INTRODUCTION OF PHARMACOLOGY

PHARMACOLOGY
➢ study of substances that interact with living systems through:
● chemical processes
● binding to regulatory molecules
● inhibiting or activating normal body processes
MEDICAL PHARMACOLOGY
➢ defined as the science of substances (substances may be chemicals that are administered to
achieve a beneficial therapeutic effect on some processes within the patient.)
● Used to prevent, diagnose and treat disease.
● Application: It is used to develop new pharmaceutical products
DRUG
➢ Any substance that interacts with a molecule or proteins that plays a regulatory role in living
systems.
● specific in size, charge, and shape to interact with the given receptor
MEDICATION
➢ is a drug intended for therapeutic benefit.
TOXICOLOGY
➢ branch of pharmacology that deals with undesirable effects of chemicals on living systems.
● Application: to know the toxic side effects of certain drugs.
POISONS
➢ drugs that have exclusively harmful effects.
TOXINS
➢ poisons of biologic origin synthesized by plants and animals.
ENDOGENOUS
➢ Substances are made inside the body.
Ex. hormones
EXOGENOUS
➢ Substances are made outside the body.
Ex. Xenobiotics
PHARMACOKINETICS
➢ explains what our body does to the drug once it is taken.
PHARMACODYNAMICS
➢ is the study of the biochemical and physiologic impacts of medications.
THERAPEUTIC AND TOXIC EFFECTS OF DRUGS
➢ result from their interactions with molecules in the patient.
RECEPTOR
➢ the component of a cell or organism that interacts with a drug and initiates the chain of events
leading to the drug’s observed effects.
● the central focus of investigation of drug effects and their mechanisms of action
(pharmacodynamics)
THE RECEPTOR CONCEPT
➢ important practical consequences for the development of drugs and for arriving at therapeutic
decisions in clinical practice where it forms the basis for understanding the actions and clinical
uses of drugs.
1. Receptors largely determine the quantitative relations between dose or concentration
of drug and pharmacologic effects.
● receptor’s affinity for binding a drug determines the concentration of drug required to form a
significant number of drug-receptor complexes
● the total number of receptors may limit the maximal effect a drug may produce.
2. Receptors are responsible for selectivity of drug action.
● molecular size, shape, and electrical charge of a drug determine on what affinity that binds a
particular receptor among the vast array of chemically different binding sites available in a cell,
tissue, or patient
 ● changes in the chemical structure of a drug can increase or decrease a new drug’s affinities for
different classes of receptors resulting to alterations in therapeutic and toxic effects
3. Receptors mediate the actions of pharmacologic agonists and antagonists.
● Some drugs and many natural ligands, such as hormones and neurotransmitters, regulate the
function of receptor macromolecules which are:
➔ PHARMACOLOGIC AGONIST
➢ activates the receptor to signal as
a direct result of binding to it.
➔ FULL AGONIST
➢ Can generate a maximal
response at a receptor
➔ PARTIAL AGONIST
➢ Generate a fraction of the
possible response at a receptor
➔ INVERSE AGONIST
➢ Can cause a decrease in
signaling at a receptor

➔ PHARMACOLOGIC ANTAGONIST
➢ binds to receptors but does not
activate generation of a signal.
➢ interferes with the ability of an
agonist to activate the
receptor.
➢ some of the most useful drugs in
clinical medicine.
➔ COMPETITIVE ANTAGONIST
➢ Any pharmacologic antagonist
that competes the binding of
agonist at the binding site
➔ NON-COMPETITIVE ANTAGONIST
➢ Any pharmacologic antagonist
that binds to a site on the
receptor other than the agonist
binding site.

agonist (activator)
antagonist (inhibitor)
receptor (target molecule)
chemical antagonists - interact directly with other drugs
osmotic agents - ) interact almost exclusively with water molecules

• full agonists

Many agonist drugs, when administered at concentrations sufficient to saturate the

receptor pool, can activate their receptor effector systems to the maximum extent of which
the system is capable; that is, they cause a shift of almost all of the receptor pool to the Ra–
D pool.
 • partial agonists
- bind to the same receptors and activate them in the same way but do not evoke as
great a response, no matter how high the concentration

- may act either as an agonist (if no full agonist is present) or as an antagonist (if a
full agonist such as epinephrine is present).
Because they occupy the receptor, partial agonists can also prevent access by full
agonists.

neutral antagonism
- a blocking action

- the presence of the antagonist at the receptor site will block access of agonists to the
receptor and prevent the usual agonist effect

What will happen if a drug has a much stronger affinity for the (non-active form) Ri than for
the (Activated form) Ra state and stabilizes a large fraction in the Ri–D pool?
In this scenario the drug will reduce any constitutive activity, thus resulting in effects that are
the opposite of the effects produced by conventional agonists at that receptor. Such drugs are
termed inverse agonists

orphan receptors
their natural ligands are presently unknown; these may prove to be useful targets for
future drug development.

regulatory proteins

- best-characterized drug receptors

- mediate the actions of endogenous chemical signals such as neurotransmitters,

autacoids, and hormones.
ALLOSTERIC MODULATION
➢ Drug binds to a receptor at a different site from where an agonist binds and influences the
function of the reception
THE HISTORY OF PHARMACOLOGY
➢ Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and
animal materials. Early written records list remedies of many types, including a few that are still
recognized as useful drugs today. Most, however, were worthless or actually harmful.
● These schools promulgated bizarre notions such as the idea that disease was caused by
excesses of bile or blood in the body, that wounds could be healed by applying a salve to the
weapon that caused the wound, and so on.
DEFINITION
➢ -Pharmacology, a term derived from the Greek words pharmakon (“poison” in classic Greek,
“drug” in modern Greek) and logos, meaning study. is a branch of biology and medicine
that is concerned with the study of drug action.
● Specifically, pharmacology is the examination of the interactions between a living
organism and chemicals that affect normal or abnormal biochemical functions.
MATERIA MEDICA
➢ The science of drug preparation and the medical uses of drugs.
FRANÇOIS MAGENDIE AND CLAUDE BERNARD (STUDENT)
➢ They develop experimental physiology and pharmacology.

