Pharma Lecture Final

SUBJECT
LECTURE #1 - PHARMACOLOGY
VERNON MARCIANO
1st semester | s.y. 2023 - |Laboratory/LECTURE
VETERINARY PHARMACOLOGY AND HISTORY

THERAPEUTICS 1
• Ebers papyrus ancient egypt
PHARMACOLOGY • Greek: PHARMACON
(drug) and Latin: • 800 prescriptions for salves, plasters, pills
LOGOS STUDY suppositories and other dosage forms
• the science that
• Hippocrates (460-370 BC)
deals with the origin,
nature, chemistry, • father of Medicine
effects, and uses of
drugs; or interaction • conducted systematic observations of patient’s
with the living symptoms
organism
• transitted from medicine as an art to systematic
THERAPEUTICS • Greek: therapeia
(service attendance) clinical science
and therapeuo Material Medica
(waited upon)
• In medicine, the • compilation of therapeutic substances by
branch that deals Dioscorides in 77AD and serves as the basis for works
specifically with the of Galen.
treatment of disease
and the art and • Paracelsus (Philippus Aureolus Theopastus
science of healing. Bombastus Von Hohenheim)
(medicine.net)
• Grandfather of Pharmacology
• In pharmacology,
therapeutics • “All substances are poisons; there is none which is
accordingly refers to not a poison. the proper dose separates a poison from
the use of drugs and a remedy”
the method of their
administration in the VETERINARY PHARMACOLOGY
treatment of disease
• study of the properties of drugs and all aspects
HISTORY of their interaction with living organisms
pertaining to animals.
• chinese emperor shenn-ung (2700 BC)
• Shen-nung pen ts'ao ching (Divine • response to epidemics of diseases in
Husbandman's Materia Medica) Netherlands such as Rinderpest
• Father of Chinese Medicine and introduced
acupuncture PURPOSE OF VETERINARY PHARMACOLOGY
• Pro animals?why
• to test drugs quantitatively and standardise to
• ancient egypt KAHUN PAPYRUSE
be available in a uniform and dependable form
• Examination of a woman whose eyes are aching
till she cannot see, on top of aches in her neck: • to determine how drugs produce their effects
• You should say of it 'it is discharges of the womb on the animal body
in her eyes'.
• You should treat it by fumigating her with • to develop new drugs
incense and fresh oil,
• to establish rational and safe dosage
SUBJECT
VERNON MARCIANO
VETERINARY TOXICITY • PHARMACODYNAMICS - what you did to me?
• “science of safety” • PHARMACOKINETIS - what i did to you?
• pharmacology is the study of drugs used at • TOXICOLOGY - am i BI?anung level?

doses to achieve therapeutic effects on an
• PHARMACOTHERAPEUTICS - moving on
organism, while toxicology is the study of
process…??
toxicants that produce harmful effect on an
organism. CATEGORIES OF PHARMACOLOGY
• translationational sciences (Pharma-toxicology) • MOLECULAR PHARMACOLOGY - deals with the
basic mechanisms of drug action in biological
• pharmacology —- science knowledge —— drug
systems
action and fate —- clinical therapy
• CLINICAL PHARMACOLOGY - development,
• toxicology —- knowledge science —-
effective use and the proper evaluation of drugs
fundamental science —- safeguard animal health,
for the diagnosis, prevention and cure of diseases
public health and environment
• VETERINARY PHARMACOLOGY - drugs used in
• basic research in toxicology is the prerequisite
the prevention and treatment of animal diseases
inassessing emerging risks in the process of
and the intentional alteration of animal
developing drugs, chemicals, and materials •
physiology
“One World, One Health,
DIVISIONS OF PHARMACOLOGY
• PHARMACODYNAMICS - how drugs produce

effects on living organism; where and how drugs
are disposed of in the body
• 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
• TOXICOLOGY - study of harmful effects of drugs

DRUG
• PHARMACOTHERAPEUTICS - application of
drugs for use in the diagnosis, prevention and • any substance, food or non food that is used
treatment of diseases to treat, cure, mitigate, or prevent diseases or
any non food substance that is intended to
• PHARMACY - the art and science of preparing, affect the structure or function of the individual.
compounding and dispensing of drugs
• star of pharmacology…
• Pharmacognosy - sources of drugs
• Posology - drug dosage

DRUG ACTION
• Metrology - deals with weights and measures
used for the computation of drug dosages • Drug’s response when administered to living
organisms (useful or harmful)
LETS MAKE IT EASY
SUBJECT
VERNON MARCIANO
medicine, drugs, active ingredients? • Drug action and Drug effect are mutually
dependent. To demonstrate and measure a drug
• prescription medicine —- active ingredients
effect on a certain biologic system, the system
(also an inactive ingredient) —- usually a chemical
should include both the site where the drug acts
of known structure —— drug
and the site where the effect can be observed
Physiological vs. Pharmacological effects
PHYSIOLOGICAL Maintains normal body

INTRODUCTION TO DRUG-
EFFECT functions RECEPTOR INTERACTION LESSON 2
PHARMACOLOGI alteration in the normal body

CAL EFFECTS functions
water?homeorrhesis?homeost
asis?
Selective Toxicity
• A dose of a drug maybe poisonous to one

organism but not to another.
• basis for chemotherapy.(use of chemicals to kill or

inhibit infective or parasitic living organisms
DRUG RECEPTORS GROUPS
(pathogens) which produce disease in the host
(patient) EXOGENOU - enzymes
S LIGANDS
Categories of Chemotherapeutic Drugs - transporters
• antibacterial (vs bacteria) - Channels
• antiviral (vs viruses) - Structural proteins
• antifungals or antinycotics ( vs fungi) - nucleic acid
• antiprotozoan (vs protozoa) ENDOGENO - hormones
US LIGANDS
• antineoplasms (vs cancer cells - Neurotransmitter
• antihelminthics (vs parasitic worms) - growth factor
Drugs do not create new functions in living - Autokines
organisms. They may only enhance or reduce the
functions which are inherent in the organisms. DRUG 1. cell membrane embedded
The effect of the drug therefore quantitative and RECEPTOR proteins
never qualitative. FAMILIES
2. Ligand gated ion channel
DRUG ACTION VS DRUG AFFECT 3. G-protein coupled receptor
• Drug action - where and how the effect is systems 4. transcription Factors
produced
• Drug effect - what is produced by the drug

SUBJECT
VERNON MARCIANO
SUBJECT
VERNON MARCIANO
What is a silent receptor?example?anesthesia
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
Example: MEPYRAMINE. brain and

antihistamines
SUBJECT
VERNON MARCIANO
STRUCTUREACTIVITY
RELATIONSHIP (SAR) LESSON 3
SAR -used in characterizing drug
(STRUCTUR receptors relationship,
E ACTIVITY correlation, and independence
RELATIONS between the molecular
HIP) structure of drugs and their
receptors
-Determination of the chemical

groups evokes a target
biological effect in the
organism
-Quantitative SARs (QSAR) as a

special case of SARs (when
relationship became
quantified)
QSAR -Attempts to find consistent

relationship between
variations in the values of Brown and Fraser hypothesis rejected upon the
molecular properties and the discovery of the native compound….native
biological activities fora series compound for muscle?
of compounds so that these
“rules” can be used to evaluate “Molecules that block the effects of natural
new chemical entities neurotransmitters (what is it?) generally are
-3D QSAR most powerful larger in size than the native compound”
technique available for analog Implication: same structural features, but the
based drug design arrangement and chemical functional groups
dictates the effect it will possess.
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)
SUBJECT
VERNON MARCIANO Lipholicity pH
hydrogen bonding Cosolvents
molecular volume
Additives
ionizability
ionic strength Time
TemperatuRE
Poorly soluble compounds can reduce

productivity in drug discovery and development
Complications:
- compound precipitation during serial dilution in

buffer, biochemical assays, functional and cell
3. Listing of modified compounds —- assays. assays?
CONGENERIC SERIES 4. Identification of the
pharmacological response of each series - Reduce target specificity
comparing to parent drug - Low bioavailability in animal studies
Physiochemical properties of Drugs: Predicting water solubility
1. ACID-BASE PROPERTIES empirical approach based on Carbon solubilizing
2. WATER SOLUBILITY OF DRUGS potential of several organic functional group
3. STEREOCHEMISTRY
4. ELECTRONIC PARAMETERS
Empirical approach
PARTITION COEFFICIENT - extent of distribution

of drug between the oil phase and water phase;
high P value, more hydrophobic, more or less
permeable?
WATER SOLUBILITY OF DRUGS

Log P - functional groups (hydrophobic +
Affects the routes of administration depends on hydrophilic characteristics); measure of the
structure and solution conditions solubility of entire molecule PREDICTS WATER
SOLUBILITY
SUBJECT
VERNON MARCIANO
HOMO - highest occupied molecular orbital

energy
LUMO - Lowest unoccupied molecular orbital

energy
STEREOCHEMISTRY AND DRUG ACTION
DRUG FAMILIES
composed of member drugs that act on specific

receptors that produce same kind but different
Physiochemical properties of a drug molecule magnitudes of effect
depends on:
A) functional groups in the molecule
B) spatial arrangements of the groups
EASSON AND STEDMAN HYPOTHESIS
THINK!!!!! if antagonists are not related

structurally to the agonist, can they cause
antagonism and why?
NAMING OF DRUG FAMILIES
- typical members of the group
- chemical structures
- families of antagonist derive their names from

typical
ELECTRONIC PARAMETERS
- members of their corresponding agonist
CHARGE - sum of partial charges
TYPICAL MEMBERS OF THE GROUP
Apol - sum of atomic polarizability
Atropine like agents
Dipole - dipole movement
Adrenergic stimulants
SUBJECT
VERNON MARCIANO
morphine derivatives ANTAGONIST DERIVE FROM CORRESPONDING

AGONIST Antihistamine (vs. Histamine)
Barbiturates (derivatives of barbituric acid)
Anticholinergics (vs. Acetylcholine)
Adrenergic blocking agents (vs adrenaline nor

adrenaline)
Barbiturates (derivatives of barbituric acid)
CHEMICAL STRUCTURES
Benzodiazipines
Nitroimidazoles
DRUGS having similar indications or clinical uses
Salicyclates
may not necessarily constitute a drug family
Salicylanilides
Example: Atropine, attapulgite and loperamide
Xanthine are all used to control diarrhea but each belongs
to a different drug family
derivatives
Page 43 part 1B lesson 4

SUBJECT
VERNON MARCIANO
- enzyme activity
- Membrane potential
- secretion of hormones
DOSE RESPONSE RELATIONSHIP - heart rate or contraction of muscles
DOSE RESPONSE RELATIONSHIP
systemic description of the magnitude of the

effect of the drug in relation to the dose
Describes the change in the effect of an

organism caused by differing levels of exposure
(DOSES) to a stressor (chemical) after certain
exposure time
2 TYPES OF DRR
1. GRADED DOSE RESPONSE RELATIONSHIP 4 parameters of the curve
2. QUANTAL DOSE RESPONSE RELATIONSHIP - baseline response (BOTTOM) (A)
- Maximum response (TOP) (B)
- SLOPE (C)
- drug concentration that provokes response
halfway between the baseline and maximum (D)
THRESHOLD
- dose below which have no adverse effects
from exposure to chemicals
DOSE - amount of a substance administered at

one time
DOSAGE - amount per unit weight of the
exposed individual
RESPONSE
SUBJECT
VERNON MARCIANO
SLOPE FACTOR –
also known as the HILL SLOPE

- Quantification of steepness / shallowness of
the curve
- standard curve: Hill slope of 1.0
- STEEPER: higher slope factor
- SHALLOWER: lower slope factor
IMPORTANCE OF DRUG DOSE RELATIONSHIP
DRUG POTENCY
DRUG EFFICACY
DRUG SAFETY
POTENCY
- is the measure of the drug activity expressed in
the amount of drug to produce effect
DRUG EFFICACY
- maximal response produced by the drug
GRADED DOSE RESPONSE CURVE

