
iii. It reduces blood flow to most tissues except the brain.
iv. Its antihypertensive effect is slow to develop, and the mechanism that cause the
effect are not clear. However, it inhibits the renal secretion of renin, which may
play a part.
v. It depresses sodium (Na+) excretion because it alters renal hemodynamics, an
effect that is secondary to the decr in cardiac output.
vi. Propranolol incr airway resistance by β2 blockade.
vii. Since most of the effects of catecholamines on carbo and fat metab are mediated
by β receptors, propranolol will interfere with these events.

c. Therapeutic uses. Propranolol is used for:

i. Treatment of hypertension, often in combi with a diuretic
ii. Prophylaxis of angina pectoris
iii. Prophy of supraventricular and ventricular arrhythmias
iv. Long-term prophy in patients who had an MI and are at high risk for infarction
and sudden death
v. Mangmt of hypertrophic obstructive cardiomyopathies to reduce the force of
myocardial function

d. Adverse effects and precautions

i. Propranolol can induce heart failure, esp in patients w/ compromised myocardial
function.
ii. Rapid withdrawal can lead to “supersensitivity” of β-adrenergic receptors, w/c can
provoke angina attacks, arrhyth, or MI.
iii. Because propr incr airway resistance, it must be used in asthmatics.
iv. Because of its effects in carbo metab, the hypoglycemic action of insulin may be
augmented. Therefore, diabetics being treated w/ insulin and person prone to
hypoglycemia must use propr w/ caution.
v. Rash, fever, and purpura are characteristics of an allergic response and require
discontinuation of the drug.
vi. Prolonged use may cause fatigue, depression, nightmares, sexual dysfunction,
and peripheral arterial insufficiency.

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 vii. Because of its effects on periph blood flow, it is c/I in px w/ Raynaud’s
phenomenon.

2. Timolol is a nonselective βadrenergic antagonist that is 5-10 x more potent than

propranolol.
a. Timolol lowers intraocular pressure by reducing the production of aqueous humor
in the ciliary body of the eye; the mechanism is not clear.
b. It does not change the size of the pupil, and vision is not affected.
c. Timolol, in the form of eyedrops, is therefore useful in the treatment of glaucoma.
d. Other use is the same as propranolol.
e. Timolol decrease the frequency of migraine attacks but not their duration or
severity.
f. Systemic absorption can occur with ocular use, but the amount absorbed is
usually not enough to affect px w/ asthma or heart failure.

3. Nadolol is nonselective BB that is not metabolized and is excreted unchanged in the

urine. Its effect and A/R are similar to those of propranolol.

4. Labetalol is a nonselective BB, w/c also has α1-blocking activity, it is used in the treatm
of mild to severe HTN.
a. It reduces peripheral vascular resistance while preventing reflex tachycardia.
b. When combined with either prazosin or hydralazine, labetalol is faster-acting
than other BB
c. It can be given IV for HTN emergencies.
d. Labetalol may cause postural hypotension and jaundice in addition to the A/E
seen in other BB.

5. Pindolol is a nonselective BB, w/c also has some intrinsic sympathomimetic (α-
adrenergic) activity. Unlike the case of propranolol, no rebound tachycardia occurs upon
abrupt withdrawal of pindolol.

6. Acebutolol is a BB w/ mild intrinsic sympathomimetic activity

a. Its B1-blocking effects exceed its B2-blocking effects
b. A/E, in addition to those seen in other BB, include arthritis, myalgia, and
anthralgia, and the presence of antinuclear antibodies.

7. Metoprolol is selective B1-adrenergic antagonist.

a. Pharmacologic effects
i. Metoprolol inhibits the inotropic and chronotropic cardiac responses to
isoproterenol.

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 ii. It is 1/50 as potent as propranolol in inhibiting the vasodilator response o
isoproterenol; however, it is long-acting.
iii. It is absorbed well when given orally.
b. Therapeutic uses. Metoprolol is used chiefly in the treatment of HTN.
c. Adverse effects. It produces fewer deleterious effects in asthmatic patients
because of its selective B1-antagonism, but its use in asthmatics still requires
caution. Other A/E are similar to those of propranolol.

8. Atenolol is a selective B1-antagonist, administered once a day.

9. Betaxolol is a selective B1-antagonist, administered once a day. It is more lipophilic
than atenolol. It is available as a topical formulation for the treatment of glaucoma.

C. AGENTS THAT INHIBIT THE ACTION OF ADRENERGIC NERVES

1. Reserpine
a. MOA. Reserpine, a rauwolfia alkaloid, acts via catecholamine depletion. It
inhibits the uptake of NE into vesicles, and intraneuronal degradation of NE by
MAO then occurs. This action takes place both centrally and peripherally.
b. Pharmacologic effects
i. Large doses given parenterally may cause a transient sympathomimetic
effect as stored catecholamines are released from the cell, because
uptake into vesicles is inhibited.
ii. BP decr, w/c usually triggers reflex tachycardia in normal people through
sympathetic stimulation. However, because sympathetic stores are
depleted, bradycardia may ensue in people taking reserpine.
iii. Sedation often results, owing to the depleted stores of catecholamines
and serotonin in the brain.
c. Therapeutic uses. Major use is in the treatment of HTN
d. A/E. Sedation, psychic depression that may result to suicide, abdominal cramps
& diarrhea, GI ulceration, possible incr incidence of breast carcinoma.

2. Guanithidine
a. MOA. It acts presynaptically. It impairs the response to sympathetic stimulation
by inhibiting the release of NT from peripheral adrenergic neurons. It is taken up
by adrenergic nerves and displaces NE from intraneuronal storage granules.
Much of the NE released is deaminated by intraneuronal MAO.
b. Pk. With oral admin absorption varies and the onset of action is slow. The drug
is rapidly cleared by the kidney.

Page 19 of 28
 c. Pharmacologic effects. A large IV dose causes a transient increase in BP.
This is followed by a fall in systemic and pulmonary arterial pressures that is
much more intense in the erect than in the supine individual.
d. Therapeutic uses. The major indication is a potent, long-acting antihypertensive
agent.
e. A/E. Postural hypotension, syncope esp w/ strenuous exercise, diarrhea,
edema. It is contraindicated in px taking MAOInhibs. The antiHTN effects may
be reversed by TCAs (tricyclic antidepressants), or indirect-acting
sympathomimetic amines, such as ephedrine or phenylpropanolamine (PPA).

3. Bretylium
a. Pharmacologic effects. Bretylium is taken up by adrenergic nerve terminals and
produces a block in the release of NE. It also inhibits the reuptake of NE into nerve
terminals
b. Therapeutic uses. It is no longer used for HTN but is used mainly as an
antiarrhythmic agent. It is poorly absorbed when given orally.
c. A/E. include cardiac stimulation dur to the sympathomimetic effects of bretylium, and
strong hypotension.

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 IV. PARASYMPATHETIC (CHOLINERGIC) AGONISTS
A. Acetylcholine.
1. Chemistry. It is a quaternary ammonium ester that is rapidly hydrolyzed by
acetylcholinesterase and plasma cholinesterase.

2. Pharmacologic effects
i. Cardiovascular effects. ACh produces a negative inotropic effect and a
negative chronotropic effect, vasodilation. Large IV doses cause an
increase in BP, owing to the release of catecholamines from the adrenal
medulla and activation of sympathetic ganglia.
ii. Effects on other systems. ACh increase GI motility and secretory
activity. It contracts smooth muscle in the uterus, ureters, bladder, and
bronchioles, and the constrictor muscles of the iris. It also stimulates the
salivary, sweat, and lacrimal glands.

3. Therapeutic uses. Ach is used as a miotic in cataract surgery.

B. Carbachol (carbamylcholine). It has a carbamic acid-ester link, which is not readily

susceptible to hydrolysis by cholinesterases. It has all the pharmacologic properties of
Ach. It exerts both nicotinic and muscarinic effects. Carbachol is used as ophthalmic
miotic agent.

C. Pilocarpine. It is a tertiary amine alkaloid. When applied locally to the eye, it causes
miosis and an eventual fall in intraocular pressure. Its major therapeutic indication is in
the treatm of glaucoma.

D. Metoclopramide. It stimulates the motility of the upper GIT. It is useful for the treatm of
diabetic gastroparesis (delayed gastric emptying) and GERD. It is also an antiemetic
and is used for the purpose during chemotherapy. A/E include possibly irreversible
tardive dyskinesia; acute dystonia; and prolactin secretion, which can cause loss of
libido, galactorrhea, and menstrual disorders.

E. A/E and precautions for parasympathetic agonists

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 1. Atropine will often block serious adverse effects, such as the incr of GI motility,
muscle paralysis, and stimulation of glandular secretion, that can occur with
these drugs.
2. Use of these drugs is contraindicated in px w/ coronary insufficiency,
hyperthyroidism, peptic ulcer, or asthma. In addition, Metoclopramide is c/I in px
taking phenothiazines, buterophenones, or thioxanthenes, and in px w/
pheochromocytoma or acute porphyria.

V. ANTICHOLINESTERASE AGENTS

A. Physostigmine
1. MOA. This alkaloid forms a reversible complex at the site of acetylcholinesterase
where acetylcholine is broken down.
2. Pk. Physostigmine is well absorbed from the GIT, subcutaneous tissues, and
mucous membranes.
3. Pcol effects. It mimic those of Acetylcholine
a. It produces miosis, and, thus, can antagonize the mydriasis induced by
atropine.
b. When given in large doses, it causes fasciculation, then paralysis, of skeletal
muscle because of the accumulation of Ach at the neuromuscular junction
that results when Ach is not broken down.
4. Therapeutic effects.
a. Treatment of Atropine, henothiazine, and TCA intoxication.
b. Treatm of glaucoma
c. Treatm of early stage of Alzheimer’s dis., since degeneration of cortical
cholinergic axons has been seen at autopsy in some px w/ this disorder.

B. Neostigmine. It is a synthetic reversible anticholinesterase that contains a quaternary

nitrogen.
1. Pk. It is not well absorbed orally. It does not penetrate the BBB, which minimizes
the toxicity due to inhibition of acetylcholinesterase that is in the brain. It is destroyed
by plasma esterases and is excreted in the urine.
2. Pcol effects. Neostigmine mimic those of Ach. It has a direct action on nicotinic
receptors, in addition to blocking acetylcholinesterase.
3. Therapeutic uses. Neostigmine is used to reverse the effects of competitive
neuromuscular blocking agents. It is used in the management of paralytic ileus and
atony of the urinary bladder. Also used in the symptomatic treatm of myasthenia
gravis.

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 VI. PARASYMPATHETIC ANTAGONISTS

A. Atropine is an alkaloid derived from the plant Atropa belladonna (deadly nightshade) . the
active component is the racemic mixture dl-hyoscyamine, an ester compound of tropic
acid and the organic base tropine.
1. MOA. Atropine competes reversibly with acetylcholine at muscarinic receptors. At
very high concentrations, it block Ach at ganglionic synapses and motor nerve
endings. It antagonizes the action of Ach in the CNS.
2. Pk. Atropine is rapidly but poorly absorbed when given orally. It disappears rapidly
from the blood and is excreted in the urine.
3. Pharmacokinetic effects.
a. Effects on the heart
i. The heart rate slows initially, owing to medullary stimulation of the
cardioinhibitory center.
ii. Tachycardia then follows with increased cardiac output and shortening
of the P-R interval. Higher doses cause only tachycardia.
b. Effects on BP
i. Oral or IM doses have little effect on BP.
ii. With IV injection, total peripheral resistance increases
iii. Arterial pressures increase, owing to the rise in heart rate and cardiac
output.
iv. Atropine has a direct vasodilating effect on small blood vessels.
c. Effects on CNS
i. Large doses can produce hallucinations, and, ultimately, coma, but
therapeutic doses exert little effect.
ii. Atropine possesses antitremor activity via a central antimuscarinic
mechanism.
d. Effects on involuntary muscle
i. Atropine decreases the amplitude and frequency of peristaltic
contractions and reduces the tone of the stomach, small intestine, and
colon.
ii. It also relaxes the smooth muscle of the biliary tract,
iii. Bladder and ureter tone are decreased, while vesicle sphincter tone is
increased.
e. Effects on the eye. Atropine blocks the Ach response of the ciliary
muscle of the lens and the circular smooth muscles of the iris, producing
cycloplegia and mydriasis.
f. Effects on secretions. Sweat gland secretions are greatly reduced.
Bronchial and salivary secretions are decreased. There is a reduction in

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 gastric secretion during both the psychic and gastric phases, and in reduction
in total acid content, esp at doses greater than 1 mg.
g. Effects on the bronchi. It produces slight bronchodilation.