OSWALD SCHMIEDEBERG (1838-1921)

➢ Founder of Modern Pharmacology
➢ The father of pharmacology
JOHN J. ABEL (1857-1938)
➢ The Father of the American Pharmacology
● In 1890, he became the first pharmacology chair in the United States, at the University of
Michigan.
RUDOLF BUCCHEIM
➢ A German pharmacologist who founded the first institute of pharmacology at the University of
Dorpat (Tartu, Estonia).
● He also strove to explain the chemical properties of drugs.
ORPHAN RECEPTORS
➢ The use of receptor identification methods has led to its discovery.
PHARMACOGENOMICS
➢ The relation of the individual’s genetic makeup to his or her response to specific drugs.
GENERAL PRINCIPLES THAT THE STUDENT SHOULD REMEMBER ARE:
1. That all substances can under certain circumstances be toxic.
2. That the chemicals in botanicals (herbs and plant extracts, “nutraceuticals”) are no different
from chemicals in manufactured drugs except for the much greater proportion of impurities in
botanicals; and
3. That all dietary supplements and all therapies promoted as health-enhancing should meet the
same standards of efficacy and safety as conventional drugs and medical therapies. That is,
there should be no artificial separation between scientific medicines and “alternative” or
“complementary” medicine. Ideally, all nutritional and botanical substances should be tested
by the same types of randomized controlled trials (RCTs) as synthetic compounds.
ANTIQUITY TO MIDDLE AGES
➢ Pharmacological knowledge has been recorded for thousands of years across the world. The
earliest known documentation of medical substances is the prehistoric Sushruta Samhita, and
Indian Ayurvedic treatise from the 6th century BC.
SCIENTISTS AND CONTRIBUTIONS TO PHARMACOLOGY
HIPPOCRATES (460 BC - 377 BC) ● Issued a pledge of proper conduct for
➢ Father of Medicine doctors
● Developed the separation of practicing PEDANIUS DIOSCORIDES (40 AD - 90 AD)
medicine from religious and superstitious ➢ Authored "De Materia Medica" at 65 AD
beliefs (which is about the "preparation, properties,
and testing of drugs")
PARACELSUS (1493 - 1541) ● Appointed as the Chair of Pharmacology in
➢ Pioneered the use of chemicals and Graz in 1909
minerals (like zinc) in medicine ● Proved the chemical transmission of nerve
● Opposed polypharmacy (prescribing impulses in 1921 (through his most famous
multiple ingredients on a single medicine) experiment)
FRANÇOIS MAGENDIE (1783 - 1855) ● Received a Nobel Prize in 1936 with Henri
➢ Pioneer of Experimental Physiology Hallet Dale
● Known for describing the foramen of HENRI HALLET DALE (1875 - 1968)
Magendie (or median aperture) ➢ Distinguished muscarinic and nicotinic
FRIEDRICH WOHLER receptors in 1914
➢ Challenged the vital force theory in 1828 by ● Developed "Dale's Law" (a neuron releases
synthesizing urea from inorganic only one type of neurotransmitter)
substances ● Also developed "Dale's Vasomotor
● Developed synthetic organic chemistry Reversal Phenomenon" (in BP, happens
CLAUDE BERNARD (1813 - 1878) when an alpha blocker is given before
➢ Father of Modern Experimental Medicine injecting adrenaline), demonstrated this in
● Discovered in 1842 that curare (arrow cats with Ergot alkaloids as alpha blockers
poison) acts at the neuromuscular junction ALEXANDER FLEMING (1881 - 1955)
to interrupt the stimulation of muscle to ➢ Discovered the enzyme lysozyme in 1923
nerve impulses, then demonstrated in 1856 ● Discovered the antibiotic penicillin by
● Established the existence of vasomotor chance in 1928 from the mold Penicillum
system and observed vasodilation and notatum
vasoconstriction ● Received the Nobel Prize in 1945 with
RUDOLF BUCHHEIM (1820 - 1879) Howard Florey and Ernst Chain, who
➢ Pioneer of Experimental Pharmacology purified penicillin
● Introduced bioassay to pharmacology FREDERICK BANTING (1891 - 1941)
● Built the world's first pharmacology ➢ Canadian doctor who discovered insulin
laboratory (in the basement of his home) ● Received the Nobel Prize in 1923 with
● Appointed as professor of German Macleod (which actually ignored his
pharmacology in 1847, at the University of assistant so Banting gave half of the prize
Dorpat in Estonia money to him)
OSWALD SCHMIEDEBERG (1838 - 1921) CHARLES BEST (1899 - 1978)
➢ Founder of Modern Pharmacology ➢ Chosen as Banting's assistant for winning
● Obtained his medical doctorate in 1866 with the coin toss against Clark Noble, who also
a thesis on the measurement of chloroform wanted to assist Banting
in blood
● Published "Outline of Pharmacology" in
1878 COLONEL RAM NATH CHOPRA (1892 - 1973)
● Discovered urethane as a hypnotic in 1885 ➢ Father of Indian Pharmacology
PAUL EHRLICH (1854 - 1915) ● First introduced and systematically studied
➢ Father of Chemotherapy Rauwolfia serpentina
● Noted for curing syphilis and research in ● Was issued a commemorative stamp from
autoimmunity Indian Posts and Telegraph department
● Coined the terms "chemotherapy" and GERHARD DOMAGK (1895 - 1964)
"receptor" (called by John Langley as ➢ Discovered the first commercially available
"receptive substance" in 1878), and antibiotic, which is sulfonamidochrysoidine
popularized the magic bullet concept (KI-730), marketed as the brand name
● Received the Nobel Prize in 1908 Prontosil
● Developed Salvarsan, the first widely used ● Received the Nobel Prize in 1939