SUBJECT
VERNON MARCIANO
graph relationship between varying doses and relationship between drug dose and the
response (either minimum or maximum) response (how much response is caused by the
administered amount of drug?)
UNKNOWN: relationship between the dose bio
phase and drug 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?)
QUANTAL DOSE RESPONSE Lesson 5
- 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
ALL OR NONE
ADMINISTRATION OF DRUG TO PRODUCE A - percentage of population affected
RESPONSE equals or less than threshold response
Administration —— Absorption —— Blood - NOT MAGNITUDE OF DRUGS
circulation
Physiochemical PROCEDURES
properties of the drug Define quantal dose response to be observed
Blood flow through e.g.. death
the site of administration 30 mice (same info)
Administer increase doses
less drug absorbed, less drug reach biophase, taking note of the doses where mice died record
less receptors occupied, less response smallest dose at which death occurs for each
Factors inhibiting maximal response animal (MINIMAL LETHAL/EFFECTIVE
Extent and Rate of Distribution DOSE/THRESHOLD DOSE)
Non specific binding of drugs with tissues and
plasma proteins and liberation of drugs from PURPOSE
reservoirs to allow prediction about what proportion of a
Drug biotransformation metabolism in tissues population of subjects will respond to the given
Excretion of drug before reaching the biophase doses of drug or toxin
DRUG RESPONSE STIMULUS factors: The specific effect being measure:

type and condition of the effector system Initial 1. 2 responses: YES or NO; 0 or 1 (QUANTAL and
drug effect on the effector system Local and not variable)
Systemic contra regulation of the response 2. increments and decrement of 1 unit (eg
individual) at a time PROBLEM: many units
NOTE: Magnitude of stimulus is directly sample
proportional to the number of occupied
receptors….really? agonist + activator TITRATION
finding the individual effective dose
Nature of stimulus: response relationship may Each individual - admin dose - note each effect in
depend upon the kind of response the observer every individual
is looking for as the “end effect” GROUPS
division of individual into groups
PROBLEMS OF GRADED DOSE REPONSE CURVE
KNOWN :
SUBJECT
VERNON MARCIANO
give each group only 1 of increasing dose MEDIAN EFFECTIVE DOSE

variable response (0-100%) Record percent of -(ED50) - dose required to produce 50% of the
the group responding to each dose G maximum response
MEDIAN LETHAL DOSE (LD50) - kill 50% of
experimental animal, measures toxicity
“THE LOWER THE VALUE OF LD50, TEH MORE
HAZARDOUS
PHARMACOLOGY
Drug actions not involving Receptors
3 MECHANISM OF DRUG ACTION the DO NOT

DEPEND upon any DRC
1. Non-specific action and cell membrane

NORMALLY DISTRIBUTED perturbation
shape of this distribution closely resembles the 2. Interaction with small molecules and ions
shape of theoretically derived family of 3. Incorporation of drugs into macromolecules
mathematical deviation Follows the GAUSSIAN
PARAMETERS OBTAINED FROM QDRS NON SPECIFIC AND CELL MEMBRANE
Effective Dose (ED) LETHAL DOSE (LD) or TOXIC PERTUBATION
DOSE (TD) Osmotic Agents : Osmotic Diuresis
eg. MANNITOL
OSMOTIC CATHARTICS
e.g.. Magnesium sulfate EPSOMS and GAUBERS
SALT
SUBJECT
VERNON MARCIANO
URINE ACIDFIERS
ammonium chloride
contributes a hydrogen ion to the body fluids
OSMOTIC CATHARTICS when NH4 is metabolized to the neutral end
e.g.. Magnesium sulfate EPSOMS and GAUBERS product area bronchial mucosa irritant causing
SALT coughing up of exudations Ammonium salts are
gastric irritant causing nausea and vomiting
ORGANIC ANTISPETICS
eg. DETERGENTS- destroy the integrity of lipid
membranes and cause dissociation of
nucleoprotein complexes
eg. DEANTURANTS - desroy the integrity and

functional capacity of cell membranes and
proteins
GENERAL ANESTHETICS
- reversible drug induced state characterized by

analgesia, amnesia, loss of consciousness and
loss of sensory and motor function
- induced by chemical agents with diverse
chemical structures
e.g.. Nitorus Oxide, Halothane, pentobarbital,
althesin and ketamine
HISTORY
Crawford Long - uses diethyl ether in painless
ACIDS AND BASES EG. ANTACIDS like Magnesium operation; hypothesized membrane proteins in
Hydroxide neuronal membrane
inorganic and organic bases and ion exchange
resins administered orally to neutralize excessive Paul Elrich - anesthetics only act only with the
acidity in the stomach receptors: NOT TRUE because
a) molecular structures are very simple that is
why it pretty obvious for Structure Activity
Relationship (SAR)
SUBJECT
VERNON MARCIANO
b) weak affinity to the target receptors that is and expansion (thickening) due to volume
why it is acting in higher concentrations displacement –
actual structure per se is not really important
but the molecular volume
- concluded that the more space with the
membrane is occupied by the anesthetic, the
more anesthetic effect - supported by the
experiment that pressure reverses anesthetic
effect (Pressure reversal effect)
2. Physiochemical Theories
- looks into the diverse chemical nature of
general anesthesia
- anesthesia effect is exerted through some
perturbation of the lipid bilayer:
a) Changes in phase separation
b) changes in bilayer thickness
c) changes in order parameters
d. changes in curvature elasticity

VON MEYER OVERTON CORRELATION
Von Bibra - (1847) - anesthesia — dissolves the LATERAL PHASE SEPARATION THEORY
fatty component of the membrane —- fluidizing the nerve membranes to a point where
anesthesia effect
critical lipid regions disappear
HANS HORST MEYER - potency is related to lipid
solubility less able to facilitate the conformational changes
OVERTON - same with Meyer after 2 years in proteins
Principles: a) ion gating

Concentration of anesthesia is independent of
b) synaptic transmitter release
the delivery (route of administration)
The greater is the lipid solubility of compound in c) transmitter binding to receptors
olive oil, the greater the anesthetic potency
anesthesia has an additive effect
OUTDATED LIPID HYPOTHESES OF GENERAL
ANESTHETIC ACTION
MILLER and SMITH Hypothesis “LIPID BILAYER

EXPANSION HYPOTHESIS
- busy and hydrophobic (lipophilic) regions in
neuronal lipid membrane causing its distortion
SUBJECT
VERNON MARCIANO
4 weaknesses of the Physiochemical Theories

1. Stereoisomers of an anesthetic drug have
very different anesthetic potency
whereas their oil/gas partition
coefficients are similar
Stereoisomers that represent mirror images MODERN LIPID HYPOTHESIS anesthetic effect
of each other are termed enantiomers or happens if solubilization of general anesthetic in
optical isomers (for example, the isomers of the bilayer causes a redistribution of membrane
R-(+)- and S-(−)-etomidate). Physicochemical lateral pressure
effects of enantiomers are always identical in Cantor Hypothesis
an achiral environment (for example in the
lipid bilayer). However, in vivo enantiomers
of many general anaesthetics (e.g. isoflurane,
thiopental, etomidate) can differ greatly in
their anaesthetic potency despite the similar

oil/gas partition coefficients
NON IMMOBILIZERS Immobilization - absence of

movement in response to noxious stimuli;
depression of spinal cord Amnesia - loss of
memory exerted on the brain “some of the drugs DRUGS ACTING ON SMALL MOLECULES
are potent but it does no cause immobilization, Chelation - formation of coordination complexes
only anesthesia” e.g.. halogenated alkanes usually with metal ions e.g..
correlate to OVERTON MEYERS HYPOTHESIS!!
3. Temperature increases do not have anesthetic ETHYLENEDIAMINETETRACETIC ACID (EDTA) -
effect Membranes are fluidized only by large specific treatment for lead poisoning
quantities of anesthetics, but are no changes in
membrane fluidity when concentrations of PENICILLAMINE - used in removing copper from
anesthetics are small, restricted to body tissues in cases of hereditary disorder
pharmacology relevant. copper metabolism (CERUPLASMIN) leading to.
4. Effect of vanishes beyond a certain chain progressive accumulation of free copper in liver
length and brain DIMERCAPROL - British Anti-lewisite
(BAL) - with free hydroxyl group that remains
polar )water soluble or non soluble?)after it has
SUBJECT
VERNON MARCIANO
chelated with metal ions such as arsenic, gold,

antimony, and bismuth
DRUGS INCORPORATING TO MACROMOLECULES
Counterfeit Incorporation
- drug replaces a normal metabolism in the
synthesis of an important cellular constituents. -
act as a false substrate 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
DI PA MUNA
Result of Counterfeit Incorporation:

1. increase sensitivity to X-radiation
2. Increase frequency of chromosome breakage
3. Mitotic abnormalities in mammalian cells
THEORETICAL INTERPRETATION OF
SIMULTANEOUS ACTION OF TWO DRUGS
Why use two drugs? 1. Optimize the beneficial

effect of each drug being used. e.g.. medication
against tuberculosis
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
SUBJECT
VERNON MARCIANO
PHARMACOLOGY
Drug actions not involving Receptors
3 MECHANISM OF DRUG ACTION the DO
NOT DEPEND upon any DRC
1. Non-specific action and cell membrane
perturbation
2. Interaction with small molecules and ions
3. Incorporation of drugs into
macromolecules
NON SPECIFIC AND CELL MEMBRANE

PERTUBATION
Osmotic Agents : Osmotic Diuresis eg.
MANNITOL
OSMOTIC CATHARTICS
ACIDS AND BASES

EG. ANTACIDS like Magnesium Hydroxide
inorganic and organic bases and ion
SUBJECT
VERNON MARCIANO
exchange resins administered orally to

neutralize excessive acidity in the stomach
HISTORY
Crawford Long –uses diethyl ether in
painless operation; hypothesized membrane
proteins in neuronal membrane
Paul Elrich - anesthetics only act only with

the receptors: NOT TRUE because:
a) molecular structures are very simple that

is why it pretty obvious for Structure Activity
Relationship (SAR)
b) weak affinity to the target receptors that is
why it is acting in higher concentrations
URINE ACIDFIERS ammonium chloride

contributes a hydrogen ion to the body fluids
when NH4 is metabolized to the neutral end
product area bronchial mucosa irritant
causing coughing up of exudations
Ammonium salts are gastric irritant causing
nausea and vomiting
ORGANIC ANTISPETICS
eg. DETERGENTS- destroy the integrity of

lipid membranes and cause dissociation of
nucleoprotein complexes
eg. DEANTURANTS - desroy the integrity
and functional capacity of cell membranes
and proteins
VON MEYER OVERTON CORRELATION
GENERAL ANESTHETICS
- reversible drug induced state characterized Von Bibra - (1847) - anesthesia — dissolves
by analgesia, amnesia, loss of the fatty component of the membrane —-
consciousness and loss of sensory and anesthesia effect
motor function - induced by chemical agents HANS HORST MEYER - potency is related
with diverse chemical structure to lipid solubility
OVERTON - same with Meyer after 2 years
e.g.. Nitorus Oxide, Halothane, Principles: Concentration of anesthesia is
pentobarbital, althesin and ketamine independent of the delivery (route of
administration) The greater is the lipid
solubility of compound in olive oil, the greater
the anesthetic potency anesthesia has an
additive effect
SUBJECT
VERNON MARCIANO
Stereoisomers that represent mirror

OUTDATED LIPID HYPOTHESES OF images of each other are termed
GENERAL ANESTHETIC ACTION enantiomers or optical isomers (for
example, the isomers of R-(+)- and S-(−)-
etomidate). Physicochemical effects of
1. MILLER and SMITH Hypothesis enantiomers are always identical in an
“LIPID BILAYER EXPANSION achiral environment (for example in the
HYPOTHESIS” lipid bilayer). However, in vivo
enantiomers of many general
- busy and hydrophobic (lipophilic) regions in anaesthetics (e.g. isoflurane, thiopental,
neuronal lipid membrane causing its etomidate) can differ greatly in their
distortion and expansion (thickening) due to anaesthetic potency despite the similar
volume displacement oil/gas partition coefficients
- actual structure per se is not really
important but the molecular volume
- concluded that the more space with the
membrane is occupied by the anesthetic, the
more anesthetic effect
- supported by the experiment that pressure
reverses anesthetic effect (Pressure reversal
effect)
2. Physiochemical Theories
- looks into the diverse chemical nature of
general anesthesia
- anesthesia effect is exerted through some
perturbation of the lipid bilayer: 2. NON IMMOBILIZERS
a) Changes in phase separation Immobilization - absence of movement in
b) changes in bilayer thickness response to noxious stimuli; depression
c) changes in order parameters of spinal cord
d) changes in curvature elasticity
Amnesia - loss of memory exerted on the
LATERAL PHASE SEPARATION THEORY brain “some of the drugs are potent but it
fluidizing the nerve membranes to a point does no cause immobilization, only
where critical lipid regions disappear less anesthesia” e.g.. halogenated alkanes
able to facilitate the conformational changes
in proteins correlate to OVERTON MEYERS
HYPOTHESIS!!
a) ion gating
b) synaptic transmitter release 3. Temperature increases do not have
c) transmitter binding to receptors anesthetic effect
4 weaknesses of the Physiochemical Membranes are fluidized only by large

Theories quantities of anesthetics, but are no
changes in membrane fluidity when
1. Stereoisomers of an anesthetic drug concentrations of anesthetics are small,
have very different anesthetic restricted to pharmacology relevant.
potency whereas their oil/gas 4. Effect of vanishes beyond a certain
partition coefficients are similar chain length
SUBJECT
VERNON MARCIANO
MODERN LIPID HYPOTHESIS DRUGS ACTING ON SMALL MOLECULES

anesthetic effect happens if solubilization Chelation - formation of coordination
of general anesthetic in the bilayer complexes usually with metal ions e.g..
causes a redistribution of membrane
lateral pressure ETHYLENEDIAMINETETRACETIC ACID
(EDTA) - specific treatment for lead
poisoning
PENICILLAMINE - used in removing copper
from body tissues in cases of hereditary
disorder copper metabolism
(CERUPLASMIN) leading to. progressive
Cantor Hypothesis: accumulation of free copper in liver and brain
DIMERCAPROL - British Anti-lewisite (BAL)
- with free hydroxyl group that remains polar
)water soluble or non soluble?)after it has
chelated with metal ions such as arsenic,
gold, antimony, and bismuth
DRUGS INCORPORATING TO
MACROMOLECULES Counterfeit
Incorporation
-drug replaces a normal metabolism in the
synthesis of an important cellular
constituents. -act as a false substrate
SUBJECT
VERNON MARCIANO
e.g. injection of
Yohimbine to reverse
Result of Counterfeit Incorporation: the sedative effect of
1. increase sensitivity to X-radiation xylazine
2. Increase frequency of chromosome
breakage 3. Mitotic abnormalities in Interaction Between drugs
mammalian cell
THEORETICAL INTERPRETATION OF
SIMULTANEOUS ACTION OF TWO
DRUGS
Why use two drugs?

