#1 VETERINARY PHARMACOLOGY AND
THERAPEUTICS
Pharmacology
• Greek: pharmacon means drug and Latin: logos
means study
• the science that deals with the origin, nature,
chemistry, effects, and uses of drugs; or interaction
with the living organism
Therapeutics
• Greek: therapeia means service attendance and
therapeuo means waited upon
• In medicine, the branch that deals specifically with the
treatment of disease and the art and science of healing.
• In pharmacology, therapeutics accordingly refers to
the use of drugs and the method of their administration
in the treatment of disease
• Fluid therapy – using fluid para mabalik kung ano
nawala
• Physical therapy – muscle na hindi nagagamit ay
pinapabalik in order to prevent muscle atrophy
History
Chinese emperor shenn-ung (2700 BC)
• Author of Shen-nung pen ts’ao ching
o Earliest extant Chinese pharmacopoeia
o This includes 365 medicines derived from
minerals, plants and animals
o The true authorship of this work is still
unknown
o This is the divide husbandman’s materia
medica
• Father of Chinese medicine and introduced
acupuncture
o Acupuncture is specific in small animal
medicine
• Pro animals
o this legendary emperor taught his people how
to cultivate grains as food, so as to avoid
killing animals
Ancient Egypt Kahun Papyruse
• one of the largest manuscripts dating from the late
Middle Kingdom
• dinedescribe nito kung ano ginagawa sa nakikita nil
ana problema sa isang tao
• Examination of a woman whose eyes are aching till
she cannot see, on top of aches in her neck:
• You should say of it 'it is discharges of the womb in
her eyes'.
• You should treat it by fumigating her with incense and
fresh oil,
• fumigating her womb with it, and fumigating her eyes
with goose leg fat.
• You should have her eat a fresh ass liver
Ebers papyrus ancient Egypt
• one of Egypt’s oldest and most comprehensive
medical documents which contains a wealth of
medical knowledge.
• 800 prescriptions for salves, plasters, pills
suppositories and other dosage forms
Hippocrates
• father of Medicine
• conducted systematic observations of patient’s
symptoms
• transitted from medicine as an art to systematic
clinical science
Materia medica
• compilation of therapeutic substances by Dioscorides
in 77AD
• serves as basis for works of Galen.
Paracelsus
• Philippus Aureolus Theopastus Bombastus von
Hohenhein
• Grandfather of Pharmacology
• “All substances are poisons; there is none which is not
a poison. the proper dose separates a poison from a
remedy”
Veterinary Pharmacology
• study of the properties of drugs and all aspects of their
interaction with living organisms pertaining to
animals.
• response to epidemics of diseases in Netherlands such
as Rinderpest.
o Rinderpest is a cattle place
Purpose of Veterinary Pharmacology
• to test drugs quantitatively and standardise to be
available in a uniform and dependable form
• to determine how drugs produce their effects on the
animal body
o as well as the human body as vets are also
responsible of the public health.
▪ Sakit ng animals na nakakahawa sa
tao
▪ Vets have the responsibility to
euthanize or cull
• to develop new drugs
o penicillin cured gonorrhea
▪ gonorrhea is considered to be highly
curable
o Alexander Fleming – discovered penicillin
▪ "The thoughtless person playing
with penicillin treatment is morally
responsible for the death of the man
who succumbs to infection with the
penicillin-resistant organism. i hope
this evil can be averted."
• to establish rational and safe dosage
Veterinary Toxicology
• “science of safety”
• pharmacology is the study of drugs used at doses to
achieve therapeutic effects on an organism, while
toxicology is the study of toxicants that produce
harmful effect on an organism.
• Known as translationational sciences such as Pharma-
toxicology
o In regards of veterinary toxicology,
pharmacology and toxicology goes hand and
hand
o Pharmacology is for the drug which is for the
good effects and toxicology is for the bad
effect.
o Pwede na yung drug eh magresult sa good
effect pero pwede magproduce ng bad effect
kapag mali yung dosage na naibigay
o Pharmacology is under niya yung toxicology
• pharmacology — science knowledge —— drug action
and fate — clinical therapy
o ex: Ehrlichiosis – blood parasitism
▪ meron kang knowledge about this
and meron kang clinical observation
about don sa patient
▪ thus, alam mo yung magiging drug
of choice mo
 ▪ so, kaya mo binigay yung drug kasi
alam mo yung magiging effect nung
drug or the drug action and fate nito
sa pasyente kaya yun yung binigay
mo na clinical therapy
▪ ung clinical therapy yung kung ilang
araw mo itetake yung gamut para
maging okay yung pasyente.
• toxicology — knowledge science — fundamental
science — safeguard animal health, public health and
environment
o example is kapag may drug residues and
meron tinatawag na withdrawal period sa
farm animals
▪ kunwari tuturukan yung farm
animal, merong withdrawal period
bago siya katayin ganon
▪ if nakatay during that period, pwede
magkaroon ng drug residue
▪ etong drug residue eh pwede
maconsume ng tao which is
magiging harmful sa kanila.
• basic research in toxicology is the prerequisite
inassessing emerging risks in the process of
developing drugs, chemicals, and materials
• “One World, One Health,
Divisions of Pharmacology
1. Pharmacodynamics – how drugs produce effects on
living organism; where and how drugs are disposed of
in the body
• This is the pharmacological effect, clinical
response, and toxicity
2. Pharmacokinetics – subdivision of
pharmacodynamics
• Study of the processes and factors
determining the amount of drugs at the sites
of actions at various times following
administration
• Eto yung nakikita sa clinical practice
o dose of drug administered
o drug concentration in systemic
circulation
▪ drug in tissues of
distribution
▪ drug metabolized or
excreted
▪ drug concentration at the
site of action
3. toxicology – study of harmful effects of drugs
4. pharmacotherapeutics – application of drugs for use
in the diagnosis, prevention and treatment of diseases
5. pharmacy – the art and science of preparing,
compounding and dispensing of drugs
a. pharmacognosy – sources of drugs
b. posology – drug dosage
c. metrology – deals with weights and
measures used for the computation of drug
dosages
Categories of pharmacology
1. molecular pharmacology – deals with the basic
mechanisms of drug action in biological systems
• in order to understand this, you need to
understand also the clinical pharmacology
2. Clinical pharmacology – development, effective use
and the proper evaluation of drugs for the diagnosis,
prevention and cure of diseases
3. Veterinary pharmacology – drugs used in the
prevention and treatment of animal diseases and the
intentional alteration of animal physiology
Medicine, Drugs, active ingredients
- prescription medicine — active ingredients (also an
inactive ingredient) — usually a chemical of known
structure —— drug
Drug – a chemical agent other than food that affects living
organisms.
- has side effects depending on dosages
- hindi kapareho ng food na kailangan mo laging itake
or ibigay
o kapag kailangan lang binibigay at kung may
kailangan ayusin
- any substance, food or non food that is used to treat,
cure, mitigate, or prevent diseases or any non food
substance that is intended to affect the structure or
function of the individual.
- Star of pharmacology
- Ex: deworming
o every 3 months maintenance deworming kasi
kasi dinidilaan niya yung pwet ganon, hindi
nahuhugasan after tumae, tas may contact sa
ground
o frequent na 2 months, if related sa nakakain
if raw food ganon
Food – an article use for food and drink for human and other
animals that provides tastes, aroma and nutritive value
- presumption of safety.eat too much (feel sick); gain
weight
FoodDrugs – alcohol
- intoxicating drug effects and prevention of coronary
diseases
- coffee and tea are medical antioxidants
o caffeinism is the drug addictive property
Drug Action – drug’s response when administered to living
organisms (useful or harmful)
- where and how the effect is produced
Drug effect – what is produced by the drug
- drug action and drug effect are mutually dependent. To
demonstrate and measure a drug effect on a certain
biologic system, the system should include both the
site where the drug acts and the site where the effect
can be observed.
❖ Overdose vs underdose, what is less evil?
o Less evil is overdose kasi kapag underdose,
hindi lahat ng worm ay mapapatay
❖ Minor and major duodonal – dito lumalabas ang mga
bile and other enzymes that will determine the liver
insufficiency
Physiological effect – maintains normal body functions
Pharmacological effect – alteration in the normal body
functions
❖ water – our body is composed of mostly water, if there
is an imbalance of this in our body, there will be
physiological effect.
o Ex: edema
❖ Hemeorrhesis – Tendency to maintain a biological
process, such as growth, along a particular pathway
o follows the strategy of 'positive feedback'
which reinforce the change that is occurring
rather to oppose a change in the internal
environment and causing body environment
to return to normal
▪ ex: childbirth
❖ Homeostasis – mechanism that maintains a stable
internal environment despite the changes present in the
external environment.
o follows a negative feedback which produce
an actions that is opposite to the change that
activated the system
 ▪ ex: temperature: oppose a change
(such as a drop in temperature) by
creating heat or having fall in
temperature below a normal set
point
Selective Toxicity – A dose of a drug maybe poisonous to one
organism but not to another.
- basis for chemotherapy.
o Chemotherapy – use of chemicals to kill or
inhibit infective or parasitic living organisms
(pathogens) which produce disease in the
host (patient)
- Mechanism of Pteridine
- This is found in bacteria
- Ginagawa ng drug (sulfonamides) eh pineprevent niya
yung Dihyderopteroate synthetase para yung PABA
eh di na maging Dihydropteoic acid
- Trimethoprim inhibits the Dihydrofolate reductase
para di na maging tetrahydrofolic acid
#2 INTRODUCTION TO DRUG-RECEPTOR
INTERACTION