4. Therapeutic uses
a. Ophth. administration is used for producing cycloplegia and mydriases.
b. Its ability to reduce secretions in the upper and lower respiratory tract
makes it very useful as preanesthetic agent.
c. Used in MI to treat sinus node bradycardia or a hi-grade A-V block
d. Effective prophylaxis for motion sickness
e. Combined with an opioid, it is used for the treatm of renal and biliary colic.
f. It may be used in large doses for the treatm of poisoning by
anticholinesterase agents, and for the rapid type of mushroom poisoning
because it antagonizes the action of Ach.
a. A/E. Rapid pulse, dilated pupils resulting in photophobia, dry mouth,
flushed skin, a rise in body temp esp in children, restlessness,
confusion, and disorientation.
5. The antidote for atropine poisoning is physostigmine.

B. Scopolamine (hyoscine), like atropine, is an alkaloid and is an ester of tropic acid but
with the organic base scopine.
1. Pharmacologic effects. Like atropine it has antimuscarinic actions. It is more
potent than atropine in producing mydriasis and cycloplegia, in decreasing bronchial
, salivary, and sweat gland secretions, and in its sedative effect. It is less potent
than atropine in its effect on the heart, bronchial muscles, and intestines. Atropine
has a longer duration of action.
2. Therapeutic uses and A/E are generally similar to those of atropine. Scopolamine
is excellent for motion sickness.

C. Dicyclomine is another synthetic antimuscarinic drug. At normal therapeutic doses, it

decreases spasm in most smooth muscles w/o producing atropine-like effects on the
heart, eye, or salivary and sweat glands. It is thought to act by direct relaxation of the
muscle rather than by competitive antagonism of Ach at muscarinic receptors.

D. Homatropine and eucatropine are used in ophthalmology as mydriatics.

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 VII. GANGLIONIC STIMULATORS AND BLOCKERS Comment [a1]:
Think of ganglia as the relay stations of the
body's nervous system: As one nerve enters
a ganglion, another nerve exits it. Ganglia play
an essential role in connecting the parts of the
A. Nicotine peripheral and central nervous systems.

1. MOA.
a. Nicotine interacts w/ the Ach receptor on the postsynaptic membrane of
autonomic ganglia
b. It causes an initial stimulation of the ganglion similar to the effect of Ach
c. Nicotine affects chemoreceptors in the carotid and aortic bodies and centers
in the medulla oblongata.

2. Pk. It is readily absorbed through the skin, respiratory tract, and buccal membrane.
It is metabolized in the liver, kidney, and lung, and is eliminated via the kidney. It is
excreted in the breast milk of lactating mothers who are heavy smokers.

3. Pharmacologic effects.

a. Nicotine is a CNS stimulant. Via motor cortex excitation, it produces tremors

which, with large doses can be followed by convulsion. Small doses stimulate
respiration while toxic doses depress it. It also stimulates the release of ADH.
b. Tachycardia, incr BP, incr total peripheral resistance
c. Incr bowel motility
d. Salivary and bronchial secretions are first stimulated, then blocked.
4. No therapeutic uses for nicotine exist. Its inherent toxicity has been applied in the
control of insects. Its presence in tobacco is, of course of major medical importance.

VIII. NEUROMUSCULAR BLOCKING AGENTS

These agents, which act by blocking transmission at the neuromuscular junction, can be
divided into two classes on the basis of their MOA: depolarizing agents and competitive, or
stabilizing, blocking agents.

A. MOA
1. Depolarizing agents (succinylcholine, decamethonium)
a. Like Ach, depolarizing agents react with receptors at the muscle end-plate
leading to depolarization of the excitable membrane. This phase I block is seen
clinically as fasciculation.
b. With prolonged exposure, a reduction in receptor sensitivity occurs, leading to a
phase II or desensitization, block manifested by flaccid paralysis. This phase II
block is not competitive in nature.

Page 25 of 28
 2. Competitive blocking agents (tubocurarine, gallamine, pancuronium,
atracurium,vecuronium)
a. Competitive blocking agents combine with Ach receptors at the muscle end-plate
but do not activate them.
b. By decreasing the number of available Ach receptors, these agents reduce the
height of the end-plate potential; thus, the threshold for excitation is not reached.
B. Pk.
1. After injection of a neuromuscular blocking agents, it is found in high concentration in
venous blood flowing to the heart and ultimately in the extracellular space around the
muscle end-plate.
2. Succinylcholine has a rapid onset of action, which facilitates endotracheal intubation.
3. Atracurium has a longer onset of action thn succinylcholine, and spontaneous recovery
occur after 30—60 minutes.
4. Metabolism
a. Pancuronium is deacetylated, and its metabolites show some activity.
b. Succinylcholine is rapidly metabolized to succinyl monocholine and choline, which
accounts for its brief duration of action.
c. Atracurium is inactivated in the plasma by enzymatic ester hydrolysis and by a
nonenzymatic process known as Hofmann elimination.
C. Therapeutic uses
1. Neuromuscular blocking agents are used for
a. As surgical adjuvants to anesthesia for promoting skeletal muscle relaxation, and for
facilitating ET intubation.
b. With electroconvulsant shock therapy to prevent trauma
c. In the diagnosis of myasthenia gravis (tubocurarine) although provocative tests of
this sort are potentially hazardous procedures.
2. Atracurium may be useful in patients with renal failure, since it does not rely in kidney
for excretion.
D. Adverse effects
1. All neuromuscular blocking agents do not affect the sensorium, so that despite the
paralysis, individuals remain conscious and are able to feel pain. Prolonged apnea may
occur.
2. Depolarizing agents.
a. The fasciculations can cause muscle pain; this occurs most frequently in young
patients.
b. Fasciculation of the abdominal muscles can result in increased intragastric
pressure, and it is important in patients at risk of aspirating gastric contents.
c. Contraction of extraocular muscles can lead to an increase in intraocular
pressure.

Page 26 of 28
 d. Succinylcholine may exert some action at the other Ach receptors, such as
stimulation of autonomic ganglia and muscarinic receptors.
e. The resulting effects, such as bradycardia and increased bronchial secretions,
are seen more commonly with repeated IV admin in children; cardiac arrest has
occurred.
f. In some genetically predisposed individuals, the combi of succinylcholine and
halothane results in rapid and potentially fatal rise in temperature (malignant
hyperthermia).
3. Tubocurarine. A dose-related fall in arterial pressure, the most common S/E, is the
result of both ganglionic blockade and histamine release. Histamine release can also
result in bronchospasm.
4. Pancuronium also causes an increase in the heart rate and in arterial pressure

E. Factors influencing the action of neuromuscular blocking agents

1. Serum cholinesterase is determined genetically; the normally transient effects of
succinylcholine will be greatly prolonged in an individual with deficient serum
cholinesterase.
2. Because serum cholinesterase is synthesized in the liver, hepatic disease can double
the duration of action of succinylcholine.
3. Depolarizing neuromuscular blockers increase serum potassium; this is exacerbated in
conditions that are associated with hyperkalemia, such as burns.
4. Aminoglycoside antibiotics and lincomycin exert synergestic neuromuscular
blockade when given with either competitive or depolarizing neuromuscular blocking
agents; the mechanism is presynaptic.
5. All inhalation anesthetics increase the effects of neutomuscular blocking agents.

F. Reversal of neuromuscular blockade

1. Competitive neuromuscular blockers can be antagonized by cholinesterase inhibitors,
such as edrophonium, neostigmine, or pyridostigmine.
2. No antagonists currently exist for depolarizing blockers.
3. If an anticholinesterase is given, phase I block increases, but an anticholinesterase may
reverse phase II block.

Page 27 of 28
 ANS Receptors

Location Sympathetic Sympathetic Parasympathetic

Receptor response to stimulus response to stimulus
Pupils Alpha 1 Dilation Constriction
Salivary gland Increased secretion
Coronary arteries Alpha 1 Constriction Relaxation
Beta 2 Dilation
Peripheral blood vessels Alpha 1 Vasoconstriction None
Beta 2 Vasodilation
Bladder sphincter Alpha 1 Constriction Relaxation
Uterus Alpha 1 Contraction None
Beta 2 Relaxation
Intestinal tone Alpha 1, Beta 2 Decreased Increased
Intestinal blood vessels Constriction Dilation
Heart rate Beta 1 Increased Decreased
Heart contraction Increased force Decreased force
Bronchi Beta 2 Dilation Constriction
Pulmonary blood vessels Dilation Constriction

Page 28 of 28
 NOTRE DAME OF DADIANGAS UNIVERSTY (NDDU)
College of Pharmacy
COURSE TITLE PHARMACOLOGY I COURSE CODE Pharm26
CREDIT UNITS 3 units COURSE Human Physiology and
REQUISITES Pathophysiology
CONTACT HOURS 3 hours/week Contact Hours/Date 3 hours/ Week 3
54 hours/sem for this topic
COURSE 2nd Year, Summer SME: Melba M. Roma, RPh, MSPh
PLACEMENT
MODULE 4: IV. Pharmacology of the Central Nervous System
Content Standards  Demonstrate understanding on the overview of the CNS, the concept of mood
disorders, psychotic disorders, and anxiety
 Demonstrate competence in the classifications and mechanism of action for
drugs in these disorders
Declarative • Review of anatomy and physiology of CNS
Knowledge • Outline the drugs affecting the CNS
Functional o Recall concepts of ion channels, neurotransmitter receptors, synaptic potential, sites of
Knowledge drug action and differentiate the types of neurotransmitter and other signaling
substances
o Discuss the definition of mood disorders, psychotic disorders, and anxiety, and its
pathophysiology, signs & symptoms
o Describe the pharmacokinetic properties, mechanisms of action, clinical applications,
pharmacologic and toxic effects drugs for these disorders
I. INTRODUCTION
Vidwatch:https://www.youtube.com/watch?v=WhowH0kb7n0&ab_channel=NeuroscientificallyChallengedNeuroscientificallyCh
allenged
GABA: https://www.youtube.com/watch?v=MRr6Ov2Uyc4&ab_channel=AlilaMedicalMedia
A. Transmission of nerve impulses

Page 1 of 38
 1. Information transfer. The brain and spinal cord are involved in information transfer
via electrical signals passing along axons (action potentials).
2. Synaptic transmission
a. The locus of communication between neurons is the synapse.
b. Synaptic transmission between neurons can be affected by altering the levels
of neurotransmitter (nt) in the presynaptic neuron. This can be accomplished
by various agents, which:
i. Block or enhance the biosynthesis of the nt
ii. Block or enhance the metabolic degradation of the nt
iii. After the reuptake and reutilization of the nt in presynaptic terminals
c. It is possible to alter the amount of nt that is released by activating
presynaptic receptors (autoreceptors) that are located at some synapses.
d. Many drugs are believed to bind to receptors and, bypassing the normal nt,
either to activate or block the response of the postsynaptic neuron, serving,
respectively, as agonists or antagonists.
e. Some drugs may act directly on ion channels, bypassing the nt-receptor
interaction entirely.
3. MOA. Although the basic mechanism underlying many of these agents that act on
the CNS are only partially understood, most are believed to alter either basic cellular
functioning of neurons or the communication between neurons.
a. Any agent that slows or blocks the axonal electrical conduction (e.g. local
anesthetic) will have an effect on behavior.
b. At therapeutic doses, most of the pharmacologically useful agents that affect
the CNS are believed to act at various specific synaptic sites.

B. Blood-brain barrier (BBB). The ability of an agent to affect CNS function is

dependent on its ability to cross or mediate an effect across the BBB.
1. The bbb restricts the passage of polar compounds and macromolecules from the
blood into the brain interstitium
a. Agents that are lipid-soluble, are unionized to physiologic pH, and bind poorly
to plasma proteins are better able to diffuse across the bbb.
b. Some metabolically important compounds (e.g., nutrients) apparanetly are
actively transported across this barrier.
2. The morphologic basis for the bbb appears to be the structure of the endothelial cell
layer lining the brain capillaries. Transendothelial vesicular transport (pinocytosis) is
a primary cellular mechanism by w/h plasma proteins constituents and
macromolecules pass through the cerebrovascular endothelium.