1. Optimize the beneficial effect of each
drug being used. e.g.. medication
against tuberculosis
ANTAGONISM Non Competitive

- improving the dose will not improve the
response
2. Reduce the toxic or adverse effect of one

or both drugs
e.g. Peanesthetics sedatives that required explain! receptor conformation, binding of

dose of anesthetic drug; reduces the the antagonist and the reversible and
likelihood of toxic reactions of anesthesia irreversible
3. Terminate the action of one drug when it

is no longer needed
SUBJECT
VERNON MARCIANO
Competitive antagonism Double Reciprocal Plot also known as the

Lineweaver Burke Plot
The normal sequence of an enzyme reaction

can be represented as:
where:
E = enzyme
S = substrate
E-S = enzyme-substrate complex
E-P = enzyme-product complex
P = product
A competitive inhibitor competes with the

substrate for the active site of the enzyme
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
There are three main types of reversible

inhibitor:
• competitive inhibitor
• non-competitive inhibitor
• uncompetitive inhibitor
NON-COMPETITIVE INHIBITOR reacts with

SUBJECT
VERNON MARCIANO
the enzymesubstrate complex, and slows the ADDITIVE EFFECT

rate of reaction to form the enzyme-product
complex.
SYNERGISM Drug interaction in which the
effect of a drug 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.. CO-AMOXICLAV
POTENTIATION Special case of Synergism

when one of the 2 drugs had zero intrinsic
activity. The one one with the zero activity is
the
Potentiator
Physiological Interactions occurs when drugs

acting on different receptors have their
combined effects manifested in the same or
opposite way. on the same effector organ
graphically represents in an isobole
Isobole - curves that represent the identical

effects of a combination of two drugs
includes the
following:
SYNERGISM
ADDITIVE EFFECT
Similar to synergism but the combined effect
of the drug is equal to the sum of their
POTENTIATION individual effect
SUBJECT
VERNON MARCIANO
same mechanism of action —- same

receptors —- parallel
Chemical (Pharmaceutical) Antagonism log dose response
curve different
Occurs when a drug chemically interferes mechanism of action
with another drug or poison —- different receptors
—- non parallel log
1. Neutralization between acids and bases dose response curve
eg. penicillin (acid) will be neutralized by
gentamicin (base) if both are present in the
same solution 2. Potency of the Drugs
2. Chelation of Heavy Metals e.g.
Tetracycline chelates calcium in the gut
3. Adsorption of one drug by another eg.
Kaolin (attapulgite) adsorbs most drugs
administered with it
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
3. Competitive Antagonism
is increased - virually difficult to gauge the
- in the presence of a competitive antagonist,
magnitude of change in response
the curve shifts to the right, but with a slope
corresponding to a very small increment in
parallel to the curve of the agonist alone
the dose
- Maximum response is unchanged
- Antagonist would only reduce the affinity of
LOG vs. ARITHMETIC DOSE RESPONSE
the agonist for the receptors
CURVE
Information derived from LDRC

1. Nature of Drug Action 4. Non-Competitive Antagonist
- Curve may shift to the right but with lower
slope - Maximum response is reduced
SUBJECT
VERNON MARCIANO
MEC (Minimum Effective Concentration) -

the minimum level of drug concentration
needed for the desired therapeutic effect be
present
MSC (Maximum Safe Concentration) -

maximum level of drug concentration above
5. Partial Agonist which toxic effects occurs
- Blocks the agonist binding site but cause MTC (Minimum Toxic Concentration -
less response than a full agonist minimum level of drug concentration that
- has an affinity that is increased / decreased produces toxic effects
or equal to that of an agonist what will
happen if it is alone based on the curve Maximal Effect - Greatest response that can
be produced by a drug above which no
DRUG ADMINISTRATION AND further response can be created (PEAK
ABSORPTION EFFECT
ONSET - how long before a drug is able to
exert a therapeutic effect
Duration - How long a drug effect last
Absorption refers to the passage of drugs or

other substances from the site of application
(administration) into the blood circulation
ends in the appearance of drug in the blood
or plasma involves translocation of drugs
across biological membranes
Physiological Disposition of Drugs

- changes that a drug undergoes within the
body, from the time of administration up to
the time of elimination – includes
Blood Concentration Time Profile -

relationship between the aunt of drug in the
body and its effect
SUBJECT
VERNON MARCIANO
PARENTERAL ROUTE
Intravenus
Intramuscular
Subcutaneous
Intraperitoneal
Intrapleural
Intraarterial
Intrasynovial
Inhalation
Intraconjunctival
Intranasal
Intratracheal
Intradermal
ORAL ROUTE
- by mouth, per os, per orem, p.o.
- most ancient way of administering drugs
- the safest, most economical, and most
convenient - not useful in patients with
clinical signs of vomitting an gastric irritation,
or in those patients that are vicious and
uncooperative
- Not beneficial in adult ruminants
— drugs are diluted in the rumen and maybe Local Effect vs. Systemic effect Systemic
rendered ineffective - intraluminal injection - Effect - drug maybe administered either
also form of enteral route of administration enterally or parenterally, and must be
absorbed Local Effect - drug is applied on
the site where its effect is wanted
Kinetic Considerations in Drug absorption

Kinetics - study of the rate of change from
the initial state (eg. concentration) to the final
state of a substance or drug
ORAL ROUTE
- Drugs may also be inactivated in the mono
gastric animals eg. Penicillin G is inactivated
by the gastric acid
- Oral Route is the most practical in medical
medicating a large herd or flock of animals
RECTAL ROUTE
- rarely used in animals except in giving
enema to constipated pets

SUBJECT
VERNON MARCIANO
The rate of change in the drug concentration

remaining in the muscle with the change in
time can be expressed in the form of a
differential equation dC/dt = -kC
where: k - rate constant of absorption C -

drug concentration in the site t - time
- based on the equation: rate of change in

the concentration relative to the rate of
change in time is equal to the product. of the Rate Limiting Factors in Absorption
rate constant and the concentration of the
drug why is the k negative?

example: k = 0.05/minute - 5% of the
concentration (C) remaining in the muscle at - Molecular does not seem to influence the
any time will have been absorbed after one rate of absorption
minute - 5% of C remaining at the end of the - little variation maybe observed maybe due
first minute will have been removed, and so to species difference or the difference in the
forth. blood flow in the sites of injection
- Effect of molecular weight can be
First Order Kinetics - a constant percentage associated on the diffusion of non lipid
of the drug remaining in the site of soluble substances that that of lipid soluble
administration is absorbed (or disappears substance
from the site) with time
Bioavailability - Total quantity of the drug
Zero Order Kinetics - the actual amount of absorbed intact - usually expressed as
drug absorbed per unit time is the same percent of the dose administered
regardless how much of the drug remains in
the site
SUBJECT
VERNON MARCIANO
1. Age - based on blood flow, intestinal

surface area, Gastric pH, gastric emptying
young - higher possible absorption
(achlorhydria)
2. Gastric Emptying - passage of food from
stomach to intestines, delayed when
administered with food
3. Intestinal Transit Time - longer transit time
is desired for increase absorption in the
intestine, base on: a. drugs that is desirable
in the intestines b. drugs that is dissolve only
in intestine (enteric coated)
4. GI pH - based on the dissolution and
Intravenous Administration stability that reacted on the pH
- for rapid onset of drug action – 5. Disease state - achlorhydria,
actual rate of absorption is controlled by the malabsorption and surgeries as well as
injector hepatic problem (cirrhosis) that needs first
- adverse response is more readily and more pass effect
frequently encountered
– Administration “to effect” eg. titrating the
patient (by IV injection) with the drug until the
desired effect is attained (a graded dose
response)
PROPANOLOL - drugs can also be given in
bolus example: MANNITOL; in vetmedicine,
emesis with apomorphine
Gastrointestinal absorption 1. Particle size

drugs administered for systemic effects
have generally lower bioavailability due to:
Pharmaceutical
Physiological
Physiochemical
SUBJECT
VERNON MARCIANO
2.Polymorphism and Amorphism expressed in terms of oil water partition

polymorphism - same chemical composition coefficient (ratio of drug solubility in oil and
but different crystal structure water)
High partition coefficients — more liquid
soluble —- more absorbable in the gut
Ionization - more ionized, less absorbed in

the gut
henderson Haselbach equation - determines

the degree of ionization as the pH increases,
the ionization of weak acids increases, that
of weak bases, decreases
As the pH decreases the ionization of weak

acids decreases, that of weak bases
increases
ion trapping in the stomach and intestines

weak acids are more absorbed in acidic
environment such as the stomach
amorphous is more absorbed

weak bases are more absorbed in alkaline
3.pH partition - unionized drug - high environment such as the intestine
absorption ionized drug - low absorption
4.Salt Formation of the drug
FIRST PASS EFFECT

Upon passing through the liver by the
hepatic portal system, drugs maybe partially
metabolized and maybe inactivated
Prodrugs
- administered orally in an inactive form and
are activated during the first pass effect in
the liver
absorption through respiratory tract
LIPID SOLUBILITY OF DRUGS

SUBJECT
VERNON MARCIANO
DRUG BIOTRANSFORMATION • in reduced form, microsomal enzymes bind

to carbon monoxide and absorb light at
Biotransformation 45nm
• refers to the biochemical process affecting
the pharmacological activity of drugs and Mixed Function Systems
other foreign substances • in the presence of nicotinamide adenine
• better term used than detoxification and dinucleotide phosphates (NADPH) and O2
metabolism of drugs enzyme system transfers one atom of
• detoxification - reduces drug activity oxygen to the drug while another oxygen is
• Metabolism - normal anabolic and reduced to form water
catabolic reactions in the body such a 1. NADPH + A +H+ —-> AH2 + NADP+
involving hormones and endogenous 2. AH2 + O2 —-> “active oxygen
macromolecules functions of the liver? complex”
3. “active oxygen complex” + drug
Biotransformation substrate —> oxidized drug
+A+water
• Rates varies among animal species
• e.g. Phenylbutazone (humans: half life of Phases I and II of Biotransformation
72H, dogs, cats and rats: 3-6 Hours
• when drugs are biotransformed,
metabolites or by products are produced
• generally less active than the parent
compound Phase I Biotransformation
• greater activity than the parent drug after • Involves metabolic transformation by:
biotransformation — LETHAL SYNTHESIS • oxidation
• reduction
Biotransformation • hydrolysis
• “nonspecific” -different compounds can be • a functional chemical group such as -SH, -
enacted by enzymes OH, - NH2 or -COOH is affixed to the drug
• Biotransforming enzymes only recognizes molecule
certain sonstituents or chemical groups
common to many substances, rather than Phase II
the entire substances. Thus, enzymes • involves synthetic reactions conjugating the
catalyzing drug biotransformation may also product of Phase I reactions with metabolites
be involved in the metabolism of some normally present in the body such as
endogenous substances having same glucoronide, sulfate, acetate and ornithine
chemical groups • produces more polar drug metabolites that
are suitable as substrate for excretory
Liver transfer mechanism
• the most important site of drug
biotransformation in the body Phase I Biotransformation
• drugs may undergo the first pass effect • Oxidative reactions
• other sites include the intestinal mucosa, • aromatic hydroxylation
lungs and the kidneys • aliphatic oxidation
• O-dealkylation
Microsomal enzymes • N-dealkylation
• Part of smooth endoplasmic reticulum in • oxidative deamination
the liver • desulfurization
• converts many lipid soluble drugs and • sulfoxidation
foreign compounds into more water soluble
metabolites • e.g. cytochrome P450/mixed
function oxidases • a complex of protein and
heme
SUBJECT
VERNON MARCIANO
Phase I Biotransformation • Hydroxyl (OH)