- Drug receptor interaction – for the enzymes

- If we give arsenical, it will act on isomerase, G6P
phosphatase, mutase, phosphatase (liver)
o Kapag mali ang dosage na binigay, pwedeng
matamaan yung mga nabanggit and it can
produce adverse effects
- Same goes with cyanide dyes/berzimidazoles which
reacts naman to glucose
Categories of Chemotherapeutic Drugs
- antibacterial (vs bacteria)
- antiviral (vs viruses)
- antifungals or antinycotics (vs fungi)
- antiprotozoan (vs protozoa)
- antineoplasms (vs cancer cells
- antihelminthics (vs parasitic worms)
“Drugs do not create new functions in living organisms. They
may only enhance or reduce the functions which are inherent in
the organisms. the effect of the drug therefore quantitative
o This is necessary to produce biological
functions
- drugs will interact on ligands (can be an ion or what)
and signals the macromolecular component (receptor)
and because of the interaction then there will be
biological functions
- in pathology, the biological functions sometimes has
no modification or has modification
- a receptor can be an atom then undergoes
polymerization in order to become macromolecules
o when it becomes a receptor, it should possess
some criteria
▪ strong affinity to drug
▪ possible with complementary
▪ structures of the drugs
- drugs interact to the receptor in order to produce
pharmacological functions
- in terms of receptor, we have a substrate enzyme and
complex
o same complex in terms of drug interaction
Drug receptor groups

never qualitative.”

- If nabubulag ang patient, maybe diabetes

o nanlalabo because of sugar ganon
o then bigay ng drugs, pero hindi macecreate
ng new functions or mapapalinaw ang mata
- Nasty habits – gamut sa aso na kumakain ng tae dahil
sa boredom

- the picture above is a lipid bilayer; channel in the

phospholipid
- the blue one is the receptor
- Acetylcholine (ACh) is the ligand and it should have
a strong affinity to the ligand-binding site and should
fit to the structure in order to be pharmacological
receptor
o if the 2 interacts or signal, there will be
modification for the receptor or
 magchechange yung structure para yung
sodium channel ay mabuksan at makapasok
sa cell ang sodium
- Symport – two ion moves in the same direction
- Antiport – two ions moves in the opposite direction

endogenous ligands – fit receptor exactly

- can be a neurotransmitters or hormones

- ex: Ach
- includes:
o hormones
o neurotransmitter
o growth factor
o autacoids
o nucleic acids

exogenous ligands – drugs and toxins from outside the body

- usually do not fit the receptor exactly.

- Includes:
o enzymes – catalyzes the reaction
o transporters
o channels
o structural proteins - RAA – renin angiotensin aldosterone
- hypotension – associated sa blood pressure
Channels - hypovolemia – blood itself
o regards to the volume and pressure of blood
- DIGOXIN – digitalis glycoside
o Ex: bumababa yung pressure
o Increase contraction and decrease rate is the
pharmacological effect of the drug
- FOXGLOVE – Digitalis purpurea

- kapag nagkaroon ng angiotensin II magkakaroon ng

- DIGOXIN interacts on the channel
o digoxin acts on the channel which is
associated with the sodium and potassium
channel
- blocks the na/k ATPase pump by binding into it and
inhibits their activity
- causes the cytosolic Na+ concentration to remain
higher, which in turn disrupts the Na+ gradient needed
to operate the Na+/Ca exchange pump
- a greater concentration of cytosolic Ca then occurs
inside the cell with digoxin, thereby allowing for a
Autacoids
greater degree of binding to troponin C and eventually
myosin/atin binding thus allowing for a greater force
of contraction
o troponin C is the Ca binding subunit of
troponin which initiates contraction
- How is heart rate related to contraction?
o heart rate is inversely proportional to
contraction
vasoconstriction
- then kapag may vacoconstriction mas lalakas yung
pressure – this is the pharmacological effect
- then mapepreserve na yung blood and steady state ng
hypotension or hypovolemia
- sometimes, napapasobra ang blood pressure, then
magbibigay ng drug na ACE (angiotensin converting
enzyme) inhibitors
- ACE inhibitors inhibits Angiotensin converting
enzyme para maprevent yung Angiotensin I to convert
into Angiotensin II.
o Kapag walang Angiotensin II, there will be
no vasoconstriction
- Biological molecule that acts like a hormone in short
duration
- Ex: Histamine (Histidine aa)
o Benadryl – Anti-histamine drug

Enzymes

- hazen the reaction

- Mast cell releases histamine for immune response

 - histamine is coming from the mast cell which is a
response in inflammation para magkaroon ng healing.
dahil nga sumosobra, nagkakaroon ng inflammation
o if may allergy, magiinteract sa H1 na
magcocause ng itching,
o if hindi makahinga , magiinteract to sa H1 na
magcocause sa broncho-constriction
- kapag sa H2 nag-interact ang histamine, direct sa
blood vessel
- if sa H1 peristalsis or sa intestine – if mabilis yung
peristalsis, hindi maabsorb ang nutrients
- anti-histamine – against histamine
o extensive ang pangangati, hindi na
makahinga, nagtatae na
o it interacts sa receptor (H1 or H2) then hindi
na magpoproduce ng pharmacological effect
Nucleic Acids
Hormones
- cancer – abnormal multiplication of cells
o ang ayaw ay cell mitosis
- anti-cancer drugs (hydroxyurea) - these drugs act on
the enzymes of nucleotides (receptor)
o then these will not act on DNA to produce
cell mitosis
Neurotransmitter
- ACh - brain food
o calcium - sliding filament muscle
o action potential cause the release of ACh
- Neurotransmitter – can be considered as a drug
- if the muscle is not contracting, ACh can be given in
order to cause contraction (pharmacological effect)
- if there is no ACh, no opening of channels, no calcium
released, then no contraction
- muscle fatigue - can cause paralysis
o if there is too much ACh, magcocontract ng
magcocontract yung muscle then it will cause
muscle fatigue then paralysis
- if ang aso nanganak, nagbibigay ng calcium kasi kapag
nanganak, yung uterus nila eh nagcocontract then
gumamit ng calcium, then milk let down, then
mawawalan ng calcium. then, magkakaroon ng
eclampsia (panginginig) then post-partum tetani
o hindi pwede bigyan ng calcium ang pregnant,
magreresult ng contraction edi malalaglag
yung anak
- CURARE – acts as a muscle relaxants in anesthesia
o it interacts on Ach receptor
o kapag nag-interact, there will be no
contraction and no pharmacological effect.
- androgen receptor - for musculine
o androgen will interact to the androgen
receptor causing excess sebum
o then you will give a drug (hormone) na mag-
ooccupy sa androgen receptor para di na
magproduce ng excess sebum
 - THC = Tetrahydrocannabinol

Remember: not all drugs require receptor to produce effect

- oestrogen - increase division of cells Examples: anesthetics, antacids, chelators, osmotic

o oestrogen will interact to oestrogen receptor agents
then the cell will undergo cell mitosis
- tamoxifen – interact to the oestrogen receptor then
there will be no pharmacological effect para
magsisignal sa cell na magdivide

Drug receptor families

1. cell membrane embedded proteins

2. ligand gated ion channel
3. g-protein coupled receptor systems
4. transcription factors

Lock and Key Concept

- active site's structure is complementary to the structure

of the substrate.
- enzyme's active site (lock) is already in appropriate
conformation for the substrate (key) to bind
- substrate easily fits into active site - mannitol – sa osmosis
- no alteration is needed upon binding of substrate o drug na nagpapaihi
- Each receptor has a distinctly shaped part that - kidney processes:
selectively recognizes a particular chemical o filtration
messenger. A neurotransmitter fits into this region in o reabsorption
much the same way as a key fits into a lock. o secretion
o excretion

Drug Activity

Affinity – ability to fit in receptor

Efficacy – ability to open lock-cause effect; this is the intrinsic

activity

- pag mali ang shape, hindi makakapasok yung lock

o turning of the key eh modification ng
receptor complex Ligands

Structure Activity Relationship Agonist – mimics effects of endogenous compounds

- complementary sa receptor
change in - high affinity and efficacy
modification change in
chem - then mamomodify yung receptor by having an arrow
of interaction intensity of
structure of
with receptor effect Antagonist – blocks action of agonist
drug
- ipeprevent ang formational change
- kapag nagkaroon ng change sa chemical structure ng
drug upon interaction ng ligand and receptor,
magkakaroon ng modification which then leads to a
change in the intensity of effect.
 Types of Antagonist

1. Reversible competitive – drugs that bind to the same

site as the natural ligand, agonists, or partial agonist,
and inhibit their effects.
o direct competition, antagonist will interact sa
mismong agonist receptor site