treatment for syphilis (along with his student DANIEL BOVET (1907 - 1992)
Sahachiro Hata) ➢ He and his co-workers performed
JOHN JACOB ABEL (1857 - 1938) experiments on Prontosil in the early
➢ Father of American Pharmacology 1930's, concluding that Prontosil derived its
● Established the first American university therapeutic abilities from sulphanilamide
chair in 1890 in the University of Michigan ● Discovered Pyrilamine (or mepyramine), a
● Gave the name "Pharmacology" as a very important histamine
subject (earlier known as "Materia Medica") ● Isolated succinylcholine, a muscle relaxant
● Prepared pure crystalline insulin in 1926 now used in conjunction with anesthesia
FRIEDRICH SERTURNER during surgical procedures
➢ Isolated the first alkaloid from opium in ● Received the Nobel Prize in 1957
1805 (later named as morphine) LOUIS LASAGNA (1923 - 2003)
OTTO LOEWI (1873 - 1961) ➢ Father of Clinical Pharmacology
➢ Brilliantly obtained his doctor's degree with ● Joined the faculty of Johns Hopkins
a thesis of "techniques of isolations with a University in 1954, establishing the first
frog's heart" every clinical pharmacology department
 ● Conceptualized controlled clinical trials and the world's best selling drug, later resigned
placebo effect due to the company not agreeing to his idea
● Developed "Lasagna's Law" (the incidence of treating stomach ulcers
of patient availability decreases when a ● Joined Smith, Kline, and French in 1964
clinical trial begins, and returns to the and developed cimetidine (brand name
original level when the trial is completed Tagamet) in 1975, which outsold his first
JAMES BLACK (1924 - 2010) developed drug propanolol to become the
➢ Established the physiology department at world's 1st billion-dollar drug
the University of Glascow in 1950 ● Received the Nobel Prize in 1988
● Joined ICI Pharmaceuticals in 1958, and
developed Propanolol, which later became
THE NATURE OF DRUGS
● DRUGS - any substance that brings ● CHEMICAL ANTAGONIST - interact
about a change in biologic function directly with other drugs.
through its chemical actions. ● OSMOTICS AGENTS - interact almost
● AGONIST - chemical that binds to a exclusively with water molecules.
receptor and activates it to produce a ● ENDOGENOUS DRUGS - Drugs that are
biological response. (Activator) synthesized in the body. (Ex Hormones)
● ANTAGONIST - chemical that blocks or ● EXOGENOUS DRUGS - Drugs that are not
dampens a biological response by synthesized in the body. (Ex Xenobiotics)
binding to and blocking a receptor rather ● POISONS - drugs that have almost
than activating in like an agonist. (Inhibitor) exclusively harmful effects.
● ● TOXINS - poisons of biologic origin, that is
● RECEPTOR - chemical structures synthesized by plants or animals, in
composed of proteins that receive and contrast to inorganic poisons such as lead
transduce signals that may be integrated and arsenic.
into biological systems.
THE PHYSICAL NATURE OF DRUGS ● The phenomenon of chirality
➢ To interact chemically with its (stereoisomerism) is so common in
receptor, a drug molecule must have: biology that more than half of all useful
ASESA drugs are chiral molecules; that is,
● Appropriate Size they can exist as enantiomeric pairs.
● Electrical Charge DRUG REACTIVITY & DRUG-
● Shape RECEPTOR BONDS
● Atomic Composition ➢ Drugs interact with receptors by
➢ To have a good “fit” to only one type of means of chemical forces or bonds
receptor, a drug molecule must be ● These are of three major types:
sufficiently unique in shape, charge, covalent, electrostatic, and
and other properties. hydrophobic.
DRUG SIZE ○ Covalent bonds are very
➢ The molecular size of drugs varies strong and in many cases not
from very small to very large reversible under biologic
● Most drugs have molecular weights conditions
between 100 and 1000 ○ Electrostatic bonding is much
more common than covalent
● To achieve selective binding, it
bonding in drug-receptor
appears that a molecule should in
interactions.
most cases be at least 100 MW units
○ Hydrophobic bonds are
in size.
usually quite weak and are
● Drugs much larger than MW 1000 do
probably important in the
not diffuse readily between interactions of highly lipid-
compartments of the body soluble drugs with the lipids of
● Therefore, very large drugs (usually cell membranes
proteins) must often be administered ● A drug is often administered at a
directly into the compartment where location distant from its intended site
they have their effect. of action
DRUG SHAPE ● A useful drug must have the
➢ Optimally, the drug’s shape is necessary properties to be transported
complementary to that of the receptor from its site of administration to its site
site in the same way that a key is of action
complementary to a lock. ● A practical drug should be inactivated
or excreted from the body at a
 reasonable rate so that its actions will Ex Propranolol is metabolized and
be of appropriate duration to prevent eliminated by the liver and kidneys.
its binding to other receptors o Govern the absorption,
● These factors often determine the best
distribution, and elimination
route of administration for drugs:
○ Solid at room temperature of drugs.
(e.g., aspirin, atropine) o Important in choosing and
○ Liquid (e.g., nicotine, ethanol) administering a particular drug
○ Gaseous (e.g., nitrous oxide) for a specific patient.