• Reductive reactions • amino (NH2) groups
• Azo reductions • R-N=N-R —->. RNH2 +
H2N-R • Nitro Reaction • R-NO2 —-> R-NH2 Phase II Biotransformation
• Glucoronic Acid Conjugation
Phase I Biotransformation • important pathway of the biotransformation
• Hydrolytic Reactions • the most common • the conjugating agent is glucoronic acid,
types are those of compounds with an ester which is delivered from the glucose
or an amide linkage • Glucoronic Acid must be activated —>
• Ester linkages occurs in various types of UDPglucoronic acid before conjugation
drugs: • local anesthetics (procaine) process • catalyzed by glucoronide
• insecticides transferase
• agents acting on parasympathetic nervous
systems • Sulfate Conjugation
• antiinflammatory agents • Phenolic and alcoholic compounds maybe
• Amides (eg. procaine, lidocaine) are conjugated with sulfate to form esters
hydrolyzed by amidases, which are found (etheral sulfates)
prinispally in the soluble portion of the liver • Sulfate is first activated into 3’-
phosphoadenosine-5’-phosphosulfate
Phase I Biotransformation (PAPS)
• Ester Hydrolysis • Amide Hydrolysis • reaction is catalyzed by sulfonamides
• Acetylation
• occurs in the reticuloendothelial cells,
rather the parenchymal cells of the liver
• active conjugating agent is acetyl-CoA
• reaction is catalyzed by specific acetyl
transferase
• Glutathione conjugation
• takes place the alkyl halide, epoxide and
halides
• Methylation
• form of the conjugating agent to
Sandenosylmethionine
• reaction is catalyzed by methyl transferase
Biotransformation
• oxidation, reduction, and hydrolysis add a
functional groups to drugs so that these
process preceded conjugation reactions
Phase II Biotransformation
• Conjugation Reactions • Drugs that initially have any functional
• The combination of a drug with an groups may directly undergo conjugation.
endogenous metabolite such as glucoronide, Conjugation has 2 important features:
acid sulfate, acetate, ribosome, mercapuric • the addition of highly polar substances
acid and ornithine increases drug polarity and water solubility
• Functional groups involved in the • the free COOH (as in the case of
conjugation are formed during the phase I of glucoronide. conjugation) makes the drug
biotransformation or are originally part of the more acidic and able to undergo renal
parent drug molecules: tubular secretion
• carboxyl (COOH)
• sulfhydryl (SH) • Conjugated drugs are more inactive
SUBJECT
VERNON MARCIANO
should be administered more frequently than

Non-Microsomal Biotransformation usual
• Biotransformation also occurs in parts of
the body other than the smooth endoplasmic Factors affecting Drug Biotransformed by
reticulum (microsomes) of the liver cells Microsomal Enzymes
• Extramicrosomal sites • AGE
• In plasmas • Neonates (newly born) have less well
• eg. Butyrylcholinesterases developed drug metabolites enzymes—
(pseudocholinesterases) hydrolyse ester >more sensitive to drug actions than adults.
bonds of choline esters including • eg. Gray baby Syndrome - characterized by
acetylcholine abdominal distention, vomitting, respiratory
• Neurons and NMJ difficulty, cyanosis, and muscle flaccidity
• eg. Acetylcholinesterases • Neonates (specially human infants) and
(true)cholinesterases) specifically hydrolyses adult cats have low glucoronyl transferase
acetylcholine activity, and therefore the biotransformation
and renal excretion of chloramphenicol is
• In Mitochondria deficient
• e.g. monoamine oxidase (MAO) degrades
biogenic amines such as epinephrine, • in most species, it takes 3-6 weeks for the
histamine, norepinephrine and serotonin (or drug metabolizing enzymes to be fully
5-hydroxytryptamine) developed
• In intestinal microbial organism • Except in the horse in which enzymes
• Glucoronidases in anaerobic bacteria and reach adult level of activity within 3 days
in lactobacilli hydrolyze glucoronide after birth
conjugates • very old patients may also have depressed
• Glucoronide-conjugated (inactivated) rate of drug biotransformation
drugs which are excreted in the bile maybe
acted upon by glucoronidases— >drugs Factors affecting Drug Biotransformed by
maybe reactivated and reabsorbed— Microsomal Enzymes
>prolonged systemic effect—>ENTERO • SPECIES
HEPATIC RECYCLING • Quantitative difference - difference in the
rates of biotransformation
• Glycosidases in ruminants. Certain plans • Qualitative difference - difference in the
glycosides maybe biotransformed to release metabolic pathways by which the drug is
cyanogenic (cyanide-forming) or cardiotonic biotransformed
glycosides
• Amidases —> hydrolysis of
phthalysulfathiazole to release sulfathiazole
(an antibacterial sulfonamides)
• Reducing enzymes such as those
responsible for reducing chloramphenicol
and parathion
• reduced biotransformation—> increased • Cats

duration of action—>no change in the • more sensitive to drugs and chemicals
intensity of drug effect than other species because of their relatively
• in multiple administrations(with short slow rates of drug biotransformation, usually
intervals between doses)—>drug sensitivity of drug receptors in them, and
accumulates and alter drug-receptor their grooming habits
interaction—>toxic effects • deficient in glucoronide conjugation,
• increased rate of biotransformation —> hydroxylation reactions, and ddealkylation
reduced duration of biotrnasformation— reactions
>reduced intensity of response—>drug
SUBJECT
VERNON MARCIANO
• can form UDP-glucoronic acid but the • example:

activity of glucoronide transferase is very low • anesthetics (methoxyflurane)
• can form glucoronidases of endogenous • Hypnotics and sedatives
metabolites such as bilirubin, thyroxin and • Tranquilizers
steroid hormones • Muscle relaxants
• Analgesics
Factors affecting Drug Biotransformed by
Microsomal Enzymes ENZYME INDUCTION
• Dogs cannot acetylate primary amines • Characteristics of Inducers
such as sulfonamides • relatively lipid soluble
• Pigs do not carry out sulfate conjugations • There is no relationship between
• Only primates convert phenyl acetate to pharmacological action or chemical structure
phenylacetylglutamate and the ability to induce enzymes
• Birds and reptiles form ornithine • Mechanism of Induction
conjugates • Increased rate of synthesis of enzymes,
• Goldfish and perch apparently do not form decreased degradation or both
glucoronide, but some other fish may do
ENZYME INDUCTION
• Diseases and Starvation • Observation that indicates increased
• can depress the rates of biotransformation synthesis • increased in the weight and
• defects in glucose metabolism by way of protein content of the liver
the pentose phosphate shunt may lead to • increased in mRNA
reduce NADPH, an important coenzyme in • increased incorporation of amino acids
drug biotransformation by the microsomal from tRNA
enzymes • increased cytochrome P450 (2-3 fold)
• Gender • increased cytochrome P450 reductase (2
• male rats metabolize drugs at a greater folds) • increased endoplasmic reticulum
rate than females (SER)
• related to hormonal status of the animal • enzyme induction can be blocked by
inhibitors of protein synthesis such as
• Genetic Differences methionine, puromycin, ad actinomycin
• Gunn rats cannot form glucoronides
• some mouse restraints have 500% CONSEQUENCES OF ENZYME
difference in duration of hexobarbital INDUCTION
anesthesia • Clinical Drug Interactions
• Several analgesics and sulfonamides • Between phenobarbital and warfarin - this
induce hemolytic anemia in subject deficient has produced fatal hemorrhages in humans
in glucose-6-phosphate dehydrogenase • between phenobarbital and phenytoin
• some human patients (and pigs too; • between phenobarbital and digoxin
sometimes dogs and horse) manifest n • Carbon tetrachloride (used to control liver
malignant hyperthermia characterized by flukes in ruminants)— >metabolized by the
very high body temperature and muscular mixed function oxidasesof the smooth
rigidity, in response to anesthetic agents endoplasmic reticulum—>activated for free
such as halothane radicals or lipid peroxides—>hepatic tissue
damage
ENZYME INDUCTION • Some plants used as fodder may contain
• Chronic treatment of a patient with many enzyme inducers (eg.flavones) and therefore
drugs can enhance the rate of drug being may enhance the toxicity of carbon
biotransformation by the mixed function tetrachloride by increasing the rate of the
oxidases metabolism
• A given drug may enhance its own
biotransformation, as wella s those of many ENZYME INDUCTION
other drugs
SUBJECT
VERNON MARCIANO
• Phenobarbital, phenytoin and chlorinated Glomerulus Pressure+Osmotic Bowman’s

hydrocarbons enhances the endogenous Capsule Pressure) • effects of blood
cortisol metabolism, resulting in defects pressure dehydration in GFR
attributable to deficiency of steroid hormones
• Clinical uses of Enzyme Induction
• reduction of DDT and dieldrin residues in
cattle by feeding 5g
phenobarbital/animal/day
• hyperbilrubinemia in children
• phenobarbital induces the synthesis of
bilirubin glucoronyl transferase and the
hastens the formation of more readily
excitable form of bilirubin
DRUG EXCRETION
Excretion
• removal of drug and drug metabolites from
the body
• one of the three ways drug actions are
terminated
• biotransformation - inactivates most of the
drugs
• Redistribution - terminates drug activity by
removing (or sequestering) the drug from it's
site of action into other sites within the body
renal mechanism of excretion

• GLOMERULAR FILTRATION
• All drugs undergo some degree of
glomerular filtration except those that are
bound to protein • substances with MW of
less than 7,000 will pass through the
glomerulus
• driving force for the filtration of plasma is
the blood pressure (hydrostatic pressure)
• GFR=Filtration Constant × (Hydrostatic
Glomerulus Pressure– Hydrostatic
Bowman’s Capsule Pressure)–(Osmotic
SUBJECT
VERNON MARCIANO
another weak acid by blocking the renal

secretion of penicillin
• Tubular reabsorption
• exceedingly important for homeostasis
• more than 90% of filtered sodium is
reabsorbed; 100% glucose and about 80%
water • depends upon the physiochemical
properties of the drugs:
• pH
• Lipud solubility
Renal Mechanism of Excretion
• Drugs more polar or less lipid soluble can
• Inulin (most of the species) and creatinine
pass thru the tubules easily
(dogs) are used in measuring the GFR due
• manipulated to enhance the excretion of
to nontoxicity characteristic, not affecting the
drugs or poisons
renal function and not absorbed or secreted
• poisoning with a barbiturate (a weak acid,
by the renal tubules
urine can be alkalinized with IV sodium
• TUBULAR SECRETION
bicarbonate
• Effective Renal Plasma Flow (ERPF) -
• in weak bases such as morphine and
estimated substances that are vigorously
neostigmine, acidification of the urine
secreted by the renal tubules that the plasma
enhances its excretion
is completely cleared of it in a single
passage
• Urine flow can be increased with the used
of diuretic agents
• volume of plasma perfusing the proximal
• urine flow increases, the time tubular
tubules that is delivered to the kidneys by
reabsorption shortens
way of the renal arteries every minute
• sometime sdangerous it may cause
• penicillin G and p-aminohippuric acid (PAH)
dehydration
with clearance of 650ml/min are used to
estimate the ERPF
Clearance
• at low plasma concentration both are
• indicates the rate at which drug is cleared
completely cleared from the blood
(removed) from the body
• volume of plasma (mL) from which all drug
• clearance does not reach zero but always
is removed from a given time.
constant at a lower value. this constant
• expressed as mL per unit of time (minutes)
clearance is the combined result of the
• clearance of most substances is the rate
constant filtration rate and the secretion rate
net effect of glomerular filtration, tubular
that has constant because of the saturation.
reabsorption and tubular secretion
• secretion is an active process and
saturable
Glomerular Filtration
• bathtub model…same water rate from the
• passive filtration of the blood as it flows to
faucet and the same rate of the water
the glomeruli of the kidney
coming out from the drainage. water is the
• depends on the molecular size, protein
concentration.it will just depend on the size
binding, ionization, polarity and kidney
of the
function • renal clearance (CLren)
• CLren = GFR (Fu)
• Drugs of similar properties compete for the
• normal GFR: 5.48 ml/kg/min
secretory sites so that the secretion of the
• normal renal blood flow: 163-171 ml/min
weak acid is blocked by another weak acids,
• so, for 9 kg Bodyweight dog, determine the
and a weak base by another weak base.
percentage of blood filtered?
• eg. probemacid (a weak acid without
antibacterial action) has been used to
• answer: 30% of the blood filtered
prolong the systemic effect of penicillin,
SUBJECT
VERNON MARCIANO
• note that for the case kidney dysfunction, • major route of excretion of certain drugs
fu is equivalent to 1 if it is base on creatinine with MW exceeding 300
clearance due to none protein binding • biliary excretion is an active transport
CLren=GFR mechanism, it can be saturated and other
substances may compete for the secretory
• Tubular secretion sites • Drugs secreted in the bile:
• can increase the CLren since it secretes • acids - penicillins, tetracyclines,
the drug glucoronides and bile acids (cholic acid and
• depends on the transporter efficiency chenodeoxycholic acid)
• slow transporter, CLren will depend on the • weak bases - isoproterenol, atropine
fu • Neutral compounds - digoxin and digitoxin
• efficient transporter, CLren reaches the
maximal and CLren=RBF and thus, upper
limit of the drug
• Tubular reabsorption
• drugs reabsorbed after being filtered
• Clren is smaller in value because of the
filtration If a drug is “completely” reabsorbed
after filtration and no active secretion takes
place, the renal clearance will be limited to
the amount of drug that leaves the kidney as
the urine flows into the bladder.
• ClRen = (urine flow) * fu
compute for the CLren, and if it needs

filtration, reabsorption for the clearance of
the drug. Note that drug C is protein bound
drug
• CLren = GFR (Fu) • ClRen = (urine flow) *
fu
• normal GFR: 5.48 ml/kg/min
• normal renal blood flow: 163-171 ml/min
http://pharmacy.ufl.edu/files/2010/10/Renal_
Clearance_2.pdf NOTE: if the drug is below
the CLren, then it must be reabsorbed and if
it’s the same as the CL res, given without the
secretion, then its fine. but if the drug is
protein bound, and the CLren is very low
computed, then the drug is being secreted
again.
Biliary mechanism of Excretion

