OUR LADY OF FATIMA UNIVERSITY

COLLEGE OF PHARMACY
PHARMACOLOGY 1
LECTURER: Mr. Jemar Wilian N. Labausa
• It is defined as the study of substancesthat interact with living
systems through chemical processes by binding to regulatory
molecules and activating or inhibitingnormal body
processes.
DRUG + RECEPTOR = EFFECT
PHARMACOKINETICS: WHAT THE BODY DOES TO THE DRUG
PHARMACODYNAMICS: WHAT THE DRUG DOES TO THE BODY

WHAT IS
PHARMACOLOGY
 Clinical pharmacology
 With added focus on the application of pharmacological principles and
methods in the medical clinic and towards patient care and outcomes.
-PATIENT ORIENTED PHARMACY PRACTICE (INDIVIDUAL PATIENT)
 Neuropharmacology
 Effects of medication on central and peripheral nervous system
CNS: BRAIN AND SPINAL CORD
PNS: MOTOR AND SENSORY

What are the Divisions

of Pharmacology?
 Pharmacogenetics orPharmacogenomics-

 Study of genetic variations that cause

differences in drug response among
individuals orpopulations.

What are the Divisions

of Pharmacology?
-The relation of the individuals genetics make up to his or her response
to specific drug
ISONIAZID – ANTI-TB (ACETYLATION – METABOLISM PROCESS OF
ISONIAZID) (POLAR, INACTIVE)
FAST ACETYLATOR – ASIANS
SLOW ACETYLATORS – CAUCASIANS

ISONICOTINIC HYDRAZIDE (INH)

Pharmacoepidemiology-study of the effects of
drugs in large numbers of people
Pharmacoeconomics-to quantify the cost and
benefit of drug used therapeutically
Toxicology- study of the adverse effects,
molecular targets, and characterization of drugs
or any chemical substance in excess (including
those beneficial in lower doses
TOXICOLOGY: MECHANISM OF TOXICITY
UNIVERSAL ANTIDOTE: ACTIVATED CHARCOAL, Mg
OXIDE, TANNIC ACID. 2:1:1

What are the Divisions of

Pharmacognosy
a branch of pharmacology dealing
especially with the composition, use, and
development of medicinal substances of
biological origin and especially
medicinal substances obtained from
plants.
EFFECT OF CRUDE DRUGS:
= DRUGS THAT HAS UNDERGONE THE PROCESS OF
COLLECTION ANF DRYING (PLANTS)

What are the Divisions

of Pharmacology?
 Environmental pharmacology
a new discipline and its focus is being
given to understand;
gene–environment interaction,drug- environment
interaction and toxin- environment interaction.
= AFTER ELIMINATION TO HUMAN AND ANIMALS ASPOST
THERAPY

What are the Divisions

of Pharmacology?
Any substance that brings about a
change in biologic function through
its chemical actions

SO THEREFORE;WHAT ISA
DRUG?
 DTCMP = DIAGNOSIS (SCREENING THE CONDITION)(DIAGNOSTIC AGENT),
TREATMENT( MANAGEMENT OF DISEASES) , CURE( TOTAL ERADICATION OF DISEASE),
MITIGATION(LOWERING OFF THE SYMPTOMS)(STAGE4 CANCER- ANALHESIC)
PREVENTION ( AVOIDING THE OCCURRENCE OFF DISEASE)

(VACCINE- ORIGINATED FFROM THE MICROORGANISM CAUSINGTHE DISAEASE -

+ PHENOL OR FORMALDEHYDE = DEACTICATED/KILLED = ANTIBODY = IMMUNE
SYSTEM – PREVENT OUR BODY FROM DISEASES)

It is used in:
Prevention=Ex: YaGG1nes; Oral Contraceptive Pills (OCPs)
Diagnosis —Ex: BaS04 as contrast medium in the X-ray
examination of the gastrointestinal tract. Mitigation=Ex: Analgesic
drugs Treatment/Cure=Ex: Antibiotic
 Size and MolecularWeight

 Sizes from MW 7 (Lithium) to over MW

50,000 (thrombolytic enzymes, other proteins)

 Majority of drugs have MW between 100 and 1000.

Dugs smaller than MW 100 are rarely sufficiently selective,

whereas drugs much larger than MW 1000 are often poorly
absorbed and poorly distributed in body
LITHIUM - BIPOLAR DISORDERI

Nature of Drugs
Drug-Receptor Bonds
• Drugs bind to receptors with
a variety of chemical bonds.

Nature of Drugs
*Strong covalent bonds (STRONG) (which usually
result in irreversible action).
*Somewhat weaker electrostatic bonds (WEAK)
(between a cation and an anion).
Much weaker interactions (hydrogen bond, van
der Waals interactions, and hydrophobic bonds).
REVERSIBLE
EXAMPLE:
• 2- (p-isobutylphenyl propionicacid)-
CHEMICALNAME
• IBUPROPEN-GENERIC NAME
• Motrin®-Trade name(proprietary
name/brand name)

How are drugs Named?

TAKE NOTE: Chemical name The drug's chemical
composition and molecular structure

IBUPROPEN-GENERIC -NAME( NON-PROPRIETARY NAME)

(INN/USAN) -INTERNATIONAL NAME OF THE DRUG

INN - INTERNATIONAL NON-PROPRIETARY NAME

USAN - UNITED STATES ADOPTED NAMES

ACETAMINOPHEN/PARACETAMOL

Ex: Tade name (proprietary name/brand name) The drug

has a registered trademark; use
Functional Modifiers
Replenishers
Diagnostic Agents
Chemotherapeutic Agents

Classification of Drugs
according to use
1. Functional Modifiers
 alter or modulate the normal physiologic
functions
 Examples:
 Analgesic drugs
 Anti-pyretic drugs
 Anti-inflammatory drugs
 Anti-hypertensive drugs

Classification of Drugs
according to use
2. Replenishers
Supplement endogenous substances that are
lacking or deficient in the body
 Examples:
 Hormones
 IV Fluids/Electrolyte/ORS
 Multivitamins

Classification of Drugs
according to use
In the case of pernicious anemia (autoimmune disease) that
destroys parietal cells which secretes HCl and intrinsic factor,take
VIT B12

Note: Pernicious anemia may also be caused by PPIs, H2 Blockers,

and Fish Tapeworms.
VIT B9 – FOLIC ACIS DEF. ANEMIA- lead to neural tube defects-
valproic acid
B12- permicious

APPLICATION
 3. Diagnostic Agents
Agents used to determine the presence or absenceof
a condition or a disease.
Examples:
 Edrophonium (Tensilon’sTest)
 Histamine
 some Radiopharmaceuticals
 Barium sulfate
 Dobutamine and Dipyridamole for “Pharmacologic Stress
Testing” for CAD and MI.

NOTE: Stress Test is an electrocardiographic test of heart function

before, during, and after a controlled period of increasingly strenuous
exercise.

Classification of Drugs
according to use
TENSILON- FOR MYASTHENIA GRAVIS
(AUTOIMMUNE DISORDER - OUR OWN IMMUNE SYSTEM
ATTACKS OUR OWN CELL) - muscle weakness
Dobutamine (Bl agonist) and Dipyridamole (Antiplatelet) for
"Pharmacologic Stress Testing for CAD - CORONARY ARTERY
DISEASE and Ml- MYOCARDIAL INFARCTION
Technetium 99m (for Dx of ischemia- BLOOD SUPPLY while
Thallium 209 for Dx of infarction - HEART ATTACK
 4. Chemotherapeutic Agents
 Agents used to kill or inhibit growth of
cells or nucleic acid considered as foreign
to the body. Selective toxicity is
considered
Antineoplastics/ANTI CANCER=
CYTOTOXIC ANTIBIOTICS =
DOXORUBICIN
 Anti-infectives=AMINOGLYCOSIDES

Classification of Drugs
according to use
BUY AT 30S (AMINOGLYCOSIDE, TETRACYLINE)
CEL @ 50S (CHLORAMPHENICOL, ERYTHROMYCIN
AND LINCOSAMIDE)
PHARMACOKINETICS
PHARMACODYNAMICS

TWO MAIN AREAS OF

PHARMACOLOGY
It refers to the movement of
drugs within the biological
systems, as affected by uptake,
distribution, elimination and
biotransformation.

What is
Pharmacokinetics?
REVIEW OF
PHARMACOKINETIC
PRINCIPLES
LIBERATION-(NOT ALL DRUGS WILL UNDERGO LIBERATION -
ORAL AND SOLID DOSAGE)
ABSORPTION -SMALL INTESTINE
DISTRIBUTION - CELLS/TISSUE/ORGAN
METABOLISM - LIVER(MAIN ORGAN)
EXCRETION - KIDNEY (MAIN ORGAN)
RESPONSE-
TOXICITY -
ELIMINATION -METABOLISM + EXCRETION
DISPOSITION - DISTRIBUTION + METABOLISM + EXCRETION
.... LADME R T....
IN VIVO - performed or taking place in a living
organism
IN VITRO - performed or taking place in a test
tube, culture dish, or elseehere outside a living
organism

What is the fate of the drug in vivo?

The release of active ingredient
from its dosage form.
-
• Disintegration a state in which any residue of the tablet,
except fragments of insoluble coating, remaining on the screen
of the test apparatus in the soft mass have no palpably firm
core

• Dissolution - (rate-limiting step) in absorption of solid

dosage forms and consequently onset, intensity, and
duration of action of the drug).

LIBERATION
ONLY ORAL AND SOLID DOSAGE FORM ARE
CAPABLE UNDERGO YOUR DELIVERATION PROCESS
DIVIDED INTO TWO ;
Disintegration--(process that a larger particle to
smaller particle)
Dissolution -Rate limiting step of absorption
(PROCESS WITH THE SLOWEST RATE CONSTANT)
-SOLID TO LIQUID
• Factors that influence the dissolution rate:
• Surface area – reducing the particle size increase the surface
area
• Salt forms – salt forms dissolve much readily when
compared to the drugs in its free form
Ex: Sodium and potassium salts of weak organic acids
and hydrochloride salts of weak organic bases dissolve
much more readily than the free forms.
• State of hydration – anhydrous form is more readily soluble
than the hydrated form
Ex:Ampicillin anhydrous was shown to have greater rate
of solubilitythan the trihydrate form.

LIBERATION
Surface area
DECREASE PARTICLE SIZE, INCREASE SURFACE AREA, INCREASE
ABSOPTION, INCREASE THE BIOAVAILABILITY

INCREASE PS, DECREASE SA, DECREASE ABSORPTIO, DECREASE BIOA

Salt forms
CAPTOPRIL FREE FORM
CAPTOPRIL HCL- SALT FORM – READILY DISSOLVE CAMPARED TO YOUR
FREE FORM

State ofhydration
ANHYDROUS VS HYDRATED
Anhydrous – MORE LIKELY TO BE ACTED UPON BY WATER
 Bioavailability - The proportion of a drug
that is delivered to its site of action in the
body.

RATE and EXTENT of DRUG

entry into the systemic circulation

ABSORPTION
• If we put an acidic drug in an environment
with a lot of H+ (low pH) what will this
equilibrium do?

HA H+ +A-

System at Equilibrium

Non-ionized formpredominates!
ACIDIC DRUG + ACIDIC ENVIRONMENT = ABSORPTION
(NON-IONIZED) – EASILY ABSORBED

ACIDIC DRUG + BASIC ENVIRONMENT = EXCRETED

(IONIZED) – EASILY EXCRETED

BASIC DRUG + BASIC ENVIRONMENT=ABSORPTION

BS+ AE = EXCRETION
 • Aspirin is an acidic drug. In the stomach
will it exist mostly in ionized ornon-ionized
form?

Why?

APPLICATION
ASPIRIN IS ACIDIC STOMACH
IS ACIDIC
=NON-IONIZED = ABSORPTION
 Lipid Bilayer
Ionized form
(charged) A-

Non-Ionized
form HA HA
(uncharged)
ACIDIC DRUG are best absorbed from
acidic environments

BASIC DRUG are best absorbed from basic

environment

Moral of thestory...
Gastric emptying – time it takes
for the stomach to empty its
contents

ABSORPTION
GASTRIC EMPTYING TIME –STOMACH WILL
EMPTY ITS CONTENT GOING TO SMALL
INTESTINE (MAIN ORGAN OF ABSORPTION)

MABILIS TIME – STOMACH EMPTY ITS CONTENT

– INCREASE IN ABSORPTION

MABAGAL TIME – STOMACH EMPTY ITS

CONTENT DECREASE IN ABSORPTION
↑GET, ↓GER, ↓ABS ↓GET, ↑GER, ↑ ABS

Fatty meal Cold foods

Hot meal Mild exercise
Stress Motility
Lying on theleft side Lying on theright
Heavy exercise side
Anti motility Standing position
Metoclopramide – increase gastric emptying rate –
antimetic – to help with emptying of the stomach in
people which delayed stomach
emptying,prokinetic agent
Gastric emptying time – shorter
Increase the gastric emptying rate
First-pass effect - some drugs are partially
metabolized in the liver or portal vein before
passing into circulatory system.
Examples of routes that bypass the liver:
• Sublingual Transdermal
• Buccal Vaginal
• Rectal* Intramuscular
• Intravenous Subcutaneous
• Intranasal Inhalation

ABSORPTION
SL-CATAPRES, ISDN (ISOSORBIDE DINITRATE)
BUCCAL – FENTANYL
a.k.a. “first pass effect”
Examples:
Morphine
Meperidine
Pentazocine
Catecholamines
Propanolol’ Beta
Blockers
TRANSPORT MECHANISMS
- means of movement of drug molecule across
cell membrane
 PASSIVE Along concentration gradient, Without Weak organic acids, Weak organic bases,
the use of energy Organic nonelectrolytes (alcohol,
major transmembrane process for amidopyrine, urea), Cardiac glycosides
most drugs.

ACTIVE Against concentration gradient, With Na, K, I, hexoses, monosaccharides, amino

the use of energy, acids, strong organic acids and bases,

FACILITATED Along concentration gradient, Without Vit B12

the use of energy,
VESICULAR This is the only transport process that Fats, glycerin, starch, Parasite eggs,
- PINOCYTOSIS does not require a drug to be in aqeous Vitamins A, D, E and K, Sabin
- PHAGOCYTOSIS solution to be adsorbed: polio vaccine

ION-PAIR Formation of neutral ion pair Quaternary ammonium compounds

complexes with endogenous materials Sulfonic acids
-- Absorbed by passive diffusion

CONVECTIVE Passing through channels in the cell Inorganic and organic electrolytes up to
AKA: paracellular membrane (pores) 150 to 400MW
transport Ions of opposite charge of pore lining
Ionized sulfonamides
PASSIVE DIFFUSION – ALONG THE CONCENTRATION GRADIENT
-HIGHER CONCENTRATION TO LOWER CONCENTRATION
- NO ENERGY REQUIREMENT
- - NO CARRIER REQUIREMENT

ACTIVE – AGAINST THE CONC GRADIENT

-LOWER TO HIGHER CONC
-REQUIRES ENERGY
-REQUIRES A CARRIER

FACILITATED – ALONG THE CONC GRADIENT

-NO ENERGY REQUIREMENT
-HAS A CARRIER REQUIREMENT Ex: VIT
B12
VESICULAR
- PINOCYTOSIS – CELL DRINKING
- PHAGOCYTOSIS – CELL EATING
• Distribution
• The processes of distribution of a drug from the systemic circulation to
organs and tissue involve its permeation through membrane barriers and are
dependent on its solubility (recall that only nonionized drugs cross
biomembranes), the rate of blood flow to the tissues, and the binding of
drug molecules to plasma proteins.
• Factors Affecting Distribution
a. Rate of Distribution
- Membrane permeability
- Capillary wall structure
- Drug’s pKa and blood pH
- Blood Perfusion
b. Extent of Distribution
- Lipid solubility
- pH-pKa
- Tissue localization
- Plasma-proteinbinding
LIPID SOLUBLE DRUG/ NON- IONIZED – EASILY PERMEABLE INTO
THE CELL MEMBRANE

BLOOD PERFUSION – RATE LIMITING STEP OF DISTRIBUTION PROCESS

INCREASE BLOODE PERFUSION, INCREASE DISTRIBUTION

Plasma-proteinbinding
FREE DRUG – NOT BOUNDED BY A PROTEIN
-EASILY DISTRIBUTED, ACTIVE DRUG (BIND INTO THE
RECEPTOR)

PROTEIN BOUND DRUG – BOUNDED BY A PROTEIN

-NOT EASILY DISTRIBUTED, INACTIVE DRUG ( NOT CAPABLE OF
BINDING INTO THE RECEPTOR)
DRUG DISTRIBUTION
• Central Compartment
The central compartment includes the well-perfused
organs and tissues (heart, blood, liver, brain and kidney)
with which drug equilibrates rapidly.
• Peripheral Compartment(s)
The peripheral compartments include those organs which
are less well-perfused, and with which drug therefore
equilibrates moreslowly.
• Special Compartments
These include cerebrospinal fluid (CSF) and central
nervous system (CNS) , the blood-brain barrier , pericardial
fluid, bronchial secretions and fluid in the middle ear
BBB(BLOOD BRAIN BARRIER) –ONLY
LIPID SOLUBLE CAN ENTER
• Special Barriers to Distribution
Placental: most small molecular weight drugs cross the
placental barrier, although fetal blood levels are usually lower
than maternal
Blood-brain: permeable only to lipid-soluble drugs or those
of very low molecular weight
• Plasma Protein Binding
-Many drugs bind to plasma proteins, including albumin, with
an equilibrium between bound and free molecules (recall that
only unbound drugs cross biomembranes).
-Competition between drugs for plasma protein binding sites
may increase the "free fraction," possibly enhancing the
effects of the drug displaced.
IgG (IMMUNOGLOBULIN)- THE ONLY ONE
CAN ENTER PLACENTA

BOUND DRUGS ARE

PHARMACOLOGICALLY INACTIVE FREE,
UNBOUND DRUG CAN ACT ON TARGET
SITES
• PROTEIN BINDING
Albumin
• Major plasma proteincomponent
• Reversible drug binding
• Acidic drugs
Alpha-1Acid Glycoprotein(AAG) and Globulin
• Basic drugs
Lipoproteins
• macromolecularcomplexes of lipids +proteins
• Binds drugs when albumin sites become saturated
RBC
• May bind both endogenous and exogenous compounds.
Globulin:
• may be responsible for the transport of certa in endogenous substances such as
corticosteroids
ALBUMIN – RESPONSIBLE FOR MAINTAINING
OSMOTIC PRESSURE OF THE BLOOD AND FOR THE
TRANSPORT OF ENDOGENOUS AND EXOGENOUS
SUBSTANCE
• Volume of distribution (VD )
• Estimatethe extent of drug distribution in the body
• Relates the plasma conc to the amount of drug
present in the body
• theoretical volume in which the total amount of drug
would need to be uniformly distributed to producethe
desired blood concentration of a drug
The apparent volume of distribution is used
to estimate the extent of drug distribution in
the body
CIRCULATORYSYSTEM 5L

EXTRACELLULARFLUID 10-20L

INTRACELLULARFLUID 25-30L

WHOLE BODYFLUID 40L

Location of DRUGbased
on VD
• Metabolism
Biotransformation is the metabolic conversion of drugs,
generally to less active compounds but sometimes to isoactive or
more active forms.