Page 2 of 38
 I. ANXIOLYTICS, SEDATIVE-HYPNOTICS
A. Barbiturates
1. Chemistry
a. The parent compound, barbituric acid, is derived from a
dehydration of urea and malonic acid. Barbituric acid itself has
no depressant effects on the CNS.
b. Changes in structure that favor increased lipid solubility will
speed up the onset of action, shorten the duration of action, and
increase the hypnotic potency.
c. When the oxygen at C-2 of oxybarbiturates is replaced with
sulfur, it becomes a thiobarbiturate, a compound with enhanced lipid solubility.

2. Classification. Barbiturates are classified on the basis of their onset and duration of
action (DOA).
a. Ultra-short-acting barbiturates (e.g. thiopental) act within seconds, and their DOA
is 30 min. their principal use is as IV adjuvants to anesthesia.
b. Short-acting barbiturates (e.g. pentobarbital) have a DOA of about 2 hrs; their
principal use is as sleep-inducing hypnotics.
c. Intermediate-acting barbiturates (e.g. amobarbital) have an effect lasting 3-5 hrs.
their principal use is as hypnotics; however, they have a “hangover” liability, the
result of residual depression of the CNS.
d. Long-acting barbiturates (e.g. phenobarbital) have a DOA greater than 6 hrs.
They are effective hypnotics and sedatives and at low doses are used as
antiepileptic agents, but they are likely to cause hangover.

3. MOA: At low doses, barbiturates either have a γ- aminobutyric acid (GABA)-like action
or enhance the effects of GABA, an inhibitory nt.
a. When GABA receptors are activated, chloride channels open. Chloride enters the
cell, hyperpolarizes it, and produces decreased excitation.
b. Barbiturates are less selective than benzodiazepines, which also have GABA-like
actions because elevating the dose of barbit produces a generalized CNS
depression in addition to selective depression at synaptic sites.

4. Pk.
a. The duration of action of a barbiturate depends on
i. Its rate of metabolic (hepatic) degradation
ii. Its degree of lipid solubility
iii. The extent to which it binds to serum proteins, which reduces renl excretion.
b. Long- acting barbiturates are metabolized principally in the liver by a slow oxidation
of the radicals at C-5, which produces more polar derivatives with low lipid solubility.

Page 3 of 38
 c. Ultra-short acting barbiturates are highly-lipid soluble, and, thus, have a short onset
and DOA.
i. High lipid solubility allows rapid transport across the BBB.
ii. Removal of the ultra-short-acting barbits from the brain occurs via
redistribution to other tissues (e.g. muscle).
d. Barbiturates are absorbed from the stomach, small intestine, rectum, and IM sites.
e. They readily cross the placental barrier, and concentrations in the fetal blood
approach those in maternal blood.
f. Barbiturates and their metabolites are principally excreted via renal route.
i. If renal function is impaired, barbiturates can cause severe CNS and CV
depression
ii. Alkalinization of the urine profoundly expedites the excretion of barbiturates
with lower lipid solubility, such as phenobarbital. These drugs are only
partially bound to plasma protein and are weak organic acids.

5. Pharmacologic effects
a. Barbiturates depress the CNS at all levels in a dose-dependent fashion. A
barbiturate plus another CNS depressant (e.g., phenothiazide, ethanol, or
antihistamine) can result in marked depression.
b. As hypnotics, they decrease the amount of time spent in REM sleep.
c. Barbiturates are not analgesics and, at low doses, are thought to be
hyperalgesic.
d. All barbiturates will suppress convulsant activity if given in sufficient doses.
e. At sedative doses, barbiturates have little effect on the CV system. As the dose
is increased, depressed ganglionic transmission results in decreased BP and
HR.
f. Most barbiturates, but esp phenobarb, are capable of inducing the hepatic
microsomal drug-metabolizing enzyme system. This result in increased
degradation of the barbiturate, ultimately leading to tolerance. It also causes
inactivation of other compounds, such as anticoagulants, phenytoin, digitoxin,
theophylline, and glucocorticoids, leading to potentially serious problems with
drug interactions.
6. Therapeutic uses
a. Although still used as sedative-hypnotics, barbiturates are being replaced for this
purpose by the benzodiazepines because of the following disadvantages:
i. Narrow therapeutic-to-toxic window
ii. Suppresses REM sleep
iii. Tolerance develops relatively quickly
iv. High potential for physical dependence and abuse
v. Frequent D/I second. to microsomal enzyme induction

Page 4 of 38
 b. Due to their rapid onset of action (OOA), barbiturates are used in emergency
treatment of convulsion, but in adults, the benzodiazepines are the DOC.
c. The ultra-short –acting barbs are useful as IV adjuncts to surgical anesth.
d. Barbs, esp in anesth.doses, significantly decrease O 2 utilization by the brain
e. The ability of barbs to stimulate liver glucuronyl transferase has been applied
successfully in the treatm of hyperbilirubinemia and kernicterus in the neonate.
7. Adverse effects
a. Depressant effects include oversedation and ↓ REM sleep.
b. Skin eruptions and porphyria can occur.
c. Physiologic and psychological dependence. Withdrawal may result in grand mal
seizures, severe tremors, vivid hallucinations, and psychoses. Abrupt withdrawal
should therefore be avoided.
d. Acute overdosage can result in coma, diminished reflexes, severe respi
depression, hypotension leading to CV collapse, and renal failure. Treatment of
acute Overdosage
i. Primarily, support respiration and circulation
ii. Excretion of the drug is by alkalinizing the urine and promoting diuresis
esp w/ long-acting barbs.
iii. Hemodialysis or peritoneal dialysis is often needed.

B. Nonbarbiturate sedative-hypnotics
1. Chloral hydrate
a. Pk. Chloral hydrate is metabolized in the liver by alcohol dehydrogenase to
trichloroethanol, which is thought to be the active metabolite producing the
CNS effects. In addition, it enhances the ability of hepatic microsomes to
metabolize drugs. It is excreted in the kd as the glucuronide conjugate
trichloroacetic acid.
b. Therapeutic uses. Relatively a safe hypnotic drug in a half-hour, and lasts
about 6 hrs and causes small reduction in REM sleep. It is used mainly in
children and in the elderly and is most effective when used for 1-3 nights to treat
transient insomnia. It should not be used in px w/ significant kd or liver disease.
c. A/E. it is quite bad-tasting and is irritating to the GIT. The CNS effects are
potentiated by alcohol (the combi being dubbed as “Mickey Finn”). Addiction can
occur where the px often presents with chronic gastritis and skin eruptions and
dependent indiv may lose mechanisms that detoxify the drug.

2. Paraldehyde
a. Chemistry. Paraldehyde is a trimer of acetaldehyde.
b. MOA. It produces hypnosis in about 15 min, and its effects last 4-8 hrs. Its
CNS activity resembles that of alcohol, chloral hydrate, and the barbiturates.

Page 5 of 38
 c. Route of admin can be orally, parenterally, or rectally.
d. Therapeutic uses. Used exclusively for px undergoing withdrawal from
alcohol. Used for px with hepatic or renal failure because it is mainly eliminated
via the lungs.
e. A/E. Its strong odor and disagreeable taste limit its use to hospitals. It irritates
GIT. Pulmonary disease and peptic ulcer disease are relatively C/I. It should not
be used with disulfiram.

C. BENZODIAZEPINES (BZDs) are widely used anxiolytic drugs and are generally
considered to be the preferred drugs for sedation-hypnosis. They have largely
replaced barbiturates and meprobamate in the treatment of anxiety and insomnia,
because BZDs are generally considered to be safer and more effective. Though they
are commonly used, they are not necessarily the best choice. Certain antidepressants
with anxiolytic action, such as SSRIs, are preferred in many cases, and non BZD
hypnotics and antihistamines may be preferable for insomnia.

1. MOA. The targets for benzodiazepine actions are the GABA. Note that GABA is the
major inhibitory neurotransmitter in the CNS. The GABAA receptors are composed of
combination of five α, β, and γ subunits that span the postsynaptic membrane and for
each subunit, many subtypes exist. Binding of GABA to its receptor triggers an opening
of the central ion channel, allowing chloride through the pore. The influx of the chloride
ions causes hyperpolarization of the neuron and decreases neurotransmission by
inhibiting the formation of each potentials.
2. Pharmacologic actions. All benzodiazepines exhibit the following actions to some
extent:
a. Reduction of anxiety. At low doses, the BZDs are anxiolytic by selectively
enhancing GABAergic transmission in the neurons having the α2 subunit in their
GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the
brain.
b. Sedative-hypnotic. All benzod.have sedative and calming properties, and some
can produce hypnosis at higher doses. The hypnotic effects are mediated by the
α1-GABAA receptors.
c. Anterograde amnesia. Temporary impairment of memory with the use of
benzod.is also mediated by α1-GABAA receptors. The ability to learn and form
new memories is also impaired.
d. Anticonvulsant. The effect is mediated by α1-GABAA receptors, the effect is
partially.
e. Muscle relaxant. At high doses, the benzod.relax the spasticity of skeletal
muscle, probably by increasing presynaptic inhibition in the spinal cord, where

Page 6 of 38
 the α2-GABAA receptors are largely located. Baclofen ® is a muscle relaxant
that is believed to affect GABA receptors at the level of the spinal cord.

3. Therapeutic uses.

a. Treatment of anxiety
b. Anesthetic premedication (midazolam is a parenteral benzid. that will replace
diazepam for preop use; its advantages include less tissue irritation, faster
OOA, and more rapid elimination)
c. Sedative-hypnotics
d. Management of seizure disorders
e. Treatm of alcohol withdrawal symdrome
f. Use as central skeletal muscle relaxant
g. Treatment of night terrors.
4. Adverse effects. Partially age- and dose-dependent.
a. Ataxia, drowsiness, and sedation
b. Paradoxically increased anxiety, including psychosis, esp with high doses.
c. Reversible confusion in the elderly
d. Menstrual irregularities, including anovulation
e. Withdrawal symptoms are influenza-like muscle aches and nausea.
f. Agent-specific effects include:
i. Triazolam may cause rebound insomnia
ii. Lorazepam and triazolam have a greater risk of inducing anterograde
amnesia
iii. Flurazepam at higher doses (30mg) is assoc. with daytime residual
sedation.

Page 7 of 38
 III. AGENTS USED IN THE TREATMENT OF SEIZURES

A. Barbiturates
1. Pharmacologic effects. As antiseizure agents, the barbiturates have a narrow
margin of safety. However, phenobarbital possesses more selectivity in its
Page 8 of 38
 anticonvulsant action than in its sedative effect. When used during pregnancy,
the neonate can experience withdrawal symptoms.
2. Therapeutic uses. Barbiturates are DOC for status epilepticus in infants and
children, but no longer a preferred treatm for prophylactic control of general
seizure states.
3. A/E. Sedation, physical and psychological dependence

B. Hydantoins. These are highly fat-soluble and are insoluble in water. Phenytoin
(Dilantin®) (diphenylhydantoin) is the most commonly prescribed hydantoin.
1. Pk. Phenytoin acts by stabilizing membranes by decreasing Na+ conductance
during high-frequency repetitive firing. It exerts its dampening effect only when
neuronal activity is abnormally high. It allows the normal conduction of action
potentials but halts seizure activity. Nearly 90% is bound to plasma protein. The
drug is metabolized by the microsomal system and is excreted first n the bile and
then in the urine.
2. Therapeutic uses. Phenytoin is used in the treatm of grand mal epilepsy and
tonic-clonic seizure disorders. Its use is contraindicated in liver disease and in
patients with absence seizure (petit mal epilepsy) or with convulsions resulting
from fever or barbiturate withdrawal.
3. A/E.
a. GI irritation, thus it should be taken with meals
b. Ataxia and diplopia
c. Blood dyscrasias
d. Hypersensitivity rxn, including Stevens-Johnson syndrome and SLE;
phenytoin should be stopped if a rash occurs.
e. Gingival hyperplasia, hirsutism, increased collagen proliferation, and
bone growth
f. Hepatitis
g. CV collapse, CNS depression, which may occur with IV admin
exceeding 50mg/min
h. Drug intrxns: ↑ plasma conc of phenytoin can occur due to inhib of its
inactivation by concurrent admin of chloramphenicol, INH, cimetidine,
dicumarol, disulfiram, and certain sulfonamides.
i. Phenytoin is teratogenic; fetal malformations can occur.
C. Succinimides
1. Ethosuximide
a. MOA. Although unknown, it may involve the release of GABA
b. Pk. It is absorbed from the GIT. About 80% is metabolized in the hepatic
microsomal metabolizing agent; 20% is unchanged and both would appear in
the urine.