• continuously produced in the liver cells and
stored in the gall bladder in most species
• with pH ranging from 5 to 7.5 in most
animals (8 to 8.8 to humans)
• excreted in the duodenum where it aids in
digestion of fats DRUG DISTRIBUTION
SUBJECT
VERNON MARCIANO
Distribution
• movement of a drug from the plasma
compartment into the various fluid and tissue
compartments including the sites of action
• begins when the drug is being absorbed
BODY FLUIDS compartments

• Total Body Fluids
• measured with isotopic water or
antipyrine(a weak base with pK 5), which
Body Fluid Compartments readily cross all epithelial barriers
• compartments of body fluids maybe • Intracellular fluid volume
measured indirectly by the use of certain • difference between total body fluid and
substances with varying volumes of ECF
distribution in the bodyeg. • Interstitial fluid volume
• Eg. Evan’s blue or 131 I-albumin, when • difference between the ECF and the
injected into the circulation, stays confined to plasma volume
the cardiovascular system • Extracellular fluid volume
• Volume of distribution = plasma volume • plasma plus interstitial fluid
• Inulin and EDTA, freely diffuse out of the • Transcellular fluid volume
blood vessels but do not enter the cells • ECF but are enclosed within epithelial
• used to measure ECF tissues
• synovial, intraocular, cerebrospinal,
peritoneal, pericardial, and pleural fluid
SUBJECT
VERNON MARCIANO
• Binding to Tissue Constituents

Rate and Extent of Drug Distribution • some drugs bind to cell membranes and to
• Physiochemical Properties soluble intracellular components
• Eg. a highly soluble drug such as thiopental • Tissues are the major binding sites of
(a barbiturate sedative anesthetic) is readily antibiotics and other dugs in the body -
distributed and taken up by tissue due to WITHDRAWAL PERIOD
high fat content • Binding to plasma proteins
• Concentration of the Drug • almost all drugs bind to plasma proteins,
• Not necessarily correlated with the intensity mostly to albumin, in the circulation
of response • binding of the drugs to plasma proteins
• eg. Digitalis has primary action in the heart does not produce an effect
but its concentration in the heart is low • weak acids generally bind to plasma
relative that in other tissues proteins more extensively than do weak
bases
Factors Affecting Drug distribution • 2 forms of drugs: bound and unbound
• Drugs are distributed more readily to these
well perfused organ than those receiving
less blood flow • percent binding determines to some extent
• The equilibrium of drug concentration the effectivity of the drug
between given tissue and blood may depend • a drug with higher %plasma protein binding
upon blood flow maybe less potent than a similar drug with
lower percent binding
Redistribution (or sequestration) to other • inversely proportional relationship between
tissues can terminate the action of certain concentration of the drug in plasma and
drugs percent binding
• e.g. Thiopental • if the albumin is reduced to below 2mg/dL,
• readily accumulates in the brain following a there is a significant decrease in percent
single intravenous injection binding • eg. WARFARIN low therapeutic
• concentration of the drug in the brain index and phenylbutazone (antiinflammatory
eventually equilibrates when its drug). the percent binding of warfarin can be
concentration in the plasma reduced by phenyl from 97% to 92%, nearly
• drug concentration in plasma wanes 300% increase in free drug concentration
• drug diffuses from the brain back to the • some diseases may influence plasma
plasma and re circulated protein binding of drugs
• eg. Uremia reduces binding of penicillins,
Factors affecting Drug distribution cephalosporins and sulfonamides
• accumulation in fat, but does not readily
return to the circulation Distribution of Drugs in specialized
• Physiochemical properties of drugs compartments
• Lipid solubility, pKa and molecular size • Blood Brain barrier
determine the rate of distribution of a drug • continuos layer of tight junctions between
• Ion trapping - more lipid soluble drugs capillary endothelial cells in the CNS. These
distribute more widely in the body than less cells do not do pinocytosis
less soluble ones • Drugs must be highly lipid soluble to be
• Concentration Gradient able to cross the barrier
• Since the usual barriers between body • Latentation - a lipophilic group is attached
compartments consists of lipid-rich biological to the drug to pass the BBB
membranes, the arte of diffusion of drugs • eg. Heroin
across membranes are dictated by lipid
solubility
SUBJECT
VERNON MARCIANO
High Lipid-Solubility may increase the

albumin binding of certain drugs
• Species differences show marked
variations in drug albumin binding
• Competing molecules may produce
important drug interactions of clinical
importance ie., one drug may displace other
from binding sites
• Age of the animal - most species have
lower plasma albumin concentration at birth
which increases to adult values in 2-3 weeks
SUBJECT
VERNON MARCIANO
Part 3 pharma
PHARMACOLOGY
part3
Autonomic Pharmacology
• INTRODUCTION
• anatomical organization of the nervous system
• comparison at the parasympathetic and
sympathetic decisions of the autonomic nervous
system
• drugs affecting nervous system stimulate or
inhibit its cholinergic or adrenergic component
• PERIPHERAL NERVOUS SYSTEM

• Cranial and spinal nerves
• somatic -supplies the muscles and the skin
• Autonomic nervous system (supplies the
smooth muscles, cardiac and the glands)
• Parasympathetic Nervous System
• Sympathetic Nervous System
Preganglion neuron
Postganglionic
SUBJECT
VERNON MARCIANO
• postganglionic fibers are called adrenergic

fibers • response mediated is called the
adrenergic response
• The chromatin cells. at the adrenal medulla
are modified adrenergic cells. Stimulation of the
splanchnic nerves causes the release of the
epinephrine into blood circulation
• ACETYLCHOLINE
• acetylcholine is released at:
• Postganglionic parasympathetic fibers at the
neuroeffector junction
• Preganglionic parasympathetic fibers
Fight and flight • Preganglionic systemic fibers
cranial, cervical • Splanchnic nerve at the adrenal medulla
Thoracic lumbar • Somatic nerve terminals as in the
Sacral neuromuscular junctions. These are somatic
nerves and not included in the ANS
Rest and digest
Types of Receptors in the Autonomic Nervous
Parasympathetic Sympathetic System
• Cholinergic Receptors
• Muscarinic receptors
• specifically stimulated by muscarine, a
poisonous substance from certain species of
mushroom
• Stimulation of this receptors produce
muscarinic effects which are similar to the effect
of acetylcholine in the neuroeffector auction int
he autonomous nervous junction
• Nicotinic Adrenergic Receptors
• specifically stimulated by nicotine, a substance
derived from tobacco
• STATE OF TONUS • produces nicotinic effects which are similar to
• a state where there is predominance of one the acetylcholine at the sites other than the
division into another. parasympathetic effector junctions. These other
• Note that most organs are innervated by the sites include the somatic (motor) nerf fibers and
two divisions and have antagonistic effects sympathetic and parasympathetic ganglia
• eg. HEART…tachychardia with sympathetic
stimulation and Bradychardia with Types of Receptors in the Autonomic Nervous
parasympathetic stimulation System
• Adrenergic Receptors
MAJOR NEUROCHEMICAL TRANSMITTERS • they may ediate the effects of adrenergic
released at the neuroeffector junctions transmitters
• NOREPINEPHRINE / EPINEPHRINE • also • Beta adrenergic Receptors
known as adrenaline is the major • Beta-1 • Beta-2
neurotransmitter at the terminals of the
postganglionic fibers in the sympathetic division, • Alpha Adrenergic Receptors
that is at the neuroeffector junction • Alpha-1 • Alpha-2 • Dopaminergic Receptors
SUBJECT
VERNON MARCIANO
• All these receptors can be stimulated by the

different adrenergic transmitters but produce
varying degrees of response
Cholinergic Transmission
• Na+ and choline transport in the membrane
through channels. The Choline reacts with Acetyl
CoA to for the ACETYLCHOLINE with the action of
the Acetylcholinetransferase
• Transportation of Ash to vesicles to prevent
degradation
• Action potential causes the voltage sensitive
calcium channel open causing influx of Calcium
ions inside thus causing the release of Ach from
the vesicles
• Binding of Ach to post synaptic receptors
leading to the cholinergic response
• Ach can also bind to presynaptic receptors that
inhibits release and binding of Ach to
postsynaptic cleft (NEGATIVE FEEDBACK LOOP)
• Acetylcholinesterase breaks up Ach to Choline
and acetate. Choli e is taken up again and goes
back to the presynapse
General Categories of Drugs acting on the

autonomic Nervous System
• Stimulator of the Neurotransmitter synthesis
• Inhibitor of the Neurtransmitter synthesis
• Modifier of the Neurotransmitter storage
• Stimulator of the release of neurotransmitter
• Inhibitor of the release of the neurotransmitter
• Stimulator of the removal of neurotransmitter
• Inhibitor of the removal of neurotransmitter
CHOLINERGIC DRUGS
lesson 2
SUBJECT
VERNON MARCIANO
REMINDERS:
*** Gq receptors are coupled with G proteins
that increases the influx of calcium ions causing
increasing secretion, contraction and
transmission of the nervous system
***. Gi increases the influx of potassium ions
which causes hyperpolarization and reduction of
heart rate *** N receptors are influx of sodium
ions
SUBJECT
VERNON MARCIANO
• Dosage:
• Dog: 50mcg/kg once SC; 0.5-1 mg/kg q6h oral
• Cat: 2.5-5 mg total dose oral
• Horse: 0.05 mg/kg SC
categories of Cholinergic Drugs
• NATURAL ALKALOIDS (plant origin)
• Muscarine
• belongs to the mushroom family of genus
Amanita
• of toxicological importance only and not use in
therapeutics
categories of Cholinergic Drugs • signs of muscarine toxicities are salivation,
• CHOLINE ESTERS lacrimation, dyspnea, colic, diarrhea, and
• Metacholine cardiovascular collapse
• derivatives of Acetylcholine • ATROPINE is the antidote
• act directly on muscarinic receptors, no effect categories of Cholinergic Drugs
on muscarinic receptors • Pilocarpine
• typical muscarinis effects such as increase • derived from the leaves of Pilocarpus
glandular secretion, bradycardia and jaborandi.
hypotension • has most marked effects on the murcarinis
• Cattle: 50ml of 20% solution of iodide form, IV receptors in the eye and exocrine glands
or SC • causes pupillary constriction, open the canal
• Dog: 11 mcg/kg, IV of chloride form Schlemm, it used for the treatment of glaucoma
categories of Cholinergic Drugs • also used in gut impaction in large animals but
• CHOLINE ESTERS it is very dangerous, not recommended
• Carbachol (Carbamylcholine)
• has an amine group instead of the methyl in
the esoteric end of Act molecule which make sit
resistant to acetylcholinesterase
• marked effect on urinary bladder and the gut
• treatment of hypo motility and bladder
paralysis, also for glaucoma
• ophthalmic solution dosage: IM or IV
• Cattle: 2-5mg
• Horse: 2-5mg
• Foal: 0.5-1mg
• Pig: 0.5-2mg
• Sheep: 0.25mg-0.5mg categories of Cholinergic Drugs
• Dog: 0.5-1 ml of 1:1000 solution for emesis • NATURAL ALKALOIDS
• Dog: 0.5-1 ml of 1:10000 solution for purgativ • Arecholine
• derived from the fruit of Areca catechu (betel
categories of Cholinergic Drugs nut)
• CHOLINE ESTERS • has both muscarinic and nicotinic effects
• Bethanecol • maybe used to eradicate tapeworms by its
• resistant to cholinesterase with action lasting purgative effects but may cause toxicities in host
for several hours categories of Cholinergic Drugs
• used in cases of neurogenic bladder paralysis • CHOLINESTERASE INHIBITORS
and post surgical treatment of esophageal • 2 types:
achalasia • a. Acetylcholinesterase (aChE)
SUBJECT
VERNON MARCIANO
• can hydrolyze acetylcholine only • Stage III. Aging

• location: nerve terminals in the PNS, NMJ, CNS • Stage IV. Biosynthesis of new cholinesterase
gray matter, erythrocytes
• b. Pseudocholinesterase (pChE)
• can hydrolyze acetylcholine and other esters of
choline and some local anesthetics
• location: plasma, CNS white matter
• Generally, a cholinesterase maybe inhibited by:

• ACETYLATION: readily reversible (in seconds)
and does not cause clinical problems
• CARBAMYLATION: carbamylated enzymes
takes longer time (hours) to restore activity and
may cause signs of poisoning in patients
• PHOSPHORYLATION: generally irreversible
inhibition of cholinesterase
Indirectly acting cholinergic drugs
• IRREVERSIBLE CHOLINESTERASE INHIBITORS
• includes organophosphates compounds (OP)
which are used commonly as insecticides/
acaricides, pesticides, anthelminthics and
agricultural pesticides to which domestic animals
maybe exposed
organophosphates
• highly soluble, well absorbed and widely
distributed
• volatile that they can be absorbed through the
lungs and skin
organophosphates
• extensively metabolized in the liver
• Pharmacological effects of OP:
• dealkylation may lead to either activation
• CNS effects: excitation and mania progressing
(lethal synthesis) or inactivation of the
to convulsion and coma
compounds
• Respiratory failure: usually death:
• mainly excreted in the urine as inactive
bronchoconstriction, dyspnea, excessive
metabolites
salivation and mucus secretion, paralysis of the
respiratory muscles
• Treatment of OP:
• 1. Atropine: blocks the muscarinis effects but
Organophosphates
not the nicotinic effects. Given IV to effect.
• based on the ability to undergo lethal
synthesis, OP can be: overdosage may cause hyperthermia and CNS
• Directly-acting: inhibit cholinesterase without stimulation. Dosage: 0.2-2 mg/kg (give 1/4 dose
prior metabolism (eg. phosphonates) IV, the rest SC and IM)
• Indirectly-acting: those that need to • 2. Pralidoxime (2-PAM) is clinically useful only
metabolized first before they can inhibit during the early stages of poisoning. Dose: 10-
50mg/kg IM, IV q12h.
cholinesterase (eg. phosphothionates)
Indirectly acting cholinesterase inhibitors
• STAGES OF CHOLINESTERASE INHIBITION by
OP: • REVERSIBLE
• Stage I. Phosphorylation of the enzyme • Physostigmine (eserine)
• Stage II. Spontaneous phosphorylation or • tertiary amine alkaloid derived from the caliber
recovery of the enzymes bean or ordeal bean (Physostigma venosum)
SUBJECT
VERNON MARCIANO
• binds to the esteraticsite of cholinesterase,

inhibiting for a few hours
• bond sponstaneously breaks off to leave a
fully active enzymes
• effects: (mainly muscarinic) increased gut
motility, mild bradycardia, mitosis and stimulus
of the gravid uterus.
• clinical use:
• to relieve glaucoma
• to reverse the effect of atropine in the eye
Indirectly acting cholinesterase inhibitors
• REEVERSIBLE
• Neostigmine
• synthetic quaternary wine analogue of CHOLINERGIC BLOCKING AGENTS
physostigmine and has a dual action • Anticholinergics or paraympathomimetic drugs
• inhibit cholinesterase are more specifically antagonist of acetylcholine
• directly stimulates the cholinergic receptors at the muscarinic receptors
• the dramatic clinical uses: • have little or no action on the nicotinic sites
• gut hypo motility • ex. ATROPINE
• urinary bladder paralysis ATROPINE
• myasthenia gravis • a racemic mixture of D and L-hyocyamine is the
• counteract the muscle paralysis caused by such prototype of parasympathomimetic drugs
drugs like curare or ahminoglycosides antibiotics • important therapeutically rather than
Indirectly acting cholinesterase inhibitors toxicologically
• REEVERSIBLE • active poisons in deadly nightshade (Atropa
• Edrophonium belladonna), jimsyn weed (Dature stramonium)
• similar to neostigmine but shorter duration and henbane (Hyocyamus niger).
• clinical uses: • well absorbed orally, parenterally and from the
• to differentiate muscles weakness and eye.
myasthenia graves • distributes widely and crosses the blood brain
• Ambemonium and pyridostigmine are barrier (BBB) and produces central nervous
moderately long acting effects
• Carbamate insecticides are used to control • Goats and rabbits are resistant to atropine due
external parasites of both large and small to the presence of ATROPINASE (esterases that
snimals. Carbamates cause carbamylation of the breaks down atropine).
esteratic site of the cholinesterase and blocks its • Horses and castles are also quite resistant to
action of the cholinesterase oral administration but responsive parenteral.
• example: Carabaryl (sevin) proposer, Moban • Pigs, dogs and cats are not resistant to either
adicar oral or parentera
ATROPINE
• pharmacological effects:
• Heart: tachycardia, in some cases preceded by
initial bradycardia
• Blood vessels: little effect because blood
vessels tone is primarily under the control of the
sympathetic nervous system and rapid IV
administration may cause fall in blood pressure,
perhaps due to histamine release
• Smooth muscles: relaxation resulting in
antispasmodic effect
SUBJECT
VERNON MARCIANO
• Secretion: decreased exocrine secretions effect is biphasic initial stimulation and then
• Eye: relaxation of the ciliary muscles causing inhibition.
cycloplegia (loss of ability to accommodate for • example: Nicotine. absorb from all sort of
near vision); increase intra ocular pressure due administration
to the closure of the canal of Schlemm (avoid in • uses: wildlife capture drug and as insecticide
glaucoma)
• CNS: large doses lead to CNS stimulation and ADRENERGIC DRUGS
hyperthermia followed by secondary CNS CATECHOLAMINES
depression • all endogenous adrenergic neurotransmitters
• clinical uses: • DOPA
• preanesthetic agents • Norepinephrine - alpha agonist property
• produce mydriasis i eye • Epinephrine - mixes (alpha and beta agonist)
• treatment of OP poisoning • Dopamine - immediate precursor of NE
• Antispasmodic therapy and management of • isoporoteronol - selective beta agonist
certain types of colic CATECHOLAMINES
• To couter the affect of cholinergic drug abuse • catecholamine structure contains catechol
other atropine like drugs moiety which is a benzene ring, with
• Scopolamine - natural congener of atropine, adjacenthydroxy groups at position 3 and 4(3,4
has more CNS effects on atropine. used in Dihydroxybenzene) and an amine group
women to produce twilight sleep during
childbirth
• Homatropine - shorter duration of action than
atropine and has only 10% of atropine’s potency
• Eucatropine - shorter duration of action than
atropine produces mydriasis with little
cycloplegia
• Glycopyrrolate - preanesthetic anticholinergic
agent, 5 times more potent than atropine, lacks
the initial decrease in heart rate usually observe
with atropine. less CNS effects than atropine
• Propantheline - synthetic atropine substitute.
has high ganglionic blocking to antimuscarinc
activity. used as GI antispasmodic agent
Ganglionic Blocking agents

• block cholinergic receptors in the autonomic
ganglia in both parasympathetic and
sympathetic divisions
• 1. Non depolarizing blockers: compete with
Ach for receptor sites in the ganglia and adrenal
medulla.effects include:
• fall in blood pressure (blockade of sympathetic
tone)
• decreased gut motility and constipation
• examples: tetraethylammonium (TEA),
Hexamethonium, Pentolinium, Mecamylamine
• 2. Depolarizing blockers - powerful and Synthesis of Norepinephrine

persistent stimulation of cholinergic receptors
leading to receptor blockade and fatigue. the
SUBJECT
VERNON MARCIANO
Properties of Adrenergic Receptors

• very important for direct application in clinical
use of adrenergic antagonist and agonist
• History
• AlQUIST (1948) investigated the potency of the
3 catecholamines (NE, EP, and IS)
• observed 2 orders of potency:
• 1)EP>NE>IS and 2) IS>EP>NE
• in the second order, beta receptors are
involve:
• a) Beta 1 - chiefly in the heart
• b) Beta 2 - blood vessels, liver, bronchi, etc.
• c) Beta 3 - Fat tissues
• in the first order, alpha receptors are involved
• a) alpha 1 -postsynaptic fibers, smooth muscles
• b) alpha 2 -pre and post synaptic fibers make
an outline of the receptors to know the effects
Clinical Uses of Sympathomimetic Agents

• adjunct to local anesthesia (vasoconstriction
prolongs the effect of anesthesia)
• Mydriatic in eyes and used in examining the
interior of the eye. versus atropine, does not
cause cycloplegia
• in anaphylactic reactions, EPINEPH is drug of
choice due to hypotension and bronchospasm
• as Bronchodilator, best treatment for
bronchial asthma (Beta 2 adrenergic agonists)
• ISOPROTERONOL affects bronchi and Beta 1
effect on heart
• EPHEDRINE causes CNS effects to increase
bronchodilation
• treatment of local skin - alpha adrenergic
SUBJECT
VERNON MARCIANO
• Decongestant. alpha adrenergic agonists • Postural hypotension is specifically prominent

• Diagnosis of heaves in horses when there is massive release of epeineph, or
(ISOPROTERONOL) when epitaph s concurrently administered
• treatment of cardiac arrest: intracardiac • remember, epinephrine when given in absence
injection of Beta1 adrenergic stimulants of alpha adrenergic blocker causes an increase
• treatment of hypertensive conditions: rather than a decrease in blood pressure
DOPAMINE • little effect on GIT
• used in treatment of PHEOCHROMOCYTOMA
catecholamine secreting tumor of the adrenal
medulla adapted from EF Landicho’s note
Beta adrenergic blockers
• dichloro-isoproteronol
• propranolol (Inderal)
• Timolol • Alprenolol
• pindolol • Nadalol
• Sotalol
• Metoprolol (selective B1 blockers)
• butoxamine ( selective B2 blockers
EFFECTS OF BETA BLOCKERS

INDIRECT ACTING
Ampethamine
Metamphetamine
Ephedrine
Pseudoephedrine
Hydroxyampethamine
Metaraminol (Boths direct and indirect)
ADRENERGIC BLOCKING AGENTS
• ALPHA ADRENERGIC BLOCKERS
• Phenoxybenzamine, dibenamine,
phentolamine (Regitime HCL), Tolazoline
(priscoline HCL), piperoxan, dibozane, azapetine
and prazosin.
• ergot alkaloid such as ergocristine and
ergocryptine blocks alpha receptors and directly
stimulate smooth muscles
• phenothiazine and butyrophenone • cardiac depression, aggravation of heart
tranquilizers such as chlorpromazine, failure
acepromazine, and haloperidol blocks alpha 2 • may cause bronchoconstriction due to Beta 2
adrenergic receptors. adrenergic receptors
• YOHIMBINE reverses xylazine effects in • Clinical Uses:
animals • drug of choice for treatment of essential
Pharmacological effects of Alpha Adrenergic hypertension in humans
Blockers • Used for reversing digitalis-induced cardiac
• little effect on resting blood pressure • arrhythmia
postural hypertension dependent on alpha • For treatment of obstructive cardiomyopathy;
receptors rare disease of dogs and cats
• hypotension maybe severe to cause cerebral • Used to block the effect of excessive
and hypoxia and ataxia epinephrine in pheochromocytoma
SUBJECT
VERNON MARCIANO
Epinephrine- assetel coliin

Caterol benzemne ring animo group hydrogen adrenoceptors
EPINEPHRINE
EPINEPHRINE
EPINEPHRINE EFFECTS
Cardiovascular system
SUBJECT
VERNON MARCIANO
EPINEPHRINE
EPINEPHRINE
EPINEPHRINE
ISOPROTERONOL
SUBJECT
VERNON MARCIANO
ISOPROTERONOL
DOPAMINE
ISOPROTERONOL
DOPAMINE
SUBJECT
VERNON MARCIANO
AMPETHAMINE
SUBJECT
VERNON MARCIANO
NEUROMUSCULAR DRUGS AND MUSCLE • local anesthetics applied or around the nerve
RELAXANTS fibers as in induction of the epidural anesthesia.
They are commonly used for muscle relaxant
NEUROMUSCULAR DRUGS AND MUSCLE effect but are used more for the reason of
RELAXANTS sensory blockade.
• agents that induce relaxation of the skeletal Site Of Action and examples of muscle relaxants
muscles • Motor Nerve Terminal
• many substance can cause muscle relaxation • no clinically used for this group.
(paralysis) but only a few are used for this • occurs in poisoning with botulinum toxins and
purpose aminoglycosides antibiotics
• relaxation maybe induced to restrain animals • substances prevent the release of
and relieve muscular spasms acetylcholine from nerve endings
• Calcium is needed for the release of
Site Of Action and examples of muscle relaxants Acetylcholine and maybe the reason for skeletal
• CENTRAL NERVOUS SYSTEM muscle paralysis in milk fever. adapted from EF
• can relax skeletal muscle by depressing the Landicho’s not
flow of impulse long the somatic nerves
Site Of Action and examples of muscle relaxants
• Acetylcholine receptors in motor end plate
• non depolarizing neuromuscular blocking drugs
compete with acetylcholine for cholinergic
receptors in the end plate
• D-Tubocurarine (Curare) from Chondendron
spp. also known as South American Arrow
Poison
• charged quaternary ammonium
• poorly absorbed from the gut and not
metabolized but excreted in urine and bile
• given IV, onset of action is 5 minutes lasting for
• CNS
20-30 minutes to 24 hours
• centrally acting skeletal muscle relaxants do
• sequence of muscle blockade: eye
not depress CNS thus there is no loss of
muscle>neck muscles>extremities>abdominal
consciousness and some sedation occurs
muscles>intercostal msucles>diaphragm
• meprobamate
• clinically given at a dose to relax the muscle
• mephensin
and then put the patient on a positive pressure
• guafenesin (Gyceryl guaiolate)
ventilation that release histamine causing
• methocarbamol
hypotension.
• used clinically for relief of skeletal muscle
• in surgery, used to obtain an adequate skeletal
spasms in vertebral disc protrusion
muscles relaxation; in orthopedic, relieves
• Guaifenesin is used as 5% solution to cast
muscle spasms for setting bone fractures
horses and cattles
• useful in stopping convulsions due to
• In horses, under chloral hydrate necrosis, 3-
strychnine poisoning, tetanus, and status
4mg/kg guaifenesin causes abdominal muscle
epileptics.
relaxation lasting for 10-15 minutes without
• Dose: Dog (0.4mg/kg) Pig (0.3mg.kg) Horse
significant respiratory depression
(0.22-0.25mg/kg)
• laryngeal paralysis to facilitate endotracheal
intubation