Drug BiotransformationReactions
1. Active drug  polarmetabolite
2. Active drug  inactivemetabolite
3. Active drug  activemetabolite
4. Inactive drug  active metabolite
5. Active drug  reactivemetabolite
More polar, inactive, non-toxic

PREPARATION PROCESS FOR EXCRETION POLAR – EXCRETED

REACTIVE METABOLITE – TOXIC METABOLITE
INACTIVE TO ACTIVE – PRODRUG (DRUG THAT MUST UNDERGO THE PROCESS OF
METABOLISM BEFORE IT CAN BE ACTIVE

These are inactive substance that must be biotransformed in the body to

metabolites (PRODUCT OF METABOLISM) that have pharmacologic activity THE
GOAL IS TO PREPARE THEM TO EXCRETION

LIVER – MAIN ORGAN OF METABOLISM

MIXED FUNCTION OXIDASE (MFO’S) – RESPONSIBLE FOR OXIDATION AND
REDUCTION OF DRUGS
HEPATIC PARENCHYMAL CELLS- CONTAINS MFO’S WITH E.R

MICROSOME – FRAGMENTED AND CENTRIFUGE

USING ULTRACENTRIFUGE

The cytochrome enzymes originate from - microsomes

 • Phase I reactions
-Include oxidation (especially by the cytochrome P45- group of enzymes also
called mixed function oxidases), reduction, deamination and hydrolysis
-Reactions that convert the parent drug to a more polar (water-soluble) or more
reactive product by unmasking or inserting a polar functional group such as -OH,
-SH, or -NH

• Phase II reactions
- Synthetic reactions that involve addition (conjugation) of subgroups to -OH,
-NH 2, and -SH functions on the drug molecule.
-The subgroups that are added include glucuronate, acetate, glutathione,
glycine, sulfate, and methyl groups.
- Most of these groups are relatively polar and make the product less lipid-
soluble than the original drug molecule.
- This metabolism phase reaction is responsible for the
formation of the final metabolic product of the drug to be
excreted
Phase 1 reactions - FUNCTIONALIZATION (POLAR FUNCTIONAL GROUP –
OH, SH, NH) PHASE

PHASE 2- CONJUGATION – WITH ENDOGENOUS COMPOUNDS 1

PHASE 1
A.OXIDATION
B.REDUCTION
C.HYDROLYSIS

PHASE 2
1. GLUCORONIC ACID CONJUGATION / GLUCORONIDATION DRUG +
GLUCORONIC ACID = POLAR
2. SULFATE CONJUGATION / SULFATION DRUG + SULFATE = POLAR
3. GLUTATHIONE CONJUGATION
4. ACETYLATION (ACETYL GROUP)
5. METHYLATION (METHYL GROUP)
6. AMINO ACID CONJUGATION (GLYCERINE , CYSTEINE)
Maturation of Metabolic Processes in infant
AGE METABOLISM CAPACITY
DEVELOPED
Birth Sulfation
1st week Reduction, Oxidation
1 month Acetylation
2 months Glucoronidation
3 months Glycine conjugation
Glutathione conjugation
Cysteine conjugation
NEW BORN INFANTS
X CHLORAMPHENICOL – GLUCORONIDATION
- TOXIC METABOLITE – GRAY BABY SYNDROME
 enzyme
inducers
Substances that increase the metabolic activity
of an enzyme either by binding to the enzyme and
activating it
usually decrease the pharmacologic action of
coadministered drugs
66
DRUGS THAT INDUCES THE ENZYME TO SPEED UP
METABOLISM
INCREASE METABOLISM
DECREASE EFFECT
Enzyme Inducer
• Examples:
 Carbamazepine
 Phenobarbital
 Phenytoin
 Rifampicin
 Smoking
 Chronic Alcoholism

68
enzyme
inhibitors
Substances that inhibit cytochrome
P450 enzyme activity.
Reduce the metabolism of endogenous
substrates and coadministered drugs
through competitive inhibition
INHIBIT THE ENZYME TO SLOW DOWN THE
METABOLISM

DECREASE IN METABOLISM
INCREASE IN EFFECT
TOXICITY
Enzyme Inhibitor

Examples:
 Cimetidine
 Ketoconazole
 Chloramphenicol
 Disulfiram
 Grapefruit Juice
 AcuteAlcoholism
47
• EXCRETION:
• Clearance
• Clearance is defined as the volume of blood cleared of the drug in unit
time. It represents the relationship between the rate of drug elimination
and its plasmalevel.

• CREATININE CLEARANCE
-Volume of blood plasma that is cleared of creatinine by kidney filtration
per minute (mL/min)
-Normal adult male range is 75-125 mL/min
COMPUTED BY:
- Cockroft & Gault
- - JELLIFE- For adults with unstable renal function,
creatinineclearancemay be computed
1. GLOMERULAR FILTRATION
2. ACTIVE RENAL SECRETION
3.TUBULAR REABSORPTION

CLEARANCE – mL / min
Creatinine clearanceeq.
A. COCKCROFTANDGAULT
CrCl
(140-Age)(BW in kg)
(72)(serum conc. in mg/dL)
female = CrCl x0.85
unit: mL/min

EXCRETION
 B. JELLIFE EQ
CrCl
98-[(0.8)(Age in years - 20]

serum creatininein mg/dL

females = CrCl x0.90

EXCRETION
• Reabsorption of water and passive excretion of lipid
soluble drugs
• Depends on urinepH
• Based of Henderson-Hasselbalchequation

Acidic Urine + Acidic Drug = Reabsorb

Acidic urine + Basic Drug = Excreted
Basic urine + Acidic drug = Excreted
Basic urine + Basic drug = Reabsorb

Tubular reabsorption
Pharmacodynamics
 Pharmacodynamics

- A branch of pharmacology that focuses on the study of

the biochemical and physiological effects of drugs
and the mechanisms by which they produce such
effects.
Mechanisms of Drug Action
•

•
1. Non – target protein mediated mechanism
1. 1. Colligative mechanism – osmoticpressure
1. 2. Chemical reaction
• NEUTRALIZATION
• LOCAL
• SYSTEMIC
• CHELATION
• OTHERS
• CN + Sodium thiosulfate
1. 3. Counterfeit incorporation m e c h a n i s m  Certaindrugs
that are structurally analogs of normal biological chemicals may be
incorporated may be incorporated into cellular components that may
alter its function. EXAMPLE: analogs of pyrimidines and purines that
can be incorporatedinto nucleic acids
SITES OF DRUG ACTION

Target protein – biologic site

of action of drugs
Target protein – biologic site of action of drugs

1. Structural protein
Microtubule important site of
action
Drugs that inhibit microtubule
synthesis/ spindle protein
Griseofulvin
Vinca alkaloids
Colchicine
2. Regulatory Proteins

 mediates the transmission of endogenous chemical

signals such as neurotransmitters, autacoids, and
hormones.
1. Transports/Channels
2. Enzymes
3. Carrier Molecules
4. Receptors

58
 2.1. Channels/transport
 Proteins that take part in
tranmembrane signaling and regulates
ionic composition Voltage-gated Na
channel
Voltage-gated Ca channel
e.g. drugs act on:
• Na channel  Local
anesthetic, CBZ, PHENYTOIN
• Ca++ channel  Ca++
channel blockers
2.2. Carrier molecules
Na+-K+ ATPase pump- Digitalis glycosides
(inhibitor)
H+-K+ ATPase pump- PPI

Na+-K+-2Cl- cotransport –Loop Diuretics

 2.3. Enzymes
 protein catalysts
Xanthine oxidase - allopurinol
Cyclooxygenase - NSAID’s
ACE - ACE inhibitors
MAO - MAOI
Phenelzine
Isocarbozaxid
Tranylcypromine
Acetylcholinesterase - Edrophonium
COMT -ENTACAPONE,TOLCAPONE
2.4.Receptors
 Functional macromoleular componentsof
cells with specific stereochemical
configuration and in which a ligand
interacts
 SPECIFICITY
It is a membrane bound or intracellular macromolecular protein
which is capable of binding the specific functional groups of
the drug or endogenous substance.
 SELECTIVITY
Ligand- any chemical that has ability to bind selectively to
a particular receptor or sites
 AFFINITY
 the capacity of drug to form the complex with its receptor
 INTRINSIC ACTIVITY
the pharmacologic response
Type of Receptors

1. Type I Receptor
2. Type II Receptor
3. Type III Receptor
4. Type IV Receptor
HYPERPOLARIZATION- EFFLUX OF K,
INFLUX OF CL-, CHANGE IN
CELLMEMBRANE P O T E N T I A L  NO
NERVE IMPULSE

DEPOLARIZATION- INFLUX OF NAAND

CA– CELL BECOMES P O S I T I V E 
INCREASING THE NERVE IMPULSE

REPOLARIZATION- CHANGE IN THE

MEMBRANE POTENTIAL THAT RETURNS IT
TO NEGATIVE, HAPPENS AFTER
DEPOLARIZATION
 1. Type I receptor - Ionotropic
receptor
Controls movement of ions
 LOCATION: cell membranes
 Stimulated in: milliseconds
EXAMPLES:
 GABA receptors control Cl- ions
-Benzodiazepines
-Barbiturates
 Nicotinic receptors
• controls the entry of Na+
• inhibited by neuromuscular blocker.
Ionotropicreceptor

Neurotransmitter
Ions
2. Type II receptors - G-protein linked receptor/
G-protein coupled receptor/Metabotropic
receptors

GTP-binding signal transducer protein is G-Protein

G-protein modulates production of an intracellular
second messenger
location: cell membrane
onset: in seconds

*7 transmembrane(7-TM or heptahelical)
receptors This means that the polypeptide
Chain traverses the membrane seven times.
When a chemical - a hormone or a pharmaceutical agent - binds to the
receptor on the outside of the cell, this triggers a series ofchemical reactions,
including the movement and binding of the G-protein, transformation of GTP
into GDP and activation of second messengers.  Second messengers (e.g.,
cyclic AMP) start a cascade of enzymatic reactions leading to the cellular
response. This signaling method is quite fast and, more importantly, it
amplifies the signal
 Second messengers
Cyclic Adenosine Monophosphate (cAMP)
Cyclic Guanosine Monophosphate (cGMP)
Inositol Triphosphate (IP3)

1.FROMATPcAMP(activates protein kinase)

COMMON EFFECT: CONTRACTION IN HEART,
BRONCHODILATION INLUNGS
2.FROM GTP cGMP (increase cGmp) COMMON
EFFECT: relaxation,VASODILATION
3. PHOSPHATIDYLCHOLINE IP3, DAG (increase calcium)
COMMON EFFECT: CONTRACTION
  Examples of G-proteins:
 Gs-stimulates adenylyl cyclase
 Gi-inhibits adenylyl cyclase
 Gq-increases IP3, DAG

72
G proteins are so-called because they bind the guanine nucleotides GDP and GTP.
They are heterotrimers (i.e., made of three different subunits) associated with. the
inner surface of the plasma membrane and. transmembrane receptors of hormones,
etc. These are called G protein-coupled receptors (GPCRs).
PHOSPHORYLATION– ACTIVATESACTINANDMYOSIN
One of the major mechanism through
which the effects of Nitric Oxide are
mediated the production of the second
messenger cyclic GMP (cGMP). Nitric
Oxide can stimulate production of
cGMP by interacting with the haem
group of the enzyme soluble guanylate
cyclase (sGC). This interaction allows
sGC to convert GTP into cGMP.

Active PKG is ultimately responsible

for many of the effects of Nitric Oxide
including its effects on blood vessel
relaxation (vasodilation). Activation
of PKG by cGMP leads to activation of
myosin phosphatase which in turn leads
to release of calcium from intracellular
stores in smooth muscle cells.
1. G s  Receptors for GLUCAGON,Histamine,Serotonin
>Activated by Cholera toxin which blocks GTPase
activity thus preventing inactivation
 INC.Adenylyl cyclase=INC cAMP

2 . G i  Receptors for Opioids,acetylcholine

 Blocks by pertussis toxin
Dec Adenylyl cyclase=dec cAMP=Open cardiac
potassium channels =dec heart rate

3.Gq for prostanoid receptors

Activates phospholipase C=INC production of IP3 and
DAG=cytoplasmic calcium
Examples of Type II receptors

Alpha receptors
Beta receptors
Muscarinic receptors
3. Type III receptors/Tyrosine Kinases-linked
receptors

Tyrosine kinase - catalyze phosphorylation of

tyrosine residues to modulate a number of
biochemical processes
Janus kinase (JAK) a family of intracellular,
nonreceptor tyrosine kinases that transduce cytokine-
mediated signals via the JAK-STAT pathway.
JAK STATKINASE-receptors do not have intrinsic activity
but agonist induced dimerization increases affinity.
E x a m p l e  Growth hormone and Interferons
 glucokinase
glucose =====glucose-6-phosphate

location: nucleus
onset: hours
  Examples:
Imatinib  Gastrointestinal
stromal tumors (GIST)
Gefitinib  Epidermal growth
factor receptor
 Erythropoietin receptor
Receptor for Insulin  utilization
of glucose

80
4. Type IV receptor/gene transcription-
linked receptors
Central dogma
-Replication  (DNA copied
into complimentary DNA)
-transcription  (DNA template is copied
to RNA)
-translation  (RNA synthesize
protein)
-location: nucleus/cytosol (cytoplasm)
-onset: hours
 Drugs that act on Type IV
receptors
 Corticosteroids
 Mineralocorticoids
 Sex steroids
 Vitamin D
 Thyroid hormone
Theories of Drug Receptor Interaction

1. Clark Hypothesis

“ The Pharmacologic effect

of the drug depends on the
percentage of the receptors
occupied”
 Theories of Drug Receptor Interaction

2. Lock and KeyTheory

-the drug molecule must “fit into
a receptor” like a “key fits into a
lock”.

11
3. Induced-Fit Theory
-as the drug approaches the receptor, it
alters the conformation of its binding
site to producedrug-receptor complex.
4. Rate Theory
-the activation of receptors is directly
proportional to the total number of
encounters of the drug with its receptors
per unit time.

11
5. Hypothesis of Ariensand
Stephenson
 A theory which states that
effectiveness lasts as long as the
receptor is occupied

6. Hypothesis of Paton-RATE
THEORY
“ Effectiveness of a drug does not depend on
the actual occupation of the receptor but by obtaining
properstimulus”
Dose & Response
relationships
Graded Dose-Response Relations

It describes the relationship between the

magnitude of the effect of a drug in an
individual and the doses of the drug.
Generally, as the dose of the drug increases, the
effect produce will reach a maximumlevel.
It allows comparison for drug efficacies and potencies.
Efficacy of a drug is measured by its
maximum effect.
Potency refersto the concentration
(EC50) or dose (ED50) of a drug required to produce
50% of the drug's maximal effect
Graded dose-response curves for four drugs, illustratingdifferent
pharmacologic potencies and different maximalefficacies.
Which is the most
potent among these
drugs?
A. POTENCY
Drugs A and B are said to be more potent than drugs C and D
because of the relative positions of their dose-response curves
along the dose axis

B. Maximal Efficacy
This parameter reflects the limit of the dose-response relation on
the response axis. Drugs A, C,and D have equal maximal
efficacy, while all have greater maximal efficacy than drug B.
C. Shape of Dose-Response Curves
reflects the ability of the drug to
produce an effect.

The STEEPER the slope, the more readily

the drug will bind with receptors.
Extremely steep dose-response curves (eg, curve
D) may have important clinical consequences if
the upper portion of the curve represents an
undesirable extent of response (eg, coma caused
by a sedative-hypnotic)
Steep dose-response curves in patients could result
from cooperative interactions of several different
actions of a drug
(eg, effects on brain, heart, and peripheral vessels, all
contributing to lowering of blood pressure).
Quantal Dose-Effect Curves
-All-or-none response
-It describes the relationship between
the number of patients
EXHIBITING a defined response
produced by a specified dose of the drug.
Quantal dose-effect plots. Shaded boxes indicate the frequency
distribution of doses of drug required to produce a specified
effect; ie, the percentage of animals that required a particular
dose to exhibit the effect. The open boxes indicate the
cumulative frequency distribution of responses, which are log
normally distributed.
The quantal dose-effect curve is often
characterized by stating the median
effective dose (ED50), the dose at
which 50% of individuals exhibit the
specified quantal effect.
Median toxic dose (TD50)- the
dose required to produce a
particular toxic effect in 50% of
animals.
Quantal dose-effect curves may alsobe
used to generate information regarding
the margin of safety to be expected
from a particular drug used to produce a
specified effect
Plasma concentration vs time curve
Therapeutic Index- the dose
of a drug required to produce a
desired effect to that which
produces an undesired effect
Variation in Drug Responsiveness

Idiosyncrasy
- Unusual drug Response
caused by genetic differences in metabolism of the
drug or by immunologic mechanisms, including allergic
reactions.
Hypo reactivity - the intensity of effect of a
given dose of drug is diminished

Hyper reactivity- the intensity of effect of a

given dose of drug is increased in comparison
to the effect seen in most individuals.
Hyper reactivity
 It is also known as supersensitivity
It occurs when target cells are subject to long-
term exposure to receptor antagonists
followed by abrupt cessation of drug
administration.
This can involve receptor up-regulation
through synthesis of new receptors.
Hypersensitivity -refers to allergic
or other immunologic responses
to drugs.
 Hypersensitivity Reactions
TYPE OTHER NAMES EXAMPLES MEDIATORS
• Atopy
I Allergy (Immediate) • Anaphylaxis
IgE
• Asthma

II •Autoimmune IgM or IgG

Cytotoxic, Antibody Hemolytic Anemia
dependent • Thrombocytopenia
• Erythroblastosis
fetalis
• Grave’s Disease
• Myasthenia Gravis

• Serum sickness
III Immune Complex • Systemic Lupus
IgG
Disease Erythematosus (SLE)

• Contact Dermatitis
IV Delayed-Type • Mantoux Test
T-cells
Hypersensitivity •Chronic Transplant
Rejection
• Multiple Sclerosis
* A n a p h y l a x i x  is a serious, life-
threatening allergic reaction, SHORTNESS
OF BREATH, ITCHING AND FLUSHING
* A t o p  a tendency to develop
allergic disease ( hay fever)
*Erythroblastosisfetalis hemolytic
anemia in neonates
*Graves D i s e a s e  Results of over
active thyroid gland(hyperthyroidism)
 Tolerance - it refers to a
decreased responsiveness to
the drug, a consequence of
continued drug administration
Tachyphylaxis - This refers to rapidly
acting tolerance

Responsiveness diminishes rapidly after

administration of a drug
Alterations in Number or Function of
Receptors
Down-regulation of receptors
it is caused by continuous prolonged
exposure of receptors to drugs that disrupt
the homeostatic equilibrium and result in
altered levels of the receptors.
This disruption involves endocytosis of
ligand-bound receptors, resulting in
sequestration of receptors from the
cell surface and possibly accelerated
degradation of the receptors, or
inactivation of the receptors.
Desensitization
 It is the result of down-regulation.
The target cells become desensitized, and the
effect of subsequent exposure to the same
concentration of the drug is reduced.
Classification of drugs according to
receptor interaction

1. AGONIST
 Able to bind (with affinity)
 With intrinsic activity
1.1 Full agonist
 Full response
Stimulate all different variant of
receptors even the new receptors
1.2 Partial agonist
Less than the expected
response
 A drug that can activate receptor
but are unable to elicit the maximal
response.
2. ANTAGONIST
• With affinity but no intrinsic activity
• It prevents the binding of agonist
 Types of Antagonism

A. PHARMACOLOGICANTAGONIST

 utilizes the same receptor

produce an effect opposite of agonist by binding to the same
receptor
 Beta blocker and Beta agonist
(Propranolol) (epinephrine)
 Types of Antagonism

PHARMACOLOGIC ANTAGONISM

A.1. Pharmacokinetic Antagonism

It occurs when the effect of one drug is reduced by another drug
via alteration in LADMER
Examples: DIGOXIN+Cholestyramine
WARFARIN+Phenobarbital
 Types of Antagonism
PHARMACOLOGIC ANTAGONISM

A.2. Pharmacodynamic Antagonism

It occurs when the effect of one drug is inhibited/reduced by another

drugvia competition or binding to the same receptor
Example: EPI+ PROPRANOLOL
 Types of Antagonism
PHARMACODYNAMIC ANTAGONISM
CompetitiveAntagonism
 It occurs when the effect of the antagonist can be
overcome by increasing the concentration of agonist
 A.K.A Surmountable antagonist
 Example: Interleukin 1 receptor
 Interleukin-inflammatory subs.
 Example of drug-ANAKINRA-decrease inflammatory
property of Interleukin
 Types of Antagonism

B.PHARMACODYNAMIC ANTAGONISM
B1. Reversible Competitive Antagonism
receptor antagonist that binds to agonist receptor site and
equilibrates sufficiently rapidly with the receptors that its
occupancy is reduced when the agonist concentration is
increased

EXAMPLE:Atropine is a competitive antagonist ofAch.