BIOAVAILABILITY PHARMACODYNAMIC PRINCIPLES
➢ is defined as the fraction of Most drugs must bind to a receptor to bring
unchanged drug reaching the about an effect. However, at the cellular level,
systemic circulation following drug binding is only the first in a sequence of
administration by any route. steps:
● For an intravenous dose,
● Drug (D) + receptor-effector (R) →
bioavailability is assumed to be equal
to unity (100) drug-receptor-effector complex →
● For a drug administered orally,
effect
bioavailability may be less than 100%
eg, only 70% of a dose of digoxin ● D + R → drug-receptor complex →
reaches the systemic circulation effector molecule → effect
● D + R → D-R complex → activation
of coupling molecule → effector
molecule → effect
● Inhibition of metabolism of
endogenous activator → increased
activator action on an effector
molecule → increased effect
The final exchange in function is accomplished
by an effector mechanism. The effector may be
part of the receptor molecule or may be a
separate molecule. A very large number of
DRUG-BODY INTERACTIONS receptors communicate with their effectors
Drug-body interactions refer to the interaction through coupling molecules.
between the drug and the body. It is divided into
two classes: The pharmacodynamic process
and the Pharmacokinetic process.
● Pharmacodynamics - the action of
drugs on the body, in simpler words,
what the drug does to the body. Ex
Propranolol, a beta-adrenergic
antagonist, lowers blood pressure and
heart rate. The lowering of the blood
pressure and heart rate is the action
of the propanol on the body.
o Plays a big role in deciding
whether that group is the
appropriate therapy for a
particular symptom or
disease.
● Pharmacokinetics – actions of the
body on the drug; in other words, this
is what the body does to the drug.
A. TYPES OF DRUG RECEPTOR INTERACTIONS
AGONIST DRUGS/AGONISM
➢ drugs bind to receptor and activate the receptor in some fashion, causes biological response
• Full Agonist - can generate maximal response at a receptor
• Partial Agonist - generate fraction of the possible response at a receptor
• Inverse Agonist - cause a decrease in signal at receptor
PHARMACOLOGIC ANTAGONIST/ANTAGONISM
➢ drugs binds to a receptor, but does not activate receptor and prevent binding by other molecules
o Ex. acetylcholine receptor blockers such as atropine are antagonists because they
prevent access of acetylcholine and similar agonist drugs to the acetylcholine receptor site
➢ they stabilize the receptor in its inactive state (or some state other than the acetylcholine-activated
state).
• Reversible Competitive Antagonism - compete with an agonist for is binding site; their effect could
be overcome with the addition of more agonist
• Irreversible Competitive Antagonism - from a stable bond with an agonist’s binding site; they can
reduce the agonist maxima effect regardless of how much agonist is present
B. AGONISTS THAT INHIBIT THEIR BINDING MOLECULES
➢ Molecules that bind to specific receptors and cause
a process in the cell to become more active are
called agonists. An agonist is something that causes
a specific physiological response in the cell. They
can be natural or artificial.
• Natural Agonist :
o Ex. Endorphins are natural agonists of
opioid receptors. But morphine – or heroin
that turns into morphine in the body – is an
artificial agonist of the main opioid receptor.
• Artificial Agonist:
o Ex. An artificial agonist is so structurally
similar to a receptor’s natural agonist that it
can have the same effect on the receptor.
Many drugs are made to mimic natural
agonists so they can bind to their receptors
and elicit the same – or much stronger –
reaction.
C. AGONISTS, PARTIAL AGONISTS AND INVERSE
AGONISTS
➢ Receptor is suggested to exist in the inactive, non-
functional form (Ri) and activated form (Ra).
• Agonist: The drug binds to a receptor, causing a
biological response.
➢ Agonists have a much higher affinity for the Ra
(activated form) configuration and stabilize it, so
that a large percentage of the total pool resides in the Ra-D fraction and a large effect is
produced.
KINDS OF AGONISTS DRUGS:
➢ Full agonists - it can generate a maximal response at a receptor when administered at
concentrations, sufficient to saturate the receptor pool.
➢ Partial agonists - bind to the same receptors and activate them in the same way; but generate
only a fraction of the possible response at a receptor, no matter how high the concentration.
o Partial agonists can prevent access by full agonists; may act as either agonist (if no full
agonist is present) or antagonist (if a full agonist is present like epinephrine).
➢ Inverse agonists - bind to and prevent constitutive (essential) receptor activity in the absence of
an agonist; can cause a decrease in signaling at a receptor.
 ➢ Thermodynamic considerations indicate that even in the absence of any agonist, some of
the receptor pool must exist in the activated form (Ra) some of the time and may produce
the same physiologic effect as agonist-induced activity.
• This effect, occurring in the absence of an agonist, is termed constitutive activity. The
constitutive activity of a receptor may be blocked by an inverse agonist.
NEUTRAL ANTAGONISM: The presence of the antagonist at the receptor site will block access of
agonists to the receptor and prevent the usual agonist effect.