Page 9 of 38
 c. Therapeutic Uses. It is considered the DOC in the treatm of petit mal
epilepsy (absence seizures)
d. A/E. It exacerbates grand mal epilepsy; GIT rxns such as anorexia and
nausea; CNS effects such as drowsiness, headaches, hiccups;
extrapyramidal symptoms, photophobia; hypersensitivity rxns; psychotic
episodes.

D. Benzodiazepines. Besides the value of BZDs as sedative-hypnotics and mild

tranquilizers, some are very effective in seizure control.
1. Diazepam given IV is now considered the DOC for status epilepticus in adults.
Should be given with caution in px receiving barbiturates.
2. Clonazepam is useful in the treatm of absence seizuresand myoclonic seizures
in children. It is well absorbed from the GIT, and its central effects develop
rapidly. Its chief therapeutic limitation is the development of tolerance, w/c can
be overcome by increasing the dose, however, sedation is induced.
3. Clorazepate is a useful adjunct in the treatm of complex partial seizures.

E. Other anticonvulsants
1. Carbamazepine (Tegretol®) is an iminostilbene and is related chemically to the
TCAs
a. It is used in the treatm of grand mal epilepsy, often as an adjunct to phenytoin
therapy
b. Its anticonvulsant actions are similar to those of phenytoin
c. Other uses include the treatm of trigeminal neuralgia and occasionally in the
treatm of bipolar illness.
d. Chronic use results in induction of drug-metabolizing enzymes, thereby
reducing serum levels.
e. A/E. diplopia, ataxia, nausea, bone marrow depression, aplastic anemia,
CHF, atropine-like symptoms, Kd and liver toxicity.
2. Valproic acid (dipropylacetic acid) Depakene®, Depacon®. Had been used
as a solvent in the screening of certain compounds for antiepileptic activity. It is
rapidly absorbed from the GIT. MOA involves inhibition of GABA transaminase.
A/E includes teratogenicity, pancreatitis, hepatic failure esp with other antiseizure
medication, anorexia, nausea, sedation, ataxia, alopecia.
3. Dantrolene. MOA. Its antispasticity works peripherally in the muscle by
decreasing Ca2+ release from the sarcoplasmic reticulum. Used in the treatm of
malignant hyperthermia. A/E include generalized skeletal muscle weakness nad
the life-threatening hepatic disfunction of an idiosyncratic or hypersensitivity type.

Page 10 of 38
IV. AGENTS USED IN THE TREATMENT OF PARKINSONIAN DISORDERS

A. Levodopa (L-dopa)
1. MOA. A dopamine deficiency in the striatum needs to be corrected in the
treatment of parkinsonism.
a. Dopamine does not cross the BBB; thus L-dopa, the precursor of
dopamine is given instead.
b. L-dopa is formed from L-tyrosine and is an intermediate in the
synthesis of catecholamines.
c. L-dopa itself has minimal pharmacologic activity, in contrast to its
decarboxylated product, dopamine.
d. L-dopa is rapidly decarboxylated in the GIT. Prior to the advent of
decarboxylase inhibitors (carbidopa), large oral doses of levodopa
were required; thus, toxicity from dopamine was a limiting factor.
2. Pk. L-Dopa is well absorbed from the small bowel; however 95% is rapidly
decarboxylated in the periphery. Peripheral dopamine is metabolized in the
liver to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA),
which are then excreted in the urine.
3. Pharmacologic effects. The effects on bradykinesis and rigidity are more
rapid and complete than the effects on tremor. Other motor defects in
Parkinson‟s disease improve. The psychological well-being of the patient is
also improved. Tolerance to both beneficial and adverse effects (e.g.
nausea) occurs with time.
4. A/E
a. Since the decarboxylation of L-dopa increases peripheral
concentrations of dopamine (DA), prominent α- and β-adrenergic
effects are seen, but these effects are significantly less severe than
those seen with epinephrine, NE, or isoproterenol.
b. Principal A/E include:
i. Anorexia, nausea& vomiting upon initial administration, which
often limit the initial dosage
ii. CV effects, including tachycardia, arrhythmias, and orthostatic
hypotension
iii. Mental disturbances including delusions and hallucinations
iv. A decrease in prolactin secretion
v. Dyskinesia upon long-term administration
5. Drug interactions
a. Pyridoxine reduces the beneficial effects of L-dopa by enhancing its
extracerebral metabolism. The decarboxylation of L-dopa to DA is
mediated by an enzyme that is pyridoxine-dependent.

Page 11 of 38
 b. Phenothiazides, reserpine, and butyrophenones antagonize the
effects of L-dopa because they lead to a junctional blockade of DA
action.
c. Therapy with MAO inhib must be stopped 14 days prior to the
initiation of L-dopa therapy.
d. Anticholinergic agents act synergistically with L-dopa, further improving
many of the symptoms of parkinsonism.

B. Carbidopa (Sinemet®)
1. Pk. It is an inhibitor of dopa decarboxylase. Since it is unable to penetrate
the BBB, it acts to reeduce the peripheral conversion of L-dopa to DA. As a
result, when carbidopa and levodopa are given concomittantly, then:
a. L-dopa blood levels are increased, and drug-half life is lengthened.
b. The dose of L-dopa can be significantly reduced, also reducing toxic
s/e
c. A shorter latency period precedes the occurrence of beneficial effects
2. Preparations. Sinemet is the trade name of a preparation that combines
carbidopa and levodopa in fixed proportions (1:10 and 1:4). It is considered
the most effective treatment for Parkinson‟s disease.

C. Amantadine. It is an antiviral agent used in the prophylaxis of influenza A2. It

was found to improve parkinsonian symptoms by stimulating the release of DA
from dopaminergic nerve terminals in the nigrostriatum and delaying its reuptake.
It may be more efficacious in parkinsonism than the anticholinergic atropine
derivatives, but is less effective than levodopa. It is well absorbed orally and is
excreted unchanged in the urine. Tolerance is observed in 6-8 weeks.

D. Bromocriptine. An ergot derivative, it mimics the action of dopamine.

Bromocriptine is expensive but probably provides additional therapeutic benefit
when added to L-dopa therapy. A/E such as hallucinations, hypotension, and
livedo reticularis.

E. Anticholinergic agents. Since the deficiency of DA in the striatum augments

the excitatory cholinergic system in the striatum, the blockade of this system by
anticholinergic agents, such as trihexyphenidyl, helps to alleviate the motor
dysfunction. Improvement in the parkinsonian tremor is more pronounced than
improvement in bradykinesia and rigidity. A/E such as mental confusion and
hallucinations due to central muscarinic toxicity can occur as can peripheral
atropine-like toxicity

Page 12 of 38
 F. Selegiline is a new drug as a selective MAO type B inhibitor also known as
deprenyl that works by slowing the breakdown of certain natural substances in
the brain (neurotransmitters such as dopamine, norepinephrine, and serotonin).

V. ANTIPSYCHOTIC AGENTS

A. General considerations
1. These agents are prescribed for the management of psychotic symptoms; they
are sometimes referred to as major tranquilizers.
2. They are useful in both acute and chronic psychoses and in nonpsychotic
individuals who are delusional or excited. They improve the mood and behavior
without producing excessive sedation.
3. As a group, these agents produce little physical dependence or habituation but,
notably, are capable of causing extrapyramidal symptoms (EPS), both reversible
(parkinsonian symx, akathisia) and irreversible (tardive dyskinesia).

1st gen 2nd gen

AKA Typical antipsych Atypical antipsych
MOA Block D2 receptors only Block D2 and 5HT2A receptors
EPS More likely to cause EPS Less likely to cause EPS
Metabolic Less likely to have metabolic More likely to cause abnormalities
abnormalities abnormalities (elevated glucose, lipids, and weight gain)

Page 13 of 38
 Common Phenothiazide Derivatives
Frequency of adverse effects
Drug Major use Orthostatic EPS
hypotension
Chlorpromazine (Thorazine®) Antipsychotic Emetic Moderate Moderate
Clozapine (Clozaril®) Antipsych,antichol,antihist Low Low
Thioridazine (Melleril®) Antipsych Moderate Low
Fluphenazine (Prolixin®) Antipsych Low High
Prochlorperazine(Compazine®) Antiemetic Low Low-moderate
Promethazine(Phenergan®) Antihistaminic Moderate Low

B. Phenothiazides
1. Chemistry. The phenothiazides have a three-ring structure in which two
benzene rings are linked by a sulfur and a nitrogen atom. Differences within this
group result from substitution on the nitrogen.

2. Pk. Phenothiazides are erratically absorbed from the GIT. They are highly
protein-bound and enter the fetal circulation. Their biologic effects last 24 hrs,
allowing once-daily dosing and are metabolized in the hepatic microsomal
system by hydroxylation, followed by conjugation with glucuronic acid. In
addition, the formation of sulfoxides is an important metabolic pathway. At least
five metabolites appear in the urine.

3. Pharmacologic effects.
a. CNS Effects
1) The psychotic patient has fewer hallucinations and delusions.
Improvements in behavior are most often noted with long-term therapy;
tolerance are rarely seen. Antipsychotic effects are believed to be due to
antagonism of dopaminergic neurotransmission in the limbic, nigrostriatal,
and hypothalamic systems.
2) Extrapyramidal symptoms occur most often with chronic administration
which arise because of antidopaminergic effects in the basal ganglia.
Phenothiazides having the greatest antihistaminic and anticholinergic
properties will exhibit the fewest EPS.

Page 14 of 38
 3) The neuroleptic effects of the antipsychotic drugs consist of emotional
quieting, reduced physical movement, and a potential for neurologic side
effects. The drugs have little effect on the intellectual functioning of the
patient.
4) Most phenothiazides are antiemetic. They antagonize agents, such as
apomorphine, which stimulate the chemoreceptor trigger zone. In high
doses, it may directly depress the medullary vomiting center.
5) Phenothiazides are capable of altering temperature-altering mechanisms.
Normally, they produce hypothermia; however, in a hot climate they can
cause hyperthermia because of failure to lose body heat.

b. Peripheral effects
1) An α-adrenergic blocking activity is seen, esp with the prototypic
phenothiazide, chlorpromazine.
2) Anticholinergic effects can result in blurred vision, constipation, dry mouth,
decreased sweating, and urinary retention, miosis.
3) Chlorpromazine is a potent local anesthetic.
4) Antihistaminic is seen with most phenothiazide derivatives.
5) Inhibition of ejaculation without interference with erection can occur, esp
w/ thiordazine.
6) Inhibition of ADH secretion by chlorpromazine can result in a weak diuretic
effect.
7) Orthostatic hypotension is due to the central action of phenithiazides and
inhibition of NE reuptake mechanisms. But chlorpromazine has an
antiarrhythmic effect upon the heart.
8) Phenothiazides enhance the pharmacologic effects of barbiturates,
narcotics, and ethyl alcohol.

4. Therapeutic uses. Used chiefly in the treatment of psychotic disorders,

including mania, paranoid states, schizophrenia, and psychosis assoc. with
alcoholism (alcoholic hallucinosis). Several phenothiazides are effective in the
treatm of drug-induced nausea & vomiting. Also useful as antihistaminics.
5. Adverse effects
a. CNS effects. A parkinsonian syndrome may occur. Acute dystonia may be
seen with initial drug therapy where patients display facial grimacing and
torticollis. Tardive dyskinesia is seen w/ chronic therapy.
b. CV effects include ortho.hypotension results in syncope, and reflex
tachycardia.
c. Allergic reactions occur during the first few months of therapy; cholestatic
jaundice, blood dyscrasias,dermatitis photosensitivity.

Page 15 of 38
C. Thioxanthene derivatives are similar chemically and pharmacologically to the
phenothiazide derivatives, these are chlorprothixene and thiothixene.

D. Butyrophenones
1. The prototype is haloperidol, which resembles the phenothiazide derivatives
pharmacologically. It has potent antiemetic properties, antagonizing stimulation
of the chemoreceptor trigger zone. Significant EPS are assoc. with its use.
2. Another butyrophenone is droperidol (Innovar®), is often combined with a
potent narcotic analgesic, such as fentanyl, to produce neuroletanalgesia.