Phentolamine-alpha 2 receptor antagonist
 Types of Antagonism
B.PHARMACODYNAMIC ANTAGONISM
B2. Irreversible-Competitive Antagonism
Is a receptor antagonist that COVALENTLY binds to the
receptor target and in general CANNOT be removed
 A.K.A Competitive insurmountable antagonism

EXAMPLE: PHENOXYBENZAMINE-it is an alpha 2 receptor

antagonist
 Types of Antagonism
B.PHARMACODYNAMICANTAGONISM
C. Non-CompetitiveAntagonism
It occurs when the effect of antagonist binds to a
distinctly separate binding site from the agonist
exerting their action to that receptor via other binding site
 A.K.A (allotropic or allosteric antagonism)
Example:CYCLOTHIAZIDE
Cyclothiazide (CTZ), known as a blocker of AMPA receptor
desensitization, produced a non-competitive inhibition of [Ca2+]i
PHYSIOLOGIC ANTAGONISM
- occurs when the drugs act
independently at different
receptor sites, often yielding
opposing actions.
e.g. HISTAMINE + EPINEPHRINE
CHEMICAL ANTAGONIST
 No receptor is involved
occurs when two drugs bind with
each other to form an inactive
compound.
Via direct chemical interaction
Protamine SO4 + Heparin SO4  forms
complex devoid of action

Protamine- (+) charged at physiologicpH

Heparin – (-) charged at physiologicpH

Chelating agents
Deferoxamine – Iron (Fe)
Allosteric Modulation
 Is the regulation of an enzyme or
other protein by binding an effector
molecule at the proteins allosteric site
Allosteric activators areeffectors
that enhances the proteinsactivity
Allosteric Inhibitors are effectors
that decreases the protein’sactivity
 Types of Allosteric Modulation
1. Positive Allosteric Modulation
Occurs when the binding of one
ligand enhances the
attraction between
substrate molecules and
other binding sites
A.K.A. “allosteric activation”
Example: Hgb and Oxygen
Haemoglobin is an allosteric protein. This means that the binding
of oxygen to one of the subunits is affected by its interactions with
the other subunits.
  haemoglobin's oxygen binding affinity is inversely
related both to acidity and to the concentration of
carbon dioxide.
S i n c e carbon dioxide reacts with water to
form carbonic acid, an increase in CO2 results ina
decrease in blood pH, resulting in hemoglobin
proteins releasing their loadof oxygen.
C o n v e r s e l y, a decrease in carbon dioxide
provokes an increase in pH, which resultsin
hemoglobin picking up more oxygen.
 Types of Allosteric Modulation
1. Negative Allosteric Modulation
Occurs when the binding of one
ligand decreases the affinity for
substrate at other binding sites
A.K.A “ allosteric inhibition”

Example: Glycine andStrychnine

• Glycine inhibitory neurotransmitter
• Glycine receptor=Sedation
• Strychnine-( Strychnos nux-vomica)Withhigh
affinity=Convulsion/seizure
 POISONING INTERACTIONS
ADDITIVE  combined effect is the same as the sum of effects when
given alone
(1+1 =2)
Example: Alcohol + CNS depressant/BZD
SYNERGISM  combined effects are much greater than the sum
of effects when given alone
(1+1=3)
Example: Cotrimoxazole, CCl4 +Alcohol
Pyrethroids + Piperonyl butoxide (PBO)
POTENTIATION  exposure to a chemical with no toxicity increases
the toxicity of another compound
(1+0=2)
Example : Sinemet  Levodopa +Carbidopa (-) DOPA
decarboxylase, Co- amoxiclav  Clavulanic acid +
Amoxicillin, CCl4 + Isopropanol
ANTAGONISM  co-administration of two chemicals interferes with
the toxicity of both or one of them
(1+1=0)
Basic & Clinical Evaluation
of New Drugs
New Chemical Entities
Are compounds which emerge from the
process of a drug discovery.
This will have a promising activity
against a particular biological target
thought to be important in disease
management
DRUG TARGET
Naturally existing cellular or
molecular structure involved in
the pathology of interest that
the drug on development meant
to act on
DRUG DESIGN
 The inventive process of
finding new medications based
on the knowledge of biological
DRUG REPOSITIONING target
Application of known drugs
and compounds to new
indication
 Example: Sildenafil- VIAGRA
Viagra- was initially designed to help lower blood
pressure but is now typically used to treat erectile
dysfunction.
Types of drug design
1. LIGAND BASED DRUG DESIGN”A.K.A
“indirect drug design”-relies on knowledge of
other molecules that bind to the biological target
of interest
2. STRUCTURE BASED DRUG DESIGN-Relies
on knowledge of three dimensional stucture of
the biological target obtained from X-ray,NMR
3. COMPUTER AIDED DRUG DESIGN-using
computational chemistry to discover, enhance or
study drugs and related bi0logically active
molecules
 Organic Synthesis
New ChemicalEntity Molecular Modification

Isolation from Plants

Chemistry
Pre-Clinical Studies Physical Properties
Biological

Pre-formulation

Investigational New Drug

Clinical Trials
Phase 1 Pre-Clinical Studies
Phase 2 (continued)
Phase 3 New Drug Long term animaltoxicity
Application
Product Formulation
(NDA)
Manufacturing Control
Package and Label design

Postmarketing (Phase 4)
Indirect drug design
Drug a- receptor a
New drug - receptor a

Main purpose of IND application is to provide data showing it is reasonable to

begin tests of a new drugs on humans. This is to protect the rights and safety of
the subjects and to ensure that the investigational plan is sound and design to
achieve the stated objectives

NDA- submission
FDA review preapproval plany inspection
FDA action

Phase 1 - several months ; safety 20-100 patients

Phase 2 - several months to 2 years ; safety but mainly effective 100-500
patients
Phase 3 - 1-4 years ; safety, effectiveness and dosage 500-5000 patients
Phase 4 / post marketing surveillance - long term adverse effect and toxicity
 Drug Screening
It involves a sequence of experimentation and
characterization of drugs.
Determination of the ff.
• Pharmacologic profile of the drug
• Effects on cell function
• Pharmacologic activity and selectivity of the
new compound in comparison with reference
compounds
Pharmacologic ProfileTests.

Experimental Method or Target Organ:

Systems – Blood pressure
Species or Tissue: Dog, cat (anesthetized)
Route of Administration: Parenteral
Measurement: Systolic-diastolic changes
Experimental Method or Target Organ:
Respiratory effects
Species or Tissue: Dog, guinea pig
Route of Administration: Parenteral
Measurement: Effects on respiratory rate and
amplitude, bronchial tone
 Preclinical Safety & ToxicityTesting
The major kinds of information needed frompreclinical
toxicity studies are

1.Acute toxicity - Acute dose that is lethal in

approximately 50% of animalsand the maximum
tolerated dose.
• Usually two species, two routes, single dose.

ACUTE TOXICITY- REFER TO THOSEADVERSE EFFECTS

OCCURING FOLLOWING ORAL ADMINISTRATION OF
SINGLE DOSE OF A SUBSTANCE OR MULTIPLE DOSES
GIVEN WITHIN24HRS
HOWTO MEASUREACUTE TOXICITY?

Approximate LethalDose  the lowest dose

atwhich mortality occurs in apopulation

MEDIAN LETHALDOSE (LD50)

T h e amount of material, given all at once, which causes
the
death of 50 % (one half) of a group of test animal.

MEDIAN LETHALCONCENTRATION (LC50)

T h e concentration of chemical that kills 50 % of the
test animal during the observation period.
2. Subacute toxicity -
• Three doses, two species.
• 4 weeks to 3 months may be necessary prior to clinical
trial.
• The longer the duration of expected clinical use,the
longer the subacute test.
3. Chronic toxicity
• Rodent and non-rodent species.
• 6 months or longer
• Required when drug is intended to be used inhumans
for prolonged periods.

• Usually run concurrently with clinical trial.

Goals of subacute and chronic
tests are to show which organs
are susceptible to drug toxicity.
3 dose levels plus controls.
4. Effect on reproductive Performance
• Effects on animal mating behavior,
• reproduction,parturition, progeny, birth
• defects, postnatal development.

• Examines fertility, teratology, perinatal and postnatal

effects, lactation.
5. Carcinogenic Potential
• Two years, two species.
• Required when drug is intended to be used inhumans
for prolonged periods.

• Hematology, histology, autopsy studies. Tests in

transgenic mice for shorter periods may be
permitted as one species.
6. Mutagenic Potential
Effects on genetic stability and mutations in bacteria
(Ames test) or mammalian cells in culture
• dominant lethal test and clastogenicity in mice.
The Ames test is a widely employed method that uses bacteria
to test whether a given chemical can cause mutations in the DNA of
the test organism. More formally, it is a biological assay to assess the
mutagenic potential of chemical compounds.
7. Investigative Toxicology
• Determine sequence andmechanisms
of toxic action.
• Discover the genes, proteins,
pathways involved.
• Develop new methods forassessing
toxicity.
Quantitative estimatesare determined
1. "no-effect" dose— the maximum dose atwhich a
specified toxic effect is notseen
2. minimum lethal dose — the smallest dose that is
observed to kill any animal
3. median lethal dose (LD50) — the dose that kills
approximately 50% of the animals
FDACategories for useof
medication in pregnancies
Category
A
B- Diphenhydramine- benadryl
C- imodium- loperamide
D- clonazepam- klonopin
X- warfarin - coumadin ; isotretinoin- accutane

There are no adequate and well-controlled studies in pregnant

women

Category D valporic acid and streptomycin (TV at CPS)

Lithium carbonate (ebstein anomaly)

Ebstein anomaly tricuspid valve doesn’t function (return of

blood from atrium to ventricle)

Category X teratogenic - it can affect the fetus inside the

patient
Categor Animals Human Descripti Example
y s on
A Y Y SAFE Folic Acid, Ferrous
SO4
B Y N SAFE PARACETAMOL
Amoxicillin
C Y N UNSAFE Rifampicin
Theophyline
D UNSAFE Tetracycline, Valproic a
Y Y (B>R) Phenytoin, Strepto
Carbamazepine

X TERATO Isotretinoin
Y Y GENIC
Thalidomide
Diethylstilbestrol
AUTACOIDS

 Endogenous substances
with biological activity.
 A.K.A. “Local hormones”.
 Not released or stored in
glands.
 Not circulated in blood.
 Are formed at the site of
action.
 Produce localized action.
Edongeneous there are naturally present in
our body.
CLASSIFICATION OF AUTACOIDS

1. Biologically Active Amines

1. Histamine
2. Serotonin
2.Lipid derived autacoids
( Eicosanoids)
1. Prostaglandins
3. Leukotrienes
4.Thromboxanes
3.Ergot Alkaloids
4.Peptide Autacoids
1. Kinins
2. Renin
3. Angiotensin
Kinins related to BRADYKININ and KALIDIN
They act locally to induce vasodilation (Dilating of
Blood Vessel) (Decrease in BP) and contraction
of smoothmuscle.
Kinins as of today it belongs to Peptide Autocoids
CLASSIFICATION OFAUTACOIDS

4. Vasoactive Polypeptides
} Kinins
} Angiotensin
} Endothelin
} Natriuretic peptide
} Vasopressin
} Substance P
5. Endothelium Derived Autacoids
} Nitric oxide
HISTAMINE  A.K.A imidazolyethylamine;
1H – imidazole-4-ethenamine (chemical name )

 it is a small molecule
produced by
decarboxylation of the
amino acid L-Histidine.
 it is catalyzed by the
enzyme L-Histidine
decarboxylase in a
reaction that requires
pyridoxal phosphate.
L- histidine  when you remove the carboxyl group of
histidine amino acid it will be Histamine.

L-Histidine Decarboxylase  enzyme coverting Histidine to

Histamine

Pyridoxal Phosphate  active form of VIT. B6

Histamine  need to remove carboxyl group of histidine then
add Pyridoxal Phosphate.

Metabolism
 Monoamine oxidase
 Diamineoxidase orHistamine
 Imidazole N-methyl transferase / Histamine N-methyl
transferase
 Aldehyde Dehydrogenase
TISSUE DISTRIBUTION

¡ Mast Cells  gE-primed mast cell releases

granules and powerful chemical mediators,
such as histamine, cytokines, granulocyte
macrophage colony-stimulating factor (GM-
CSF),leukotrienes, heparin, and many proteases
into the environment.
¡ Basophils
¡ CNS
¡ Respiratory Tract
¡ Gastrointestinal Tract
¡ Skin
6
Mast cells  associatedwith ImmunoglobulinE
Histamine release

 These is the main cell release HISTAMINE

These chemical mediators cause acharacteristic
symptoms of allergy

Basophil- WBC Granulocyte that are active in

inflammatory response.
 Types of Histamine Receptors
Receptor Distribution Post Organ System Effects
Type Receptor
Mechanism

H1 Smooth muscle, IP3, DAG(Gq)  urticarial response

endothelium,brain  Bronchoconstriction
 Extravascular smooth muscle
contraction,Vascular smooth muscle
relaxation, Endothelial cell
contraction

H2 Gastric mucosa,cardiac cAMP (Gs)  gastric acid secretion, gastric

muscle,mast cells,brain pepsin, and intrinsic factor
production

H3 Presynaptic:brain, cAMP,Ca2+  modulates the release of

myenteric plexus (Gi) acetylcholine, amine, and peptide
transmitters.
H4 Eosinophils,neutrophils, cAMP,Ca2+  mediate mast cell
CD4T-cells (Gi)
chemotaxis 7
H1 Bronchoconstriction
Constricted Bronchial tube  causesAsthma and difficulty in
Breathing

Urticarial response  urticariaA.K.A Hives  outbreak of swollen ,pale

red bumps or plaques on the skin.

H1: Physioligic antagonist: Epinephrine

Tx. of Anaphylacticshock
Histamine lungs bronchoconstriction
Blood Vessels (vascular smooth muscle) cause vasodilation  cause
decrease in Blood Pressure  and can causeAnaphylactic shock

Pharmacologic antagonist: H1 Antihistamine Prototypic Antagonist:

Diphenhydramine

H2: Prototypic Antagonist:Cimetidine

A. Histamine Agonist  drugs or substances
that will activate different histamine receptor.

1. Histamine  strongest
2.Betazole  Isomer of histamine and acts on H2
receptor .
 It is used for diagnosis of gastric acid secretion.
3.Betahistine  It is analogue of histamine and
acts on H1 receptor , it is used in the treatment of
Meniere's disease.
4. Impromidine
5.R-alpha methylhistamine  H3 SPECIFIC
AGONIST
8
Betahistine is used in the treatment of
Meniere's disease inner ear disorder causing tinnitus(ringing
of the ear) vertigo and hearing loss.
 Anti vertigo drug

Impromidine (INN)  is a highly and specific histamine H2

receptor agonist. It has been used diagnostically as a gastric
secretion indicator.
 Use to increase gastric acid secretion.

Gastrointestinal tract increase gastric acid  causing

Gastrointestinal upset

 Agonist response
 Antagonist  babalikatrin mo lang siya
Clinical Uses: Adverse Effects:
¡ Allergy Testing ¡ Flushing
¡ Bronchial ¡ Hypotension
Hyperactivity ¡ Tachycardia
Test ¡ Headache
¡ Test of Gastric ¡ Wheals
Secretory ¡ Bronchoconstriction
Function ¡ Gastrointestinal upset
Flushing  redness of the skin (because of Dilated
Blood Vessels) Decreasein Blood Pressurecausing
Hypotension Shock

Tachycardia fast heart beat

Wheals  an area of the skin which is

temporarily raised, typically reddened and usually
accompanied by itching. Just like URTICARIAL
RESPONSE
10
ANTIHISTAMINE ANTAGONIST OF H1RECEPTOR
H1Antagonist
H2Antagonist

Example:
Antihistamine +Antiserotonin
Cyproheptadine  inc.apetite

Antihistamine+Antiadrenergic/ Antialpha Adrenergic

Promethazine  Phenotiazine (specific drug)

Antihistamine +Anticholinergic
Diphenhydramine
Promethazine  (Antihistamine +AntialphaAdrenergic +
Anticholinergic )
B. Histamine Antagonist
1. H1-Anti-histamines
MOA: Block H1 receptors especial y in Mast Cels
CLINICAL USES: allergic rhinitis, allergic contact
dermatitis

1.1st Generation/ Sedating

(nakakaantok)
2. 2nd Generation/Non-sedating
 (hindi nakakaantok)
11
B.1. 1st Generation/ Sedating
H1-Anti-histamines
1. ETHANOLAMINE
2. ETHYLENEDIAMINE
3. PIPERAZINE
4. ALKYLAMINE
5. PHENOTHIAZINE
6. MISCELLANEOUS

12
B.1.1.1.ETHANOLAMINE most sedating; has
significant anticholinergic; used as sleepingpills;
 mx of EPS(atropine-likeeffects)
1. Diphenhydramine
2.Diphenhydramine+ Calamine Benadryl®,
Caladryl®
3. Dimenhydrinate Gravol®
4. Carbinoxamine. Palgic®
B.1.1.1.4. Doxylamine Unisom®

2. ETHYLENEDIAMINE
1. Pyrilamine
B.1.2.2.Tripelennamine

B.1.1.3.PIPERAZINE
1. Hydroxyzine Iterax®
2. Meclizine.Bonamine®,
B.1.3.1.Cyclizine Valoid®
ETHANOLAMINE Antihistamine+
Anticholinergic
Atropine(anticholinergic drug) likeeffect

Extrapyramidial Symptoms (EPS)  (cholinergic like

effect)  adverse effect of Antipsychotic Agents
Type of movementdisorder
B.1.4. ALKYLAMINES
B.1.4.1. Brompheniramine
B.1.4.2.Brompheniramine + Phenylephrine Dimetapp®
3. Chlorpheniramine Antamin®
4.Chlorpheniramine-containing Bioflu®, Neozep®,
Sinutab®, Decolgen forte®

5. PHENOTHIAZINE
1. Promethazine Phenargan®, Phenerzin®, Promet®, Zinmet®

6. MISCELLANEOUS
1. Cyproheptadine Periactin®
ALKYLAMINES
Paracetamol +Phenylephrine + Chlorphenamine  Antihistamine drug
present in Bioflu,Neozep.

PHENOTHIAZINE
Promethazine  as anesthetic (Antihistamine +Antialpha Adrenergic +
Anticholinergic)

MISCELLANEOUS
Cyphoheptadine Periactin®  for serotonin syndrome ;has significant
blocking effects on 5 – HT receptors
 Antihistamine +Antiserotonin

Serotonin A.K.A (5 – HT receptors or Hydroxytryptamine/Serotonin

Receptors)

Serotonin syndrome  excessiveserotonin

 Causing high temperature, high blood pressure, increasing reflexes, tremor,
sweating , dilated pupils, diarrhea, seizure.
 Sedation
 First-generation H1 receptor antagonist
 Anti-nausea & antiemetic actions
(PREVENTION OF MOTION SICKNESS)
 DOXYLAMINE ( in BENDECTIN) used widely in the past
for the treatment of N/V for pregnancy
 Anti-Parkinsonism Effects
Diphenhydramine-for acute suppressant effects on
extrapyramidal symptoms associated with anti-psychotic
drug (acute dystonic reactions)

15
Sedation sleep aids , not use in day time
x pilot

Diphenhydramine antihistamine + cholinergic

Because antihistamine’s have mild anticholinergic
properties.
MILD BLOCKAGES OF MUSCARINIC RECEPTOR
Extrapyramidal  movement disorder in
coarse,tremors, rigidity, bradykinesia
Tx. of Parkinson’s or Antipsychotic
 Anticholinergic effects
 FIRST generation- Ethanolamine and Ethylenediamines
 Adrenoceptor-blocking actions
 PHENOTHIAZINE
 Serotonin-blocking actions
 Cyproheptadine causes gain weight
 Local Anesthesia
 Diphenhydramine and Promethazine are actually more
potent than procaine
 Cardiac arrhythmias
 Overdosage of Astemizole((Hismanal®) and
TERFENADINE((Seldane®) 16
Ethanolamine and Ethylenediamines have significant
antropine like effects on Peripheral Muscarinic Receptors

TERFENADINE  active metabolite

TERFENADINE and Astemizole  withdrawn from the market
because of causing Cardiac Arrhythmias

Terfenadine liver toxic and CardiacArrhythmias

withdrawn

Phenothiazine  Promethiazine  can cause Orthostatic

Hypertension  (severe drop in Blood Pressure upon sudden
changing in the position) (Ex. Lying to Standing)

Serotonin  blocking actions Cyproheptadine  gain

weight because of increase in apetite
 B.1. 2. 2nd Generation/ Non-
sedating
MOA: Competitive pharmacologic block of peripheral
H1 receptors. No autonomic or anti-motion sickness
effects
CLINICAL USES: Hay fever, angioedema
Less sedating
Cetirizne Alnix®, Zyrtec®
Acrivastine. Benadryl allergyrelief®
True non-sedating
Loratadine Allerta®,Claritin®, Clarihist®,Zylohist®,
Cardura ®, Lorid®
Fexofenadine Fenafex®,Telfast®
Desloratadine Aerius®
Levocetirizne Xyzal® 1
7
B.2. H2- Anti-histamines found in
Gastrointestinal Tract
¡ MOA: Block H2 receptors especial y in Parietal
cel s of the stomach (decrease Gastric acid
secretion)
¡ CLINICALUSES:Alternative drug for PUD &GERD
¡ Potency: (most toleast)
Famotidine(most)  Nizatidine = Ranitidine 
Cimetidine(least) Prototype H2 antagonist  1st
Antihistamine

18
PUD  Peptic Ulcer Disease
GERD  Gastro Esophageal Reflux Disorder 
Gastric acid secretion

H2 receptor stimulation leads to: Gastric acid

secretion
¡ Cimetidine Tagamet®
¡ Ranitidine Zantac®,Ulcin®
¡ Famotidine H BLOC®,Hista-Bloc®
¡ Nizatidine Axid®, Nolcer®  have an almost
complete oral bioavailability
Nizatidine Biovailability is100%

Tagamet®, Zantac®, Pepcid®(Famotidine)

undergo first pass metabolism and thereby
Biovailability is50%
 It was known as a potent vasoconstrictor
 Found when the blood is allowed to clot
 Neurotransmitter and Local hormones
 Metabolite of 5-hydroxytryptophan are:
 SEROTONINANDENTERAMINE
34
Serotonin  present in blood clot
Serotonin produce melatonin
 It is called HAPPYHORMONE
 Precursor of MELATONINhormone producing sleepiness

Serotonin receptor they are Excitatory/ Inhibitory Neurotransmitter

Excitatory increasing the amount of Neurotransmitter
Inhibitory decreasing the amount of other Neurotransmitter

Serotonin comes fromTryptophan

from the serotonin doon naderived ang melatonin

Seratonin  is thought to be especial y active in constricting the smooth

muscle, transmitting impulses between nerve cel s, regulating cyclic body
processes and contributing to well being and happiness.