Team Gap
Leader: Rochyne Daphne Kate Sapio
Members: Jeanly Perez
Nicole Audrey Salamida
Muffy Joy Sarausa
Clea May Marie Sarin
G PROTEINS AND SECOND MESSENGER

G PROTEIN
➢ also known as guanine nucleotide-binding proteins
➢ family of proteins that act as molecular switches inside cells
➢ involved from a variety of stimuli outside a cell to its interior.
G PROTEIN COUPLED RECEPTORS (GPCR)
➢ also known as GPCR
• they have 7 trans membrane helicases – very important
• cell surface receptors – respond to external signals
• only found in eukaryotes
• 1000 known GPCR in humans
• each GPCR has different functions
• largest known class of membrane receptors
• target of 30% - 50% of modern medicinal drugs
➢ GPCRs make up the largest receptor family and are also called “seven-transmembrane”
(7TM) or “serpentine” receptors because the receptor polypeptide chain “snakes” across the
plasma membrane seven times
Ligands: • Behavioral
• Light sensitive compounds • Mood
• Odor G – Proteins
• Pheromone • very diverse
• Hormone • over 1000 known g-proteins within
• Neurotransmitters human body
Regulate: • can stimulate or inhibit activity
• Immune system Heterotrimetric – have 3 different subunits
• Growth • Alpha
• Sense of smell • Beta
• Taste • Gamma
• Visual

GPCR BINDING WITH G-PROTEIN PROCESS

1. Ligand binds with GPCR.
 2. GCPR undergoes a conformational change.
3. Once GPCR undergoes conformational change, the “alpha” subunit of the G-protein, exchanges
GDP to GTP.
4. Once GTP is bound to “alpha” subunit, “alpha” subunit disassociates/separates itself from “beta”
and “gamma” subunit.
5. The two units, “alpha” subunit and “beta-gamma unit” will look for proteins within the membrane
and regulate its function.
a. “alpha” subunits finding and regulating proteins are more common than “beta-gamma” unit
regulation.
b. Target Proteins can be:
i. Enzymes that produce second messengers
ii. Ion channels that let ions be second messengers
6. Once target protein is activated, it relays a signal. As long as the Ligand is bound to GPCR, the
process above will happen repeatedly
7. GTP is hydrolyzed to GDP
a. GTP – lose a phosphate (hydrolysis) -> becomed GDP
8. Ligand will remove itself from GPCR. GPCR will have no ligand, g-protein is intact, but unattached
to GPCR.
a. Once other ligand removes itself from the GPCR, another ligand can then take its place.
b. Happens on its own.
c. RGS Protein – regulation of g-protein signaling, can speed up this step.
• EXAMPLE:
1. Epinephrine (ligand) binds to GPCR (Adrenergic Receptor)
2. GPCR (Adrenergic Receptor) will undergo conformational change
3. “alpha” subunit will swap GDP to GTP
4. “alpha” subunit dissociates from “beta” and “gamma” subunit
5. “alpha” subunit will seek target protein (Adenylate Cyclase) and activate it to regulate its function
6. Target Protein (Adenylate Cyclase) takes ATP (Adenosine Triphosphate) to produce cAMP (cyclic
Adenosine 3’-,5’ – Monophosphate
a. TP takes 2 Phosphates from ATP -> Monophosphate (cAMP)
b. cAMP – Second Messenger
i. Epinephrine undergoes the process and transformed into another signal – cAMP
ii. Be able to signal cells other activities such as:
1. Increase heartrate
2. Dilate blood vessels
3. Breakdown Glycogen to Glucose
G PROTEIN AND THEIR RECEPTORS AND EFFECTORS
➢ G protein coupled receptor have large extracellular ligands binding domain
• G protein ligands binds to its domain and undergoes Conformational Change
• Conformational Change is a change in shape of a macromolecule, often induced by
environmental factor.
• Trimeric G Protein is composed of a three sub-unit:
o Alpha
o Beta
o Gamma
ALPHA AND BETA SUBUNIT - have a covalently attached lipid tails.
ALPHA SUBUNIT - has a GDP bound if there’s is an absence of signal.
➢ When G Protein is inactive, it is associated with inactive receptor.
 ➢ (Activated receptor induces a conformational change in the alpha subunit causing the GDP to
dissociate GTP.)
o GDP - Guanosine diphosphate
o GTP - Guanosine Triphosphate (abundant in the cytosol)
• (GTP binding causes a conformational change in the g protein, activating the alpha subunit
and beta gamma complex)
• Activated alpha subunit —>dissociate —> beta gamma complex (Both activated components
can regulate the target protein from the plasma membrane)
TARGET PROTEIN - are functional biomolecules that are addressed and controlled by biologically
active compounds.
• Plasma Membrane - are the cell's constituents, often large, water-soluble, highly charged
molecules such as proteins, nucleic acids, carbohydrates, and substances involved in
cellular metabolism.
ACTIVATED TARGET PROTEIN - relay the signal to the other component to the signaling cascade.
➢ Signaling Cascade - known as “Biochemical cascade” or “signaling pathway” is a series of
chemical reactions that occur within a biological cell when initiated by a stimulus.
• (Alpha subunit hydrolysis its bond GTP to GDP which inactivated the subunits. It is accelerated
by the binding of another protein RGS)
• RGS - stands for “Regulator of G protein signaling” are protein structural domains that
function to activate the GTPase activity of heterotrimeric G-protein α-subunits.
• Signaling receptors remains stimulated as it continues to activate g protein.
• Receptors eventually inactivate
• A receptor kinase phosphorylate the cytosolic portion of the activated receptor.
• (Once the receptor phosphorylate, it binds to)
ARRESTIN PROTEIN - arrestins are a small family of proteins important for regulating signal
transduction at G protein-coupled receptors.
➢ preventing its interaction with g protein
• also acts as a adaptor protein and recruit the phosphorylated reception to clathrin coated pits
from where the receptor is endocytose.
• can be degraded to lysosome or activate a new signaling pathways.
Protein Effector
Gs ⬆️ INCREASE cAMP
Gi. ⬇️ DRECREASE cAMP
Gq Promotes the release of ip3 and
diacylglycerol to release calcium.
cAMP - Cyclic adenosine monophosphate
➢ a second messenger important in many biological processes.
➢ is a derivative of adenosine triphosphate (ATP) and used for intracellular signal
transduction in many different organisms, conveying the cAMP-dependent pathway.
IP3 - mobilize Ca2+ from storage organelles and to regulate cell proliferation and other cellular
reactions that require free calcium.
➢ refer as Inositol triphosphate