E. Clozapine is a tetracyclic-N-methyl-piperazinyl-dibenzodizepine analog. At least 80%

of orally administered appears in the urine or feces as metabolites. The t ½ is 12 hrs.
It lacks EPS, also differs from typical neuroleptics by having low affinity for D1 & D2 DA
receptors. It has a potent anticholinergic activity. It can be effective in treating some px
with psychosis who are unresponsive to standard neuroleptic drugs. A/E is potential
fatal agranulocytosis, thus monitor closely.

VI. AGENTS USED IN THE TREATMENT OF ANXIETY

A. General considerations. Unlike the antipsychotics, these agents are used to treat
anxiety or neurosis. They are not used in the treatm of psychosis. These drugs,
therefore, are known as antianxiety agents or minor tranquilizers. It has sedative
and even hypnotic properties and possess some skeletal muscle relaxant activity.

B. Meprobamate is a propyl alcohol derivative (propanediol carbamate). It was widely

used antianxiety agent but largely been replaced by BZDs.
1. Pk. it is well abrorbed from the GIT, its peak serum concentration is reached in
about 1 ½ hrs. metabolism occurs in the liver; its inactive metabolites are
excreted via the kidney.
2. Pharmacological effects. It depresses the CNS in a fashion similar to that of
barbiturates, esp phenobarbital but is short-acting. It promotes sleep but
decreases the REM phase
3. A/E. drowsiness, blood dyscrasias, habituation and physical dependence with
long-term therapy, thus gradual withdrawal only.

Page 16 of 38
C. Benzodiazepines are considered DOC in the treatm of anxiety partly because of their
high therapeutic index. All BZDs are soluble in lipids and cross BBB. Plasma levels
reflect brain levels. Therapeutic doses have minimal effects on the CV systems.

1. Therapeutic uses. Treatment of anxiety, anesthetic premedication,sedative-

hypnotics, management of seizures, treatm of alcohol withdrawal syndromes,
skeletal muscle relaxant, treatm of night terrors.
2. A/E are partially age- and dose- dependent. This include ataxia, drowsiness,
and sedation. Paradoxically increased anxiety, psychoses, especially with high
doses. Reversible confusion in the elderly, menstrual irregularities, including
anovulation. Withdrwal symptoms are influenza-like muscle aches and nausea.
Agent-specific effects include: Triazolam for rebound insomnia, Lorazepam and
triazolam have greater risk of inducing anterograde amnesia, Flurazepam at
higher doses (30mg) is assoc with daytime residual sedation.

D. Buspirone is an antianxiety agent that is not chemically or pharmacologically related to

the barbiturates, or other sedative-hypnotic drugs.

1. MOA. It can bind to DA and serotonin receptors. It does not bind to BZD
receptors and does not have muscle-relaxant, anticonvulsant, or hypnotic
activity.

2. Pk. Buspirone (Buspar®) is rapidly and completely absorbed from the GIT. It
undergoes an extensive first-pass effect. One hydroxylated metabolite is
pharmacologically active. Buspirone is highly protein-bound and it is partly
excreted in the urine and has an elimination half-life 4-8 hours.

3. Therapeutic uses. It is used for the short-term treatment of generalized anxiety.

It may require 1-2 weeks for a therapeutic effect to take place.

4. A/E. Include restlessness and dysphoria with high doses. Buspirone is

remarkably free of other A/E and it has little potential for abuse.

VII. MOOD-ALTERING DRUGS

A. Lithium carbonate is used in the treatment of mania and manic episodes of bipolar
disorder (manic-depressive disorders)

Page 17 of 38
 1. MOA. This is thought to be related to lithium‟s inhibition of hormone-sensitive
adenylate cyclase and the greater stabilization of DA and β-adrenergic receptors.

2. Pk. Lithium ions is well-absorbed from the GIT and eventually reaches
equilibrium between plasma and tissues. It is eliminated by renal excretion; 80%
of the lithium is reabsorbed in the proximal tubule. Lithium ion is secreted into
breastmilk.

3. Route of admin. It is given orally and since lithium has a low therapeutic index,
serum conc must be carefully maintained between 0.8 to 1.5mEq/L.

4. Therapeutic uses. The major indications are the prevention of bipolar illness
and the treatm of acute mania. It has no effect on schizophrenia and does not
produce psychotropic effects in normal individuals.

5. A/E. high serum concentration is assoc with anorexia, vomiting, diarrhea,

excessive thirst, and polyuria. The latter two symptoms probably involve the
ability of lithium to inhibit the action of ADH on renal adenylate cyclase. This
ultimately can result in diabetes insipidus; it is the most common cause of
nephrogenic diabetes insipidus. CV effects are hypotension and cardiac
arrhythmias. Chronic use can result in thyroid enlargement. Intoxication can
usually be reversed by osmotic diuresis and in more severe cases, dialysis.

B. Antidepressant agents

1. General considerations

a. Depression is an alteration of mood characterized by sadness, worry, and

anxiety. The patient may suffer from losses of weight and libido.

b. Most antidepressants are believed to improve mood by increasing

catecholamine stores, although recent evidence suggests that there may be
correlation between improvement in mood and a decrease in adenylate cyclase.

c. There are various pharmacologic modalities that may be useful, and selection
often depends on the patient‟shistory and symptomatology.

Page 18 of 38
2. Monoamine oxidase (MAO) inhibitors

a. Chemistry. Chemically, the MAOinhib consist of two major groups, the

hydrazides and the nonhydrazides. The hydrazide derivatives include
isocarboxazid, phenelzine. The prototypic nonhydrazide is tranylcypromine
which structurally resembles dextroamphetamine.

b. MOA. The MAOIs form stable complexes with the enzyme MAO, irreversibly
inactivating it, thereby preventing the oxidative deamination of biogenic amines,
such as NE, epi, DA, serotonin, and tyramine. These biogenic amines are, thus
increased significantly in the brain , intestines, heart, and blood. The increased
biogenic amines in the brain is thought to cause the observed antidepressant
effects.

1) There are two types of MAOIs which are distinguished by differing

responses to specific inhibitors and by differing preferences for
substrates.

i. Type A deaminates serotonin and NE but not phenylethylamine

ii. Type B deaminates phenylethylamine better than serotonin or NE

and it is inhibited by deprenyl. MAO-B is the type found largely in
the CNS.

c. PK. All MAOIs are rapidly absorbed from the GIT, but inexplicably, the
observed therapeutic response does not occur for 2-3 weeks. The hydrazide
derivatives are cleaved, resulting in biologically active products. Inactivation
occurs by acetylation, and in patients who are slow acetylators, conventional
doses of agents, such as phenelzine, may produce exaggerated effects.
Enzyme regeneration terminates the drug effect, but this frequently takes
weeks after use of the drug is stopped. When swithching antidepressant
therapy, a minimum of 2 weeks‟ delay is required after termination of MAOI
therapy.

d. Pharmacologic Effects

1) CNS effects. Besides their effect on depression, MAOIs are effective

in sleep disorders, including narcolepsy. They suppress REM sleep.

Page 19 of 38
 2) CV effects. Postural hypotension can result from the ability of MAOIs
to affect ganglionic transmission and reduce the release of NE in
certain organ systems. This effect is believed to be due to the uptake
and release of “false transmitters” such as tyramine. MAOIs can
interact with foods containing high tyramine content, such as
cheese, beer , and chicken liver. The high concentration of tyramine
absorbed from these foods cannot undergo oxidative deamination.
The tyramine can, therefore induce the release of large amount of
catecholamines from nerve terminals and this can participate in the
hypertensive crisis, which is the most serious A/E of MAOIs.

3) Hepatic effects. MAOIs interfere with the detoxification of many drugs.

They enhance the action of general anesthetics, sedatives, atropine-
like agents, narcotics (esp meperidine, w/c can result in hyperpyrexia),
and TCAs.

4) Therapeutic uses. MAO-A Inhibitors are especially effective in the

treatment of atypical depression, characterized by symptoms such as
hypersomnolence, hyperphagia, and hyperanxiety. Deprenyl is a
MAOIs-B, w/c may be useful in the treatm of Parkinson‟s disease.

5) A/E. the most serious effect is marked HTN from an intraction

between a MAOI-A and certain amines or their precursors. Hydrazide-
derived MAOIs can cause hepatocellular damage. Overdosage can
result in agitation, headache, hallucinations, convulsions, and hypo or
hypertension. Treatment of overdosage is usually supportive. Since
the effects of MAOIs are lengthy, px should be observed in the hospital
for at least 1 week.

3. Tricyclic antidepressants (TCA)

a. Chemistry. Chemically, the TCA and their desmethyl derivatives are similar to
the phenothiazides.
b. Specific agents.
1) Imipramine is closely related to the phenothiazides
2) Amitriptyline is thought to be better tolerated than imipramine in older
psychotic or depressed patients. It is effective in multiple sclerosis patients
with pseudobulbar palsy, the syndrome of pathologic laughing and
weeping.
3) Desipramine, the monodesmethyl derivative of imipramine, is less
sedating than its parent compound.

Page 20 of 38
 4) Nortriptyline, like desipramine, produces less sedation than its parent
compount amitriptyline.
5) Doxepin is also effective in treating depression when anxiety is present.
6) Protriptyline has a 3-to 5-day half-life and causes little sedation.
c. MOA. TCAs potentiate the action of biogenic amines by blocking the
inactivating reuptake of the amines after release from the presynaptic neuron.
TCAs have both antihistaminic and α-adrenergic properties. It also possesses
antimuscarinic action and block the reuptake of serotonin. Tertiary amines
(imipramine, amitriptyline) are more effective at blocking serotonin reuptake.
d. Pk. the TCAs are well absorbed from the GIT. Because of their lipophilic nature,
these agents become widely distributed and have relatively long t ½.
Hydroxylation, N-demethylation, and conjugation with glucuronic acid are the
major metabolic pathways. Excretion is via the kd.
e. Pcol effects.
1) CNS. Effects. A nondepressed person experiences sleepiness when a
tca is administered. In addition, anxiety and toxic anticholinergic effects
may be experienced. In the depressed patient, an elevation of mood
occurs 2-3 weeks after administration begins. The latency period can be
as long as 4 weeks. TCAs can cause EPS and ataxia. High doses are
capable of producing seizures and coma.
2) CV effects. Orthostatic hypotension and arrhythmias are two common
effects. Tachycardia in response to the hypotension and interference w/
AV conduction similar to that produced by quinidine can occur. The most
ANS effect is anticholinergic. Amitriptyline possesses the most potent
antimuscarinic effects.
3) Therapeutic uses. These agents are the DOC for severe endogenous
depression. In terms of overall efficacy, the various TCAs are equivalent
at appropriate doses. Enuresis has been successfully treated with
imipramine. Obsessive-compulsive neurosis accompanied by
depression, and phobic-anxiety syndromes, chronic pain, and neuralgia
may respond to TCAs.
4) A/E. It often resembles those seen with phenothiazides, owing to the
common structural features of the two groups of drugs. Sweating is
common. The elderly may suffer from dizziness and muscle tremor.
Amitriptyline produces the highest incedence of antimuscarinic effects.
Acute poisoning is often treated with activated charcoal, gastric lavage
and physostigmine is used as adjuncts. Seizures, ventricular arrhythmia,
death can result from overdoses. The combi of MAOIs and TCAs should
be avoided, since hyperpyrexia, convulsions, and coma can result.

Page 21 of 38
 4. Selective Serotonin Reuptake Inhibitors (SSRIs)

The SSRIs specifically inhibit serotonin reuptake, having 300- to 3000 –fold greater
selectivity for the serotonin transporter, as compared to the NE transporter. This
contrasts with the TCAs and serotonin/norepinephrine reuptake inhibitors (SNRIs) that
nonselectively inhibit the reuptake of NE and serotonin. Moreover, the SSRIs have little
blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors. Therefore
common side effects assoc with TCAs, such as orthostatic hypotension, sedation, dry
mouth, and blurred vision, are not commonly seen with the SSRIs. Because they have
different A/E and are relatively safe even in overdose, the SSRIs have largely replaced
TCAs and MAOIs as DOC in treating depression.