• Motor Nerve Fibers
SUBJECT
VERNON MARCIANO

• SPECIFIC AGENTS
• Amino esters agents Epinephrine effects
• 1. PROCAINE (low potency, short duration of
action, allergy due to PABA metabolite) Heart
• 2. CHLOROPROCAINE (rapis onset, low Iso … epi >>> norepi
systemic toxicity)
• 3. TETRACAINE (high potency, long duration of 1. Increase the force of myocardial
action, undergoes slow hydrolysis in plasma, contraction
greater systemic toxicity) 2. Increase the rate of contraction
• 4. COCAINE (used as surface anesthetics and an 3. Excess stimulation leads to arrhythmias
abused drug)
• Amino amid Agents

• Lidocaine (most versatile anesthetics, high
potency, ;rapid onset and moderate duration of
action)
• Mepivacaine (similar to lidocaine, not used in
obstetrics due to prolonged metabolism in fetus)
• Bupivacaine (slow onset, long duration of
action, separation of sensory analgesia and
motor blockade and exhibit more serious
cardiovascular toxicity 4.
Smooth muscles and uterus

Site Of Action and examples of muscle relaxants Alpha receptors cintractions release of
• Amino amide Agents intracellular ca
• Etidocaine - cause profound muscular
relaxation, similar to bupivacaine in duration of Metabolic effects
acton but has more rapid onset) Carbohydrate metablosim
• Prilocaine (similar to lidocaine but with lower Glycogenolysis in liver release of glucagon and
potential for systemic reactions) release of insulin
• Dibucaine (very potent and long duration of
action) Lipid metabolism
• agents restricted to ophthalmological use Raises concentration of free fatty acids in blood
• Benoxamine Stimulates beta receptors of adipose
• Proparacaine tissues\activates adenylate cylase
• Agents used to anesthetize less delicate cAMP stimulates li[pase for hydrolysis of
mucous membranes and skin: truacylglyceros fatty acid and glycerol
• Cyclomethycaine, Dimethisoquin, Diclonin,
Hexyclaine, Pramoxine, Butamben
SUBJECT
VERNON MARCIANO
epinephrine
pharmacokinetics
oraaly not effective and rapid by MAO and
COMT
rapidly absorbed after IM injection
for immediate effects IV
on inhalation action restricted to respiratory

tract local action
Epinephrine
Drug choice for treatment of type 1
hypersensitivity reaction
In critical conditions drowning suffocation shock

and electroculation
Because of vasocontriction property used in

combination with local anesthetics
Doses
Norepinephrine
SUBJECT
VERNON MARCIANO
Ineffective when given orally

Poorly absorbed from S/C site
Inactivated by MAO COMT
4-16 % administered drug excreted in urine
Norepinephrine
Clinical conditions
NE HAS LIMITED USE BUT THERAPEUTICALLY

IMPORTANT IN INTENSIVE CARE UNIT
IN PATIENT WITH CRITICAL HYPOTENSION
VASODILATORY SHOCK VIZ SEPTIC SHOCKS AND
NEUROGENIC SHOCK
IN THE TREATMENT OF BP, NE IS ADMINISTERED
BY IV INFUSION DOSE TITRATED TO PRESSOR
RESPONSE
MAJOR LIMITATION BLOOD SUPPLY TO KIDNEY
DOSES
ALL SPECIES
@ 0.1 – 0.2 MICROGRAM/ KG/MIN IV INFUSION
IN 5 % DEXTROSE OR 5 % DETROSE SALINE
SOLUTION BUT NEVER USE NS SOLUTION ALONE
Organs
Arteries heart
Alpha action vasoconstriction = rise in BP
Arrhythmia @ higher dose
ISOPRENALINE/ ISOPROTERENOL
Blood vessel > vasoconstriction DIRECT ACTING SYNTHETIC ca WITH CHEMICAL
Bp . dose related incrase in systolic and diastolic NAME D, 1-b ALPHA-ISOPROPYL
BP AMINOETHANOL HCL
Heart . potent myocardial stimulant
Smooth muscles . relaxation of intestinal of SM=
retention of ingestion
Metabolic effect . hyperglycemia
SUBJECT
VERNON MARCIANO
Clinical indication doses

For sinoatrial arrest
PHARMACOLOGICAL EFFECTS
1. CARDIOVASCULAR SYSTEM
Decreased pheripheral resistance
relaxation of skeletal mucscles
Markedly decreases diastolic
Isoproteronol
GIT
Potent inhibitory effect
Dopamine
Repiratory effects
Potent BRONCHODILATOR
SUBJECT
VERNON MARCIANO
Dopamine
MOA mix adrenergic action
Metamphetamine
Adjunctive
Noncatecholamines
Ampethamine
Methyl phenidate
SUBJECT
VERNON MARCIANO
Phenyl propanolamine
Oxymetazoline
Visine
SUBJECT
VERNON MARCIANO
LOCAL ANESTHESIA • Synthetic nitrogenous compound – eg.

procaine, benzocaine,
General Anesthesia lignocaine & bupivacane
Local • Non Nitrogenous compounds – benzyl
alcohol
• Miscellaneous – clove oil , phenol.
II. According to structure:

1 Esters :
Benzoic acid esters:
• Benzocaine
• Cocaine
Para-amino benzoic esters:
• Tetracaine
• Chlorprocaine
• Procaine
LOCAL ANESTHESIA • Propoxycaine
• reversible loss of perception of pain or
other motor TYPES of LOCAL
response to stimuli in local or regional part of
the body ANESTHESIA
• not accompanied by loss of consciousness
• substances which when applied about the • SURFACE or TOPICAL ANESTHESIA
nerve terminals • drug is applied to skin and mucous
or nerve fibers prevent the conduction of membranes (eyes, nose,
both sensory and mouth, throat, tracheobronchial tree, urinary
motor impulses in axons and dendrites. tract and
• distinguished from the muscle relaxants gastrointestinal tract) to cause loss of
which block the sensory perceptions
normal neural transmission at the synapse • application on the mucous membranes may
• COCAINE is the first local anesthetics lead to rapid
discovered absorption and toxicity.
• Most local anesthetic agents are ineffective
when applied on
unbroken skin because cornfield epithelium
limits penetration.
• includes agents such as cocaine,
hexyclaine, lidocaine,
tetracaine and cyclomethyclaine.
TYPES of LOCAL
ANESTHESIA
• PERIPHERAL BLOCK ANESTHESIA
• drug is injected into the area immediately
surrounding
CLASSIFICATION OF the nerve or group of nerves (plexus).
• the anesthesia diffuses into the nerve
LCOAL ANESTHESIA trunks and
anesthetize the area innervated by this
I. Based on bioavailability nerves.
• Natural – eg. cocaine. • results in the blockade of the sensory,
motor and
SUBJECT
VERNON MARCIANO
autonomic pathways.
• commonly used are: lidocaine,
mepivaccaine and
Bupivacaine
PHYSIOLOGICAL DISPOSITION
OF LOCAL ANESTHETICS
-administration at the site of action

-initial absorption and distribution reduces
pharmacological effects
-toomuch absorption may result into adverse
TYPES of LOCAL systemic effects
-absorption in the blood circulation
ANESTHESIA -retardation of the anesthesia by
incorporation of a vasoconstrictor
• SPINAL (INTRATHECAL) ANESTHESIA -agent such as epinephrine or phenylephrine
• seldom used in animals
• injected in the CSF of the subarachnoid PHARMACODYNAMICS
space.
• Anesthesia is due to the action of the drug • local anesthetics affects small
in the nonmyelinated nerve
spinal nerve roots and in the dorsal root of fibers more than the myelinated
the • they can act only at the nodes of ranvier
ganglia thus causing both sensory and motor • the order of blockade is as follows:
blockade with rapid onset sympathetic flow,
pain, thermal, and proprioceptive sensation
TYPES of LOCAL and lastly,
motor activity
ANESTHESIA • Certain highly lipid soluble local anesthesia
• EPIDURAL ANESTEHSIA such as
• drug is injected in the epidural space of the ETIDOCAINE can cause greater motor
spinal blockade than
canal posterior to the end of the spinal cord. sensory blockade
• used in obstetrics, perineal and lower
extremity
procedures METABOLISM
• agents commonly used include lidocaine, Ester local Anesthetics
mepivacaine, buoivacaine, etidocaine, amd • Hydrolyzed in the plasma by enzyme
chloprocaine Pseudocholinesterase .
• Site – Plasma.
SUBJECT
VERNON MARCIANO
• Rate of hydrolysis – Varies and inversely 5. Stable with soda lime, as well as plastics
proportional to toxicity. and metals
• Action of biotransformation products. 6. Environmentally friendly – no ozone
• Allergic reaction – PABA responsible for depletion
causing allergic reactions. 7. Cheap and easy to manufacture
• Atypical Pseudocholinesterases – Causes
inability to hydrolyze ester local Biological properties
anesthetics and other chemically related 1 Pleasant to inhale, non-irritant, induces
drugs (Succinyl choline) bronchodilatation
2 Low blood: gas solubility – i.e. fast onset
AMIDE LOCAL ANESTHETICS 3 High oil: water solubility – i.e. high potency
• Primary site – liver 4 Minimal effects on other systems – e.g.
• Rate of biotransformation – influenced by cardiovascular, respiratory, hepatic, renal or
liver function and hepatic perfusion. endocrine
• Poor liver function – unable to biotransform 5 No biotransformation – should be excreted
amide local anesthetics at a normal rate. ideally via the lungs, unchanged
• Action of biotransformation products 6 Non-toxic to operating theatre personnel
• Monoethylglycinexylidide
• Glycinexylidide OTHER IDEAL PROPERTIES
• Methemoglobinemia – in patients receiving
large doses of prilocaine. • Specific action
• Produced not by prilocaine but by its • Reversible action
primary metabolite orthotoluidine. • Rapid onset of action
• Sedative effect – Produced by two • Suitable duration of action
metabolites of lidocaine. • Active whether applied topically or injected
• Nonirritant
EXCRETION • Causes no permanent damage
• Primary site – kidneys • No systemic toxicity
• Esters – Appear in small concentration as • High therapeutic ratio
parent • Chemically stable and a long shelf life
compound in urine since hydrolyzed • Ability to combine with other agents without
completely in loss of properties
plasma. • Sterilizable without loss of properties
• Amides – Present in urine as parent • Non-allerenic
compound in a • Non-addictive
greater percentage because of their more
complex
process of biotransformation.
• Renal disease – Relative contraindication
to local
anesthetic administration.
• Increase blood levels and potential for WHERE DO LOCAL
toxicity of local
anesthetic compounds esp. cocaine. ANESTHESIA ACT
IDEAL PROPERTIES
L.A can interfere with excitation process in
Physical properties nerve membrane
1. Non-flammable, non-explosive at room in one or more of the following ways:
temperature 1 Altering the basic resting potential of nerve
2. Stable in light. membrane.
3. Liquid and vapourisable at room 2 Altering the threshold potential
temperature i.e. low latent heat of 3 Decrease rate of depolarization
vaporization. 4 Increase prolonging rate repolarization.
SUBJECT
VERNON MARCIANO
ANESTHESIA
• art and science relating to the production
reversible loss of
sensibility and consciousness
• TYPES OF ANESTHESIA:
• General Anesthesia: subject loses
consciousness,
lowered sensitivity to stimuli from the
SPECIFIC AGENTS • AMINO-ESTER environment and
AGENTS diminished motor response to stimuli. whole
• PROCAINE body is
affected.
• low potency • Local or Regional Anesthesia: Only certain
• short duration of action regions
• allergy due to PABA metabolite of the body lose perception of pain or motor
response
• CHLOROPROCAINE to stimuli. There is no loss of consciousness.
• rapid onset of action
• low systemic toxicity • ANESTHETIC AGENTS: any substance
that
• TETRACAINE produces controllable and reversible loss of
• low systemic toxicity, high potency, long consciousness and absence of response to
duration of action noxious stimuli.
• undergoes slow hydrolysis in plasma, and
greater systemic toxicity • ANALGESIC AGENT: any substance which
temporarily abolishes the sensation of pain
• COCAINE
• used as surface anesthetics • NARCOTIC: any substance which
• abused drug produces
insensibility or stupor from which simple
SPECIFIC AGENTS stimuli
• Amino amide Agents such as noise, and can produce, at most,
• Etidocaine - cause profound muscular temporary arousal.All general anesthesia are
relaxation, similar to bupivacaine in considered narcotics
duration of acton but has more rapid onset)
• Prilocaine (similar to lidocaine but with • HYPNOTIC: any narcotic agent used to
lower potential for systemic reactions) induce
• Dibucaine (very potent and long duration of sleep, a state which maybe consider
action) physiological
• agents restricted to ophthalmological use and from which the subject can easily
• Benoxamine aroused by a
• Proparacaine wide margin of stimuli.
• Agents used to anesthetize less delicate
mucous membranes and skin: • SEDATIVES: any narcotic agent which is
• Cyclomethycaine, Dimethisoquin, Diclonin, used to
Hexyclaine, Pramoxine, Butamben calm a nervous vicious or excited subject.
adapted from EF Landicho’s notes may
cause drowsiness.
DRUGS ACTING ON THE
CNS: GENERAL • ATARACTIC OR TRANQUILIZERS:
CONSIDERATIONS ` substance
SUBJECT
VERNON MARCIANO
which produces sedation without the at the • STAGE III: Surgical Anesthesia
same
time causing drowsiness. • Phase 1
• Phase 2
• NEUROLEPTIC: tranquilizer which is used • Phase 3
in • STAGE IV: Overdose
human beings in the treatment of psychoses.
It is a STAGE I: INDUCTION OR STAGES
powerful agent in animals to produce OF INVOLUNTARY EXCITEMENT
profound • Consciousness is still present
sedation • Forcible effort to avoid being anesthetized
• breath holding, but not maybe observed in
• LOCAL ANALGESIC OR LOCAL all cases
ANESTHETIC: • Fear and apprehension leading to
substance which is when applied the nerve increased
terminal or nerve fibers prevent the respiratory rate and pulse rate.
conduction of • Pupillary dilation (mydriasis)
impulses by the nerve tissues. Analgesia is • Urination and defecation
produced by the interference with
transmission of STAGE II: STAGE OF
sensory impulses concerned with INVOLUNTARY EXCITEMENT
appreciation of • Loss on consciousness
pain. • Reflex response to stimuli such as
exaggerated limb movement;
• DISSOCIATIVE AGENT: substance which may become violent necessitating restraint
produces human beings a feeling of • pronounced vocalization
dissociation • Umpredictable degree of violence which
from surroundings. unconsciousness, bears no relationship
catalepsy, with normal temperament of the animal
vivid dreams and analgesia. It is used in • irregular respiration; sometimes breath
animals to holding
produce a state of thought resembling • Persistent pharyngeal reflex which
anesthesia becomes progressively
inw which the animal does not show depressed
response to
stimuli. STAGE III. SURGICAL
SIGNS AND STAGES OF ANESTHESIA
GENERAL ANESTHESIA • PHASE I