DAG - diacylglycerol
➢ help of the calcium released from the endoplasmic reticulum, activates the calcium-
dependent Protein Kinase C.
ALPHA RECEPTORS • Kidney
➢ Alpha 1: o Activation: lead to inhibition of
• (Gq) protein coupled receptor renin release (renin- an enzyme
• Activation causes stimulatory that is secreted by the kidney;
response involved in regulation of blood
• mediate increased intracellular pressure)
calcium Activation of Alpha 1 receptors lead to sympathetic
➢ Located: response.
• Vascular smooth muscle (main ➢ Alpha 2:
location) • (Gi) protein coupled receptors
o Activation: lead to • primarily located on presynaptic nerve
vasoconstriction Endings
• Dilator muscle of the iris o Activation: caused in decrease
o Activation: lead to mydriasis in production of intracellular
(dilation of pupil) cAMP
• Urinary sphincters • lead to inhibition of further release of
o Activation: lead to contraction norepinephrine
& urinary retention • found in pancreatic islets
• Liver o Activation: lead to insulin
o Activation: lead to secretion
glycogenolysis (breakdown of
glycogen to glucose)
BETA RECEPTORS: coupled with (Gs)
proteins o Activation: leads to relaxation of
➢ Beta 1: blood vessels (vasodilation)
➢ Located: • Smooth muscle in GI tract & uterus
• Heart o Activation: lead to smooth
o Activation: lead to increase heart muscle relaxation which results
rate; increase cardiac in GI decrease in motility; in
contractility; increase AV node uterus it causes in inhibition in
conduction labor
• Chucks of glomerular cells in the • Pancreas
kidney o Activation: lead to increase in
o Activation: lead to increase renin insulin secretion
release results in increase of ➢ Beta 3:
blood pressure ➢ Located:
➢ Beta 2: • Adipose tissue
➢ Located: o Activation: lead to increase in
• Lungs (bronchial smooth muscles) lipolysis (breakdown of stored
o Activation: leads to fats)
bronchodilation • Urinary bladder
• Vascular smooth muscle & arteries of o Activation: relaxation of bladder
Scutum muscle & prevention of urination
SECOND MESSENGERS
• Are molecules that relay signal from receptors on the cell surface to target molecules inside
the cell.
• They amplify the strength of the signal causing to change the activity of the cell.
• THEY ARE A COMPONENT OF CELL SIGNALING PATHWAYS.
• Earl Wilbur Sutherland Jr. discovered second messengers.
• Removal or degradation of second messengers terminate the cellular response.
FOUR CLASSES OF SECOND MESSENGERS
1. CYCLIC NUCLEOTIDE
➢ composed of three functional groups:
✓ sugar
✓ nitrogenous base
✓ single phosphate group
➢ 2 Types:
• Cyclic Adenosine Monophosphate (cAMP)
✓ synthesized by Adenyl Cyclase
✓ major secondary messenger
✓ activates protein kinase A
✓ mediates such hormonal responses as the mobilization of
a. stored energy (the break-down of carbohydrates in liver or
triglycerides in fat cells)
b. conservation of water by thekidney (mediated by vasopressin)
✓ Ex of cAMP action: Adrenaline, Glucagon, Luteinizing Hormone (LH)
• Cyclic Guanosine Monophosphate (cGMP)
✓ synthesized from GTP using guanyl cyclase
✓ response of the rods of the retina to light
2. PHOSPHOINOSITIDES (MEMBRANE LIPIDS DERIVATIVES)
➢ activated by G proteins
➢ hydrolysis ofphosphatidylinositol-4,5-bisphosphate(PIP2), splits into two second
messengers
a. diacylglycerol (DAG)
➢ stimulate protein kinase C
➢ inactivated by phosphorylated
b. inositol-1,4,5-trisphosphate (IP3 or InsP3).
➢ trigger the release of CA2+
➢ inactivated by dephosphorylation

3. CALCIUM (CA2+)
➢ most important and widely used messenger
➢ Acts in two ways:
a. Binds to an effector molecule – such as enzyme
b. Binds to intermediary cytosolic protein binding calcium – such as calmodulin
✓ Calmodulin – when activated causes contraction of smooth muscles
4. NITRIC OXIDE (NO)
➢ free radical that can diffuse through the plasma membrane & affect nearby cells
➢ synthesized from arginine and oxygen by the NO synthase
➢ activates soluble guanylyl cyclase, which when activated produces another second
messenger cGMP
➢ cause of many other functions like relaxation of blood vessels,apoptosis, etc.
 HYDROPHOBIC HYDROPHILIC GASES