Types of agonist

1. full agonist – able to fully bind to and activate their

cognate receptor, thereby inducing the complete
response capable of that receptor
o fit na fit, high affinity and efficacy
2. partial agonist – bind to the cognate receptor;
however, they only induce a partial response
o hindi parehong pareho yung structure pero
yung affinity is buo parin pero deminished na 2. Non-competitive – drugs that bind to a different site
yung effect on the receptor than the natural ligand, agonist, or
3. inverse agonist – binds to the same receptor as an partial agonist, and inhibit the biological function of
agonist; however, it exerts the opposite biological the receptor
response of an agonist.
o decreased efficacy
o pinapababa yung intrinsic efficacy

3. Irreversible – arises from covalent modification of

the receptor
o antagonist blends irreversively to the
blending site
o different induced fit means that the receptor
is not activated
o covalent bond is formed between the drug
and the receptor
o messenger is blocked from the binding site
o increasing messenger concentration does not
reverse antagonism

properties of agonist

1. acute signalling
2. desensitization
3. sequestration
4. resensitization

Dualist – an agonist acting on specific receptors with certain

magnitude of intrinsic activity, is a competitive antagonistic to
another agonist with greater intrinsic activity and is acting on
same receptor

- ex: Mepyramine. Brain and antihistamines Affinity Intrinsic Effects

❖ Silent receptor – ability to bind chemokines with high activity
affinity in the absence of any demonstrable signaling Agonist Check Check Check; even
function without
 endogenous o Kapag nauna si antagonist, hindi na
ligands makakapasok si agonist
Antagonist Check Cross Check;
competitive endogenous
agonist
Antagonist Check Cross Check
non-
competitive
Dualist Not
agonistic
and
antagonistic

Drug Receptor Interaction for irreversible antagonism

Covalent Share pair of -- Irreversible

electrons , broken by
increase
temperatur
e
Ionic bond Coulomb -- --
forces/electrostati
c
Hydrogen Proton accepts Weaker --
bond electron pair than
covalent
, but
stable
with - In non-competitive antagonism, may sariling site
many H yung antagonist and agonist.
bond o Pero, kapag nagbind yung antagonist sa
Intermolecula Binds between Weakest -- receptor, babaguhin niya yung shape ng site
r forces/Van dipoles kung saan magbabind yung agonist so, di na
der waals siya makakapasok
- Antagonist: phenoxybenzamine and propranolol
#3 STRUCTURE ACTIVITY RELATIONSHIP (SAR) accounts for low blood pressure
- Agonist: norepinephrine and isoproterenol accounts
for high blood pressure.

- The mechanism of action of these: Carbaryl, Gearing

and Petgard is the nhibition of acetylcholinesterase
o Acetylcholinesterase is an enzyme
associated to the acetylcholine and esters

Cholinergic Transmission

- in order to have biological functions, the drug first

needs to bind to a ligand. Then, the ligand interacts
with the macromolecular component, the receptor,
which will then result to biological functions.
- in the picture above, the agonist is the isoproterenol.
o If it binds to the receptor, it will result to a - Ach (agonist) interacts with the receptor in order to
high blood pressure produce pharmacological effect (contraction)
- The antagonist is the propranolol - It interacts on the cholinoreceptor in order to contract
o If it binds to the receptor, it will result to a the muscles
low blood pressure. - CURARE is the antagonist
- So, in the case of competitive antagonism, same site o Competitive antagonism
nagbabind yung antagonist and agonist.
 o Kapag nagbind yung CURARE, magsstop na
yung muscle contraction
- If you give more acetylcholine, mas mataas yung
chance na yung acetylcholine yung mag-occupy sa
receptor kasi mas marami sila
o Binibigay ito kapag nagkaroon ng muscle
paralysis
o Yung drug na ganto ay tawag ay
acetylcholinesterase inhibitors like yung mga
petgard shampoo on the image below.
- Botulinum (botox) is an enzyme that cuts SNARE
proteins and inhibits release of ACh
o So, ang ginagawa eh magrawrap yung
SNARE proteins sa botulinum then
mapuputol yon.
o Kapag naputol, edi di na makakapagproduce
ng ACh
▪ No ACh = reversible chemical
denervation or paralysis

- In a normal neuron, we have synaptic vesicle that

contains ACh and we have vesicle associated
membrane protein or the V-SNARE (Synaptobrevin)
and we have the terminal associated membrane
proteins or the T-SNARE (SNAP-25)
- Kapag nagbind yung mga SNARE proteins, it allows
the docking of the vesicle and the release of ACh
- In terms of the botox, pinuputol niya yung SNARE
proteins para di magdock yung vesicle sa cleft
- Choline is being transported into the presynaptip cell
and it binds with acetyl-CoA which is coming from the
mitochondria to form acetylcholine
- Acetylcholine then gets transported sa vesicle and para
marelease yung nasa loob ng vesicle papunta sa
synaptic cleft two things need to happen:
o Action potential comes down and i-open niya
yung voltage-gated calcium channel and we
get the influx of calcium into the cell
o Which then leads to the interaction of the
SNARE the proteins:
▪ V-SNARE – vesicle associated
membrane protein (VAMPs)
• Aka synaptobrevin
▪ T-SNARE – Synaptosome-
associated proteins (SNAPs); this is
the nerve terminal
- CURARE and OP (organophosphate) cause muscle
• Aka SNAP-25, synatxin
paralysis, but different mechanism of action
▪ If the SNARE proteins (docking
o Organophosphate (OP) acts on the
proteins) interacts, it allows the
acetylcholinesterase (receptor)
expulsion of the Ach
▪ Dadami yung acetylcholine,
(neurotransmitted) into the synaptic
magcocontract ng magcocontract
cleft
yung muscle thus leading to muscle
- After the acetylcholine is out, hindi siya nagtatagal
paralysis
kasi mamemetabolize siya agad ng acetylcholine
esterase (ACHe) into choline and acetate Structure Activity Relationship (SAR)
o ACHe acts on Ach to form choline + Acetate
o ACHe is the primary determinant of the - used in characterizing drug receptors relationship,
duration of action of the Ach correlation, and independence between the molecular
structure of drugs and their receptors
Important points: o so, dito eh inaassociate mo na yung chemical
- So, different drugs that we give that act like ACh, groups or yung chemical structure
- Determination of the chemical groups evokes a target
they’re going to have different sensitivities to the
biological effect in the organism
acetylcholine esterase
o Chemical groups yung functional groups
- If we block AChE, we can indirectly increase the
- Quantitative SARs (QSAR) as a special case of SARs
levels of ACh specifically sa nerve terminals
(when relationship became quantified)
o Increase ACh = increase binding in
cholinoreceptor
Quantitative SAR (QSAR)

- Attempts to find consistent relationship between

variations in the values of molecular properties and the
biological activities for a series of compounds so that
these “rules” can be used to evaluate new chemical
entities
- 3D QSAR is the most powerful technique available for
analog based drug design

History

- So sa SAR, tinitignan na yung structure ng drug, for
example yung tamoxifen, and titignan yung pag-
interact nito sa receptor then if yung result ba eh
nagkaroon ng modification or not
Brown and Fraser – “many compounds containing tertiary
amine groups became muscle relaxants?? When converted to
quaternary ammonium compounds”
- Sinabi lang dito na kapag daw yung tertiary amine
group naging quaternary compounds, magiging
muscle relaxant to.

- Estrogen receptor (ER), a nuclear steroid hormone

receptor
- Estradiol (agonist) – if magbind siya sa ER
magkakaroon ng modification that can lead to
Klinefelter syndrome. This syndrome results in
smaller than normal testicles, which can lead to lower
production of testosterone
- Tamoxifen (antagonist) – eto yung drug na ibibigay
mo in order to decrease the affinity of the agonist - Nareject yun kasi gawa ng nadiscover yung structure
(estradiol). Then, maiinhibit yung estrogen-responsive of the native compound for muscle which is the ACh
genes na pwede magcause ng klinefelter syndrome. - Kasi hindi naman muscle relaxant ang muscle, eto
yung nagpapacontract ng muscle.