Increase the amount of serotonin lead / link with DEPRESSION

Serotonin  is regarded by someresearchers asa chemical that is
responsiblefor maintaining mood balance,and that adeficit of serotonin
leadsto
DEPRESSION.

Constrictor  contraction of vascular and smooth muscle

Vasoconstriction  constriction of Blood Vessles 

responsible forincreasing Blood Pressure

Autocoidsconsideredlocal hormones becausethey produce

local effect and they realease at local site of action.
Serotonin
¡ A.K.A. “5-
Hydroxytryptamine”/ 5-HT
¡ It is an indole ethylamine
formed in biologic systems
from the amino acid L-
tryptophan by hydroxylation of
the indole ring followed by
decarboxylation of amino acid.
¡ Hydroxylation at C5 is the
rate-limiting step.
37
2 step to realease serotonin Convertion of Tryptophan
to Serotonin

Tryptophan there will be

Hydroxylation (addition of Hydroxyl group(OH))

Decarboxylation of Amino acid (removal of Carboxyl

group)
Enzyme responsible for the convertion of L-tryptophan to 5-Hydroxy-L-
tryptophan(5-HTP)
 L-tryptophan-5-monooxygenase
 Tryptophan hydroxylase (TPH)

Enzyme responsible for the convertion of 5-Hydroxy-L-tryptophan(5-HTP) to

Serotonin
 5-Hydroxytryptophan decarboxylase
 Aromatic acid decarboxylase

2 enzyme for the metabolizing of serotonin

 Monoamineoxidase (MAO)
 Aldehyde dehydrogenase

Metabolite 5-Hydroxyindoleacetic acid (5-HIAA) productionof

serotonin + MAO & Aldehyde dehydrogenase

When there is a abundant amount of MAO  Decrease the amount of Serotonin

40
G-protein coupled producing secondarymessenger
(cAMP, cGMP, IP3 andDAG)

Type 1  Ionotropic Receptor(5HT3)

Type 2  Metabotropic /A.K.A G-protein coupled
receptor (The rest of Serotonin 5HT receptor)
Buspirone Buspar®
anxiolytic Treatment of Anxiety
DOC For Chronic and Persistent Anxiety
¡ Sumatriptan Sumigran®,
Imigran®
¡ Naratriptan Naramig®
¡ Zolmitriptan Zomig®
¡ Rizatriptan Maxalt®
 MOA: 5-HT1D agonist;causesvasoconstriction; modulates
neurotransmitter release
 CLINICALUSES:Migraine and cluster headache(same w/ 5-HT1B)
 CI:Patient w/ Ischemic Heart Diseasebecauseoftheir Vasospastic Effect
IschemicHeart Disease constricted yung BloodVessles
Triptans potent Vasoconstrictor(contractionof
Blood Vessel)
Target peripheralnociceptors
Selective agonist for 5-HT1D & 5-HT1B receptor
Sumatripan  is metabolized by a MOA-
A(MonoamineoxidaseA) so can’t be used in patients
who are taking MAO inhibitors (MAOI)

MAOI  Monoamineoxidase inhibitor Decrease the

amount of MAO,MAOI + Triptans = decrease amount of
MAO, no enzyme will metabolize triptan will cause
toxicity of triptan/ excessiveamount of triptan.
 Cisapride
 used for the treatment of
gastroesophageal reflux and motility
disorder.
 increase motility
¡ Tegaserod Zelnorm®
 MOA: Partial agonist at5-HT4 receptors
 CLINICAL USE:Constipation-dominant
irritable bowel syndrome (restricted use)
Toxicity: Diarrhea, IschemicColitis
Tegaserod  increase motility  treatment of
constipation

Ischemic Colitis  inflammation / too much

constraction in thecolon.
Phenoxybenzamine  has long acting blocking action at
5-HT2 receptors.
 treatment of carcinoidtumor(diarrhea, bronchoconstriction, flushing)
symptoms
Cyproheptadine  Resembles the phenothiazine antihistaminic agents in
chemical structure and has potent H1 receptor-blockingas
well as 5-HT2-blocking actions. side effect gain weight

Ketanserin  Blocks 5-HT1c and 5-HT2 receptors and has little or no

reported antagonist activity at other 5-HT or H1 receptors.
 Used for CARCINOID SYNDROME
Ritanserin  Another 5-HT2 antagonist, has little or no alpha blocking
action. It has been reported to alter bleeding time and to
reduce thromboxane formation, presumably by altering
platelet function.
Granisetron Kytril®,  5-HT3 antagonist used in the prevention of nausea and
Sancuso® vomiting associated with surgery and cancer therapy.
Ondansetron
Zofran®, Nozuka®
Clozapine  specific 5HT2A- and 5HT2C – receptor antagonist
(Clozaril)-
Risperidone  antagonist at 5HT2A-, 5HT2C-, and dopamine (D2)-
(Risperdal)- receptors
Due to its 5-HT2A receptor antagonism,phenoxybenzamine is
useful in the treatment of Carcinoid Tumora neoplasm that
secretes large amount ofserotonin

Carcinoid (also Carcinoid Tumor) leading to cancer

 Is a slow-growing type of neuroendocrine tumor originating in
the cel s of the neuroendocrine system.

Cyproheptadine, sold under the brand name Periactin® or

Peritol®
 Is a first generation antihistamine with additional
anticholinergic, antiserotonergic and local anesthetic properties.

Ketanserin available in Europe for the treatment of

Hypertension and Vasopastic conditions but has not been
approved in the U.S.A.
CARCINOID SYNDROME  is a paraneoplastic
syndrome comprising the signs and symptoms that
occur secondary to Carcinoid Tumors. The syndrome
includes flushing and diarrhea and less
frequently,heart failure, vomiting and
bronchoconstriction. It is caused by endogeneous
secretion of mainly Serotonin and Kallikrein.
Ergot Alkaloids

 are a large group of compounds produced by fungi

that attack a wide variety of grass species, including
small grains, during the growing season.

The major ergot fungus is Claviceps which produces

sclerotia in several grass species with C. purpurea being the
most commonly foundspecies.

 Claviceps  type of fungi that produces Ergot Alkaloids

Claviceps purpurea  most commonly found species
producing different types of Ergot alkaloids
¡ Accidental ingestion of ergot alkaloids
in contaminated grains.
¡ Characterized by: dementia withflorid
hallucinations; prolonged vasospasm,
which may result in gangrene; and
stimulation of uterine smooth
muscle, which in pregnancy may result
in abortion.
¡ a.k.a. “St. Anthony’s Fire”.
29
Ergotism  increasein the amount of Ergot
Alkaloids

Common Symptoms
Sleep deprivation andPsychosis

Gangrene form of Necrosis (Death Tissues)

Contraction of Uterus in pregnancy can cause
ABORTION.
 Structure
 Ergot alkaloids are classified among the inhole alkaloids
and are derived from the tetracyclic ergoline ring system.
 Ergot alkaloids are classified into two classes

1.Clavine Alkaloids or Clavines: Have ergoline as a

basic structure but contain no peptide bonds.
Ex. Festuclavine, Dihydroelymoclavine ,etc.,
Lysergic acid alkaloids or Ergo alkaloids:
2.In these component D-lysergic acid is linked with tricyclic
peptide.
Ex. Ergometrine , Ergocorine , etc.,
Classification of Ergot Alkaloids

I. Natural – Derivatives of the tetracyclic

compounds (Lysergicacid)
Amine alkaloids - Ergometrine (ergonovine)–
oxytotic
Amino acid alkaloids – Ergotamine , Ergotoxine…
Vasoconstriction &a – blocker
I. Semi-synthetic – Bromocriptine, Methysergide ,
Dihydro-ergotamine (DHE)
2. Synthetic – (non lysergic acid derivative)
Metergotine
Natural  tetracyclic compound  LSD – Lysergic
Acid Diethyl Amide (type of Dangerous Drug)

Oxytocic  may cause contraction of uterus

1. CNS
¡ powerful hallucinogenscan lead to dilusions(LSD)
¡ suppress prolactin secretion from pituitary cells
by activating regulatory dopamine receptors
2. Vascular Smooth Muscle
¡ vasoconstriction of blood vessels
3. Uterine Smooth Muscle
¡ Contraction of the uterus
4. Other Smooth Muscle Organs
¡ Nausea, Vomiting and Diarrhea
3
0
LSD Lysergic Acid Diethylamide Anatural
alkaloid
Prolactin  milkhormone

Increase Prolactin  production of milk

Producing HALLUCINATIONS decreaseproduction

of mik

Ergot  drecrease PROLACTINLEVELS

1. Migraine
} Characterized by a brief that may involve visual
scotomas or even hemianopia, and speech
abnormalities, followed by a severe throbbing
unilateral headache that lasts for a few hours to1-
} 2Sduamyast.riptansare currently First-line therapy for
severe migraine attacks.
} Ergotamine
} Dihydroergotamine is used for treatment of
intractable migraine
} Methylsergide, Propranolol, Amitriptylline, Valproic
Acid, Flunarizine, and Verapamil are used for migraine
prophylaxis
60
Scotoma is an area of partial alteration in the field of vision
consistingof apartially diminished or entirely degenerated visual
acuity that is surrounded by afield of normal or relatively –well –
preserved –vision.

Ergot Alkaloid
• Dihydroergotamine
• Methylsergide

Triptans  selective agonist for 5-HT1D and 5-HT1B receptors.

Hemianopia  blindness over half the field of vision.

Migraine
Sumatripan Imitrex
Ergotamine Ergomar
2. Hyperprolactinemia
¡ Increased serum levels of the anterior pituitary
hormone Prolactin are associated with secreting
tumors of the gland.

DRUGS USE TO TREAT Hyperprolactinemia

¡ Bromocriptine

¡ Pergolide

¡ Cabergoline
62
3. Postpartum Hemorrhage
¡ Oxytocin is the preferred agent for
control of postpartum hemorrhage,
but if this peptide agent is ineffective,
Ergonovine maleate, 0.2 mg usually
given intramuscularly, can be tried.

3
3
Ergonovine=Ergotrate

Oxytocin  use foruterine contraction

4. Diagnosis of Variant Angina
¡ Ergonovine given intravenously
produces prompt vasoconstriction
during coronary angiography to
diagnose variant angina if
reactive segments of the
coronaries are present.
34
Variant Angina A.K.A Prinz Metal Angina
 Is a syndrome typically consisting of Angina
(Cardiac Chest Pain) at rest that occursin cycle.
5. SenileCerebral Insufficiency
¡ Dihydroergotoxine a mixture of
Dihydroergocryptine and three similar
Dihydrogenated peptide ergot
alkaloids (Ergoloid mesylates), has been
promoted for many years for the relief of
senility and more recently for the
treatment of Alzheimer's dementia.
3
5
Senile Cerebral Insufficiency
 Weakness or mental infirmity of old age.
 Related to Dementia and Alzheimer’s
Disease
1. Prostanoids
a.TX
b.PG
c.Prostacyclin
2. Leukotrienes

3
EICOSANOIDS- DEFINE AS INFLAMMATORY MEDIATORS
ORIGINATED FROM PHOSPHOLIPID PRECURSOR—
ARACHIDONIC ACID a 20 CARBON ATOM FATTY ACIDS

CHEMICAL NAME: 5, 8, 11, 14-EICOSATETRAENOIC ACID

PROSTANOIDS
 TX – THROMBOXANE
 PROSTAGLANDIN
 PROSTACYCLIN / PGI2
PGI2  TREAT PULMONARY HTN
TXA2 EFFECTS: PLATELET AGGREGATION AND
VASOCONSTRICTOR
CAUSES BLOOD CLOTTING, AND NARROWING OF BLOOD
VESSEL
1. Arachidonic acid
¡ The most common precursor of the
eicosanoids, is formed by two pathways:
a. Phospholipase A2-mediated production from
membrane phospholipids

b. Phospholipase C-concert with diglyceride

lipase can also produce free arachidonate.

38
CELL MEMBRANE MADE UP OF PHOSPHOLIPID BY
LAYER CONVERTED TO AA BY PLA2

LOX PATHWAY – (LIPOXYGENASE) LKT

COX PATHWAY – (CYCLOXYGENASE) PG AND TX

CORTICOSTEROID INHIBITS PHOPHOLIPASE ENZYME

(ANTI INFLAMMATORY)

NSAID- NON STEROIDAL ANTI INFLAMMATORY DRUGS

ASPIRIN- ACETYL SALICYLIC ACID –ANTI
INFLAMMATORY- INHIBITS COX ENZYME
26
5
26
6
COX OTHER NAME: PGH2 SYNTHASE
COX 1
COX2
AA ACTED UPON PGH2 SYNTHASE OR COX IT WILL
BE CONVERTED INTO PROSTAGLANDIN H2
PGH2PGD SYNTHASE PGD2
PGH2PGE SYNTHASEPGE2PGF2
PGH2PROSTACYCLIN SYNTHASEPGI2PGF1
ALPHA (6 KETO PGF1 ALPHA)
PGH2 THROMBOXANE SYNTHASE ThromboxaneA2
43
* FLAP – FIVE- LOX ACTIVATING PROTEIN
*LTC 4 AND LTD4 – POTENT
BRONCHOCONSTRICTION AND PRIMARY COMPONENTS OF
THE SLOW REACTING SUBSTANCE OF ANAPHYLAXIS –
(SRS-A)
AA CONVERTED TO PGG2 UNSTABLE PEROXIDES
CONVERTED BY PEROXYGENASE TO PGH2
PG H 2  T XA2
SYNTHASETXA2(PLATELET AGGREGATION,
VASOCONSTRICTION, AND
BRONCHOCONSTRICTION)
PGH2 – PGI2 SYNTHASEPGI2 (VASODILATION, INHIBIT
PLATELET AGGREGATION)
2. Eicosanoids
a.Prostaglandin H-Synthase
Pathway
} A.K.A. “Cyclooxygenase” or COX
} It produces thromboxane, the primary
prostaglandins (PGE, PGF, or PGD),
and prostacyclin (PGI2).

4
1
1. COX 1
} Located in the endothelial cells, kidneys,
gastrointestinal tract, and other locations.
} provide active action on the Gastric Mucosa and
in the kidney.
2. COX 2
} Found in abundance in connectivetissues.
} Highly inducible by numerous factors associated
with inflammation

4
2
b. Lipoxygenase Pathway
¡ Produces leukotrienes,
Hydroperoxyeicosatetranoic
acids (HPETE’s), and
Hydroxyeicosatetranoic acids
(HETE’s).
4
3
VASODILATOR DILATE BLOOD VESSELS
DECREASE BP
VASOCONSTRICTION NARROW OF BLOOD VESSELS
 INCREASE BP
POLYMORPHO NUCLEIC LEUKOCYTES
27
4
27
5
27
6
27
7
ASPIRIN DECREASE COX- CAUSE ANTI
INFLAMMATORY AND INDUCED ULCER, AT THE
SAME TIME IT INCREASES LEUKOTRIENE.
BRONCHOSPAM  ASTHMA

ASPIRIN INDUCED ASTHMA

¡ TXA2
¡ MOA: ActivatesTP,receptors, causes
platelet aggregation, vasoconstriction
THROMBOPLASTIN RECEPTOR (BLOOD CLOTTING)
ASPIRIN TX INHIBITOR
ANTIPLATELETPROPHYLAXIS

MYOCARDIAL INFARCTION (heart attack)

1.2.1.PGE1

Alprostadil injectableform for erectile dysfunction

Caverject  used as a palliative treatment to maintain
®, Muse® neonatesw/ ductusarteriosus
 naturally occurringprostaglandin

Misoprostol  MOA: Activates EP2 receptors, causes increased

Cytotec® HCO3– and mucus secretion in stomach;
uterine contraction
 CLINICALUSES:Protective agentin peptic ulcer
disease; abortifacient ;Cytoprotectant
TOXICITY: Diarrhea, UterineCramping
PATENT DUCTUS ARTERIOSUS (PDA) IS A CONDITION
WHEREIN THE DUCTUS ARTERIOSUS FAILS TO CLOSE AFTER
BIRTH.
DUCTUS ARTERIOSUS IS A BLOOD VESSEL CONNECTING
THE MAIN PULMONARY ARTERY TO THE PROXIMAL
DESCENDING AORTA. IT ALLOWS MOST OF THE BLOOD FROM
THE RIGHT VENTRICLE TO BYPASS THE FETUS FLUID FILLED
NON FUNCTIONING LUNGS.
MISOPROSTOL USED AS CYTOPROTECTANT/ ANTIULCER
MISOPROSTOL + MIFEPRISTONE = PROGESTIN ANTAGONIST
A PROGESTIN IS A SYNTHETIC PROGESTOGEN.
PROGESTOGENS ARE USED MOST COMMONLY IN
HORMONAL BIRTH CONTROL AND MENOPAUSAL HORMONE
THERAPHY.
PGE2

Dinoprostone  natural prostaglandin, used to terminate pregnancy from 12th

Cerviprime® week through the 2nd trimester.
 MOA: Low concentrations contract, higher concentrations
relax uterine and cervical smoothmuscle
 CLINICAL USES:Abortifacient; for induction of labor-causes
uterine contraction; cervical ripening
 TOXICITY: Cramping, fetaltrauma
PGF2 alpha analog
Carboprost used to induce second-trimester abortions
Tromethamine is usually administered as a single 2.5 mg intra-amniotic injection.
15-methyl-PGF2a)-

Latanoprost  MOA: Increases outflow of aqueous humor, reduces intraocular

Xaltan® Pressure
 CLINICAL USE/S: Glaucoma
 TOXICITY: Color change iniris
PROSTAGLANDIN F2A  (PGF2A IN
PROSTANOID NOMENCLATURE)
PHARMACEUTICALLY TERMED

CARBOPLAST  IS A NATURALLY
OCCURING PROTAGLANDIN USED IN
MEDICINE TO INDUCE LABOR AND AS
ABORTIFACIENT.
PGI2:

Epoprostenol MOA:Activates IP receptors, causes

Flolan® Vasodilation, reduces plateletaggregation
 C L I N I C A L USES:Vasodilator in pulmonary
hypertension, antiplatelet agent in
extracorporealdialysis
TOXICITY:Hypotension, Flushing Headache

PGI2 analog, treprostinil: parenteral for pulmonary

hypertension
PROSTACYCLIN ( ALSO CALLED PROSTAGLANDIN I2 OR
PGI2)
PGI2 (PROSTACYCLIN / EPOPROSTERENOL)
PULMONARY HYPERTENSION  IS A TYPE OF HIGH
BLOOD PRESSURE THAT AFFECTS THE ARTERIES IN YOUR
LUNGS AND THE RIGHT SIDE OF YOUR HEART
 LTB4
¡ MOA: Chemotactic factor ininflammation

 LTC4, LTD4
¡ MOA: Bronchoconstrictors important in
anaphylaxis; causeedema

TOXICITY: Inflammatory Mediator

1. SALICYLATES ( OLDEST NSAIDS )
1. ACETYLATED A S P I R I N
2. NON- ACETYLATED:
 Magnesium CholineSalicylate
 Sodium Salicylate
 Salicyl Salicylate
2. COX-2 SELECTIVE INHIBITOR Celecoxib
Etoricoxib, Rufecoxib,Valdecoxib, Meloxicam,
AspirinAspilet®
325mg/day, 1st line in the primary & secondary
prevention of acute thromboticevents’
absorbed in the stomach & in the small intestine
in the unhydrolyze form

¡ EXCRETION:<600mg/d -1ST order; >600mg/d-Zero

order
¡ (its excretion, enhance w/ alakalination of the urine;
follows Michaelis Menten Elimination Kinetics)
Aspirin Aspilet®
¡ MOA: Irreversibly inhibits COX-1 andCOX-2;
reduce synthesis of prostaglandins/
¡ Acetylation of COX-1 and COX-2 results in
decreased prostaglandin synthesisCLINICAL
AspirinAspilet®
¡ USES:Analgesia, antipyretic(Inh. CNSresponse
to Interleukin-1), anti-inflammatory,
¡ Antithrombotic(irreversible acetylation of COX
enzyme in platelets); prevention of coloncancer
¡ 3.2-4g/day usual adult dose of Aspirin for its
Anti-Inflammatory Effect

ANTIPYRETICANDANALGESIC- 325-650 mg
orally/rectally once every 4-6 hours as needed
ASPIRIN (ACETYLATED)
 A.K.A ACETYLSALICYLIC ACID
 NON SELECTIVE- INHIBITS BOTH COX1 & COX2
 PROTOTYPE AGENT OF NSAID
 RAPIDLY ABSORBED IN STOMACH
 RAPIDLY HYDROLYZED TO ACETIC ACID AND
SALICYLATE BY ESTERASE IN TISSUE AND BLOOD
 USE AS ANTIPLATELET- 325 MG PER DAY
 ANTI-INFLAMMATORY- 3.2- 4G PER DAY
 ANTIPYRETIC/ ANALGESIC – 325-650 MG (EVERY 4-