•DAG •cAMP •NO

•cGMP
•IP3
•Ca2+

PHARMACOLOGIC ANTAGONIST
- any drug that binds to a
receptor and prevents the activation of
the receptor
COMPETITIVE ANTAGONIST
- binds to the receptor at the agonist binding site
- competes with agonist at the agonists binding site
NON-COMPETITIVE ANTAGONIST
- any pharmacologic antagonist that binds to a site on the receptor other than the agonist
binding site
- has its own site where it can deactivate the receptor
CHEMICAL ANTAGONIST
- Drug that binds directly to the agonist and deactivates the agonist
PHYSIOLOGIC ANTAGONIST
- Any drug or chemical that has an opposite effect but through completely
differentreceptors and physiologic pathways like histamine and epinephrine
- Example: histamine and epinephrine
PHARMACOKINETICS
- What the body does to a drug

PHARMACOKINETICS PROCESS (A D M E)
1. ABSORPTION
drug has to absorb and once it gets absorbed either through
skin or through stomach. Drug gets into your bloodstream and then from there it
gets distributed into the fluids outside and inside the cells.
2. DISTRIBUTION
Drug gets distributed all over the body. The body starts metabolizing it.
3. METABOLISM (in the LIVER)
The body starts metabolizing the drug. Modifying the drug so that it's easy to excrete this is
done primarily by a liver but it can also be done by other tissues
DRUG PASSES THROUGH LIVER GETS BIOTRANSFORMED AND FINALLY IT GETS
ELIMINATED.
4. ELIMINATION
Drug and its metabolites get excreted primarily in bile urine and feces

ABSORPTION DISTRIBUTION METABOLISM (Liver)

ELIMINATION

ABSORPTION
1. PASSIVE DIFFUSION
- Most drugs are absorbed by passive diffusion
- drugs move from area of high concentration to area of lower
concentration

EXAMPLE:
- water-soluble molecule will easily move through a channel or a pore that's in the
membrane
- lipid soluble will just easily pass through a membrane without any help

2. FACILITATED DIFFUSION
- When drugs especially larger molecules will pass with the help of carrier proteins
- also move from area of high concentration to area of low concentration
3. ACTIVE TRANSPORT
- transported across membrane via active energy dependent transport
- energy for this process is derived from ATP
- when ATP undergoes hydrolysis to ADP there is a high energy that comes from breaking
of a phosphate bond
4. ENDOCYTOSIS
- For drugs of very large size
- transported via engulfment by cell membrane
NOTE: ABSORPTION is a variable process depending on: (P S B)
- pH
- surface area
- blood flow

Note: A 100 milligram tablet taken orally is not absorbed a 100 percent. Because unlike a drug
taken intravenously, oral medication gets metabolized in the liver and a good portion of it gets
cleared out before it reaches systemic circulation.
A drug given Intravenously would start at a concentration of 100 percent because it bypasses
the whole absorption process.
A drug given orally would have to get absorbed first and then some of it would get eliminated
before it even reaches systemic circulation

AUC (Area under the ROC Curve)

- helpful in making comparisons between formulations and routes of administration

BIOAVAILABILITY
- AUC for the oral drug over AUC for the IV drug times 100
- fraction of unchanged drug reaching the systemic circulation following
administration by any route.
-

DISTRIBUTION
- dependent on factors such as
▪ lipophilicity - lipophilic drug will dissolve through some membrane
much easier than the hydrophilic drug next (LIPOPHILIC DRUG ,
HYDROPHILIC DRUG )

▪ blood flow - some organs such as the brain receive more blood flow
than other parts of the body. EXAMPLE: a drug can pass through blood -
 brain barrier it will accumulate much faster in the brain as opposed to in
the skin
BRAIN SKIN

▪ capillary permeability - capillaries in the liver have lots of slit

junctions through which large proteins unlike the brain that there are no
slit junctions at all.
LIVER BRAIN
▪ PLASMA & TISSUE BINDING - due to their chemical properties some
drugs will accumulate in some tissues more than the others
Example : Many drugs will bind to albumin which is a major drug
binding protein that will significantly slow the distribution process
ALBUMIN

▪ VOLUME OF DISTRIBUTION - theoretical volume that the drug would

have to occupy in order to produce the concentration that's present
in blood plasma

- can be calculated by taking amount of drug in the body and dividing it by

concentration of drug in blood plasma

- helps predict whether the drug will concentrate largely in the blood
or tissue
- helpful in estimating drug dosing

EXAMPLE: FOR high molecular weight drugs- tend to be extensively

protein bound and don't pass through the capillaries as easy as smaller
molecules thus they have higher concentration in blood plasma and lower
volume of distribution

For lower molecular weight drugs (lipophilic) s which will distribute

extensively into tissues and will result in larger volume of distribution.
NOTE: if drug has large volume of distribution, we would need to administer a larger dose
to achieve desired concentration

ELIMINATION - refers to clearing of a drug from the body mainly through

hepatic renal and biliary route
-
TOTAL BODY CLEARANCE = SUM OF INDIVIDUAL CLEARANCE PROCESSES
ELIMINATION OF DRUGS HAPPENS BY:
A. FIRST ORDER KINETICS - amount of drug eliminated over time is directly
proportional to the concentration of drug in the body

FOR EXAMPLE: starting with 1000 milligrams of a drug the amount eliminated per each time
period will be different but the fraction will be constant. so, in this example per each time period
constant of 16 percent of a drug gets eliminated. However, the milligram amount changes and if
we were to collect these samples and plot them the graph would produce a curve that looks

B. ZERO ORDER KINETICS

- amount of drug eliminated is independent of drug concentration in the body
Example: Aspirin

Rate Of Elimination Is Constant

FOR EXAMPLE: 1000 milligrams; this time amount of drug eliminated is the same per
each time
period which is 200 milligrams but the fraction the percentage is different and if we were to
graph it the zero order elimination would produce a straight line.