- “Molecules that block the effects of natural

neurotransmitters (acetylcholine, glutamate, CCK)
generally are larger in size than the native compound”
- Same lang dito, kapag nagbigay ng drug na mag- o Ex: CCK antagonist, memantine (antagonist
iinhibit sa estrogen like tamoxifen, mapeprevent yung for glutamate)
estrogen to bind to the oestrogen receptor. If naprevent
ito then mapeprevent yung breast cancer.
 ▪ gives an idea about to which side the
equilibrium is favored

- Weak acids are more absorbed in acidic environment

- Same sila ng structural features, pero yung
arrangement and chemical functional groups yung
magdidictate nung magiging effect nila
such as the stomach
o Mas gusto ng stomach ang acidic, yung mga
protonated ganern
- So, mas maaabsorb ang drug kapag HA
- Reaction niya is forward

General Procedures in SAR Study

1. Identification of appropriate biological response to a

prototype or parent drug
2. structural modification of prototype drug (removing,
adding, substituting chemical groups)
3. Listing of modified compounds —- CONGENERIC
- Weak bases are more absorbed in alkaline
SERIES
environment such as the intestine
4. Identification of the pharmacological response of each
- So, mas gusto niya yung RNH3 kaya backward
series comparing to parent drug
reaction
2. Water solubility of drugs
o Affects the routes of administration
o Depends on structure and solution conditions
▪ Lipholicity – in drugs, we want
lipophilic (fat-loving) and
hydrophobic (water-fearintg) para
maabsorb agad.
• Kasi cell membrane is
made up of lipid (fats)
bilayer
• So, mas maaabsord ng cell
yung drug kasi
magiinteract agad yung
drug sa cell membrane and
iiwas siya sa water so di
siya ma-eexcrete.
• If we want to excrete drugs
naman, we want
lipophobic (fat-fearing)
- Yung parent drug is the original structure, for example and hydrophilic (water-
yung epinephrine loving)
- Then, babaguhin mo yung structure non, either • Para di mag-interact sa cell
magreremove ka ng functional group or what, or you membrane and pwede siya
can add something or substitute – eto yung congeneric ma-excrete through
series osmosis
o Then, magiging ephedrine and ▪ Hydrogen bonding
metamphetamine ▪ Molecular volume
- Then, titignan mo yung magiging biological response ▪ Ionizability
nito. ▪ pH
- Then, compare mo yun naging response sa response ▪ cosolvents
ng parent drug ▪ additives
o Naging better ba or what ▪ ionic strength
Physiochemical properties of Drugs ▪ time
▪ temperature
1. Acid-base properties – quantitatively predict the o poorly soluble compounds can reduce
degree of ionization of a molecule by knowing if the productivity in drug discovery and
functional groups are acidic or basic in a given pH development
o pH – measure of the hydronium ion
concentration in a particular aqueous solution Complications:
▪ scale that can be used to measure the ▪ compound precipitation during
acidity or basicity in a solution serial dilution in buffer, biochemical
o pK – inherent property of a compound or assays, functional and cell assays.
functional group • Assays – determination of
▪ related to the degree of being an acid
the potency of a drug or
other substance by
 comparing the effects it
has on animals with those
of a reference standard.
▪ Reduce target specificity
▪ Low bioavailability in animal
studies
3. Stereochemistry
4. Electronic parameters
Predicting water solubility
Empirical approach – based on Carbon solubilizing potential
of several organic functional groups
- Intramolecular interaction = reduce water solubility
- Partition coefficient – extent of distribution of drug
between the oil phase and water phase; high P value,
more hydrophobic, more or less permeable
o Low P value, lypophobic, hydrophilic
𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑜𝑐𝑡𝑎𝑛𝑜𝑙
𝑃=
𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑎𝑞𝑢𝑒𝑜𝑢𝑠 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛
o Log P – functional groups (hydrophobic +
hydrophilic characteristics); measure of the
solubility of entire molecule
▪ Predicts water solubility
- Kapag hydrophilic drug, mabilis magpapass sa cell
membrane
- Kapag hydrophobic, maaabsorb siya sa cell membrane
- Kapag very hydrophobic, mas maaabsorb siya sa cell
membrane and matagal yung epekto niya kasi matagal
siya bago maexcrete
- Pinapakita lang dito yung passage ng solute
- So, sa simple diffusion, no need na ng mga channel
diretso pasok lang
- Sa channel-mediated diffusion and carter mediated
diffusion through passive transport sila, no need for
energy pero need ng channel to pass through the
membrane
- Sa active transport, need ng energy and channel to pass
through
Stereochemistry and drug action
Physiochemical properties of a drug molecule depends on:
1. Functional groups in the molecule
2. Spatial arrangements of the groups
Easson and Stedman hypothesis – also known as the three-
point attachment theory, a theory which proposes that three
groups or moieties in a drug molecule must simultaneously
interact with three complimentary sites on the receptor
molecule.
- Determination of pharmacophore – may mga three-
point fit na meron lang specific na functional group na
magfifit don
- Also known as three-point fit
Electronic parameters
- CHARGE – sum of partial charges
o intermolecular forces
- Apol – sum of atomic polarizability
- HOMO – highest occupied molecular orbital enegy
- LUMO – lowest unoccupied molecular orbital energy
- Small hydrophobic molecules: O2, CO2, N2, benzene
can easily pass through the lipid bilayer
 - Small uncharged polar molecules: H2O, glycerol,
ethanol can easily pass through the lipid bilayer
- Larger uncharged polar molecules: amino acids,
glucose, nucleotides and IONS: H+, Na+, HCO3-, K+,
Ca2+, Cl-, Mg2+ cannot easily pass through the lipid
bilayer

Drug Families – composed of member drugs that act on

specific receptors that produce same kind but different
magnitudes of effect

o So, may sukat kung ano yung maximum na

pwede maano nung drug
o For example yung peanut M&Ms eh pinakain
sa aso, di siya agad-agad mamamatay ganern
kasi may certain point bago mareach yung
toxicity
o If tama naman yung sukat nung bigay nung
owner, di siya magiging toxic.
- families of antagonist derive their names from
typical or antagonist derive from corresponding
agonist
- Yung drug 1, 2 and 3, will act on the same receptor o Antihistamine (vs. Histamine)
pero yung biological effect nila is magkakaiba o Anticholinergics (vs. Acetylcholine)
o Adrenergic blocking agents (vs adrenaline
Naming of Drug families
nor adrenaline)
- typical members of the group o Barbiturates (derivatives of barbituric acid)
o Atropine like agents
o Adrenergic stimulants
o morphine derivatives
o Barbiturates (derivatives of barbituric acid)

o Codeine and Morphine are in the same

family, but different in magnitude
- chemical structures
o Benzodiazipines
o Kapag binigyan ng anti-histamine,
o Nitroimidazoles
mabablock nito yung histamine receptor by
o Salicyclates
inhibiting it then marereduce na yung allergic
o Salicylanilides
reaction (pharmacological response)
o Xanthine derivatives
- members of their corresponding agonist

Drugs having similar indications or clinical uses may not

necessarily constitute a drug family

- ex: Atropine, attapulgite and loperamide are all used

to control diarrhea but each belongs to a different drug
family

#4 DOSE RESPONSE RELATIONSHIP

Dose – amount of a substance administered at one time

- kinocompute ito para sa pasyente kaya kinukuha yung

body weight

Dosage – amount per unit weight of the exposed individual

o Nag-add lang sila ganon sa original chemical - predetermined na ito, eto yung nakalagay sa gamut
structure then nagkaroon na sila ng different o ex: 125mg per 5 mL ganern
effect.

- so yung dosage, eto yung kunwari sa Dog/Cat: 10-
15mg/kg oral BID
o eto yung pagbabasehan mo para makuha
yung dose.
o So kapag mali yung dosage, kunwari bumaba
edi hindi magiging effective.
o Kapag tumaas naman, magiging toxic yon sa
pasyente
- Sa dose naman, need mo kunin yung body weight para
malaman yung tamang dose. After non, edi yun na
o If mali yung dose, pwede yun maging toxic
sa pasyente.
o kinocompute: ex. 5kg dog and u want to use
10-15 mg/kg
▪ so mumultiply lang, 5 times 10 =
50mg
▪ then, gagamitin mo eh liquid kasi di
mo mahahati capsule
▪ tas convert mo 50mg to ml ganern
basta lalabas 2.5ml
- terms:
o BID – twice a day
o Q12h – every 12 hours
Dose Response Relationship
- systemic description of the magnitude of the effect of
the drug in relation to the dose
o eto yung intensity
o kapag ba binigyan ng dose na ganito eh how
intense ba yung magiging epekto
- Describes the change in the effect of an organism
caused by differing levels of exposure (DOSES) to a
stressor (chemical) after certain exposure time
- So, dito titignan mo na yung intensity ng drug
- Kapag ba binigay mo kunwari ng particular drug,
madodouble ba yung intensity? Ganon.
- Edi sa picture, di ba 5 yung drugs na magbabind sa
ligand then, mag-iinteract sa receptor, titignan mo
kung gaano kaintense yung epekto (modification or no
modification)
- If for example, yung drug is alcohol. May certain point
kung saan magiging tipsy ka ganon
- So same lang sa dose, kapag ba tinaasan yung dose ng
particular drug, ano ba magiging epekto nito. Kasi di
ba, pwedeng iba yung maging result sa iba’t ibang tao.
- As per example nga yung sa alcohol, iba yung epekto
ng alcohol level ng normal brain (yung mga di
manginginom) sa mga addicted brain (yung mga
malalakas mag-inom)
2 types of DDR
1. Graded Dose Response Relationship
2. Quantal Dose Response Relationship
Graded Dose Response Relationship
- As the concentration of a drug increases, its
pharmacological effect also gradually increases
until all the receptors are occupied (the maximum
effect)
- It is directly proportional to the maximum effect
or up to the extent
- Kapag grinaph to ang tawag na is graded dose
response curve
- Edi rito, 5 yung sa drug na mag-iinhibit sa
estradiol and 5 lang din yung available na
receptors.
- Once na maoccupy niya yun lahat, yung intensity
ng effect non is hanggang don lang
- Parang pasensya, may certain point lang yung
pasensya mo. Kapag naubos na (reach na yung
maximum) wala nang maibibigay. Ano gets na?
- The picture above is the graded dose response
curve
- Edi rito, habang tumataas yung dose, tumataas din
yung response
- Kapag nareach na yung maximum (1.0), magiging
stable na yon or constant.
 o So bakit narireach yung maximum? Ibig
sabihin lang nito na wala nang available
na receptor for the ligand to bind
o So, kahit magdagdag tayo ng dose,
hanggang don na lang yung response.