6HRS AS NEEDED)
¡ SE:GI discomfort, GI ulceration, CNS
salicylism, vertigo, Hypersensitivity
reaction=Reye’s Syndrome,Asthma
¡ Reye’s Syndrome manifest as hepatic failure &
encephalopathy
 happens when there is a previous or current
viral infection
WHEN MEDICATION SUCH AS NSAIDS OR ASPIRIN BLOCK THE
COX-1 ENZYME, PRODUCTION OF THROMBOXANE AND MORE
ANTI-INFLAMMATORY PROTAGLANDINS IS DECREASED, AND IN
PATIENTS WITH ASPIRIN INDUCED ASTHMA, THIS RESULTS IN THE
PRODUCTION OF PRO- INFLAMMATORY LEUKOTRIENES.
ASPIRIN IS COINTRADICTION WITH VIRAL INFECTION IT WILL
PRODUCE REYES SYNDROME.
SIDE EFFECT OF ASA: REYES SYNDROME, ASTHMA, GI
DISCOMFORT
¡ ADMINISTRATION: Must be given w/ orafter
heavy meal
Or take proton-pump inhibitor before taking
aspirin
¡ RISK FACTORS:Taking multipleNSAIDS:
causesGastritis (blood in the stools)
¡ Concurrent use of Glucocortcoids:Increase
inhibition of cytoprotectant action of COX
NON-SELECTIVE COXINHIBITOR
Phenylpropionic acid  Ibuprofen Advil®, Dolan FP®, Medicol®,
Midol®, Nuprin®,Motrin®
Pyrrolealkanoic acid derivative TolmetinTolectin®
PropionicAcid D e r i v a t iv e  Flurbiprofen Ocufen® ophthalmicsoln
Ketoprofen Orudis®
Oxaprozin
Indole derivative  Indomethacin Infree® , VI-Gel®
Pyrazolone derivativePhenylbutazone, Oxyphenbutazone,
Sulfinpyrazone -Anturane®
Phenylacetic acid derivativeDiclofenac
Fenamate  Meclofenamate acid
O x i c a m  Piroxicam Feldene®
Non-acid N S A I D  Nabumetone
Naphthylpropionic acid derivative  Naproxen Flanax®, Naprosyn®
Anthralinic acid  FlufenamicAcid
 MeclofenamicAcid
 MefenamicAcid olfenal®,Gardan®,Ponsran®
DICLOFENAC  IS USED TO TREAT MILD TO
MODERATE PAIN, OR SIGNS AND SYMPTOMS
OFOSTEOARTHRITIS OR RHEUMATOID
ARTHRITIS.
1.SE: Hematologic toxicities-Aplastic Anemia,Agranolocyte;
ATN(Acute tubular necrosis)
2.USED FOR PDA/ Patent DuctusArtriosusfailure to close ductus
 preferredfor the mx of pain of an acute attacks of gout
3.sulfur-containingdrugs
 causesSJS(StevenJohnsonSyndrome)
 for ArthritisOsteoarthritis
AnkylosingSpondylitis

4.has minimalanti-inflammatory aactivitythatare primarilyindicatedas

analgesic especiallyin the mx of post-operativepain
5.All known NSAIDs areweak acids,except

6.not anti-inflammatory AND antipyretic, but only ananalgesic

must be given for not more than 5 says never give it to children
more toxic thanaspirin

7.is an arylaceticacidderivative
appears comparable to aspirinIn the tx of RA, with a lower incidenceof
side effects also been approved for use in primary dysmenorrheal
prescribedforHemophiliacPatientfor RA
existsboth as R-& S- enantiomers(S-enantiomeristhe only active form)
1. PYRAZOLONE DERIVATIVES
2. INDOMETHACIN
3. SULINDAC
4. ETODOLAC
5. NABUMETONE
6. FENAMATES
7. IBUPROFEN
¡ (Advantage: Less incidence of gastric
irritation or ulceration)
¡ MOA: Selectively reversibly inhibits COX-2
CLINICALUSE/S: Analgesia, antipyretic,and
anti-inflammatory
Toxicity: Nephrotoxicity; hypersensitivity dueto
increased leukotrienes; less risk of GI toxicity
than nonselective
¡ NSAIDs; greater risk of thrombosis than
nonselective NSAIDs
Celecoxib (CELEBREX)  10-20times selectivefor COX-2 than COX-1
CLINICAL USES: ANALGESIA,  It is a sulfonamide derivative, therefore it may cause
ANTIPYRETIC AND ANTI- rashes
INFLAMMATORY
 It interacts with Warfarin due to CYP2C6

ETORICOXIB (ARCOXIA)  Bipyridine derivative secondgeneration

Cox-2 selectiveinhibitor with the highest selectivity ratio
of any “COXIB” for inhibition of COX-2 relative toCOX-1
 Structurally similar withDICLOFENAC

MELOXICAM ( MOBIC)  Enocarboxamide related toPIROXICAM

 Lowest therapeutic dose of 7.5 mg/d
 NOT selective as other “Coxibs”
 Known to inhibit synthesis of thromboxane
 MOST potent COX inhibitor
Rofecoxib (Vioxx®)  have been withdrawn from the market or are marketed w/
“black box” warning because of
its increase risk of Thrombosis & cardiac death

VALDECOXIB( BEXTRA)  Di-aryl-substituent isoxazole derivative

 Serious reaction with sulfonamide
 Hepatotoxic
¡ alters/ slows down joint destruction
SAArTs (slow-acting antirheumatic
drugs)

ANTI-RHEUMATIC DRUGS.
DMARDS  METHOTREXHATE
SAARTS  HYDROXYCHLOROQUINE,
CHLOROQUINE, PENICILLAMINE, GOLD AND
SULFASALAZINE
Methotrexate  1st line DMARDS in RA
Zexate®, Alltrex®  Important to pyrimidine synthesis
 MOA:
1. Cytotoxic to rapidly dividing immune cells due to inhibition of
dihydrofolate reductase
2. Inhibit AICAR (aminoimidazole carboxanide tribonucleotide)
3. Inhibits DNA transcription
 CLINICAL USE/S: Anticancer, rheumatic disorders
S E : Hepatotoxicity ( FolicAcid- hepatoprotectant)
 TOXICITY: Nausea, Mucosal Ulcers, Hematotoxicity,
Hepatotoxicity,Teratogenicity
 ALTERNATIVE: Leflunamide

Anti-MalarialAgents
Chloroquine Chloromax®
Hydroxychloroquin Hydroxychloroquine Plaquenil®
AICAR INVOLVED IN PURINE BIOSYNTHESIS
PURINE  INVOLVE DNA SYNTHESIS
RHEMATOID ARTHRITIS (RA) IS THE MOST COMMON TYPE
OF AUTOIMMUNE ARTHRITIS. IT IS CAUSED WHEN THE
IMMUNE SYSTEM (THE BODYS DEFENSE SYSTEM) IS NOT
WORKING PROPERLY.
RHEMATOID ARTHRITIS  CAN CAUSE PAIN, SWELLLING AND
DEFORMITY. AS THE TISSUE THAT LINES YOUR JOINTS (SYNOVIAL
MEMBRANE) BECOMES INFLAMEF AND THICKENED, FLUID BUILDS
UP AND JOINTS ERODE AND DEGRADE.
RHEMATOID ARTHRITIS CAUSE PAIN AND SWELLING IN WRIST
AND SMALL JOINTS OF THE HAND AND FEET.
TREATMENT OF RHEMATOID ARTHRITIS CAN STOP JOINT PAIN
AND SWELLING.
Gold Auranofin Ridaura®
Compound Aurothiomalate Myochrysine®
s Aurothioglucose Solganal®

SE:hypersensitivity reaction

Sulfasalazine  has 2 metabolites: Sulpapyridine

Azulfidine® and I-aminosalicylate (IBD)
GOLD  OLDEST DRUG FOR RA
AUROTHIOMLATE & AUROTHIOGLUCOSE  50%
GOLD (INTRAMASCULAR)
AURANOFIN 29% GOLD (ORAL)
SULFASALAZINE  INFLAMMATORY BOWEL
DISEASE (SAARTS)
Biologic Adalimumab Humiral®
Agents Inflximab. Remicade®
Etanercept Enbrel®

 MAB (Monoclonal Antibodies)

 InhibitTNF- & also blockinflammation.
subjecting patients toinflammation
TUMOR NECROSIS FACTOR (TNF, TUMOR NECROSIS
FACTOR ALPHA, TNFa, CACHEXIN OR CACHECTIN) IS A
CELL SIGNALING PROTEIN (CYTOKINE) INVOLVED IN
SYSTEMIC INFLAMMATION AND IS ONE OF THE
CYTOKINES THAT MAKE UP THE ACUTE PHASE
REACTION.
 IT IS PRODUCED CHIEFLY BY ACTIVATED
MACROPHAGES, ALTHOUGH IT CAN BE PRODUCED BY
MANY OTHER CELL TYPE SUCH AS CD4
LYMPHOCYTES, NK CELLS, NEUTROPHILS, MAST
CELLS, EOSINOPHILS AND NEURONS.
TNF BLOCKERS SUPPRESS THE IMMUNE SYSTEM
BY BLOCKING THE ACTIVITY OF TNF.
Leflunomide  alternative of Methotrexate
Arava®
Azathioprine  metabolize into6-mercaptopurine
Imuran®

Penicillamine  for copper toxicity/ Wlison’sDisease

Cuprimine®  alter the function ofWBC
 for progressive rheumatoidArthritis

 is a degradation product of penicillin-type

antibiotics also usefulin treatingLead poisoning
& RA
LEFLUNOMIDE
 IS AN IMMUNOMODULATORY DRUG (ALTERS THE
FUNCTION OF IMMUNE SYSTEM) THAT ACHIEVES ITS
EFFECT BY INHIBITING THE MITOCHONDRIAL ENZYME
DIHYDROOROTATE DEHYDROGENASE (DHODH), WHICH
PLAYS A KEY ROLE IN THE DE NOVO SYNTHESIS OF
URIDINE MONOPHOSPHATE (rUMP), WHICH IS REQUIRED
FOR THE SYNTHESIS OF DNA AND RNA.
GOUT  Increase level of
uric acid
Deposition of uric acid in subcutaneoustissue

Uric Acid strong negative birefringent needles of (MSU)-

monosodium urate

Formation of UricAcid:
Purine  hypoxanthinexanthineuric acid
w/ allopurinol alloxanthine cannot be converted to
uric acid
PURINES ARE NITROGEN CONTAINING COMPOUNDS.
WHICH ARE MADE INSIDE THE CELLS OF YOUR BODY
(ENDOGENOUS), OR COME FROM OUTSIDE OF YOUR
BODY, FROM FOODS CONTAINING PURINE (EXOGENOUS).
PURINE BREAKS DOWN INTO URIC ACID. INCREASED
LEVELS OF URIC ACID FROM EXCESS PURINES MAY
ACCUMULATE IN YOUR TISSUES, AND FORM CRYSTALS.

COLCHICINE ACUTE GOUT

ALLOPURINOL CHRONIC GOUT
1.Colchicine Goutnil®, Rhea®
¡ 1st line treatment of acute gout (usual dose: 15mg oncea
week)
¡ Microtubule assembly inhibitor(decreases macrophage
migration and phagocytosi)
¡ MOA: Inhibition ofAICAR (aminoimidazolecarboxamide)
¡ CLINICALUSE/S:Chronic and acute gout, familial
Mediterranean fever
¡ TOXICITY:Diarrhea, Severe Liver & Kidney Damagein
Overdose(mimimized w/ Leucovorin)
NO MICROTUBULE- NO DNA
SYNTHESIS
2. NSAIDs

3.Glucocorticoids (GC)
¡  Methyl Prednisolone
¡ to inhibit inflammation systemic management of RA,
¡ Life threatening SLE(Systemic Lupus Erythematus)
Intrasynovial
1.Colchicine
1st line initial treatment of chronic gout after 2-3 weeks
MOA: Inhibits the synthesisofMicrotubules

2.Allopurinol Zyloprim®,Alpurase®,Al urase®, Purinase®,Lopric®,

Loricid®
 Drug of choice for chronicgout
 1st line hypourecemicagent in chronicgout
 Xanthineoxidase inhibitors
MOA:Active metabolite irreversibly inhibits xanthineoxidase and lowers
production of uricacid
CLINICALUSE/S:Chronic gout;Adjunct to cancer chemotherapy;Mx of
recurrent renal uratestones
TOXICITY:GIUpset, Hypersensitivity Reactions,BoneMarrowSuppression
3. ProbenecidBenuryl® (prolong the action of penicil in antibiotic)
¡ Uricosurics(induce loss of uric acid in urine
SodiumBicarbonate to increase uric acid
secretion
¡ MOA:Inhibitionof renal reuptakeof uricacid
CLINICALUSE/S:Chronicgout,prolongationof antimicrobialdrug action
¡ TOXICITY:Exacerbationofacutegout,hypersensitivityreactions,
¡ inhibitsrenal tubular secretionof weakacidssuchasmethotrexate

4. Sulfinpyrazone Anturane®
¡ Uricosurics
¡ Similar toprobenecid

5. Penicillamine C u p r i m i n e
Angiotensin
¡ A peptide, causes blood vessels to constrict,
and drives blood pressure up.
¡ It is part of the renin-angiotensin system,
which is a major target for drugs that lower
blood pressure.
¡ It stimulates the release of aldosterone from

the adrenal cortex. Aldosterone promotes

sodium retention in the distal nephron, in the
kidney, which also drives blood pressure up.
31
8
Angiotensin Is a peptide that causes
vasoconstriction(constrict BV and Inc. BP) and
a subsequent in blood pressure.

Part of RAAS(Renin Angiotensin

Aldosterone System)  major target for
Antihypertensive Drugs.

Aldosterone Function:
Promotes Na (sodium) retention
Action: Inc. Na, Inc. in Water, Inc. in Blood
Volume, Inc, BP.
Juxtaglomerular cells(synthesized / realease renin)  present in
nephron of kidney

Low BP our body try to adopt with this changes in the BP 
stimulates the release of renin

When renin is release it will form Angiotensin 1

Renin A.K.A ANGIOTENSINOGEN
 Enzyme that coverts angiotensinogen  Angiotensin 1

(ACE) A1  A2  it is a potent vasoconstriction (causes Inc. BP)

A2 in Adrenal Gland @ Zona Glomerulosa stimulates realease

of Aldosterone

Aldosterone Increase reabsorption of Na (sodium), Inc. BV, Inc BP.

RAAS SYSTEM

32
1
¡ An aspartyl protease that specifically
catalyzes the hydrolytic release of the
decapeptide angiotensin I from
angiotensinogen,
¡ it is synthesized as a preprohormone that
is processed to prorenin, which is inactive,
and then to active renin, a glycoprotein,
consisting of 340 amino acids.
¡ Within the kidney, it is synthesized and
stored in the juxtaglomerular apparatus of
the nephron. 32
2
Renin comes from PRORENIN

Decapeptide: a polypeptide (as angiotensin1)

that consists of a chain 10 amino acid
1. Renal Vascular Receptor vascular muscles of kidney
¡ functions as stretch receptor, decreased
stretch leading to increased renin release.
2. Macula Densa
¡ Decreases in distal delivery of sodium or
chloride result in stimulation of renin
secretion.
3. Sympathetic Nervous System
¡ Maneuvers that increase renal nerve activity
causing stimulation of renin secretion, while
renal denervation results in renin secretion. 77
Macula Densa
1st reason
Decrease BP  renin release

2nd reason
Decrease Na (sodium), Dec.
Water, Dec. BV, Dec. BP
4. Angiotensin II
¡ inhibits renin secretion.
5. Pharmacologic Alteration of Renin Release
¡ Stimulated by vasodilators
(Hydralazine,Minoxidil, Nitroprusside), B-
adrenoceptor agonist (isoproterenol), a-
adrenoceptor antagonists, phosphodiesterase
inhibitors (theophylline, Milrinone, Rolipram),
and most Diuretics and Anesthetics.

32
6
A2  inc. BP, Dec. Amount of renin
release, dec BP

Vasodilators  drug that dilates

Blood Vessels there by Decrease BP

PHAMACOLOGIC ALTERATION OF RENIN

RELEASE
VASODILATOR – DECREASING BP
Angiotensinogen
¡ Protein substrate from which renin
cleaves angiotensin I.
¡ It is synthesized in the liver.
¡ The production is increased by
corticosteroids, estrogens, thyroid
hormones, and angiotensinII.

32
8
Angiotensin I
¡ It acted on the plasma or tissue
aminopeptidases to form
angiotensin I; this in turn is
converted to angiotensin II by
converting enzyme.

32
9
Angiotensinogen by the
action of (renin) it will be
converted to A1.

A1(ACE) will be converted to

A2
Converting Enzyme
¡ Is a dipeptidyl carboxypeptidase that catalyzes the
cleavage of dipeptides from the carboxyl terminal of
certain peptides.
¡ A.K.A. “Peptidyl Dipeptidase” or “Kininase II”.
¡ its important substrates are angiotensin I, which it
converts to angiotensin II, and bradykinin.
¡ it is prevented by a prolyl residue, and angiotensin II.

10
0
Actions of Angiotensin II
1. Blood Pressure
¡ Increase the release of Epinephrine and
Norepinephrine.
2. Adrenal Cortex
¡ Acts directly on the zona glomerulosa to
stimulate aldosterone biosynthesis.
3. Kidney
¡ Cause renal vasoconstriction, increase
proximal tubular sodium reabsorption, and
inhibit renin secretion. 82
BLOOD PRESSURE
 INCREASE IN EPI AND NOR EPI – INC BP
 EPI & NE ARE PRIMARY NEURO
TRANSMITTER AT SYMPATHETIC NERVOUS
SYSTEM
4. Central Nervous System
¡ Stimulate drinking (dispogenic effect) and
increase the secretion of vasopressin, and
adrenocorticotropic hormone (ACTH).
5. Cell Growth
¡ a mitogenic for vascular and cardiac muscle
cells and may contribute to the development
of cardiovascular hypertrophy.

10
2
VASOPRESSIN  A.K.A “ANTIDIURETIC
HORMONE”
 PREVENTS URINATION
Angiotensin II Receptors
1. AT1
¡ Have high affinity for Losartan(LOSARTAN –
ARBS ANGIOSENTIN RECEPTOR BLOCKER’s)
and low affinity for PD123177 (an experimental
non-peptide antagonist).
¡ Binding of angiotensin II in vascular smooth
muscle results in activation of phospholipase C
and generation of IP3 and DAG.

10
3
2. AT2
¡ Have high affinity for PD 123177 and a low
affinity for Losartan.
¡ Involves the serine and tyrosine
phosphatases, phospholipase A2, nitric oxide,
and cyclic guanosine monophosphate
(cGMP).
¡ Upregulated in pathologic conditions
including heart failure and myocardial
infarction.
10
4
Drugs that block Renin
Secretion
¡ Clonidine (CATAPRESS®)
)Propranolol (INDERAL®)

Renin Inhibitors
¡ Remikiren
¡ Enalkiren 86
 Angiotensin Converting Enzymes (ACE)
Inhibitors
¡ Captopril (CAPOTEN®) & Enalapril (VASOTEC®) are the
prototype agents.
¡Lisinopril (ZESTRIL®)
¡ Benazapril
¡ Fosinopril (MONOPRIL®) ACE when inhibits will result
dcrease of A2 (No
¡ Moexipril vasoconstriction)(decrease in BP)
¡ Perindopril
¡ Quinapril (ACCUPRIL®)
¡ Ramipril (ALTACE®)
¡ Trandolapril
339
 Angiotensin Receptor Blocking
Agents®
¡ Losartan & Valsartan (DIOVAN®)
were the first marketed blockers of
angiotensin II type 1 (AT1) receptor.
¡ Candesartan ATACAND®
¡ Eprosartan TEVETEN®
¡ Irbesartan AVAPRO®
¡ Telmisartan MICARDIS®
340
Kinins
¡ Formed enzymatically by the
action of enzymes known as
kallikreins or kininogenases acting on
protein substrates called kininogens.
¡ Potent vasodilator peptides.
KININOGENS (KALLIKRENS ENZYME) 
KININS
341
Kallikreins
¡ Are glycoprotein enzymes produced in the liver
as prekallikreins and present in plasma and in
several tissues, including the kidneys,
pancreas, intestine, sweat glands, and salivary
glands.
¡ They are serine proteases with active sites and
catalytic properties similar to those of enzymes
such trypsin, chymotrypsin, elastase, thrombin,
plasmin, and other serine proteases.
342
KALLIKREINS ARE SERINE PROTEASES THAT
LIBERATE KININS

SERINES  IS IMPORTANT IN METABOLISM IN

THAT IT PARTICIPATES IN THE BIOSYNTHESIS
OF PURINES AND THAT PYRIMIDINES
Kininogens
} The precursor of kinins and substrates of
kallikreins which are present in plasma, lymph,
and interstitial fluid.
Forms of Kininogens
1. Low-Molecular Weight Kininogen
} Crosses capillary walls
2. High-Molecular Weight Kininogen
} Confined to the bloodstream and serve as the
substrate for plasma kallikrein.
344
Actions of Kinins
1. Effects on the Cardiovascular System
} Produce marked vasodilation in several beds,
including the heart, kidney, intestine, skeletal
muscle, and liver.
2. Effects on Endocrine and Exocrine Glands
} Modulate the tone of salivary and pancreatic
ducts and help regulate gastrointestinal
motility.