HALF-LIFE - time that is required to reduce drug concentration in plasma by a half

- can tell us a lot about duration of action of a drug
- also helps us predict steady state concentrations so when doses of a drug are
repeatedly administered a drug will accumulate in the body until the rate of
administration equals the rate of elimination
STEADY STATE

if after each additional dose the peak and trough concentrations stay the same we know we
reached steady state.
- attained in about 4 to 5 half-lives
- concentration of a drug must be high enough to be effective but not too high to be
toxic so the goal is to: maintain steady state concentration within therapeutic range

now there are situations

FOR life-threatening infections: to compensate for accumulation time large loading dose
can
be administered on treatment initiation to reach desired concentration more rapidly

IMPORTANT ROUTE OF ELIMINATION – KIDNEY - excrete drugs into the urine however
can't efficiently get rid of lipid soluble drugs as there passively reabsorbed

LIVER- comes to the rescue by transforming lipophilic drugs into water

soluble substances that are then easily removed by kidneys
lipophilic drugs water soluble substances

TWO METABOLIC REACTIONS OF THE LIVER:

▪ PHASE 1
▪ PHASE 2
PHASE 1 REACTIONS (OH-R OXIDATION,HYDROLYSIS, REDUCTION))
- makes a drug more hydrophilic
 - involve introduction or unmasking of a polar functional group
- oxidation
- hydrolysis
- reduction
- catalyzed by cytochrome p450 enzymes
- CONJUGATION REACTION – process where metabolites undergo from phase 1 if
they still too lipophilic. This involves addition of a polar group and this is what happens
in phase 2

PHASE 2 REACTIONS
▪ glutathione conjugation
▪ acetylation
▪ sulfation
▪ glucuronidation
- these reactions produce polar conjugates which cannot diffuse
across membranes SO they are easily eliminated from the body

CYTOCHROME P450
- large family of enzymes
- essential for the metabolism of drugs
- catalyze vast majority of phase 1 reactions
- many drug interactions arise from drug's ability to induce or inhibit these enzymes

EXAMPLES OF CYTOCHROME P450:

▪ CYP 3A4/5
▪ CYP 2D6
▪ CYP 2C8/ 9
▪ CYP 1A2

IMPORTANT INDUCERS : (P C R A B S)
▪ Phenytoin
▪ Carbamazepine
▪ Rifampin
▪ Alcohol with chronic use
▪ Barbiturates
▪ St. John's Wort
IMPORTANT INHIBITORS ("GPACMAN”)
▪ Grapefruit
▪ Protease inhibitors
▪ Azole antifungals
▪ Cimetidine
▪ Macrolides (exception of Azithromycin)
▪ Amiodarone
▪ Nondihydropyridine calcium channel blockers (Diltiazem and
Verapamil)

PHARMACOKINETICS QUIZ #2

When doses of a drug is repeatedly administered. The drug will accumulate in the body
until the rate of administration equals the rate of elimination – STEADY STATE

The amount of drug eliminated is independent of drug concentration in the body

so the rate of elimination is constant – ZERO ORDER KINETICS

Which among the route of administration is the most common, convenient and
undergoes first pass effect – ORAL

Which among the route of administration has the highest percentage bioavailability
– INTRAVENOUS

Which of the following is TRUE about drug distribution? – For lipophilicity, highly
lipophilic drug will dissolve through some membrane much easier than
hydrophilic drug

In Endocytosis – Drug of very large size get transported via engulfment by cell
membrane

Diffusion where larger molecules need help from carrier proteins – FACILITATED
DIFFUSION

Which of the ff. is not true – Lipid soluble molecule will easily move through a
channel or a pore that is in the membrane

Drugs get eliminated by – BILE URINE & FECES

The drug passes through the liver and get eliminated. FALSE. The drug tgat get
eliminated will then undergo biotransformation. FALSE. BOTH FALSE

Which of the following is true – Bioavailability means a portion of 100mg of tab will
be absorbed in unchanged form.

Defined as the fraction of unchanged drug reaching the systemic circulation

following administration by any route – BIOAVAILABILITY

The time required to change the amount of drug in the body by one-half during
elimination – Half Life

Relates to the amount of drug in the body to the concertation of the drug in blood
or plasma – Volume of Distribution

The fastest way to bring the drug in systemic circulation – INTRAVENOUS

QUIZ # 3

What is the name of the drug that inhibits sodium-independent transporter? –

HEMICHOLINIUMS

The product when epinephrine is metabolized by MAO – Dihydroxymandelic acid

The product when dopamine is metabolized by MAO – Dihydroxyphenylacetic acid

What enzyme converts dopamine in the vesicle to Noreph- Dopamine B-

hydroxylase

The enzyme that converts tyrosine to dopamine – Tyrosine hydroxylase

Edrophonium’s duration of action – 5-15 minutes

Which among the choices is Echothiopate used for? – Glaucoma

What is the effect of direct0acting cholinoceptor stimulants sphincter muscle of

the iris – Miosis

What is the effects of direct-acting cholinoceptor stimulants sphincters -

Relaxation