The Response is based on:

o Enzyme activity – pagpapabilis ng effect

o Membrane potential – for absorption
o Secretion of hormones – ex: RAA
o Heart rate or contraction of muscles -
ACh
a. Enzymes – would result to the interactions
specifically sa prodrugs wherein it undergoes
metabolism then become inactive metabolite.
- associated with the effects of the drug nirerecord
kung ano yung nangyayari
- Ex: chocolate toxicity

- Example: mechanism ng paracetamol sa normal

na tao (A) vs sa cats (B)
- A – kapag nagtake ng paracetamol yung tao, 95%
non is mag-uundergo metabolism para maexcrete
sa urine. Mangyayari lang ito if merong
paracetamol conjugates
o 5% naman nito is mag-uundergo
CYP450 metabolism then magiging sa
NAPQI (toxic byproduct produced
during xenobiotic metabolism of the
- Kapag yung drug direct na ininhibit yung enzyme, analgesic paracetamol). Then, meron
madedecrease yung potential ng enzyme to siyang dalawa na pwedeng maging
convert the drug into metabolite resulta.
- Sa indirect inhibition, magkakaroon naman ng 1. Yung structure niya
decrease sa enzyme content due to repression and (NAPQI) is pwedeng
pwede maalter yung physiology na magcocause maconvert into glutathione
ng nutritional deficiency or hormonal imbalance. which then leads to
conjugation non-toxic then
maeexcrete siya in urine
2. Yung isa naman is yung
structure niya eh
macoconjugate with
proteins, nucleic acids na
magiging result ng
hepatotoxicity.
- B – in cats naman, absent sa kanila yung
paracetamol conjugates edi 95% non eh di
maeexcrete sa urine. Tapos absent din yung
glutathione na need din para ma-excrete yon sa
urine
o So mangyayari, yung drug is lahat mag-
uundergo ng CYP450 metabolism, then
magiging NAPQI
o Tapos lahat ng yon is magreresult sa
hepatotoxicity
▪ Hepatotoxicity – liver toxicity

- In terms of chocolate toxicity, may certain point

din kung how much ang pwedeng ibigay sa dogs.
 - Hindi porke napakain mo kunwari ng konting
konti lang eh mamamatay agad ganon
- So, kunwari napakain mo yung chihuahua mo ng
30-50 grams na milk chocolate magiging result
non is mild lang. vomiting, diarrhea ganon
o So, if tama naman yung nabigay mo,
kunwari binigay mo lang is 10 grams edi
hindi yun magiging toxic sa kanila.
b. Secretion of Hormones
- It’s not just because women tend to be smaller
than men.
- It is said na, women metabolize drugs differently
because they have a higher percentage of body
fat and experience hormonal fluctuations and
the monthly menstrual cycle, “Some drugs are
more water-based and like to hang out in the blood
- eto yung normal action potential, yung action
(hydrophilic), and some like to hand out in the fat
potential kapag nagkaroon ng presence ng
tissue (lipophilic),” said Wesley Lindsey
tetrodotoxin sa katawan is sobrang iba.
o Di ba sabi kanina, mas gusto natin yung
lipophilic and hydrophobic para mas
maabsorb, so bakit sabi some drugs are
more water-based? Hydrophilic ganon?
▪ Maaagsorb pa rin yung drug
kahit water-based kasi
magsstay sila sa blood as blood
plasma contains 5% water diba.
Magstay sila ron kasi gawa ng
bioavailability. Dito, tinitignan
if yung drug ba na nasa dugo eh
maaabsorb sa mga tissue in
order to produce
pharmacological effect. Kaya
nga may iba’t ibang angle yung
sa injection dba. Gets? Gets. - Tetrodotoxin (TTX) comes from puffer fish
▪ PERO kapag nagstay lang siya which affects membrane potential channels
sa blood, edi walang naproduce - Kapag naka-intake ka ng 1-2mg of tetrodotoxin
na pharmacological effect kasi magcocause na siya agad ng paralysis and
dapat maabsorb siya sa tissue. nakamamatay yon
o So, bakit naman ang anesthesia eh - Ang ginagawa kasi niya is binoblock niya yung
mabilis maabsorb? Lipophilic kasi ito Na, edi walang mangyayaring depolarization.
and hydrophobic para mabilis maabsorb o No depolarization = no action potential
ng katawan. Kaya sa injection, diretso
siya sa muscle ganon.
- There are also sex differences in liver metabolism,
kidney function and certain gastric enzymes. Oral
contraceptives, menopause, and post-menopausal
hormone treatment further complicate the picture.
Some studies suggest, for example, that when
estrogen levels are low, women may need
higher doses of drugs called angiotensin
receptor blockers to lower blood pressure,
because they have higher levels of proteins that
cause blood vessels to constrict, said Kathryn
Sandberg
o Angiotensin kasi causes the blood - TTX interferes with regard to Na channels, if
pressure to be high, so in order to block there is no Na na makakapsok then there is no
their receptor eh need ng ACE inhibitor, action potential. Then no interaction between
or yung Angiotensin converting neurons then, no pharmacological effect
enzymes inhibitor, para mablock yung
pagconvert ng angiotensin I to
No interaction no
angiotensin II. TTS blocks Na
channel
No Na ions in
No action
potential
between pharmacological
neurons effect
c. Membrane potential

4 parameters of the curve

 a) Baseline response
b) Maximum response
c) Slope
d) Drug concentration that provokes response
halfway between the baseline and maximum

Threshold – dose below which have no adverse effects from

exposure to chemicals

- kapag sharp eh mabilis maoccupy yung drug

- Dito parang eto yung extent kung saan wala pang
effect yung drug
receptor complex then mabilis yung
pharmacological effect
o and you are increasing the risk ng
adverse effect ng drug na yon
o advisable ito if emergency talaga
o kunwari suka na ng suka ganon nonstop
- sa flat slope naman, ginagamit ito para maiwasan
nga yung toxic response
o advisable if hindi emergency ganon
❖ brachycephalic dogs are prone sa respiratory
depression and we do have brachycephalic syndrome
(short snout)
o kapag maigsi, tapos pumasok yung hangin,
eh di masyado nahuhumidify and purify kasi
nga maliit yung butas ng ilong
o tapos you have the short palate and hard
palate, magkasing size itong dalawa so hindi
nag-adjust yung soft palate.
o Tas yung extension ng soft palate, nandon sa
may daanan ng hangin. So, di makakapasok
totally yung hangin kaya nagbavibrate yung
soft palate.

Slope factor
- kaya mabilis tumaas kasi marami pang available
na receptor - also known as the HILL SLOPE
- then magkakaroon ng competition for receptors, it - Quantification of steepness/shallowness of the curve
can cause bending of the curve kasi yung intensity - standard curve: Hill slope of 1.0
eh di kaagad nataaas - STEEPER: higher slope factor
o papasok na sina antagonist cocompete - SHALLOWER: lower slope factor
kina agonist
- then kapag nagiging stable na edi unti-unti na
naooccupied yung lahat ng receptors
- kapag na-occupy na lahat edi maximum na then
hanggang don na lang.
- kahit taasan yung dose, eh di na magkakaroon ng
effect.

- Steeper: 1.5 slope

o If higher ang slope factor = increasingly
higher risk of toxic response as the dose
increases
- Shallower: 0.5 slope
o If shallower naman = effect on increase sa
dose is minimal lang
- basta yung threshold, eto yung dose na walang
effect pa
 - Sa drug 2 (red) and drug 3 (green), naoccupy niya lahat
ng receptor pero partial agonist lang siya edi less na
yung efficacy
- Same lang sa vacc ng covid, iba-iba yung efficacy ng
drugs dba ganern.