The SSRIs include Citalopram (Celexa®), Escitalopram (Lexapro®), Fluoxetine

(Prozac®), Paroxetine (Paxil®, Pexeva®), Sertraline (Zoloft®)

A. Therapeutic actions. SSRIs treat depression by increasing levels of serotonin in the

brain. Serotonin is one of the chemical messengers (neurotransmitters) that carry
signals between brain nerve cells (neurons). SSRIs block the reabsorption
(reuptake) of serotonin into neurons. This makes more serotonin available to improve
transmission of messages between neurons. SSRIs are called selective because they
mainly affect serotonin, and not other neurotransmitters. It typically takes at least 2
weeks to produce significant improvement in mood, and maximum benefit may require
up to 12 weeks or more.

B. Therapeutic uses. The primary indication of SSRIs is depression, for which they are
as effective as TCAs. It also favors obsessive-compulsive disorder, panic disorder,
generalized anxiety disorder, post-traumatic stress disorder, social anxiety disorder,
premenstrual dysphoric disorder, and bulimia nervosa (only fluoxetine is approved for
bulimia).

C. Pk. SSRIs are metabolized in the liver by cytochrome P-450 mixed function oxidase
(MFO) microsomal enzymes. They are highly bound to plasma proteins and have a
large volume of distribution. Peak plasma levels are reached in 2 to 10 hours. Half-lives
for SSRIs are variable, but most have a half-life of 20 to 24 hours. A notable exception is
fluoxetine (Prozac) and its active metabolite, norfluoxetine, which have half-lives of 2 to
4 days and 8 to 9 days, respectively. Hence, addition of serotonergic medications to a
patient's regimen must not occur until 2 to 3 weeks after discontinuation of an SSRI.
Some recommend a 5-week "wash-out" period for fluoxetine prior to initiation of a
MAOIs

D. A/E. Most people who use SSRI antidepressants don‟t have major problems, but every
kind of medical treatment carries some risk. The possible side effects of these
antidepressants include: Insomnia, Headache, Rash,Blurred vision,Drowsiness,Dry

Page 22 of 38
 mouth,Agitation or nervousness,Feeling dizzy,Pain in the joints or muscles,Upset
stomach, nausea, or diarrhea,Reduced sexual desire.

Some people, especially children and young adults, may be more likely to have
suicidal thoughts when they take SSRIs.

E. Overdose. SSRIs does not usually cause cardiac arrhythmias, with the exception of
citalopram, which may cause QT prolongation. (Note that TCAs have a significant risk of
arrhythmias in overdose.) Seizures are a possibility because all antidepressants may
lower the seizure threshold. All SSRIs have the potential to cause serotonin syndrome,
which may include the symptoms of hyperthermia, muscle rigidity, sweating, myoclonus,
and changes in mental status and vital signs.

F. Discontinuation syndrome. Even though SSRIs aren‟t habit-forming, it can be

dangerous to stop them suddenly or miss several doses in a row. Doing this can lead to
a condition called discontinuation syndrome that causes withdrawal-like symptoms.

Discontinuation syndrome include feeling like having the flu and/or notice symptoms
like: nausea, dizziness, uneasiness, fatigue or lethargy.

5. Serotonin /Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs block the reabsorption of both serotonin and norepinephrine. Like SSRIs,
SNRIs improve the way your brain sends and receives messages. These agents may be
effective when SSRIs are ineffective. Examples of this type of antidepressant are
desvenlafaxine (Khedezla®, Pristiq®), duloxetine (Cymbalta®), levomilnacipran
(Fetzima®), venlafaxine (Effexor®).

A. Venlafaxine is a potent inhibitor of serotonin reuptake, and at medium to high doses, is

an inhibitor of NE reuptake. Desvenlafaxine is the active, demethylated metabolite
of venlafaxine. The most common S/E are nausea, headache, sexual dysfunction,
dizziness, insomnia, sedation, and constipation. At high doses, there may be increase
in blood pressure and heart rate.

B. Duloxetine inhibits serotonin and NE at all doses. It is extensively metabolized in the

liver to inactivate metabolites and should be avoided in patients with liver dysfunction.
GI S/E are common, including nausea, dry mouth,, and constipation.

C. Levomilnacipran is an enantiomer of milnacipran (an older SNRI). The A/E is

similar to other SNRIs.

Page 23 of 38
 VIII. CNS STIMULANTS

PSYCHOMOTOR STIMULANTS and HALLUCINOGENS are two groups of drugs that act
primarily to stimulate the CNS. The psychomotor stimulants cause excitement and
euphoria, decrease feelings of fatigue, and increase motor activity. Ex., Methylxanthines
(caffeine, theobromine, theophylline), nicotine, cocaine, amphetamine, atomoxetine, modafinil,
methylphenidate.

The hallucinogens produce profound changes in thought patterns and mood, with little
effect on the brainstem and spinal cord. As a group, the CNS stimulants have diverse clinical
uses and are important as drugs of abuse, as are the CNS depressants and the opioids. Ex.
Lysergic acid diethylamide (LSD), Phencyclidine (PCP), Tetrahydrocannabinol (THC),
Rimonabant.

Psychomotor Stimulants

Generic Brand Generic Brand

Amphetamine Adderall Armodafinil Nuvigil
Atomoxetine Atrattera Caffeine Cafcit, No Doz, Vivarin
Cocaine Dexmethylphenidate Focalin
Dextroamphetamine Dexedrine, Dextrostat Lisdexamfetamine Vyvanse
Methamphetamine Desoxyn Methylphenidate Ritalin,Concerta, Daytrana
Modafinil Provigil Nicotine Nicoderm CQ, Nicorette, Nicotrol
Theophylline Elixophyllin,Theo-24 Varenicline Chantix

PSYCHOMOTOR STIMULANTS

A. Methylxanthines

The methylxanthines include theophylline which is found in tea; theobromine found in cocoa;
and caffeine. Caffeine, the most widely consumed stimulant in the world, is found in highest
concentration in certain coffee products (for example, espresso), but it is also present in tea,
cola drinks, energy drinks, chocolate candy, and cocoa.

1. MOA. Several mechanisms have been proposed for the actions of methylxanthines,
including translocation of extracellular calcium, increase in cyclic adenosine monophosphate
and cyclic guanosine monophosphate caused by inhibition of phosphodiesterase, and
blockade of adenosine receptors. The latter most likely accounts for the actions achieved by
the usual consumption of caffeine-containing beverages.

Page 24 of 38
2. Pharmacological Actions

a. CNS. The caffeine contained in one to two cups of coffee (100 to 200 mg) causes a
decrease in fatigue and increased mental alertness as a result of stimulating the cortex
and other areas of the brain. Consumption of 1.5 g of caffeine (12 to 15 cups of
coffee) produces anxiety and tremors. The spinal cord is stimulated only by very high
doses (2 to 5 g) of caffeine. Tolerance can rapidly develop to the stimulating properties
of caffeine, and withdrawal consists of feelings of fatigue and sedation.

b. CV system. A high dose of caffeine has positive inotropic and chronotropic effects on
the heart. [Note: Increased contractility can be harmful to patients with angina pectoris.
In others, an accelerated heart rate can trigger premature ventricular contractions.]

c. Diuretic action: Caffeine has a mild diuretic action that increases urinary output of
sodium, chloride, and potassium.

d. Gastric mucosa: Because methylxanthines stimulate secretion of gastric acid,

individuals with peptic ulcers should avoid foods and beverages containing
methylxanthines.

3. Therapeutic uses. Caffeine and its derivatives relax the smooth muscles of the bronchioles.
[Note: Previously the mainstay of asthma therapy, theophylline has been largely replaced by
other agents, such as β2 agonists and corticosteroids.] Caffeine is also used in combination
with the analgesic acetaminophen and aspirin for the management of headaches in both
prescription and over-the-counter products.

4. Pk. The methylxanthines are well absorbed orally. Caffeine distributes throughout the body,
including the brain. These drugs cross the placenta to the fetus and are secreted into the
breast milk. All methylxanthines are metabolized in the liver, generally by the CYP1A2
pathway, and the metabolites are excreted in the urine.

5. A/E. Moderate doses of caffeine cause insomnia, anxiety, and agitation. A high dosage is
required for toxicity, which is manifested by emesis and convulsions. The lethal dose is 10 g
of caffeine (about 100 cups of coffee), which induces cardiac arrhythmias. Death
from caffeine is, therefore, highly unlikely. Lethargy, irritability, and headache occur in users
who routinely consume more than 600 mg of caffeine per day (roughly six cups of coffee per
day) and then suddenly stop.

B. Nicotine

Nicotine is the active ingredient in tobacco. Although this drug is not currently used
therapeutically (except in smoking cessation therapy), nicotine remains important because it is
second only to caffeine as the most widely used CNS stimulant, and it is second only to
alcohol as the most abused drug. In combination with the tars and carbon monoxide found in

Page 25 of 38
cigarette smoke, nicotine represents a serious risk factor for lung and cardiovascular disease,
various cancers, and other illnesses. Dependency on the drug is not easily overcome.

1. MOA. In low doses, nicotine causes ganglionic stimulation by depolarization. At high

doses, nicotine causes ganglionic blockade. Nicotine receptors exist at a number of sites in the
CNS, which participate in the stimulant attributes of the drug.

2.Pharmacological Actions

a. CNS. Nicotine is highly lipid soluble and readily crosses the BBB. Cigarette smoking or
administration of low doses of nicotine produces some degree of euphoria and arousal,
as well as relaxation. It improves attention, learning, problem solving, and reaction time.
High doses of nicotine result in central respiratory paralysis and severe hypotension
caused by medullary paralysis. Nicotine is also an appetite suppressant.

b. Peripheral effects. The peripheral effects of nicotine are complex. Stimulation of

sympathetic ganglia as well as of the adrenal medulla increases blood pressure and
heart rate. Thus, use of tobacco is particularly harmful in hypertensive patients. Many
patients with peripheral vascular disease experience an exacerbation of symptoms with
smoking. In addition, nicotine induced vasoconstriction can decrease coronary blood
flow, adversely affecting a patient with angina. Stimulation of parasympathetic ganglia
also increases motor activity of the bowel. At higher doses, blood pressure falls and
activity ceases in both the gastrointestinal (GI) tract and bladder musculature as a result
of a nicotine-induced block of parasympathetic ganglia.

c. Pk. Because nicotine is highly lipid soluble, absorption readily occurs via the oral
mucosa, lungs, GI mucosa, and skin. Nicotine crosses the placental membrane and is
secreted in the breast milk. By inhaling tobacco smoke, the average smoker takes in 1
to 2 mg of nicotine per cigarette. The acute lethal dose is 60 mg. More than 90% of the
nicotine inhaled in smoke is absorbed. Clearance of nicotine involves metabolism in the
lung and the liver and urinary excretion. Tolerance to the toxic effects of nicotine
develops rapidly, often within days.

d. A/E. The CNS effects of nicotine include irritability and tremors. It may also cause
intestinal cramps, diarrhea, and increased heart rate and blood pressure. In addition,
cigarette smoking increases the rate of metabolism for a number of drugs.

e. Withdrawal syndrome: As with the other drugs in this class, nicotine is an addictive
substance, and physical dependence develops rapidly and can be severe. Withdrawal is
characterized by irritability, anxiety, restlessness, difficulty concentrating, headaches,
and insomnia. Appetite is affected, and GI upset often occurs. [Note: Smoking cessation
programs that combine pharmacologic and behavioral therapy are the most successful
in helping individuals to stop smoking.] The transdermal patch and chewing gum

Page 26 of 38
 containing nicotine have been shown to reduce nicotine withdrawal symptoms and to
help smokers stop smoking. For example, the blood concentration of nicotine obtained
from nicotine chewing gum is typically about one-half the peak level observed with
smoking. Other forms of nicotine replacement used for smoking cessation include the
inhaler, nasal spray, and lozenges. Bupropion, an antidepressant, can reduce the
craving for cigarettes.

C. Varenicline

Varenicline is a partial agonist at neuronal nicotinic acetylcholine receptors in the CNS.

Because varenicline is only a partial agonist at these receptors, it produces less euphoric
effects than nicotine (nicotine is a full agonist at these receptors). Thus, it is useful as an
adjunct in the management of smoking cessation in patients with nicotine withdrawal
symptoms. Additionally, varenicline tends to attenuate the rewarding effects of nicotine if a
person relapses and uses tobacco. Patients taking varenicline should be monitored for suicidal
thoughts, vivid nightmares, and mood changes.