345
3. Role in Inflammation
¡ Kallikreins and kinins can produce
redness, local heat, swelling, and pain,
and the production of kinins is increased
in inflammatory lesions.
4. Effects on Sensory Nerves
¡ Are potent pain-producing substances
when applied to a blister base or injected
intradermally. 346
Metabolism of Kinins
1. Kinnase I
} Synthesized in the liver, is a
carboxypeptidase that releases the
carboxyl terminal arginine residue.
2. Kinnase II
} Present in plasma and vascular
endothelial cells throughout the body.
347
Arginine becomes nitric oxide-a blood vessels
–widening agent called a vasodilator) in the
body
Drugs Affecting the Kallikrein-Kinin System
1. Icatibant
} Second generation B2 receptor antagonist.
} Used to evaluate the role of kinins in pain,
hyperalgesia, and inflammation.
2. 3rd Generation B2 Receptor Antagonist
} FR 173657
} FR 172357
} NPC 18884
} Inhibit bradykinin-induced broncho-constriction.

349
Vasopressin
¡ a.k.a. “Antidiuretic Hormone”.
¡ Plays an important role in the long-term
control of blood pressure through its
action on the kidney to increase water
reabsorption.
VasopressinAntagonist
¡ Lithium
¡ Demeclocyline
350
VASOPRESSIN DEC URINATION, INC WATER
REABSORPTION, INC BV, INC BP

TAKE NOTE:
DEMECLOCYLINE INHIBIT THE ACTION OF
ANTIDIURETIC HORMONE IN THE RENAL TUBULE
 CAN INDUCE SENSITIVITY TO SUNLIGHT
(PHOTOSENSITIVE DRUG)
LITHIUM = BRANDNAME: LITHASE

DEMECLO  STREPTOMYCES AUREOFACIENS

Vasopressin Receptors
1. V1a Receptors
} Mediate the vasoconstriction action
2. V1b Receptors
} Potentiate the release of ACTH by pituitary
corticotropes.
3. V2 Receptors
} Mediate the antidiuretic action

352
ACTH- ADRENO CORTICOTROPIC HORMONE
 A HORMONE PRODUCED IN THE PITUITARY
GLAND THAT STIMULATES THE ADRENAL GLAND
TO RELEASE A HORMONE CALLED CORTISOL
Natriuretic Peptides
¡ One of the peptides that causes natriuresis, the excretion of an excessively
large amount of sodium in the urine. The natriuretic peptides are produced
by the heart and vasculature:
 A-type natriuretic peptide is secreted largely by the atrial
myocardium in response to dilatation.
 B-type natriuretic peptide is manufactured mainly by the
ventricular myocardium. It useful in the diagnosis of heart
failure. The finding of a low level of B-type natriuretic peptide
tends to exclude heart failure.
 C-type natriuretic peptide is produced by endothelial cells
that line the blood vessels.

354
Natriuretic promotes Excretion of Sodium
Natri salt
Uretic  urine

Clinical Significant:
Increase Heart failure, renal failure
Actions:
Decrease the secretion of renin, aldosterone and
vasopressin; decrease BP and increase sodium
excretion.
Acts via activation of guanalyl cyclase.
Vasopeptidase Inhibitors
¡ are new class of cardiovascular drugs
that inhibit two metalloprotease
enzymes,NEP(NEUTRAL
ENDOPEPTIDASES) 24.11 andACE.
¡ Omaprilat
¡ Sampatrilat
¡ Fasidotrilat
356
Endothelins
¡ is the source of a variety of substances with
vasodilator (PGI2 and Nitric Oxide) and
vasoconstrictor activities.
Three Isoforms
1. ET-1
¡ Is the predominant endothelin secreted by the
vascular endothelium
¡ Produced by the neurons and astrocytes in the CNS
and in endometrial, renal mesangial, Sertoli, breast
epithelial, and other cells.
357
2. ET-2
¡ Produced dominantly in the kidneys
and intestine
3. ET-3
¡ Found in highest concentration in the
brain but is also present in
gastrointestinal tract, lungs, and
kidneys. 358
 Physiologic and Pathologic Roles of Endothelins
¡ *Essential/Primary Hypertension-there's no identifiable cause of high blood pressure
¡ *Cardiac Hypertrophy-myocardiumresponse to various physiologic and pathologic
stimuli that cause the heart to work harder ex. Hypertensionand MI that causes
stretching of myocardial walls
¡ *Heart Failure-sometimes known ascongestive heart failure, occurs when yourheart
muscle doesn't pump enough blood
¡ *Atherosclerosis-hardening and narrowing of the arteries.
¡ *Coronary Artery Disease-Coronary heart disease (CHD) is a disease in which a waxy
substance called plaque builds up inside the coronary arteries. These arteries supply
oxygen-rich blood to your heart muscle. When plaque builds up in the arteries, the
condition is called atherosclerosis.
¡ *Myocardial Infarction-Most heart attacks are caused by a blood clot that blocks one of
the coronary arteries. The coronary arteries bring blood and oxygen to the heart. If the
blood flow is blocked, the heart is starved of oxygen and heart cel s die.The medical term
for this ismyocardial infarction.
¡ *Pulmonary HTN-high blood pressure that affects the arteries in your lungs and the
right side of your heart.
¡ *Asthma-airways narrow and swell and produce extra mucus. This can make breathing
difficult and trigger coughing, wheezing and shortness of breath.

359
Endothelin Antagonist
¡ Bosentan
¡ Sitaxentan
¡ Ambrisentan
Adverse Effects:
¡ Systemic hypotension, increased
heart rate, facial flushing, nausea,
and headache.

360
Bosentan a complete antagonist of both ETA
and ETB receptors and blocks the action of
endothelin at different target sites.
 Is indicated for pulomonary hypertension.

ADR teratogenicity and liver toxicity

Vasoactive Intestinal Peptides (VIP)
¡ a peptide hormone containing 28 amino
acid residues and is produced in many
areas of the human body including
the gut(genitourinarytract), pancreas and
suprachiasmati nuclei of the
hypothalamus in the brain.
¡ It produces marked vasodilation in most
vascular beds.
¡ Causes coronary vasodilation and exerts
positive inotropic and chronotropic effect.

362
Substance P
¡ is a neuropeptide: an undecapeptide that functions
as a neurotransmitter and as a neuromodulator.
¡ It belongs to the tachykinin neuropeptide family.
¡ Its closely related neuropeptide neurokinin A (NKA)
and neurokinin B (NKB) are produced from a
polyprotein precursor after differential splicing of
the preprotachykinin Agene.
¡ Aprepitant-NK1 receptor antagonist approved for
the prevention of chemotherapy induced nausea
and vomiting.

363
SUBSTANCE P(PAIN) – A COMPOUND
THOUGHT TO BE INVOLVED IN THE SYNAPTIC
TRANSMISSION OF PAIN AND OTHER NERVE
IMPULSES. IT IS A POLY PEPTIDE WITH 11
AMINO ACID RESIDUES (PRESENT IN DORSAL
HORN OF SPINAL CORD ACTS AS AN AFFERENT
NT FROM THE SENSORY FIBERS, PLAYS
NEUROGENIC INFLAMMATION)

TACHYKININ  class of substances formed in

response to injury and having a rapid stimulant
effect on smooth muscles (potent vasodilators)
Neurotensin
¡ is a tridecapeptide that was first isolated
from the central nervous system but
subsequently found to be present in the
gastrointestinal tract and in the circulation.
¡ It is synthesized as part of a larger
precursor that also contains neuromedin
N, a six-amino-acid neurotensin-like
peptide.
¡ Neurotensin agonist used for
schizophrenia and Parkinson’s Disease.
Acts Dopamine Receptors

365
Calcitonin Gene-Related Peptide
¡ Is a member of the calcitonin family of
peptides which also includes calcitonin,
adrenomedullin and amylin.
¡ Consists of 37 amino acids and displays
approximately 30% structural homology
with salmon calcitonin.
¡ Causes hypotension and tachycardia.
¡ Most potent vasodilator yet discovered.

366
Calcitonin Gene-Related Peptide(CGRP) 
present in the parafollicular cells of the thyroid
gland similar to calcitonin

CNS hypetension/ loss of apetite

Systemic Circulation  hypotension and
tachycardia.
Adrenomedullin it increase when
have Hypertension
¡ Is a 52-amino-acid peptide that was
discovered in human adrenal medulary
pheochromocytoma tissue.
¡ Presents in several organs including
adrenals, lungs, heart, vascular tissue,
and kidneys.
¡ Elevated in patients with hypertension, as
well as in patients with renal failure, heart
failure, and septic shock.

368
Pheochromocytoma(disease) 
tumor on the adrenal
medulla(chromaffin cells)that
secretes cathecolamines.

Septic shock
Neuropeptide Y

¡ Is a member of the family that also includes

peptide YY and pancreaticpolypeptide.
¡ Each peptide contains of 36 aminoacids.
¡ One of the most abundant neuropeptides in both
the central and peripheral nervous system.
¡ BIBP3226-first nonpeptide Y1 receptor antagonist
used in cardiovascular disorders including
hypertension and heart failure.
¡ BIIE0246-first nonpeptide Y2 receptor antagonist
 VASOCONSTRICTOR

1
9
0
CNS Inc. food intake and Decraese physical
activity
Urotensin
¡ Was originally identified in fish, but isoforms
are now known to be present in mammalian
species including mouse, rat, pig, and
human.
¡ In vitro, it is a potent constrictor of vascular
smooth muscle.
¡ Occurs primarily in arterial vessels, where
urotensin II can be more potent than
endothelin 1.
¡ Upregulated in the heart of humans with
end-stage heart failure.
¡ Increase levels in patients with cardiovascular diseases
110
Isoforms  a protein that has the same
functions as another protein but which is encoded
by a different gene and may have small
differences in its sequence.

Major source of Urotensin is the KIDNEY.

Human urotensin II  isa an 11 amino acid

peptide present in the brain, spinal cord and
kidneys.
¡ Based on Effects:
¡ Relievers management of acute exacerbation
SABA
¡ Controllers prevention of acute exacerbation
steroids; LABA
Based on Mechanism ofAction:
1. Bronchodilators
2. Mast cell Stabilizers
3.Anti-inflammatory
1. SABA (Short-acting)1st line reliever in BA &
alternative reliever in COPD
1.Salbutamol Brecanyl®  subcutaneously given
as mx of acute episodes of bronchospasm
2.Terbutaline  subcutaneously given as mx of
recalcitrant acute exacerbation of bronchialasthma
 to increase heart rate in sympotomatic
hypertension
2. LABA (Long-acting) 1st line controller (w/ inhaled
GC)for COPD

Salmeterenol is not suitable for acute break through

attacks of bronchospasm
Formeterenol
Bambuterenol
1.Theophylline Theodor®,Asmalon®
2. Aminophylline
MOA: Adenosine Antagonist; PDE inhibitor;

¡ CLINICAL USE:Alternative bronchodilator insevere

BA attacks (reduce nocturnal attack),
¡ Respiratory Stimulant inCOPD
¡ NeonatalApnea
1.Oxytropium
2.Tiotropium
3.Ipratropium
¡ Ipratropium +Salbutamol Combivent®
¡ Ipratropium +Terbutaline Berodual®
¡ Anticholinergics primary used as relievers (more effectivein
COPDthan in Bronchial Asthma) first line relivers ofCOPD
¡ altenative reliever of bronchial asthma
¡ can be safely given at high doses by inhalations SE:Alice in
the WonderlandSyndrome
¡ controllersonly; prophylaxis;3-4 weeks

1. Nedrocromil
2. CromolynSodium/ Na Cromoglycate

¡ MOA: Induce opening of inward Cl- channels leading to influx of

Cl- into mastcells
CLINICALUSE: Mx of allergic conditions
SE: may induce bronchospam (givenSABAto prevent
bronchospasm)
Cromolyn Sodium inhibit the degranulation of mast cellsin
asthmatic patients, thereby preventingthe release of the
chemical mediators of anaphylaxis
1. LipooxygenaseInhibitor
¡ Zileuton Zyflo®
2. Leukotriene Receptor Blocker (LTD4antagonist)
¡ Montelukast Montemax®,Singulair®
¡ Zafirlukast Accolate®

¡ CLINICALUSE:alternative controllers in persistent bronchial

asthma Management of NSAIDs induced bronchial asthma
¡ SE:Unmask the symptoms of Churg-StraussSyndrome
(eosinophilic vasculitis) can be treadted with steroids
¡ Glucocorticoids
Budesonide Pulmicort®
Beclomethasone
Fluticasone
Triamcinolide
Prednisone
Prednisolone

Hydocortisone Solucortef®
Methylprednisolone Solumedrol®
¡ Locally-actinginhaledGC(Low dose)1st line control ers for BASystemic
GC(parenteral)1st line in statusasthamticus
MOA: Inhibit the synthesisof phospholipaseA2
¡ Inhibit the late phaseal ergic reactions
¡ Inhibit the releaseof interleukin by the macrophagesInhaledCorticoids
adjunctivecontrollers; COPD
¡ SE: oral candidiasisvocal cord nodulesOral thrush hoarseness
¡ Prevention of oral candidiasis:gargling(3-4x);use of spacers
¡ PO: Prednisone;Prednisolone
 are given not more than 10days(ifexceed,adrenal suppression)
¡ ShortCourseTherapy:AcuteBAExacerbation
¡ Exacerbation: Early phase airway obstruction (brochodilation) Late Phase
2-8hrs ; inflamation
¡ IV: Methylprednisolone;Hydrocortisone
 managementof severeacuteasthma exacerbation
Review Well !!!
GoodLuck!!!
Review Well !!!
GoodLuck!!!
PCOL Topic 1.1
Pharmacology divided into two
1. Pharmacodynamics – What the drug does to the
body – mechanism of action.
2. Pharmacokinetics – What the body does to the drug
– biopharmaceutics.
Mechanism of drug action
- Non-target protein mediated mechanism.
 Not targeting any protein but it is able to elicit its
mechanism of action.
- Target protein mediated mechanism.
- Have targeting protein in order to a drug exert its
pharmacologic effect or action it has to target protein.
This protein upon targeting protein will produce a
mechanism of action.
Non-target protein mediated mechanism
1. Colligative mechanism
- A good example is osmotic pressure – Example drug
in osmotic pressure. MAGNESIUM SULFATE-
acting as purgative – An osmotic pressure targeting an
osmotic pressure in our gastrointestinal tract.
 Neutralization
2. Chemical reaction – A good example is
3 example
ANTACID, neutralize the acidic of stomach in
order to counter act the acidity.
 Chelation – Used in case of metal toxicity, a
good example is Deferoxamine – Iron toxicity.
 Others – Cyanide + sodium. thiosulfate
Na2S3O3 - Most common antidote for
cyanide toxicity.
3. Counterfeit incorporation mechanism
- Example: pyrimidines (Pyrimidine Cytosine Uracil
thymine) and purines (Purine Guanine Adenine)
Flucytosine – Antifungal drug that inhibit DNA
and RNA synthesis –
incorporate into RNA of the fungi that cause
death to fungi,
SITE OF DRUG ACTION
- TARGET PROTEIN
1. Structural protein
 Griseofulvin – Antifungal drug (famous drug
it absorb increase
when there is a administration of fatty meal.
 Vinca alkaloids – Antineoplastic drug.
Example:
 Vinblastine – Example of vinca alkaloids that
derived from Vinca Rosea – Source.
 Vincristine – Alkaloids derivative that is
closely related to vinblastine.
 Vinorelbine – Semi synthetic derivative of
vinblastine.
 Colchicine – Autumn crocus, colchicine
autumnale – The
sources. for acute gout.
 Treatment
2. Regulatory protein
- Example of calcium channel blockers
– Dipine – Used for antihypertensive.