- Dito, nakikita natin na yung slope ng ethanol is

shallow
- Ibig sabihin, unti-unting umeepekto yung drug sa
katawan so andami pang dadaanan na steps bago
mareach yung maximum (death)

Importance of drug dose relationship

I. Drug potency - A + C (green) – is most efficient kasi mataas yung

II. Drug efficacy efficacy
III. Drug safety - A + D (violet) – is least efficient

Drug potency – is the measure of the drug activity expressed

in the amount of drug to produce effect

- kung gano kabilis yung effect, more potent, then mas

mababa ang threshold

Drug efficacy – maximal response produced by the drug

- Gaano katas yung intensity nung effect

- if competitive, magkakapareho ng efficacy but

different potency
- if non-competitive – same potency but different
efficacy
o nagkakaroon ng effect pero bumababa ang
maximal effect kasi the receptor is being
changed then di makakapasok ang agonist
kaya madidiminished ang effect

- A is more potent than B

- Pero yung efficacy ng B is mas maganda kesa sa A

- So, Drug A and B is maganda yung efficacy

- Drug B is more potent
- Drug C eh pangit yung potency and efficacy

Graded dose response curve – graph relationship between

varying doses and response (either minimum or maximum)

- Sa partial agonist, yung efficacy niya is lowered kasi

dba yung shape niya is hindi naman swak na swak sa
receptor unlike full agonist.
- So kunwari yung drug 1 (yellow), naoccupy niya lahat
ng receptor edi high yung efficacy niya
 - Local and Systemic contra regulation of the response
❖ Note: Magnitude of stimulus is directly proportional to
the number of occupied receptors

Nature of stimulus – response relationship may depend upon

the kind of response the observer is looking for as the “end
effect”

Problems of Graded Dose response Curve

Known: relationship between drug dose and the response (how

much response is caused by the administered amount of drug?)

Unknown: relationship between the dose bio phase and drug

- Tinitignan dito yung threshold, biological response,
and the maximum response
Administration of Drug to Produce A Response
Absorption includes:
- Physiochemical properties of the drug
- Blood flow through the site of administration
receptor complex formation leading to the formation of the
stimulus. (How many drug receptor complexes are formed with
the amount of drug in the bio phase?)
#5 QUANTAL DOSE RESPONSE
Polyscias Fruticosa – counteract the effect of ACh and
Histamine
Asthma – bronchoconstriction results in dyspnea, wheezing,
and coughing

Blood
Administration Absorption
circulation

- Less drug absorbed, less drug reach biophase, less

receptors occupied, less response

Factors inhibiting maximal response

- Extent and Rate of Distribution

- Non specific binding of drugs with tissues and
plasma proteins and liberation of drugs from
reservoirs
- Drug biotransformation metabolism in tissues
- Excretion of drug before reaching the biophase
- In normal bronchial tube, the smooth muscle is relaxed
- Whereas, if the person has asthma, the passageway of
the bronchial tube gets smaller because the smooth
muscles is tightened. This is due to the swelling and
the mucus.

- In order for the drug to be absorbed well, it needs

to be lipophilic and hydrophobic
- It need excrete, hydrophilic and lipophobic
o Pwede rin siya mapunta sa blood then
maabsorb sa tissue para magkaroon ng
pharmacological effect
- Mas naaabsorb ang non-ionized kesa ionized - As we can see in the picture, there are specific
- Pharmacophore is the stereochemistry receptors in different locations.
o may mga three-point fit na meron lang o As for example, if Atropine/ACh interacts
specific na functional group na magfifit with M5 receptor, it will affect the CNS
don - If ACh interacts with M3, it will produce contraction
o if nagfit sila perfectly, mas maganda yung of smooth muscles, particularly the longitudinal
magiging effect ng drug muscle, in the bronchiole causing the person to have
- Drug biotransformation is yung metabolic asthma
breakdown ng drugs
o Ex. Paracetamol

Drug response stimulus factors

- type and condition of the effector system

- Initial drug effect on the effector system

- In cases of histamine, if histamine reacts with H1,
particularly in Bronchial tree, it will result to broncho-
constriction which will cause shortness of breath or
can also cause asthma.
- HPE or the helichrysum plicatum extract acts like an
antagonist to histamine and ACh
- Which means that if we give HPE, it will inhibit ACh
or histamine to have no pharmacological effect.
Types of dose response curves

I. Graded dose response curve – show effects on a

continuous scale and the intensity of the effect is
proportional to the dose.

- This graph is a graded dose response curve and we can

see that if the dose increases, the response also
increases.

- Relationship of Histamine and PFE or the Polyscias

Fruticosa. Same goes with Histamine and HPE
o Inversely proportional
o So, if we give PFE to a person who have
asthma, the histamine level in their system
will go down.

- mas appropriate gamitin yung semi-log scale kasi sa

linear scale eh hindi tayo sure kung san ba talaga
umepekto yung drug

- sa graded eh tinitignan mo kung ano yung response ng
isang INDIVIDUAL
requirements:
- single biological unit or average of many such units
for each data point.
- A preparation of a single animal or organ can produce
the curve
Problem
- Poor predictors of how other specimens might respond
o Kasi sa isang tao ka lang nakafocus, edi kung
ganito di mo malalaman effect sa ibang tao
Graded (Quantitative) dose-effect relation
- A graph of the relationship between dose and response
- Minimum detectable response and a maximum
response by
- Varying the dose or drug concentration
o i.e., the curve is continuous
II. Quantal dose response curve – graph between
dose and effect
- Describes the distribution of MINIMUM doses of the
drug required to produce a defined degree of a specific
response in a population
o We are concerned about the threshold
o Kasi sa graded dose – tinitignan yung effect
kapag binigay yung dose
o Quantal – mamimili ka sa effect, example
pinili mo yung vomit, then hahanap ka ng
mga tao tas eexperiment mo then note mo at
what dose or concentration sila nagsuka if
given a certain drug
- All or none – percentage of population affected equals
or less than threshold response
o Not magnitude of drugs ang tinitignan
- for quantal, mamimili lang tayo
o ex. Sleep, then kukuha tayo ng mga tao na
kung ilan yung natulog kapag binigay mo ng
gantong dose ng drug or ilan yung
concentration na nagkaroon ng labored
breathing like that
procedures
- define quantal dose response to be observed e.g., death
- 30 mice (same info)
o Kunwari sleep yung pinilil
- Administered increase doses
- Taking notes of the doses where mice sleeps
- Record smallest dose at which sleep occurs for each
animal
o Record if minimal lethal/effective
dose/threshold dose
▪ Minimal lethal – negative effect
▪ Effective dose – favorable effect
▪ Threshold dose – no response
Purpose
- To allow prediction about what proportion of a
population of subjects will respond to the given doses
of drug or toxin
The specific effect being measure:
- 2 responses: YES or NO; 0 or 1 (Quantal and not
variable)
- Increments and decrement of 1 unit (e.g., individual)
at a time
Problem
- Many units sample (animal, humans, organs) are
required to create a quantal dose-effect curve
- From these many units, one can make predictions
about what proportion of a similar population will
respond to the drug in the same way
Titration
- Finding the individual effect dose and happens 2 ways
- Each individual – admin dose – note each effect in
every individual
Groups
- Division of individual into grops
- Give each group only 1 of increasing dose
- Variable response (0-100%)
- Record percent of the group responding to each dose4
Bell shaped curve
- Majority of responders in the middle mean response is
approx. 4.0 mg/kg
- Fewer responders at the end of bell curve (expected)
known as biological variability
- Responders at the far left of the mean are typically
hypersusceptible
- Whereas those at the far right are resistan
- Yung nasa left, malalaman na yung population na yon
is susceptible sa drug kaya nagresponse agad, sa right
naman eh resistant sila ron sa drug kaya di agad
nagresponse
Both curve provide:

- Information regarding potency and selectivity

o Potency – concentration of the drug that takes
effect
o Selectivity:
▪ Graded – alam natin yung effect
mismo sa individual
▪ Quantal – seselect tayo ng specific
effect na nangyari sa individual then
apply it to others
- But:
o Graded dose response curve indicates
maximum efficacy
o Quantal dose response indicates potential
variability of responsiveness among
individuals - Titignan yung population, ilan ba yung natulog ganon
Variations in drug responsiveness - Sa graded, paplot yung effect sa bawat individual
- Then makikita natin yung therapeutic effect and lethal
Individuals may vary considerably in their responsiveness to a effect
drug o Once we determined this, makikita natin
yung safe and toxic dose.
- Hyperactive – reduced response o So makikita na kunwari, at 5mg per
- Hyperreactive – increased response bodyweight eh maganda na yung response
- Tolerance – responsiveness decreases with continued and at 120 mg per BW eh toxic na
drug administration
- Tachyphylaxis – rapid development of tolerance Therapeutic index (TI)

Normally distributed - Distance between the therapeutic effect and toxic

- Shape of this distribution closely resembles the shape
of theoretically derived family of mathematician
deviation
- Follows the gaussian
Parameters obtained from Quantal Dose Response
effect
- Eto yung safe dose
- TI = toxic dose50/effective dose 50
- dapat mas malaki ang TI, dapat magkalayo ang graph
ng therapeutic effect at toxic effect

- Effective dose (ED)

- Lethal dose (LD) or toxic dose (TD)

Description of data

- One can define the mid-point as for the graded curve,

i.e., the ED50, the dose that produces the effect in 50%
of the best population

- Sleep is the therapeutic effect

- Labored breathing is the lethal effect

Quantal dose effect curve

- Characterized by the median effective dose (ED50) –

the dose at which 50% of individuals show the
specified quantal effect - TI rito eh 5mg to 120mg
- The dose required to produce a particular toxic effect - pag underdose eh baka walang makita na effect
in 50% of animals is called the median toxic dose - overdose eh magreresult ng toxic effect
(TD50).
Median effective dose (ED50) – dose required to produce 50%
- If the toxic effect is death of the animal, a median
of the maximum response
lethal dose (LD50) may be defined.
Median lethal dose (LD50) – kill 50% of experimental animal,
measures toxicity