D. Cocaine

Cocaine is a widely available and highly addictive drug. Because of its abuse potential,
cocaine is classified as a Schedule II drug by the U.S. Drug Enforcement Agency. The primary
mechanism of action underlying the effects of cocaine is blockade of reuptake of the
monoamines (norepinephrine, serotonin, and dopamine) into the presynaptic terminals.
This potentiates and prolongs the CNS and peripheral actions of these monoamines. In
particular, the prolongation of dopaminergic effects in the brain‟s pleasure system (limbic
system) produces the intense euphoria that cocaine initially causes. Chronic intake
of cocaine depletes dopamine. This depletion triggers the vicious cycle of craving
for cocaine that temporarily relieves severe depression.

E. Amphetamine

Amphetamine is a sympathetic amine that shows neurologic and clinical effects quite similar to
those of cocaine. Dextroamphetamine is the major member of this class of
compounds. Methamphetamine (also known as “speed”) is a derivative
of amphetamine available for prescription use. It can also be smoked and is preferred by many
abusers. 3,4-Methylenedioxymethamphetamine (also known as MDMA, or Ecstasy) is a
synthetic derivative of methamphetamine with both stimulant and hallucinogenic properties.

1. MOA. As with cocaine, the effects of amphetamine on the CNS and peripheral nervous
system are indirect. That is, both depend upon an elevation of the level of catecholamine
neurotransmitters in synaptic spaces. Amphetamine, however, achieves this effect by
releasing intracellular stores of catecholamines. Because amphetamine also inhibits
monoamine oxidase (MAO) and is a weak reuptake transport inhibitor, high levels of

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 catecholamines are readily released into synaptic spaces. Despite different mechanisms of
action, the behavioral effects of amphetamine and its derivatives are similar to those
of cocaine.

2. Pharmacological Actions

a. CNS. The major behavioral effects of amphetamine result from a combination of its
dopamine and norepinephrine release enhancing properties. Amphetamine stimulates
the entire cerebrospinal axis, cortex, brainstem, and medulla. This leads to increased
alertness, decreased fatigue, depressed appetite, and insomnia. The CNS stimulant
effects of amphetamine and its derivatives have led to their use in therapy for
hyperactivity in children, for narcolepsy, and for appetite control. At high doses,
psychosis and convulsions can ensue.

b. SNS. In addition to its marked action on the CNS, amphetamine acts on the adrenergic
system, indirectly stimulating the receptors through norepinephrine release.

3. Therapeutic uses. Factors that limit the therapeutic usefulness of amphetamine include
psychological and physiologic dependence similar to those with cocaine and, with chronic
use, the development of tolerance to the euphoric and anorectic effects.

 Attention deficit hyperactivity disorder (ADHD): Some young children are

hyperkinetic and lack the ability to be involved in any one activity for longer than a few
minutes. Dextroamphetamine, methamphetamine, the mixed amphetamine salts,
and methylphenidate can help improve attention span and alleviate many of the
behavioral problems associated with this syndrome, in addition to reducing
hyperkinesia. Lisdexamfetamine is a prodrug that is converted to the active
component dextroamphetamine after GI absorption and metabolism. Atomoxetine is a
nonstimulant drug approved for ADHD in children and adults. [Note: This drug should
not be taken by individuals on MAO inhibitors and by patients with angle closure
glaucoma.] Unlike methylphenidate, which blocks dopamine reuptake more than
norepinephrine reuptake, atomoxetine is more selective for inhibition of norepinephrine
reuptake. Therefore, it is not considered habit forming and is not a controlled substance.

 Narcolepsy: Narcolepsy is a relatively rare sleep disorder that is characterized by

uncontrollable bouts of sleepiness during the day. It is sometimes accompanied by
catalepsy, a loss in muscle control, and even paralysis brought on by strong
emotions such as laughter. The sleepiness can be treated with drugs, such as the
mixed amphetamine salts or methylphenidate. Modafinil and its R-enantiomer
derivative, armodafinil, are considered first-line agents for the treatment of
narcolepsy. Modafinil (orally) promotes wakefulness, but it produces fewer
psychoactive and euphoric effects and fewer alterations in mood, perception,

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 thinking, and feelings typical of other CNS stimulants. The mechanism of action
remains unclear, but may involve the adrenergic and dopaminergic systems.
Headaches, nausea, and nervousness are the primary adverse
effects. Modafinil and armodafinil may have some potential for abuse and physical
dependence, and both are classified as controlled substances.

 Appetite suppression: Phentermine and diethylpropion are sympathomimetic

amines that are related structurally to amphetamine. These agents are used for their
appetite-suppressant effects in the management of obesity.

4. Pk. Amphetamine is completely absorbed from the GI tract, metabolized by the liver,
and excreted in the urine. [Note: Administration of urinary alkalinizing agents such
as sodium bicarbonate will increase the nonionized species of the drug and enhance
the reabsorption of dextroamphetamine from the renal tubules into the
bloodstream.] Amphetamine abusers often administer the drugs by IV injection and/or
by smoking. The euphoria caused by amphetamine lasts 4 to 6 hours, or four- to
eightfold longer than the effects of cocaine.

5. A/E. The amphetamines may cause addiction, leading to dependence, tolerance, and
drug-seeking behavior. In addition, they have the following undesirable effects.

a. CNS effects. Adverse effects of amphetamine usage include insomnia, irritability,

weakness, dizziness, tremor, and hyperactive reflexes. Amphetamine can also
cause confusion, delirium, panic states, and suicidal tendencies, especially in
mentally ill patients. Benzodiazepines, such as lorazepam, are often used in the
management of agitation and CNS stimulation secondary to amphetamine overdose.
Chronic amphetamine use produces a state of “amphetamine psychosis” that
resembles the psychotic episodes associated with schizophrenia. Whereas long-
term amphetamine use is associated with psychic and physical dependence,
tolerance to its effects may occur within a few weeks. The anorectic effect
of amphetamine is due to its action in the lateral hypothalamic feeding center.

b. CV Effects. In addition to its CNS effects, amphetamine causes palpitations,

cardiac arrhythmias, hypertension, anginal pain, and circulatory collapse. Headache,
chills, and excessive sweating may also occur.

c. GI system effects. Amphetamine acts on the GI system, causing anorexia, nausea,

vomiting, abdominal cramps, and diarrhea.

d. Contraindications. Patients with hypertension, cardiovascular disease,

hyperthyroidism, glaucoma, or a history of drug abuse or those taking MAO
inhibitors should not be treated with amphetamine.

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HALLUCINOGENS

A few drugs have, as their primary action, the ability to induce altered perceptual states
reminiscent of dreams. Many of these altered states are accompanied by visions of bright,
colorful changes in the environment and by a plasticity of constantly changing shapes and
color. The individual under the influence of these drugs is incapable of normal decision making
because the drug interferes with rational thought.

These compounds are known as hallucinogens, and lysergic acid diethylamide (LSD) and
tetrahydrocannabinol (from marijuana) are examples of agents in this class.

Reference: https://brilliantnurse.com/nclex-cns-stimulants/

IX. NARCOTIC ANALGESICS

A. General Considerations
Analgesia is the relief of pain without loss of consciousness, as opposed to
anesthesia. The chief action of opiates and similar compounds is to impair the
normal sensory awareness and response to tissue injury. Opium is mixture of
alkaloids from the poppy plant - Papaver somniferum. Opiates are derived from the
poppy plant. The exudate of the seed capsule contains morphine, codeine, and
papaverine. The term opioid refers to both naturally occuring opiates and synthetic
drugs with similar actions.
Narcotic. From the Greek meaning „to numb or deaden‟. It is often used to denote
an opioid but also widely used to describe drugs of addiction and hence includes
nonopioid compounds.

1. MOA. Opioids decrease pain transmission to the brain by causing activation of the
descending nerve fibers coming from the periaqueductal gray within the midbrain
and raphe nuclei within the medulla that control the endogenous opioid containing
interneurons within the dorsal horn of the spinal cord. In addition, opioids directly
inhibit afferent nerve transmission by binding to µ-opioid receptors presynaptically
and postsynaptically within the dorsal horn of the spinal cord. As a result of these
various effects, the ascending pathways for pain stimuli are decreased thereby
providing pain relief for the patient.

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 Narcotic analgesics- are opioid µ-receptor agonist.

OPIOID RECEPTORS

The following is the current nomenclature for identification of the opioid receptors,
approved by the International Union of Pharmacology.

MOP - μ (mu) opioid peptide receptor

KOP - κ (kappa) opioid peptide receptor
DOP - δ (delta) opioid peptide receptor
NOP- (nociceptin orphanin FQ peptide receptor)

The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive

alkaloid in opium.

Further readings:

https://www.wfsahq.org/components/com_virtual_library/media/c96525cdf115fe1022c50fabb814b76a-
Opioid-Pharmacology--Update-24-2-2008-.pdf

Classification of Opiate receptors

Receptor type Action
µ Supraspinal anesth, respiratory depression, euphoria, physical dependence
µ1 Analgesia
µ2 Respiratory depression
Kappa (κ) Spinal anesthesia, miosis, sedation
Sigma (σ) Dysphoria, hallucinations, respiratory and vasomotor stimulation

Classification of opioids
Traditional Origin Function
Strong agonists: Naturally occurring Pure agonists morphine fentanyl
Morphine, pethidine, fentanyl, Morphine, codeine, papavarine , alfentanil remifentanil sufentanil
alfentanil, remifentanil, sufentanil thebaine
Intermediate: Semisynthetic: Partial agonist: buprenorphine
buprenorphine, pentazocine, Diamorphine, dihydrocodeine,
butorphanol, nalbuphine buprenorphine
Weak: codeine Synthetic: Phethidine, fentanyl, Agonist-antagonists: pentazocine.
sulfentanil, methadone, Nalbuphine, nalorphine
dextropropoxyphene, butorphanol, Pure antagonist: naloxone,
tramadol, levorphanol , pentazocine naltrexone
Weak agonist: tramadol

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Pharmacological actions of opioid agonists

CNS

a. Analgesia • Most effective in relieving dull, continuous and poorly localized pain arising
from deeper structures, for example the gut. Less effective against superficial and sharp
pain. Neuropathic pain can be very resistant, but patients may report that pain is still
present, but the intensity is decreased and it no longer bothers them as much.
b. Sedation • Drowsiness, feeling of heaviness and difficulty in concentrating are common.
Sleep may occur with relief of pain, although they are not true hypnotics.
c. Euphoria and dysphoria • Morphine and other opioids cause a sense of contentment
and well-being (euphoria). If there is no pain, morphine may cause restlessness and
agitation (dysphoria).
d. Hallucinations • These are more common with KOP agonists, but morphine and other
MOP agonists may also cause hallucinations.
e. Tolerance and dependence • Tolerance is the decrease in effect seen despite
maintaining a given concentration of a drug. The mechanism is not fully understood but
could involve down regulation of opioid receptors or decreased production of
endogenous opioids. Dependence exists when the sudden withdrawn of an opioid,
after repeated use over a prolonged period, results in various physical and
psychological signs. These include; restlessness, irritability, increased salivation,
lacrimation and sweating, muscle cramps, vomiting and diarrhoea.

CV System

a. Mild bradycardia • Common as a result of decreased sympathetic drive and a direct

effect on the sino-atrial (SA) node.
b. Peripheral vasodilatation • Caused by histamine release and reduced sympathetic
drive may result in a slight fall in blood pressure that may be significant in hypovolaemic
patients.

Respiratory system

a. Respiratory depression • Mediated via MOP receptors at the respiratory centres in the
brainstem. Respiratory rate falls more than the tidal volume and the sensitivity of the
brain stem to carbon dioxide is reduced. Concurrent use of other CNS depressants, for
example benzodiazepines or halogenated anaesthetic, may cause marked respiratory
depression.
b. Cough suppression • Codeine suppresses coughing to a degree similar to morphine,
but has lesser analgesic activity. Morphine and diamorphine are used in paroxysmal
nocturnal dyspnoea, as they produce sedation, reduce preload and depress abnormal
respiratory drive.

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Gastrointestinal System. Stimulation of the chemoreceptor trigger zone causes nausea and
vomiting. Smooth muscle tone is increased but motility is decreased resulting in delayed
absorption, increased pressure in the biliary system (spasm of sphincter of Oddi) and
constipation.

Endocrine System. The release of ACTH, prolactin and gonadotrophic hormone is inhibited.
Secretion of ADH is increased.

Ocular effects • MOP and KOP receptors in Edinger-Westphal nucleus of occulomotor nerve
are stimulated by opioids resulting in constriction of the pupils (meiosis).