Carrier molecule – Carry certain ion or chemical which is
very essential biological processes in our body.
Digitalis glycosides – Ex. Digoxin – acting in atrophic
agent.
Proton pump inhibitor (PPI)- Used as antacid reduce
gastric acid secretion.
- Eg: Omeprazole and Pantoprazole. Loop diuretics
– Example FUROSEMIDE. Enzyme
- Allopurinol (for chronic gout)
- Ace inhibitors – Anti-hypertensive.
- MAO (Monoamine oxidase)
- Acetylcholinesterase – Responsible breaking down
acetylcholine example drug EDOPHONIUM – used
to diagnosis of Myasthenia Gravis – Auto immune
disorder.
- COMT (Cathecol o Methyl transferase)- Responsible
for breaking down dopamine.
Eg: Entacapone and Tolocapone 
Used in
Receptors- Parkinson’s
The disease.
most common site of action of drug.
 Specificity- Drug will only act in the specific type
of receptor there are specific functional group
acting on the specific receptor.
 Selectivity- Selective drug acting only in the
single receptor.
 Affinity- Capacity of the drug to form complex
with its receptor.
 Intrinsic activity- Efficacy of drug –
Pharmacologic response.
Hyperpolarization
- Efflux- Going outside. Potassium will go outside the
cell.
- Influx- Ion will go inside the cell.
- Efflux and Influx will cause a change in cell
membrane potential (Negative)
 (handout)
Meaning wala/decrease ang amount ng
neurotransmitter.
Eg: There will be a drug acting to
promote hyperpolarization. Beneficial for people with
anxiety.
Depolarization- Influx of Sodium and Calcium ion.
Tataas yung amount ng neurotransmitter.
- Not beneficial for people with anxiety and seizure.
- Find a drug that will block depolarization. Eg:
Carbamazepine and Phenytoin  Acting to
blockyour voltage gated sodium channel thereby
blocking depolarization.
Repolarization- Opposite of depolarization. No nerve
impulse. Similar with Hyperpolarization.
Type of Receptor
1) Type I Receptor (Ionotropic receptor)
(Handout under GABA receptors control Cl- ions)
Benzodiazepines and Barbiturates 
Common examples of Anti-anxiety drugs. An agonist of
GABA receptors.
“Once a drug is an agonist receptor this will
increase the movement of Chloride ion inside the cell.”
 It will produce Hyperpolarization.
Nicotinic receptors- (Handout) Inhibited by neuromuscular cGMP- Originates from GTP (Guanosine Triphosphate)
blocker. Eg: Succinylcholine  Inhibit your nicotinic  Guanylyl Cyclase  cGMP.
receptors thereby inhibiting the movement of Sodium ion.
Guanylyl Cyclase- Enzyme. GTP 
(Picture) Once a drug binds into the receptor, the chloride cGMP.
ion will go inside the cell causing hyperpolarization.
An increase in cGMP will produce a common effect
2) Type II Receptors (G-protein linked receptor/G- (handout).
protein coupled receptor/Metabotropic receptors)
- AKA 7 transmembrane (7-TM or heptahelical - Beneficial in tx of hypertension.
receptors) Phosphatidyl Choline- Precursor of your IP3 and DAG.
- Increase in calcium  responsible for common
G-protein linked receptors- Type II
effect (handout)
receptors are associated or closely related to G-
protein. Phospholipase C- Enzyme. Responsible for converting
Phosphatidyl Choline  IP3,DAG.
“Once a receptor is linked in your G-protein this is
responsible for producing an intracellular second Examples of G-proteins:
messenger.”  Gs- there would be increase in the cAMP.
- Cholera toxin came from Vibrio chloreae
Second messenger- Inositol Triphosphate (IP3) and DAG  Blocks your GTPase
(Diacylglycerol)
 Gi- Decrease the cAMP.
cAMP- Comes from ATP (Adenosine Triphosphate) - Blocks by pertussis toxin came from
 Adenylyl cyclase  cAMP. Bordatella pertussis.
 Gq- Increase in calcium 
Adenylyl Cyclase- Enzyme. ATP  cAMP. Contraction of the muscle.
Type III receptors/Tyrosine Kinases- linked
“When there is an increase in the amount of cAMP, it will receptors
activate protein kinase.”
JAK-STAT pathway- Responsible for modulating a
Protein kinase- Is responsible for the common effect number of biochemical processes.
(handout)
Tyrosine kinase- Belong to the family of Janus kinase.
Eg: If you have an asthma, an increase of cAMP is
Type IV receptor/gene transcription- linked receptors-
beneficial in tx of asthma because it will produce
Responsible for modulating the different processes in
bronchodilation.
your
If you are experiencing hypertension and you have
increase in amount of cAMP will not be beneficial in the tx
of hypertension because it causes contraction of the heart
 may increase the blood pressure.
DNA and RNA synthesis and protein synthesis. factor wherein a drug will produce its
effectiveness.
Clark Hypothesis- The effect pf the drug is directly - Kapag maraming stimulus, mas matindi ang
proportional to the number of receptors that would be effectivity ng isang drug.
occupied.
Graded Dose-Response Relations- We are studying the
- If receptors are occupied, maximum effect is effect of the drug in relation to the dose.
obtained.
Linear dose scale- Zero  100  600. Range
Lock and Key Theory- Eg: If the receptor has a spherical is 200.
shape type of receptor. The drug with spherical shape
molecule should fit in this into the receptor. Logarithmic dose scale- The dose or drug concentration
will be by 10s, 100s and 1000s
- Kung hindi kasukat ng drug ang receptor or vice
versa, they will not produce its effect. 3 Factors of Quantal Dose- Effect curves.
Configuration 1. The number of patients.
2. The response of the patient.
 Drug- must fit into the receptor. They must have the 3. Specified dose of the drug.
same configuration in order for the drug to produce *Graded Dose Response
its effect.
Induced-fit Theory- Kahit hindi same ng configuration
2 Factors
yung drug and receptor, once the drug binds to its receptor,
the receptor will adjust or will alter the conformation in 1. The effect of the drug.
order for the drug to bind with the receptor. 2. The dose of the drug.
Induced- Ipinilit sa mismong receptor. Important consideration- LD50 (Lethal Dose 50) 
Dose which produces toxiceffect at 50% of the population.
Rate Theory- The binding of the drug and the receptor
will be dependent kung ilang receptor yung naeencounter Therapeutic Index (TI)- TD50 (Toxid Dose
ni drug. 50) / ED50 (Effective Dose 50)
The more na marami syang naeencounter na receptor, the Therapeutic Window (TW)- Range between MEC
more na maactivate na receptor producing now the effect. (Minimum Effective Concentration) and MTC (Minimum
Toxic Concentration).
Hypothesis of Ariens and Stepheson- Duration of the
effectivity of the drug as long as nakabind yung drug sa - Margin of safety.
receptor may effect yung isang drug.
Trapezoidal Rule- Used to determine AUC Therapeutic
Hypothesis of Paton-RATE THEORY- It summarizes the Window/Margin of Safety/Therapeutic Range (safe &
proper stimulus is the main effective).
Exceeded- Toxic, not safe.
Below- Not effective.
ED50 (Median Effective Dose)- Effective dose at 50% of
the population.
Quantal Dose Effect Curves- Measured by ED50 and
TD50.
*Onset Time: Beginning of drug's effectivity.
Duration of Action: How long the drug will it takes its
effectivity.
- Max – Maximum concentration.
Tmax- Maximum time/the time it takes for the drug to
reach its maximum effectivity.
Idiosyncrasy- Type B (Bizarre)- Adverse effect.
- Dose independent/unpredictable.
A: Allergic reaction – Type I (Immediate) – Allerge.
C: Cytotoxic – Type II (Autoimmune dxn) – immune system
attacks your own cell.
I: Immune complex – Type III (More antigen
compared to antibodies)
D: Delayed Type – Type IV – Not immediate.
*Flushing- all – Redness of the skin.
Vasodilation
Slide 113 memorize
*Mantoux/PPD/Tuberculin Skin Test- 48- 72hrs after
exposure to tuberculin toxin.
Slide 116: Eg: smoking.
1-stick  Nicotine  Low response.
Stick- 1 pack (Increase in intake)
✖ Stop/Abrupt Withdrawal- Withdrawal symptoms.
Withdrawal- Can produce serious adverse drug effect.
✔Gradual withdrawal of the exposure.
Slide 119: Agonist have both affinity – The ability to bind
to the receptor as well as intrinsic activity – The ability to
produce a measurable effect.
Slide 120: It is a drug that is capable at a sufficiently high
concentration producing maximal cellular response (full
response)
BETA RECEPTOR
Beta 1- heart.
Beta 2- lungs.
Eg: Isoproterenol- BN = Isuprel = B1 and B2 agonist.
It acts on B1 receptor- Increase heart rate.
B2 receptor- Bronchodilation- It is a symphatomimetic
drugs that can be used in asthma.
Slide 122: When used alone partial agonist will act as a
WEAK AGONIST pero in the presence of FULL
AGONIST it will acts as an ANTAGONIST.
 BASIC AND CLINICAL EVALUATION OF NEW DRUGS
SLIDE 143 1.) Ligand based drug design – may sinusundan na design.
Drug target – molecular structure / cellular structure
- e.g.: Drug A acting on receptor A. Your goal is to design
- it can be a receptor, a certain tissue of our body, the organ a new drug that will also bind on receptor A. This drug is
of our body that will be involved in the pathology of the more active than drug A.
disease that the drug is treating or managing. 2.) Structure based drug design – it finds
the composition of the molecule/composition of the structure
- protein, enzyme, tissue, receptor that is responsible for
of the biological target.
the pathology of the disease.
Drug design – each drug has a unique drug design. - based on the structure  amide, amine, carboxylic acid,
etc.
- e.g.: if a drug is reacting to the receptor enzyme, they 3.) Computer aided drug design – uses computational
have a separate or unique drug design for each of the new chemistry to develop new drug.
chemical entities. SLIDE 145
 New chemical entity – the new
Drug repositioning – finding new therapeutic use if an old drug/chemical compound that will be the product of the drug
- e.g.: Sildenafil – Viagra
drug. discovery.

 w a s initially designed to lower bloodpressure but is now - the product will be examined/synthesized

typically used to treat erectile dysfunction or impotence. through organic synthesis, molecular modification through
pre-clinical studies.
Pre-clinical studies – usually uses animals
SLIDE 144 - should obtain of the new information of the new chemical
TYPES OF DRUG DESIGN entities chemistry, physical
properties, biological properties, and pre- formulation - main purpose: safety bur mainly effectiveness
properties.
- inaalam na yung dosage form yung appropriate sa new - 100-500 patients
chemical entity.  goalIf it is safe, it will proceed to Phase 3 – 3- 4 years
Investigational New Drug. - main purpose: safety, effectiveness, and dosage.
Investigational New Drug – its main goal is to provide data
showing that it is reasonable to begin tests of a new drug to - 500-5,000 patients
humans. This is to protect the rights and safety of the
subjects and to ensure that the investigational plan is sound *After providing that the drug is safe and effective on
and design to achieve the stated objectives. humans, you will proceed to New Drug Application.
- safe and effective on humans.
*After NDA, the drug is ready for the market.
* after IND, it will continue to pre-clinical studies for the
long-term toxicity. It then proceeds to clinical trials: Phase Phase 4 – AKA Post-marketing surveillance  to

1, 2, 3 and identify long term adverseeffect and toxicity.

4.
*NDA submission – only applied kapag safe and effective. *10-20 years drug discovery.

*FDA review SLIDE 147

*Preapproval plant inspection Drug screening – this will determine the following:
* FDA action
 Pharmacologic profile of the drug – mechanism of
Phase 1 – several months
action of the drug.
- identify the safety of the drug using 20- 100 patients.
 Effects on the cell function – will it lower the BP,
Phase 2 – several months – 2 years  Pharmacologic
temperature, etc. activity and selectivity of
the new compound
 comparison with compounds reference are PLS READ THE DESCRIPTION!!
 thesedrugs. existing Example
A–
SLIDE 150 B – Diphenhydramine – Benadryl
1.) Acute Toxicity – after administering the drug for 24 hrs, C – Imodium - Loperamide
the drugs will produce toxicity. X – Warfarin – Coumadin and
Isotretinoin – Accutane
* acute – less than 4 hrs
- hindi talaga pwedeng ibigay.
* subacute – less than or equal to 1 month
*chronic – 3 months
SLIDE 162

SLIDE 151 Category X – pinakainiiwasan

NOTE: WATCH (30:00)
Dose – strength of the drug.

Concentration – expressed through %.

B>R – benefit will outweigh the risks
LC50 – Brine shrimp assay – determine the cytotoxicity.
Category D – Valproic acid and (TV and CPS),
Streptomycin Lithium (Ebsteain anomaly) 
LD50 – OECD  m e t h o d of determining the acute toxicity
Carbohydrate
tricuspid does not function (return of blood from atrium to
of a certain drug through different processes and parameters.
vein.)
Organization for Economic Cooperation and Development.
Teratogenic- can affect the fetus
OECD Guidelines – we can readily identify
the acute toxicity through LD0.
HISTAMINE
SLIDE 161 Histamine
Endogenous- Naturally present in our body. Anong result and product? Histamine.
Local Hormones- Not release/stored in plants rather they are
Anong enzyme yung responsible for
formed at the site of action  walang gland na involved. converting your histidine into histamine? L- Histidine
Decarboxylase/Histidine Decarboxylase.
Ergot Alkaloids- Ergotamine and Ergonovine.
Pyridoxal Phosphate- Active form of Vitamin B6.
Kinin- Related to bradykinin and kalidin.
Ang histamine before siya maform kailangan muna niyang
- They act locally to induce vasodilation 
maremove ang carboxyl group ni Histidine and then you
(Dilating of bloodvessels causing a decrease in blood
have to add Pyridoxal Phosphate.
pressure) and contraction of smooth muscle.
Metabolism
Kinins- Belongs to peptide autacoids. 1. Monoamine oxidase (MAO)
Histamine- AKA imidazolylethylamine or 1H-imidazole- 2. Diamineoxidase or histaminase
4ethenamine  chemicalname. 3. Imidazole N-methyl transferase / Histamine N-
Methyltransferase
Saan ba galing si Histamine? Saang protein ba galing si
Final4.Metabolite
AldehydeofDehydrogenase
Histamine: Imidazole acetic acid & N-
Histamine? Saang amino acid galing si Histamine? L-
methylimidazole acetic acid.
Histidine.
Histamine- When you removed the carboxyl group of
Tissue Distribution- Abundant in our mast cells.
histidine amino acid the result will be / it will be converted
into Histamine.
Mast Cells- Associated with the IgE.
Histidine Decarboxylase- Enzyme that converts the
- Main cell releasing histamine.
histidine into histamine.
Immunoglobulin E- The antibody associated with
- AKA L-Histidine. the mass cells.

Anong amino acid sya derived? Histidine.

 - The type of antibody that is involved in the Histamine- Affect mostly in the lungs is
histamine release. bronchoconstriction.
Mast cells: (Handout violet font color),
leukotrienes and heparin- These chemical - In blood vessels it affects
mediators cause the characteristic symptoms of allergy. vasodilation.

Blood Vessels- AKA Vascular smooth muscle.

Basophil- Granulocyte that are active in inflammatory
Vasodilation- May cause a decrease in Blood Pressure 
response.
Anaphylactic shock.
Diphenhydramine- Pharmacologic Antagonist of
- WBC.
Histamine 1-antihistamine Prototypic antagonist.
H1 & H2-
Types Most common
of Histamine type of Histamine receptor.
Receptors
Cimetidine- Prototypic Antagonist of H2.
IP3- Inositol Triphosphate. H1:
DAG- Diacylglycerol. Anong mangyayare kapag nainhibit ang H1? H1 antagonist
Contraction- If there is an increase of IP3 and DAG.  mababaliktad yung efect mawawala yung urticarial
response.
Constricted Bronchial Tube- Asthma and difficulty in
Instead of bronchoconstriction 
breathing.
H2:
bronchodilation.
Urticarial Response- AKA Hives.
Kapag may H2 antagonist, it will decrease the cAMP.
- Outbreak of swollen, pale red bumps or plaques on
Therefore, decreasing the gastric acid secretion.
the skin.
Gastric acid secretion- May lead into ulcer.
*Note: Focus on H1 and H2*
Epinephrine- It is the physiologic antagonist of Histamine.
Histamine Agonist- These are drugs and substances that will
- Treatment of Anaphylactic shock. activate different Histamine receptors.
 - Really important in allergy testing.
- (slide 9 clinical uses)
Histamine- Strongest.
Meniere’s disease- Inner ear disorder
(ringing of the ear), vertigo and hearing loss.
Betahistine- Anti-vertigo drug.
Wheals- An area of the skin which is temporarily raised,
typically reddened, and usually accompanied by itching.
Antihistamine- These are antagonist of H1 receptors.
causing tinnitus
H1 Antagonist- May decrease the allergic inflammation,
itching, sneezing and rhinorrhea.

- Treatment of Meniere’s disease. If there is a drug blocking your histamine receptor, decrease

Impromidine (INN)- Is a highly potent and specific ang allergic reaction, neurotransmission in the CNS.

histamine H2 receptor
- Used agonist. gastric
to increase acid If there is a drug blocking your histamine 1 receptor,
secretion.
naapektuhan din ang serotonin, adrenergic receptor, and
- It has been used diagnostically as a gastric secretion
cholinergic receptor.
indicator. Kapag mababa ang neurotransmitter sa brain, nakakaantok
Agonist- (slide 7 organ system effects) response.
sya and that would be increase in sedation. That’s why
antihistamine ay nakakaantok.
Antagonist- Babaliktarin yung organ system effects.
Ano ang example ng antihistamine + antiserotonin =
R-Alpha Methylhistamine- Acts on H3 receptor. Cyproheptadine  increasein appetite.

Histamine Agonist: (Slide 9 Adverse effects) Antihistamine + Antiadrenergic/Antialpha adrenergic =

Promethazine (Phenothiazine- specific name)
Flushing- Redness of the skin because of the dilated blood
Antihistamine + Anticholinergic = Diphenhydramine and
vessels  decrease in the blood pressure 
Promethazine.
hypotension  Shock.
Tachycardia- Fast heart rate/beat. Promethazine- Antihistamine + Antialpha adrenergic +
Anticholinergic
 *Sedating – nagkakaantok
H1 antagonist
H2 antagonist EPS – Extrapyrimidal symptoms – adverse effect of
anlipycotic agent
“H1 antagonist” – anticoli, antiadrenergic (alpha), anti- - type of movement disorder

serotonin, antihistamine Ethanolamine – atropine like effects

- histamine + anticholinergenic
Antihistamine + antiserotonin =
Atropine – anticholinergenic
cyproheptadine
PS: PLS MAGMEMORIZE THE BRAND NAME ALSO
Antihistamine + antiadreginaterhic/anti- alpha adrenergic =
promethazine (phenothiazine) Bonamine – used in/for nahihilo/ byahero
- e.g.:prevention of motion sickness
Antihistamine + anticholinergenic =
Promethazine (antihistamine + anti-aplha + adrenergic +
diphenhydramine.
anticholinergenic) Clorphenamiramine + paracetamol + phenylephrine
– antihistamine
MOA ANTIHISTAMINE: Prome thazine – antihistamine, anti-
anticholinergenic, & alpha
 Receptor (activate/block/inhibit) / bind or
produce cholinergenic.
-also used as anesthetic drug
 Effect
e.g. histamine 1 and anti-histamine Cyproheptadine – antihistamine & antiserotonin
MOA -block H1 receptor
- for serotonin syndrome – excessive amount of
Producing no urticartal response, bronchodilation vascular seronotonin causing high temperature, high BP, increase
smooth muscle construction reflexes,
tremor, sweating dilated pupils, diarrhea, seizure. pressure upon sudden changing the position)
e.g from lying to standing
- has significant blocking effect on s- hydroxy Serotonin – blocking actions
tryptamine/serotonin receptior Cyproheptadine – gain weight because of inc. appetite.

Sedation – sleep aids, not use in daytime

especially pilot
Only antihistamine for pilots
-N/V -nausea and vomiting
PS: Again, memorize the brand names
Diphen – anttihist + anticholinergenic
- because antihistamines have mild
Fount in GIT
anticholonergenic properties.
leads to: -
Mild blockage of muscarinic receptor H2 receptor stimulations
secretions gastric acid
Extrapyramidal – movement disorder in Blocks H2 receptos, Gastric Acid
Parkinson’s secretions
Peptic Ulcer Disease (PUD)
coarse and tremors, rigidity,
bradykinesia Gastro Esophageal Reflux Disease (GERD) – inc.
in the Gastric Acid secretions
Phenothiazine – promethazine
Ethanolamine and Ethylene diamines – have significant Famotidine – most potent H2 anti- histamine
atropine like effects on peripheral muscarinic receptors.  f o l l o w e d by Nizatidine = Ranitidine
 C i m e t i d i n e – least potent H2 – anti-histamine
*Terfenadine – liver toxic and cardiac arrhythmia –
withdrawn_Terfenadine and Aztemizole
- prototype H2 antagonist

Phenothiazine – Promethazine – can cause orthostatic

hypotension(severe drug in blood Nizatidine – V 100% bioavailable
Tagamet®, zantac® and Pepcid® - undergo first - From serotonin dun na derived si melatonin -
pass metabolism hormone produces sleepiness
Bioavailability – 50%
- Is thought to be especially active in
For serotonin syndrome – Excessive amount of serotonin constricting smooth muscles, transmitting impulses
causing high temperature, high blood pressure, increasing between nerve cell, regulating cyclic body processes
flexes, tremor, sweating, dilated pupils, diarrhea, seizure and contributing to well-being and happiness
- has significant blocking effects on 5- Hydroxy - Is regarded by some researches as a chemical that is
tryptamine/serotonin receptors. responsible for maintaining mood balance, and that
a deficit of serotonin leads to depression

SEROTONIN
Some serotonin receptor – they are excitatory
Serotonin – AKA 5-hydroxytryptamine also written to 5-HT
(responsible for increasing the amount of other
neurotransmitter) or inhibitory (responsible for
- potent vasoconstrictor other called
- Constrictor – responsible for constructor for decreasing the amount of neurotransmitter)

vascular and smooth muscle neurotransmitter

Serotonin
- Vasoconstrictor – responsible for
2 step to release serotonin from the tryptophan nag
constriction of blood vessels –
responsible for increasing the blood pressure kakaroon ng hydroxylation (adding of carboxyl group) after
- Parent compound of melatonin it is the precursor of that there would be decarboxylation (removal of carboxyl
melatonin – this responsible for sleepiness group) of amino acid
- Balance the appetite
- Hydroxylation – considered as rate limiting step in a
- It is happy hormone
conversion of tryptophan to a serotonin it means
- Serotonin comes from tryptophan
 that without hydroxylation there would be no - All serotonin receptors they are all G- protein
serotonin that will form coupled except for serotonin 3 receptor or 5 hydroxy
Serotonin comes from tryptophan by the action of L- tryptamine
tryptophan 5 monooxygenase and tryptophan hydroxylase - Type 1 receptor – also known as ionotropic

 That’s the two enzyme responsible for converting receptor (5HT3)

tryptophan into 5- hydroxy L-tryptophan - Type 2 – metabotropic receptor – also known as G-

 Other enzyme is 5-hyroxy protein coupled receptor (the rest of 5HT receptor)
MECHANISM OF ACTION
tryptophan decarboxylase or N- 5HT1 RECEPTOR – release serotonin which is
aromatic L-amino acid inhibitory, inhibit aldehyde cyclase, inhibit cAMP
decarboxylase – two enzyme (CNS)
responsible for converting 5- hydroxyl
5HT2 receptor – linked to PLC raising IP3 and DAG
tryptophan into serotonin
linked levels (smooth muscles, platelets, CNS)
 Enzyme responsible for metabolism
of serotonin 5-hydroxy indole acetic acid 5HT3 receptor – linked to membrane ion channels
 Remember that when there is abundant amount linked (sensory and enteric nerves)
of monoaminoxidase kapag masyadong madami the
amount of serotonin will decrease
SEROTONIN AND RELATED DRUGS

DIFFERENT TYPES OF SEROTONIN RECEPTOR

5-HT1A Partial Agonist

- G-protein coupled – type of receptor that link to G- brand name

 Buspirone Buspar –
protein producing secondary messenger – (CAMP, - Use anxiolytic – use for treatment for anxiety
buspar
CGMP, IP3 and DAG) - a drug of choice for chronic and persistent anxiety
5HT1D full agonist – triptan SEROTONIN ANTAGONIST
- the triptan – a vasoconstrictor – means may cause  Phenoxybenzamine
constructor into blood vessels - Treatment for carcinoid tumor – symptoms
– not beneficial into a patient have of diarrhea,
ischemic heart–disease
Sumatriptan is metabolized by MAO- A bronchoconstriction, flushing
Due to its 5-HT2A receptor antagonism, phenoxybenzamine,
(MONOAMINE OXIDASE-A), so
a neoplasm that secretes large amounts of serotonin
cant be used in patients who are taking MAOI
inhibitory A carcinoid (also carcinoid tumor – leading into cancer), is a
MAOI – monoamine oxidase inhibitor
slow-growing type of neuroendocrine tumor originating in
- decrease the amount of MAO –
the cell of the neuroendocrine system.
- MAOI + TRIPTANS = decrease in the amount of
MAO – thereby no enzyme that will metabolized the Cyproheptadine, sold under the brand name Periactin or

triptan that cause toxicity of triptan Peritol, is a first-generation antihistamine with additional