- the lower the value of LD50, the more hazardous


- for example, Cephalexin, ang safe dosage (TI) sa
dog/cat is 10-15mg/kg oral BID
o dapat don sa range lang na yon papatak
o pwede magbaba ng dose if nakikita mo na
mahina yung aso ganon
o if nagoverdose, magkakaroon ng adverse
effect.
- Consumption of as little as 5g/kg of onion in cats or
15-30 g/kg in dogs has resulted in clinically important
hematologic changes
o Sa liver
#6 DRUG ACTIONS NOT INVOLVING RECEPTORS
3 MECHANISMS OF DRUG ACTION that DO NOT
DEPEND upon any DRUG RECEPTIOR
1. Non-specific action and cell membrane perturbation
2. Interaction with small molecules and ions
3. Incorporation of drugs into macromolecules
Non-Specific Action and Cell Membrane Perturbation
A. Osmotic agents: Osmotic Diuresis
• Osmosis – movement of solvent or water
molecules from an area of low solute
concentration to high solute concentration
• Diffusion – movement of solutes from high to low
concentration
• Osmolarity – osmotic activity per liter of the
whole solution.
• Osmolality – osmotic activity per kilogram of
solvent.
• Ex: mannitol – which is injected intravenously in
order for the drug to go to its target organ faster
o Upon administration, through
intravenous injection, it will be filtered
at the glomerulus of kidney in order to
increase the osmolarity of urine and to
have slow reabsorption thus, resulting to
diuresis.
▪ Diuresis – increased
production of urine.
- Mannitol will come from the afferent arteriole, which
is going to the glomerulus in order for the filtration to
happen.
- Then, it will be go to the efferent arteriole (going away
from glomerulus), and be reabsorbed in the proximal
convoluted tubule.
- Then, the water will undergo a passive reabsorption
process in the descending loop of Henle. In contrast,
ions are reabsorbed in the ascending loop of Henle in
an active process.
- Then, it there will be further reabsorption of ions that
will happen in the distal convoluted tubule.
- Then, it will go to the collecting duct for more
reabsorption of water and urea. Urea is maintained to
continue the reabsorption of water in the distal
convoluted tubule and to have osmolarity in kidney.
- then, the urine will be secreted from the collecting duct
and be excreted.
- mannitol is filtered in glomerulus
- reabsorbed in descending loop of Henle
- reabsorbed in collecting duct and tubules
B. Osmotic Laxatives
• Organic substances – contains carbon
• Inorganic substances – do not contain carbon
• Saline Cathartics: MgSO4, Na2SO4, K2SO4,
Sodium phosphate
• Mechanism of action:
o Nonabsorbable salts
o Hold water in the intestine by osmosis –
increase bulk of intestinal content thus,
increasing peristalsis
o Produce defecation in few hours
• Therapeutic uses
o To accelerate passage of parasites
C. Osmotic cathartics
• Ex: magnesium sulfate EPSOMS and GAUBERS
SALT
 • Upon cleaving of MgSO4, Mg will go to the
intestinal wall, which retain the osmotic
equivalent of water in the gut. This, then increases
peristalsis.
• SO4 will not be absorbed
Drugs on small molecules
• Laxatives – fully formed fecal matter from rectum,
bururut ang lalabas
• Cathartics – evacuation of entire colon, watery ang
lalabas sa stool.
• Laxative: lactulose – increase acidification which
leads to destruction of colon bacteria
o Contraindicated in patients who require a low
galactose diet (lactose intolerant) and in
gastrointestinal obstruction.
D. Acids and Bases
• Inorganic and organic bases and ion exchange resins
administered orally to neutralize excessive acidity in
the stomach
• Ex: antacids like Magnesium Hydroxide
• Edi marami yung acid sa stomach, yung Na+HCO3-,
ang gagawin ng antacid eh i-cleave niya yon para
maneutralize yung acid.
E. Urine Acidifiers
• contributes hydrogen ion to the body fluids when NH4
is metabolized to the neutral end product area
• Ex: Ammonium chloride
• bronchial mucosa irritant causing coughing up of
exudations
• Ammonium salts are gastric irritant causing nausea
and vomiting
F. Organic Antiseptics
• Ex: detergents – destroy the integrity of lipid
membranes and cause dissociation of nucleoprotein
complexes
• Deanturants – destroy the integrity and functional
capacity of cell membranes and proteins
A. Chelation – formation of coordination complexes
usually with metal ions
• Ethylenediaminetetracetic Acid (EDTA) –
specific treatment for lead poisoning
• Stage I – kapag may injured vessel, aaction agad
si prothrombin activator (PTA)
• Stage II – pag naactivate yung prothrombin and
maginteract sa calcium eh mapoproduce na si
thrombin, na para sa clotting factor
• Stage 3 – naconvert na si thrombin into fibrinogen
then magkakaroon na nag blood clot.
B. Penicillamine – used in removing copper from body
tissues in cases of hereditary disorder copper
metabolism (CERUPLASMIN) leading to progressive
accumulation of free copper in liver and brain
• Eto yung pwedeng maapektuhan if nagkaroon ng
wilson’s disease, which is a genetic disorder causing
excessive copper accumulation in the liver, brain and
other organs • Dimercaprol – excreted through urine
• Deferoxamine – urine and feces
• D-Penicillamine – inhibits collagen polymerization

Drugs incorporating to macromolecules

A. Counterfeit Incorporation – drug replaces a normal

metabolism in the synthesis of an important cellular
constituent.
• act as a false substrate

• Absorption of copper is normal

• There is no incorporation of copper into caeruplasmin
not is it excreted into bile
• The excretion of copper in bile is decreased
• An increased copper concentration in the hepatocytes
results in an overflow of copper into the blood.
Consequently, free Cu plasma concentration is
increased
• The increased free Cu plasma concentration will lead • nagkakaroon ng mutation like yung sa mga UGA
to an increased urinary concentration. Excretion of ganon ba, substitution, addition, silent ganon sa
copper via the stool is decreased. genes

Result of Counterfeit incorporation

• increase sensitivity to X-radiation

• Increase frequency of chromosome breakage
• Mitotic abnormalities in mammalian cells

Theoretical interpretation of simultaneous action of two

drugs

Why use two drugs?

• Dito, yung drug is maguundergo metabolism para
makapasok sa cell then mabind siya sa copper na 1. Optimize the beneficial effect of each drug being used.
maglilead ng decrease concentration ng copper. • e.g., medication against tuberculosis

C. Dimercaprol – British Anti-Lewisite (BAL) – with

free hydroxyl group that remains polar after it has
chelated with metal ions such as arsenic, gold,
antimony, and bismuth
• If polar, sila ay water soluble kasi they are able to form
hydrogen bonds
 • Isoniazid – inhibits cell wall synthetase
• Ethambutol – inhibits cell wall synthetase
• Pyrazinamide – exact target unclear, disrupts
plasma membrane, disrupts energy metabolism
• Rifampin – Inhibits RNA synthesis
• the agonist and antagonist both have receptors
• kapag nagbind si antagonist, babaguhin niya yung
receptor conformation ni agonist para di yon
makapasok

• Example sa sulpha drugs like sulfonamides and

trimethoprim, ginagamit both to make sure na hindi
magconvert into DNA

2. Reduce the toxic or adverse effect of one or both drugs

• e.g, Peanesthetics sedatives that required dose of
anesthetic drug; reduces the likelihood of toxic
reactions of anesthesia
o syempre sa anesthesia pwede magkaroon ng
mga negative effects, kunwari sa dogs eh
napakain siya before surgery, ang tendency
eh masusuka siya pag naturukan ng
anesthesia. So yung peanesthetics sedatives
are then used to avoid these circumstances.
3. Terminate the action of one drug when it is no longer
needed
• e.g, injection of Yohimbine to reverse the sedative
effect of xylazine
o kumbaga magaling ka na ganon tas di na need
ng katawan mo yung isang bagay, need na
siya ilabas sa katawan mo kaya magtuturok
ka ng isang drug na magpapaterminate nito
• papaya has papain which is a muscle relaxant
• sa chronic liver disease, nagkakaroon ng apoptosis or
cell death
• yung gamut na mag-iinhibit sa NMDA receptor is
yung Ketamine HCl or yung isa sa picture. Para
maging successful, need ng supplement na mag-
iinhibit sa glycine or glutamine receptor.
• So either yung L-ornithine (supplement) will act on
the glycine recepter or yung L-aspartate na mag-
iinhibit sa glutamate receptor.
• Then, kapag nangyari ito all, hindi na maaactivate and
NMDA, and wala nang apoptosis.