Histamine release and itching • Some opioids cause histamine release from mast cells
resulting in urticaria, itching, bronchospasm and hypotension. Itching occurs most often after
intrathecal opioids and is more pronounced on the face, nose and torso. The mechanism is
centrally mediated and may be reversed by naloxone.

Muscle rigidity • Large doses of opioids may occasionally produce generalized muscle
rigidity especially of thoracic wall and interfere with ventilation.

Immunity • The immune system is depressed after long-term opioid abuse.

Effects on pregnancy and neonates • All opioids cross the placenta and if given during labour,
can cause neonatal respiratory depression. Chronic use by the mother may cause physical
dependence in utero and lead to a withdrawal reaction in the neonate at birth that can be life
threatening. There are no known teratogenic effects.

Opioid induced nausea & vomiting can be suppressed by coadministering an antiemetic

medication, such as Promethazine or Ondansetron (Zofran ®)

1. Morphine is a naturally occurring phenanthrene derivative. It is the standard drug against

which all other opioids are compared.
a. Dose. Morphine can be given orally, intramuscularly (IM), intravenously (IV),
subcutaneously (SC), rectally, epidurally and intrathecally.
b. PK. Morphine is extensively metabolized by the gut wall and the liver to morphine-3-
glucuronide (M3G) (70%), morphine-6 glucuronide (M6G) (10%) and to sulphate
conjugates. M6G is 10-20 times more potent than morphine and is normally excreted in
urine. • It accumulates in renal failure and accounts for increased sensitivity to
morphine. Neonates are more sensitive than adults to morphine due to reduced hepatic
conjugating capacity. In the elderly, owing to reduced volume of distribution, peak
plasma level of morphine is higher compared to younger patient.
a. Therapeutic Effects. The main effects are mediated through MOP receptors. It is a
potent analgesic with good sedative and anxiolytic properties. It may cause euphoria,
dysphoria and hallucination. It produces respiratory depression and cough suppression.

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 •It has minimal effect on cardiovascular system and may produce bradycardia and
hypotension. Nausea and vomiting are common side-effects. Histamine release may
lead to rash, itching and bronchospasm (in susceptible patients). Meiosis is common.
Tolerance and dependence may develop.

2. Codeine is a natural opioid and one of the principal alkaloids of opium. It has very low
affinity for opioid receptors.
a. Dose. Can be given orally and IM. The dose for an adult is 30-60mg by either route
and can be repeated at 6-hour intervals, if required. Varying doses of codeine (8-
30mg) are commonly incorporated with NSAIDs in compounds employed in the
treatment of mild to moderate pain. Codeine is also used in antitussive and
antidiarrhoea preparations.
b. Pk • Oral bioavailability of codeine is 50%. About 10% is metabolized to morphine
and the rest is metabolized to inactive conjugated compounds. Metabolism to
morphine depends on an isoform of cytochrome p450, which exhibits polymorphism,
thus poor metabolizers (approximately 10% people) may experience minimal pain
relief.
c. Therapeutic Effects • It causes little euphoria and has low abuse potential. Codeine
is less sedative and less likely to cause respiratory depression than morphine. It may
cause disorientation and excitement. Constipation is common side effect.
Dihydrocodeine is a semi-synthetic derivative of codeine with similar
pharmacologic effects. Oxycodone is more effective, but has higher abuse
potential.

3. Diamorphine (heroin). A semi-synthetic opioid, the diacetylated analogue of morphine. It

is 1.5-2.0 times more potent than morphine. It is a pro-drug and is converted to the active
components of acetylmorphine and morphine by esterases in the liver, plasma and
central nervous system.
a. Dose • Diamorphine can also be given by the same routes as morphine in
approximately half the dose. Due to its higher lipid solubility, it is less likely than
morphine to cause delayed respiratory depression when used epidurally or
intrathecally. • It can be administered as hydrochloride salt by IM or SC infusion in a
smaller volume of solution than an equivalent dose of morphine. This is an important
consideration for patients with terminal malignant disease who may require large
doses of opioid for pain relief.
b. Pk. Diamorphine is 200 times more lipid soluble than morphine and, therefore,
passes more rapidly across the BBB into the CNS where it is converted to morphine.
Therefore, it has more analgesic potency and a more rapid onset of action than
morphine. Because of the extensive first pass metabolism, it has low bio-
availability.

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 c. Therapaeutic Effects • It shares common opioid effects with morphine. It is
associated with an increased tendency to cause euphoria and dependency. May
cause less nausea and vomiting than morphine.

4. Pethidine (mepiridine) Demerol®. It is a synthetic phenylpyperidine derivative and was

originally developed as an antimuscarinic agent.
a. Dose • Pethidine is available as 50mg tablets and ampoules of different strength
(10mg.ml-1 and 50mg.ml-1). For acute pain, it can be administered). The doses can
be repeated every 4 hours.
b. Pk. orally (50-150mg), SC (50-100mg), IM (50-100mg) or IV (25-100mg Pethidine is
30 times more lipid soluble than morphine. Oral bioavailability is 50%. It is
metabolized in the liver by ester hydrolysis to norpethidine and pethidinic acid that
are excreted in the urine and therefore accumulate in renal failure. At higher
concentration, norpethidine can produce hallucination and convulsions. Pethidinic
acid is an inactive compound. Pethidine is often used for labour analgesia. It readily
crosses the placenta, and a significant amount reaches to the foetus over several
hours.
c. Therapeutic Effects • There are some pharmacological differences from morphine.
It produces tachycardia, dry mouth and less marked meiosis. However as is the
case with morphine, a significant decrease in BP may occur when pethidine is
administered to elderly or hypovolaemic patients. It may produce less biliary tract
spasm than morphine. Pethidine is absolutely contraindicated in patients on MAOIs,
as serious side effects like hypotension or hypertension, hyperpyrexia, convulsion
and coma may occur.
5. Fentanyl. It is a synthetic phenylpyperidine derivative and is 100 times more potent than
morphine
a. Dose • Fentanyl is available as a colourless solution for injection in 2 and 10ml
ampoules containing 50mcg per ml. When given in small doses (1-2mcg.kg-1), it
has rapid onset and a short duration of action (30 minutes). Such doses are used
intravenously for pain associated with minor surgery. In small doses it has little
sedative effect. Higher doses are used to obtund sympathetic response to
laryngoscopy and intubation.It has been used to augment effects of local
anaesthetics in spinal and epidural analgesia at 10-25mcg and 25-100mcg doses
respectively. It is also available as a transdermal patch for chronic pain conditions
and as a lollipop to premedicate children.
b. Pk • Fentanyl is 500 times more lipid soluble than morphine, consequently it is
rapidly and extensively distributed in the body (volume of distribution 4l.kg-1). At
small doses (1-2mcg.kg-1), plasma and CNS concentrations may decrease quickly
to below an effective level during the rapid distribution phase. Fentanyl is

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 predominantly metabolized in the liver to norfentanyl which is inactive. The
metabolite is excreted in the urine over a few days.
c. Therapeutic Effects • Many properties of fentanyl are similar to morphine. It
produces respiratory depression in a dose-dependent manner. Large doses (50-
100 microgram/kg) have been used for cardiac surgery to obtund metabolic stress
response. At such high doses, sedation is profound and unconsciousness may
occur. In addition, muscular rigidity of the chest wall may affect ventilation.

6. Remifentanil. It is a synthetic phenylpiperidine derivative of fentanyl with similar potency

but is ultra-short-acting.
a. Dose • It is available as white crystalline powder in glass vial containing 1, 2 or 5mg
remifentanil hydrochloride. A range of infusion rates (0.05-3.0mcg.kg-1.min-1) are
used during maintenance of anaesthesia with controlled ventilation.
b. Pk• Remifentanil is rapidly broken down by non-specific plasma and tissue
esterases resulting in a short elimination t ½ (3-10 minutes). It is context insensitive,
in that the halflife, clearance and distribution are independent of duration and
strength of infusion.
c. Therapeutic Effects • Certain properties of remifentanil like rapid onset, rapid offset,
organ independent metabolism and lack of accumulation make it suitable for use
during various surgical procedures.

7. Tramadol is phenylpiperidine analogue of codeine. It is weak agonist at all opioid receptors

with 20-fold preference for MOP receptors. It inhibits neuronal reuptake of norepinephrine.
It potentiates release of serotonin and causes descending inhibition of nociception.
a. Dose • Oral and parenteral dosage requirements are similar, 50-100mg 4 hourly
b. Pk • Tramadol has high oral bioavailability of 70% which can increase to 100% with
repeated doses due to reduction in first pass effect. It is 20% bound to plasma
proteins. It is metabolized in the liver by demethylation into a number of metabolites
- only one of them (O-desmethyltramadol) has analgesic activity. Its volume of
distribution is 4l.kg-1 and its elimination half-life is 4-6 hours.
c. Therapeutic Effects • In equi-analgesic dose to morphine, tramadol produces less
respiratory and cardiovascular depression than morphine. Constipation is less
common, however tramadol shares most of the common side effects of other opioids
(e.g. vomiting, drowsiness and ambulatory dizziness). Tramadol is contra-indicated
in patients on MAOI or with a history of epilepsy.

PARTIAL OPIOID AGONISTS These drugs have affinity for opioid receptors but low intrinsic
activity compared to full agonists. Because of their reduced activity, they are able to
antagonise or reduce the responsiveness of a pure agonist like morphine when acting at the
same receptor. In other words, a higher dose of a pure agonist is required in presence of
partial agonist, in order to obtain full agonist response.

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They can be further divided into two groups:

A. Mixed agonist-antagonist. They exert agonist effects at one opioid receptor and
antagonistic effects at the other. Examples are pentazocine, nalbuphine and
meptazinol.
B. Drugs that do not display antagonistic effects but have diminished effects at opioid
receptors.

1. Meptazinol is a synthetic analgesic with mixed agonist-antagonist activity at opioid

receptors. It also has an action via central cholinergic pathways that may contribute to
analgesia. It produces less respiratory depression because of its selectivity for MOP-1
receptors. Its main disadvantage is a high incidence of nausea and vomiting, that can be
reduced by administration of antimuscarinic drugs. It is one-tenth as potent as morphine. It
has rapid onset of action that lasts for 2-4 hours.
2. Buprenorphine is 30 times more potent than morphine. It is highly lipid soluble, and is well
absorbed sublingually. It has low oral bioavailability. Although its terminal half-life is 3-4
hours, it has a much longer duration of action (up to 8 hours). In general, buprenorphine
and morphine produce similar effects and side effects. As buprenorphine has extremely
high affinity for MOP receptors, its effects are not completely reversed by naloxone (see
opioid antagonists). Respiratory depression may need to be treated with doxapram.
Nausea and vomiting are severe and prolonged.
3. Pentazocine has 25% of the analgesic potency of morphine. It is not very effective in
relieving severe pain, and this may be partly because of absence of euphoriant effect. It
produces an increase in heart rate and blood pressure. Nausea, vomiting, bizarre dreams
and hallucinations are more common than morphine.

OPIOID ANTAGONISTS

Naloxone and its longer acting derivative naltrexone occupy opioid receptors, but they have
essentially no intrinsic activity at these receptors. Moderate doses administered in the absence
of an opioid produce no effect; large doses, however, may have effects in which antagonism of
endorphins may play a role.

1. Naloxone is a pure opioid agonist and will reverse opioid effects at MOP, KOP and DOP
receptors, although its affinity is highest at MOP receptors. It is the drug of choice for the
treatment of opioid induced respiratory depression. The usual dose is 200-400mcg
intravenously, titrated to effect. It is imperative the naloxone be administered slowly to
avoid reactive pulmonary hypertension with the development of acute pulmonary oedema
probably from antagonism of endogenous opioid effects. Caution must be used in opioid
addicts as giving naloxone may cause an acute withdrawal state with hypertension,
pulmonary oedema and cardiac arrhythmias. Antanalgesic effects may be observed in
opioid naïve subjects who are given naloxone.

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2. Naltrexone has similar mechanism of action, but has few pharmacokinetic advantages
compared to naloxone. It has a longer half-life and is effective orally for up to 24 hours. It
has been used to treat opioid addiction and compulsive eating with morbid obesity.

 Opioid induced nausea & vomiting can be suppressed by coadministering an

antiemetic medication, such as Promethazine or Ondansetron (Zofran ®)

http://tmedweb.tulane.edu/pharmwiki/doku.php/opioid_analgesics

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