Triptan target peripheral nociceptors anticholinergic, antiserotonergic and local anesthetic

properties
5-HT4 AGONIST
- Gain weight
 Cisapride
Ketanserin
- For gastroesophageal reflux
5-HT4, PARTIAL AGONIST - Carcinoid syndrome
 Tegaserod zelnorm  Is a paraneoplastic syndrome
- Use for treatment of constipation comprising the sign and symptoms that occur
- Increase motility – treatment of constipation secondary to carcinoid tumors. The syndrome
includes flushing and diarrhea and less frequently,
Colitis – to much contruction, inflammation
heart failure, vomiting and bronchoconstriction. It is
of colon
caused
 by endogenous secretion of mainly serotonin and Structure
kallikrein. - Ergot alkaloids are classified among the indole
 Available in Europe for the treatment of alkaloids and are derived from the tetracyclic
hypertension and vasospastic conditions but has not ergoline ring system
been approved in the USA - Classified into two
Ritanserin
1. Clavinet alkaloids or clavines
- Has a capable that Alter bleeding time to reduce - Have ergoline as a basic structure but contain no
thromboxane function peptide bonds
Example: Festuclavine,
ERGOT ALKALOIDS
Dihyroelymoclavine
- Are large group of compound produced by fungi
2. Lysergic acid alkaloid or ergo alkaloids
that attack a wide variety of grass species, including
- In these component D-lysergic acid is linked with
small grains, such as growing season tricyclic peptide Example: ergometrine, ergocorine
- Major ergot fungus is Claviceps which produces
sclerotia in several grass species with C.purpurea CLASSIFICATION OF ERGOT
being the most common found species – producing ALKALOID’
ergot alkaloids  NATURAL - derivatives of the tetra- cyclic
compound (lysergic acid) – LSD – lysergic acid
Ergotism
diethyl amide (type of dangerous drug)
- Common symptoms – sleep deprivation
and psychosis - Amine alkaloids – ergometrine
(ergonovine) – oxytocic – contraction of uterus
- Increase amount of ergot alkaloids
- Amino acid alkaloids – ergotamine, ergotoxine –
- Gangrene – necrosis (death tissues)
vasoconstrictor and a - blocker
- Contraction of uterus – abortion
Classification of ergotasalkaloids
- Also known St. Anthony’s Fire
  Semi-synthetic – bromocriptine, - Ergonovine maleate – use to
methysergide, (DHE) dihydro-ergotamine postpartum hemorrhage

 Synthetic – (non lysergic acid - Ergonovine – ergotrate

Diagnosis of variant angina
derivatives) metergotine
- Variant angina “prinz metal” – a syndrome typically
ORGAN SYSTEM EFFECTS
consisting of angina (cardiac chest pain) at rest that
 CNS
occurs in cycles
- Suppress prolactin secretion
- Ergonovine – used as diagnosis test through IV
 Prolactin – milk hormone
- Cause dilution , hallucination Example:
Senile cerebral insufficiency
LSD – a natural
Clinical uses - Weakness or mental infirmity of old age.
Migraine
- Scotoma – alteration in the field of vision consisting
of a partially diminished or entirely degenerated
visual acuity that is surrounded by a field of normal –
or relatively well preserved – vision
Hemianopia – leading to blindness over half the field
of vision

Hyperprolactinemia

- Example drugs treatment:

 Bromocriptine
 Pergolide
 Cabergoline

Postpartum hemorrhage
Eicosanoids – inflammatory mediators
- from phospholipid precurson – AA (Arachidonic
a c i d )  a 20 carbon fatyacids.

1. Prostanoids – has 2 pathways

a. TX – thromboxane
b. PG – prostaglandin
c. Prostacyclin / PG12
 TXA2 – platelet aggregation (blood
clotting) & vasoconstriction your
(constrict blood vessel) /

(Causes narrowing of blood vessel)

 PG12 – treat pulmonary hypertension (increased in
the pressure/BP specifically in our lungs)

2. Leukotrienes
*Eicosanoids – derived from Arachidonic acid 
considered as a 20 carbon atom
Eicosanoids – inflammatory mediators
- from phospholipid precurson – AA (Arachidonic
a c i d )  a 20 carbon fatyacids.

1. Prostanoids – has 2 pathways

a. TX – thromboxane
b. PG – prostaglandin
c. Prostacyclin / PG12
 TXA2 – platelet aggregation (blood
clotting) & vasoconstriction your
(constrict blood vessel) /

(Causes narrowing of blood vessel)

 PG12 – treat pulmonary hypertension (increased in
the pressure/BP specifically in our lungs)

2. Leukotrienes
*Eicosanoids – derived from Arachidonic acid 
considered as a 20 carbon atom
 SUMMARY DRUGS WITH ACTIONS ON HISTAMINE AND SEROTONIN RECEPTORS; ERGOT ALKALOIDS
Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions

H1 ANTIHISTAMINES
FIRST GENERATION:
Competitive Reduces or IgE immediate Oral and parenteral • duration 4–6 h Toxicity: Sedation when used in
hay fever,muscarinic blockade symptoms, orthostatic hypotension
antagonism/ prevents histamine allergies; especially
•Interactions: Additive sedation with other sedatives, including alcohol
inverse effects on smooth hay fever, urticaria
agonism at H1 muscle, immune • often used as a •some inhibition of CYP2D6, may prolong action of some β blockers
DIPHENHYDRAMINE receptors cells sedative,antiemetic,
• also blocks and anti-motion
muscarinic and α sickness drug
adrenoceptors
• highly sedative
SECOND GENERATION:
Competitive Reduces or IgE immediate Oral • duration 12–24 h
Antagonism prevents histamine allergies; especially • Toxicity: Sedation and arrhythmias in
CETIRIZINE /inverse effects on smooth hay fever, urticaria overdose
agonism at H1 muscle, • Interactions: Minimal
receptors immune cells
Other first-generation H1 blockers: CHLORPHENIRAMINE is a less sedating H1 blocker with fewer autonomic effects.
Doxylamine, a strongly sedating H1 blocker, is available
over-the-counter in many sleep-aid formulations and in DICLEGIS (in combination with PYRIDOXINE) for use in nausea and vomiting of pregnancy
Other second-generation H1 blockers: LORATADINE, DESLORATADINE, and FEXOFENADINE are very similar to
cetirizine
H2 ANTIHISTAMINES
CIMETIDINE
RANITIDINE
NIZATIDINE
FAMOTIDINE
SEROTONIN AGONISTS
5-HT1B/1D:
Partial agonist at Effects not fully understood Migraine Oral, nasal, parenteral
5-HT1B/1D •may reduce release of calcitonin gene-related peptide and cluster • duration 2 h
SUMATRIPTAN and perivascular edema in cerebral circulation
receptors headache • Toxicity:
Paresthesias, dizziness, coronary vasoconstriction • Interactions: Additive with
other vasoconstrictors
Other triptans (ALMOTRIPTAN, ELETRIPTAN, FROVATRIPTAN, NARATRIPTAN, RIZATRIPTAN,
ZOLMITRIPTAN): Similar to sumatriptan except for pharmacokinetics (2–6 h duration of action); much more expensive than generic sumatriptan

5-HT2C
LORCASERIN Agonist at 5-HT2C receptors Appears to reduce appetite Obesity Oral • duration 11 h
• Toxicity: Dizziness, headache, constipation
5-HT4:
TEGASEROD
PRULALOPRIDE
SEROTONIN BLOCKERS
5-HT2: jrc
KETANSERIN Competitive Prevents vasoconstriction Hypertension Oral
(not blockade at 5-HT2 and • carcinoid syndrome • duration 12–24 h
5-HT3:
ONDANSETRON
ALOSETRON
TEGASEROD
GRANISETRON
DOLASETRON
SEROTONIN
ERGOT ALKALOIDS
VASOSELECTIVE:
Mixed partial agonist effects at 5-HT2 and Causes marked smooth muscle Migraine and cluster Oral, parenteral
α adrenoceptors contraction but blocks α-agonist headache • duration 12–24 h
ERGOTAMINE
vasoconstriction •Toxicity: Prolonged vasospasm causing angina, gangrene; uterine
spasm
UTEROSELECTIVE:
Mixed partial agonist effects at 5-HT2 and Same as ergotamine • some Postpartum bleeding Oral, parenteral (methylergonovine)
α adrenoceptors selectivity for uterine smooth •migraine headache • duration 2–4 h
ERGONOVINE
muscle • Toxicity: Same as ergotamine

CNS SELECTIVE :
Central nervous system 5-HT2 and Hallucinations None • widely abused Oral • duration several hours
LYSERGIC ACID DIETHYLAMIDE dopamine agonist • psychotomimetic •Toxicity: Prolonged psychotic state, flashbacks
•5-HT2 antagonist in periphery

BROMOCRIPTINE, PERGOLIDE: Ergot derivatives used in Parkinson’s disease (see Chapter 28) and
PROLACTINOMA (see Chapter 37). Pergolide used in equine Cushing’s disease

jrc
GENERIC NAME AVAILABLE AS
ANTIHISTAMINES (H1 BLOCKERS)*
AZELASTINE Generic, Astelin (nasal),
Optivar (ophthalmic)
BROMPHENIRAMINE Brovex, Dimetapp, others
BUCLIZINE Bucladin-S Softabs
CARBINOXAMINE Generic, Histex
CETIRIZINE Generic, Zyrtec
CHLORPHENIRAMINE Generic, Chlor-Trimeton
CLEMASTINE Generic, Tavist
CYCLIZINE Generic, Marezine
CYPROHEPTADINE Generic, Periactin
DESLORATADINE Generic, Clarinex
DIMENHYDRINATE† Generic, Dramamine
DIPHENHYDRAMINE Generic, Benadryl
DOXYLAMINE Diclegis (combination with pyridoxine), Unisom Sleep Tabs

EPINASTINE Generic, Elestat

FEXOFENADINE Generic, Allegra
HYDROXYZINE Generic, Vistaril
KETOTIFEN Generic, Zaditor
LEVOCABASTINE Livostin
LEVOCETIRIZINE Generic, Xyzal
LORATADINE Generic, Claritin
MECLIZINE Generic, Antivert, Bonine
OLOPATADINE Patanol, Pataday
PHENINDAMINE Nolahist
PROMETHAZINE Generic, Phenergan
TRIPROLIDINE Generic, Zymine, Tripohist
H2 BLOCKERS
CIMETIDINE
RANITIDINE
NIZATIDINE
FAMOTIDINE
5-HT AGONISTS
ALMOTRIPTAN Axert
ELETRIPTAN Relpax
FLIBANSERIN Addyi
FROVATRIPTAN Frova
NARATRIPTAN Generic, Amerge
RIZATRIPTAN Generic, Maxalt, Maxalt-MLT
SUMATRIPTAN Generic, Imitrex
ZOLMITRIPTAN Generic, Zomig
5-HT ANTAGONISTS
SEROTONIN
ONDANSETRON
GRANISETRON jrc
DOLASETRON
ALOSETRON
TEGASEROD
MELATONIN RECEPTOR AGONISTS
RAMELTEON Rozarem
TASIMELTEON Hetlioz
ERGOT ALKALOIDS
DIHYDROERGOTAMINE Generic, Migranal, D.H.E. 45
ERGONOVINE Generic, Ergotrate
ERGOTAMINE MIXTURES (INCLUDE CAFFEINE) Generic, Cafergot

ERGOTAMINE TARTRA Generic, Ergomar

METHYLERGONOVINE Generic, Methergine
ANTIOBESITY DRUGS
LIRAGLUTIDE Saxenda, Victoza
LORCASERIN Belviq
NALTREXONE/BUPROPION Contrave
ORLISTAT Alli, Xenical
PHENTERMINE Generic, Adipex-P, Lomaira
PHENTERMINE/TOPIRAMATE Qsymia

SUMMARY DRUGS THAT INTERACT WITH VASOACTIVE PEPTIDE SYSTEMS

SUBCLASS, DRUG MECHANISM OF ACTION EFFECTS CLINICAL APPLICATION

ANGIOTENSIN RECEPTOR ANTAGONISTS

Arteriolar dilation
Selective competitive antagonist of angiotensin • decreased aldosterone secretion
VALSARTAN Hypertension
AT1 receptors • increased sodium and water excretion

EPROSARTAN, IRBESARTAN, CANDESARTAN, OLMESARTAN, TELMISARTAN:Similar to valsartan

ANGIOTENSIN RECEPTOR AGONISTS
Potential for treatment of cardiovascular
COMPOUND 1 AT2 receptor agonist Beneficial cardiovascular effects
disease
CONVERTING ENZYME INHIBITORS
Arteriolar dilation
Inhibits conversion of angiotensin I to
• decreased aldosterone secretion Hypertension • heart failure
ENALAPRIL angiotensin II
• increased sodium and water
excretion

CAPTOPRIL and many others: Similar to enalapril

RENIN INHIBITOR
Arteriolar dilation
Inhibits catalytic activity of renin • decreased aldosterone secretion
ALISKIREN Hypertension
• jrc
increased sodium and water excretion
 KININ INHIBITORS
Blocks effects of kinins on pain, hyperalgesia, and
ICATIBANT Selective antagonist of kinin B2 receptors Hereditary angioedema
inflammation
CINRYZE, BERINERT: Plasma C1 esterase inhibitors, decrease bradykinin formation, used in hereditary angioedema
ECALLANTIDE: Plasma kallikrein inhibitor
VASOPRESSIN AGONISTS
ARGININE VASOPRESSIN Agonist of vasopressin V1 (and V2) Vasoconstriction Vasodilatory shock
receptors
SELEPRESSIN, TERLIPRESSIN: More selective for V1a receptor
VASOPRESSIN ANTAGONISTS
Potential use in hypertension and
CONIVAPTAN Antagonist of vasopressin V1 and V2 receptors Vasodilation heart failure
• hyponatremia
RELCOVAPTAN, SRX251: Increased selectivity for V1 receptor
TOLVAPTAN: Increased selectivity for V2 receptor
NATRIURETIC PEPTIDES
Increased sodium and water excretion
NESIRITIDE, Agonists of natriuretic peptide receptors Heart failure
• vasodilation
CARPERITIDE
ULARITIDE: Synthetic form of urodilatin
COMBINED ANGIOTENSIN-CONVERTING ENZYME/NEPRILYSIN INHIBITORS (VASOPEPTIDASE INHIBITORS)

Decreases metabolism of Vasodilation

OMAPATRILAT natriuretic peptides Hypertension • heart failure1
• increased sodium and water excretion
and formation of angiotensin II
SAMPATRILAT, FASIDOTRILAT: Similar to omapatrilat
COMBINED ANGIOTENSIN RECEPTOR ANTAGONIST/NEPRILYSIN INHIBITORS (ARNI)
LCX696 (SACUBITRIL/ Decreases breakdown of natriuretic peptides Vasodilation
VALSARTAN) and blocks angiotensin II receptors Heart failure
• increased sodium and water excretion • hypertension1

ENDOTHELIN ANTAGONISTS
Nonselective antagonists
BOSENTAN, MACITENTAN Vasodilation Pulmonary arterial hypertension
of endothelin ETA and ETB receptors
SITAXSENTAN, AMBRISENTAN: Selective antagonists for ETA receptors
COMBINED ENDOTHELIN-CONVERTING ENZYME/NEPRILYSIN INHIBITORS
Blocks formation of Vasodilation
SLV306, DAGLUTRIL endothelins and breakdown of natriuretic • increased sodium and water excretion Heart failure
peptides • hypertension1

VASOACTIVE INTESTINAL PEPTIDE AGONISTS

PB1046, VASOMERA Selective agonist of VPAC2 receptors jrcVasodilation Hypertension1
• multiple metabolic, endocrine, and other effects

SUBSTANCE P ANTAGONISTS
 Prevention of chemotherapyinduced
Selective antagonist of tachykinin NK1 Blocks several central nervous system effects of
APREPITANT nausea and vomiting
receptors substance P

FOSAPREPITANT: Prodrug that is converted to aprepitant

NEUROTENSIN AGONISTS
Potential for treatment of
PD149163, NT69L, NT79 Agonists of central neurotensin receptors Interact with central dopamine systems
schizophrenia and Parkinson’s disease

NEUROTENSIN ANTAGONISTS
Antagonist of central and peripheral Blocks some central and peripheral (vasodilator) actions
MECLINERTANT None identified
neurotensin receptors of neurotensin
CALCITONIN GENE-RELATED PEPTIDE ANTAGONISTS
Antagonists of the calcitonin gene-related Blocks some central and peripheral (vasodilator) actions
TELCAGEPANT, Migraine1
peptide (CGRP) receptor of CGRP
OLCEGEPANT
NEUROPEPTIDE Y ANTAGONISTS
Selective antagonist of neuropeptide Y1
BIBP3226 Blocks vasoconstrictor response to neurotensin Potential antiobesity agent
receptors
• BIIE0246: Selective for Y2 receptor
• MK-0557: Selective for Y5 receptor
UROTENSIN ANTAGONISTS
• PALOSURAN Potential for treatment of diabetic renal
• GSK1440115: Antagonist of urotensin receptors Blocks vasoconstrictor action of urotensin failure and asthma1
More potent than palosuran

jrc
 GENERIC NAME AVAILABLE AS
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
Captopril
ANGIOTENSIN RECEPTOR BLOCKERS
Losartan
RENIN INHIBITOR
Aliskiren Tekturna
KININ INHIBITOR
Icatibant Firazyr
KALLIKREIN INHIBITORS
C1 esterase inhibitor, human Cinryze, Berinert
Ecallantide Kalbitor
AVP RECEPTOR ANTAGONISTS
Conivaptan Vaprisol
Tolvaptan Samsca
SUBSTANCE P ANTAGONIST
Aprepitant Emend
NATRIURETIC PEPTIDE AGONIST
Nesiritide Natrecor
DRUGS USED IN PULMONARY HYPERTENSION
Ambrisentan Letairis
Bosentan Tracleer
Epoprostenol Flolan, Veletri
Iloprost Ventavis
Macitentan Opsumit
Riociguat Adempas
Selexipag Uptravi
Treprostinil Tyvaso, Remodulin

jrc
 GENERIC NAME AVAILABLE AS

Alprostadil
Penile injection, mini-suppository Caverject, Edex, Muse
Parenteral Generic, Prostin VR Pediatric
Bimatoprost Lumigan, Latisse
Carboprost tromethamine Hemabate
Dinoprostone [prostaglandin E2] Prostin E2, Prepidil, Cervidil
Epoprostenol [prostacyclin] Generic, Flolan, Veletri
Iloprost Ventavis
Latanoprost Generic, Xalatan
Misoprostol Generic, Cytotec
Montelukast Generic, Singulair
Selexipag Uptravi
Travoprost Generic, Travatan, Travatan-Z
Treprostinil Remodulin, Tyvaso, Orenitram
Zafirlukast Generic, Accolate
Zileuton Zyflo, Zyflo CR
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Aspirin, acetylsalicylic acid Generic, Easprin, others
Bromfenac Prolensa, Bromday
Celecoxib Celebrex
Choline salicylate Various
Diclofenac Generic, Cataflam, Voltaren
Diflunisal Generic, Dolobid
Etodolac Generic, Lodine
Fenoprofen Generic, Nalfon
Flurbiprofen Generic, Ansaid, Ocufen (ophthalmic)
Ibuprofen Generic, Motrin, Rufen, Advil (OTC), Nuprin (OTC),
others
Indomethacin Generic, Indocin
Ketoprofen Generic, Orudis
Magnesium salicylate Doan’s Pills, Magan, Mobidin
Meclofenamate sodium Generic
Mefenamic acid Generic, Ponstel
Meloxicam Generic, Mobic
Nabumetone Generic
Naproxen Generic (OTC), Naprosyn, Anaprox, Aleve (OTC)
Oxaprozin Generic, Daypro
Piroxicam Generic, Feldene
Salsalate, salicylsalicylic acid jrc Generic, Disalcid
Sodium salicylate Generic
Sodium thiosalicylate Generic, Rexolate
 GENERIC NAME AVAILABLE AS
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Abatacept Orencia
Adalimumab Humira
Anakinra Kineret
Auranofin Ridaura
Aurothioglucose Solganal
Belimumab Benlysta
Canakinumab Ilaris
Certolizumab Cimzia
Cyclophosphamide Generic, Cytoxan
Cyclosporine Generic, Sandimmune
Etanercept Enbrel
Gold sodium thiomalate Generic, Aurolate
Golimumab Simponi
Infliximab Remicade
Leflunomide Generic, Arava
Methotrexate Generic, Rheumatrex
Mycophenolate mofetil Generic, Cellcept
Penicillamine Cuprimine, Depen
Rilonacept Arcalyst
Rituximab Rituxan
Sulfasalazine Generic, Azulfidine
Tocilizumab Actemra
Tofacitinib Xeljanz
ACETAMINOPHEN AND OTHER ANALGESICS
Acetaminophen Generic, Tylenol, Tempra, Panadol, Acephen, others
Ketorolac tromethamine Generic, Toradol
Tramadol Ultram
DRUGS USED IN GOUT
Allopurinol Generic, Zyloprim
Colchicine Generic*, Colchrys
Febuxostat Uloric
Pegloticase Krystexxa
Probenecid Generic
Sulfinpyrazone Generic, Anturane

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