Competitive antagonism

Antagonism Non-Competitive

• improving the dose will not improve the response

• Drug A or B is the most efficient

• Drug A is the most potent
 • Drug B is the least potent
• Drug C is the least efficient

• bakit nagkaroon ng E-P?

o kasi kapag naging enzyme-substrate complex
• Sa competitive inhibition, yung potency nila is
eh mamomodify yung shape then magiging
nagdecrease unlike sa agonist pero yung efficacy is
enzyme-product complex
same
• Sa noncompetitive, same potency sa agonist but the A competitive inhibitor competes with the substrate for the
efficacy is decreased. active site of the enzyme:
Irreversible

• An irreversible inhibitor causes covalent modification

of the enzyme, so that its activity is permanently
reduced
• Compounds that act as irreversible inhibitors are often
useful as drugs that need be taken only every few days,
although adjusting the dose to suit the patient’s
response is a lengthy process with such compounds
• By contrast, the effect of a reversible inhibitor can be
reversed by removing the inhibitor, e.g., by dialysis or
gel filtration

Three main types of reversible inhibitor

• competitive inhibitor
• non-competitive inhibitor
• uncompetitive inhibitor

• the rate of reaction and the substance concentration is

inversely proportional thus, the increase in the
substrate concentration, madedecrease yung chance ng
inhibitor in binding.

• kapag walang antagonist (inhibitor) highest

• mechanism ng ivermectin: interrupts the nerve
transmission
• babind siya sa glutamate-gated chloride channels para
maincrease yung permeability ng cell membrane sa Cl
ions
• then, magreresult siya sa hyperpolarization ng nerve or
muscle cell
• edi walang magegenerate na nerve impulse, kaya
mangyayari eh mamamatay yung mga garapata
Double Reciprocal Plot
• also known as the Lineweaver Burke Plot
concentration of substrate will still have the same
Vmax
• increase concentration of inhibitor will increase the
Km with the Vmax unchanged
o yung Km eh yung concentration ng substrate
▪ eto yung ½ vmax
▪ vmax – rate of reaction when the
enzyme is saturated with substrate is
the maximum rate of reaction.
Non-competitive inhibitor
• reacts with the enzyme-substrate complex, and slows
the rate of reaction to form the enzyme-product
complex.
 Synergism

• Drug interaction in which the effect of a drug

• increasing the concentration of substrate will not
relieve the inhibition, since the inhibitor reacts with
the enzyme-substrate complex.
• So, kahit mag-increase yung concentration ng
substrate, yung hindi mawawala sa pagkabind yung
antagonist sa substrate
combination is greater than the separate effects of
individual drugs
• Occurs when the drugs are both agonist acting on the
same target organ through different receptors
• E.g., Synergistic drug-drug interaction: Xanax is a
drug which belongs to benzodiazepine class of drugs,
if it is taken along with an antidepressant like
Prothiadine, the drowsiness effect of both drugs is
enhanced and multiplied

• increase conc of inhibitor, will have decrease Vmax,

but the Km is unchanged
• Dito, may dalawang receptor for the 2 agonists (A +
o yung concentration ng substrate (Km) eh
C) which will increase the effect
ganon pa rin kasi ron magbibind yung
antagonist. Pero yung rate of reaction (Vmax) Potentiation
eh madedecrease kasi dba kapag nagbind si
antagonist, babaguhin niya yung shape ng • Special case of Synergism when one of the 2 drugs had
receptor site ng agonist. zero intrinsic activity. The one with the zero activity is
the potentiator
Physiological interactions • When the net effect of two drugs used together is
greater than the sum of the individual drug effects
• occurs when drugs acting on different receptors have
o 1 + 1 > 2 or 1 + 0 > 2
their combined effects manifested in the same or
opposite way on the same effector organ • When one drug increases the action of other drug
• graphically represents in an isobole, which is a curve o E.g., sulphamethoxazole + trimethoprim =
cotrimoxazole (bactericidal) 1 + 1 > 2
that represent the identical effects of a combination of
two drugs • or when drugs has no effect as own but increases the
effect of other drugs (1 + 0 > 2)
• includes the following:
o L-dopa and carbidopa
o Synergism – interaction ng two or more
drugs to produce a combined effect greater
than the sum of their separate effects.
▪ Kumbaga kunwari kapag solo mo
kinalaban yung third party ng bf mo,
hindi mo siya masasaktan ng full.
Pero kapag nagjoin forces kayo ng
best-friend mo, mas malakas ka.
o Potentiation – gaano kabilis umepekto yung
gamot
o Additive effect – eto yung result ng effect
kapag pinagsama mo yung dalawang drug
▪ Kumbaga sa third party uli, ano
effect kapag kasama mo yung best
friend mo? Naospital ba yung third
party or what.
 • Kumbaga yung sulfonamides is dinadagdag sa
trimethoprim para maincrease yung action nito.
• Yung DOPA and Carbidopa is parang same lang ng
structure nagkaiba lang sa functional groups
• Kapag levodopa lang yung ginamit na drug,
magcoconvert siya into dopamine KASO eto is hindi
siya pwedeng makapasok sa CNS
• PERO kapag nag-add ka ng carbidopa sa levodopa,
maiinhibit ni carbidopa yung Dopa decarboxylase
(DDC) na nasa periphery edi makakapasok na si
levodopa
• Once makapasok si levodopa, makakaencounter uli
siya ng DDC na nasa CNS and magcoconvert na siya
into dopamine.
• Adverse effects include nausea, dyspepsia, diarrhea,
constipation, gastrointestinal ulceration/bleeding,
headache, dizziness, rash, salt and fluid retention, and
high blood pressure.
• Infrequent adverse effects include esophageal
ulceration, heart failure, high blood levels of
potassium, kidney impairment, confusion, and
bronchospasm.
• Ibuprofen can exacerbate asthma, sometimes fatally
Additive effect
• Similar to synergism but the combined effect of the
drug is equal to the sum of their individual effect
• You can’t take aspirin together with alcohol kasi
magreresult ito into stomach bleeding.
• Aspirin kasi is magcucause ng nausea and vomiting
kapag namix siya with alcohol
Chemical (pharmaceutical) antagonism
• Occurs when a drug chemically interferes with another
drug or poison
a) Neutralization between acids and bases
o E.g., penicillin (acid) will be neutralized by
gentamicin (base) if both are present in the
same solution
b) Chelation of Heavy Metals
o E.g., Tetracycline chelates calcium in the gut
▪ Mababind yung calcium sa
compound na may metal ion which
is held by coordinate bonds
c) Adsorption of one drug by another
o E.g., Kaolin (attapulgite) adsorbs most drugs
administered with it
▪ Adsorb – holding tiny particles on
the surface of large solid materials
Log Dose Response Curve
• more direct manner of showing relationships between
drug dose as compared to double reciprocal plot
• transforms hyperbolic curve to a sigmoid
Arithmetic Dose Response Curve
• Rate of change is rapid at first and becomes
progressively smaller as the dose is increased
• virtually difficult to gauge the magnitude of change in
response corresponding to a very small increment in
the dose
• yung nasa taas eh arithmetic, mahirap malaman kung
kelan talaga nagkaroon ng effect yung drug
• sa baba eh log dose, mas madaling malaman kung san
umepekto yung drug
Information derived from Log Dose Response Curve
1. Nature of drug action
a. Parallel log dose response curve – same
mechanism of action and same receptor
b. Non-parallel log dose response curve –
different mechanism of action and different
receptors
2. Potency of the drugs – determine which drug is the
most or least potent
3. Competitive antagonism
 • in the presence of a competitive antagonist, the • Then, ma-ooccupy ng full agonist (heroin and
curve shifts to the right, but with a slope parallel painkillers) yung opioid receptor na magcocause ng
to the curve of the agonist alone euphoria and matigil yung withdrawal pain.
• Maximum response is unchanged • Ang nangyayari, magcecrave naman si brain ng
• Antagonist would only reduce the affinity of the opioids (eto na yung addiction)
agonist for the receptors
4. Non-competitive antagonist
• Curve may shift to the right but with lower slope
• Maximum response is reduced

• para mastop yung addiction, magiintroduce ng

antagonist (either buprenorphine or naloxone), which
is may higher affinity kesa sa opioids
• so, siya ay partial agonist kasi meron lang siyang
limited opioid effect which is enough na para matigil
yung withdrawal pain pero hindi enough to cause
• A. competitive antagonist will have different intense euphoria
potency as agonist but same effect
• B. non-competitive antagonist will have the same
potency as agonist but different effect
5. Partial agonist
• Blocks the agonist binding site but cause less
response than a full agonist
• has an affinity that is increased/decreased or equal
to that of an agonist
• what will happen if it is alone based on the curve?
o Decreased efficacy

• then madissipate na si antagonist, pero kahit ganon eh

nandon pa rin yung limited opioid effect and
macocontinue niya pa rin na iblock yung opioid sa
receptor nila.

• How does naloxone or Buprenorphine works?

• Edi sa withdrawal, nagkakaroon ng discomfort and

pain kasi there is no sufficient amounts of opioid
receptors activated. Nangyayari to sa mga tao na
naging tolerant na sa opioids na naging resulta ng
pagkasensitive nila roon kaya need nila ng maraming
opioids para makaproduce ng same effect.