• Irregular automatic breathing
• based on the presence and absence of • limb movement stops
reflex • side to side movement of the eyeball
responses in an anesthesia subject to stimuli • disappearing palpebral conuunctival and
provided by the anesthetics. corneal reflex
• brisk pedal reflex may still be present
STAGES OF ANESTHESIA • maybe adequate for minor surgery
• STAGE I: Induction or stages of voluntary STAGE III. SURGICAL

excitement
ANESTHESIA
• STAGE II: Stage Of Involuntary Excitement • PLANE II
SUBJECT
VERNON MARCIANO
• Laryngeal reflexes persist until the middle • improve other response to, and recovery
of plane 2 from general
• eyeballs fixed in the center in the hprse, anesthesia
cats, sheep, • includes: SEDATIVES, HYPNOTICS,
and pigs. downward in dogs TRANQUILIZERS,
• Pedal reflex becomes sluggish NARCOTIC ANALGESICS AND
• Progressive muscle relaxation ATICHOLINERGICS
• adequate for all surgical procedures except DISSOCIATIVE AGENTS

abdominal surgery AND INHALATION
ANESTHETICS
STAGE III. SURGICAL DISSOCIATIVE AGENTS
ANESTHESIA • agents include phencyclidine , tiletamine

• PLANE III and ketamine
• Breathing still automatic but the respiratory • cause cataleptic, analgesic and anesthetic
rate increases while the depth decreases action
• Noticeable pause between inspiration and without hypnotic effect
expiration • CATALEPSY is a characteristic state of
immobility
STAGE IV: OVERDOSE accompanied by loss of postural reflexes but
• Complete paralysis of the thoracic muscles; without
only impairment of consciousness in which the
the diaphragm functions extremities
appear to be paralyzed by motor and
• Jerky diaphragmatic movement sensory failure.
• Respiratory movement gasping in nature • characterized by complete analgesia
• Wide papillary dilatation combined with
only superficial sleep
DRUGS THAT DO NOT
PHENCYCLIDINE
INDUCE STAGE III • acts primarily on the CNS either by
• KETAMINE stimulation or
• NITROUS OXIDE by depression
• ENFLURANE • not recommended anymore in veterinary
• they induce stage II only or advance to an medicine
increased level of CNS excitation, rather
than TILETAMINE
depression resulting in myoclonic jerking • relatively new cataleptic agents for cats
followed by conclusive seizures • at 0.1-1 mg/kg, it causes salivation,
lacrimation, mydriasis and ataxia; recovery
PREANESTHTIC within
1-1.5 hours.
MEDICATIONS • no loss of consciousness, causes seizures
and clonic muscular reaction during deep
• mitigate fear and apprehension anesthetic state.
• minimize salivation that might cause • no analgesia on the skin
aspiration pneumonia • swallowing and pedal and palpebral reflex
• minimize ithervagus mediated reflexes are nt abolished
such as bradycardia and • muscles relaxation is absent
cardiac arrest • unconsciousness is induced with a dose of
• reduce pain and discomfort specially during 10mg/kg.
stage I and II
SUBJECT
VERNON MARCIANO
• IM analogie of diazepam; used as general INHALATION ANESTHETICS

anesthetics • either gas or volatile liquid
• DOAGE: 2-13mg/kg in dogs and 2-15mg/kg • TENSION OF AGENTS DISSOLVED IN A
in cat LIQUID -
pressure of agents in gas at which the liquid
KETAMINE is in
• available in 10, 50 and 100mg/ml in IV and equilibrium
IM
• shorter duration of action than • SOLUBILITY COEFFICIENT OF GASES -
phencyclidine at any
• CNS effects are similar to that of given temperature the mass of gas dissolved
phencyclidine. profound analgesia without in a
muscle relaxation; solution varies directly with the tension;
tonic clonic spasm, which occurs even governed
without surgical stimulation; increased by the solubility of gases in a particular
salivation solvent
• Respiratory effects: mild depression of
respiration, increased rate which does not
compensate
for reduced tidal volume UPTAKE OF ANESTHETICS
• tension of the gas in the brain, follows with
• Cardiovascular effects: increased arterial slightly delay its tension
blood pressure which at times can be in the alveolar air. As the concentration of
alarming due to the anesthetic in alveoli
increased circulating catecholamines decreases, the tension in the brain also
blocking the reuptake of the NE by decreases
adrenergic nerve • to maintain anesthesia, a minimum alveolar
terminals concentration (MAC) of
• Cardiac arrhythmia common. the anesthetic s maintained
• Neuromuscular effect; little muscular • rate of the tension on an anesthetic
relaxation, increased muscle tone, tendons alveolar air approaches its
reflex at brisk tension in the inspired air depends upon:
• used as chemical restraint either alone or • pulmonary ventilation
with Xylazine, acepromazine, diazepam. • uptake of the anesthetics by blood and
tissues
KETAMINE • concentration of the inspired air
SEQUENCE OF FLOW OF ANESTHETICS
• DOSAGE
FROM THE SOURCE TO THE BRAIN
• CAT • Gas is inhaled
• alone: 10-30 mg/kg IM • gas is diluted with residual air in the lungs
• with tranquilizer: 5-15mg/kg IM; 2-5mg/kg • gas is distributed to the alveoli
IV • Alveolar gas equilibrates almost
• with xylazine: 15mg/kg IM immediately with
the pulmonary blood
• HORSE • GAs dissolved in the blood is distributed
• with xylazine: 2.2 mg/kg IV throughout
• with diazepam: 2.2mg/kgIV the body; into interstitial fluid to the brain
• Ruminants: PROPERTIES
• alone: 2-5mg/kg IV
• 2.2-4.4mg/kg IV
SUBJECT
VERNON MARCIANO
NEUROMUSCULAR EFFECTS
PROPERTIES
CARDIOVASCULAR EFFECTS
NERVOUS EFFECTS
RESPIRATORY EFFECTS
SUBJECT
VERNON MARCIANO
ruminants tiger, bear and horse:

characterized by mydriasis, panting,
tachycardia, sweating (in horses) and
hyperkinesia.
• PHENOTHIAZINE and
BUTYROPHENONE tranquilizers do not
block
these excitatory effect.
• Nausea and emesis due to direct
stimulation of the chemoreceptor trigger
zone (CTZ) in the area postrema in the
medulla. can be counteracted by
phenothiazine tranquilizers.
OPIOID ANALGESICS,
NEUROLEPTANALGESIA • RESPIRATION:
• depressed by the virtue of the direct effects
AND ATICONVULSANTS on the respiratory center in
the brainstem
• OPIATES
• derived from opium
• CARDIAC:
• obtained from the milky exudate of the • no major direct effect on the BP or on the
incised unripe seed of the cardiac rate and rhythm.
poppa plant, Papaver somniferum. • most opioids cause the release of
• contains number of alkaloids but only histamine which maybe responsible for
morphine, codeine and any cardiovascular effect
papaverine have clinical usefulness • morphine produces arteriolar dilatation by a
central suppression of the
• OPIOIDS adrenergic tone.
• all other substances that bind specifically to
any of the several • GIT
subspecies of opioid receptors in the brain • delay gastric emptying, enhance segmental
and produce some contraction of the small
agonistic actions intestines and increase in the anal spinchter
• Human being and animals have tone
endogenous opioids in the form of
ENDORPHINS and ENKEPHALINS. MECHANISM OF ACTION
• The opioids exert their major • opioids bind with the opioid receptors in the
pharmcologcail effects on the CNS and GIT. brain and
The other tissues
CNS effects include: • MU RECEPTORS - mediate supra spinal
analgesia,
• analgesia without the loss of hypothermia, euphoria, miosis, bradycardia,
consciousness respiratory depression and physical
• Drowsiness and mental clouding dependency.
• Miosis due to action on the autonomic • KAPPA RECEPTORS - mediate spinal
segment of the nucleus of the analgesia,
oculomotor nerve mitosis and sedation
• excitatory effect can be elicited at low • SIGMA RECEPTORS - mediate
doses of morhine in cat, pig, excitement,
SUBJECT
VERNON MARCIANO
hyperkinesia, cardiac stimulation and

mydriasis.
CLINICAL USES
• Pain relief
• Sedation and induction of sleep
• Aid in the relief of pulmonary edema
• Cough suppression
• Treatment os secretory diarrhea
OPIOID AGONISTS
• MORPHINE
• METHADONE
• MEPERIDINE
• FENTANYL
• ETORPHINE
• DIPHENOXYLATE
• LOPERAMIDE
other OPIOID ANTAGONIST
• LEVALLOPRPHAN
NALMEFENE - used to suppress self
mutilative
behaviorinstallions at dose of 0.2-0.8mg/kg
OPIOID ANTITUSSIVES
• DEXTROMETORPHAN
• CODEINE
• NOSCAPINE
OPIOID AGONIST-ANTAGONIST
SUBJECT
VERNON MARCIANO
ETORPHINE AND
PHENOTHIAZINE
• these mixture contains intense CNS

depression with
considerable analgesia allowing major
surgery to be carried
• the effect of ETORPHINE can be reversed

with
DIPRENORPHINE (REVIVON).
NEUROPTANALGESIA • used in horses but produces excitement
• involves the use of an opioid analgesic and • not recommended for feeds and domestic
neuroleptic (tranquilizer) cats
• at low dose, can be used as heavy • pigs and dogs, the depressant effect
preanesthetic predominates
medication • DO NOT give barbiturates in dogs given
• at high dose, used to produce sufficient IMMOBILON within 36
depression hours: apnea may result
of the CNS ( a state called
NEUROLEPTHANESTHESIA) for surgery to
be
performed.
FENTANYL and
BUTYROPHENONE MIXTURES
• used in dogs, primates, and small rodents
but contraindicated inc ate
because fentanyl might cause violent
excitement
• PREPARATIONS:
• MIXTURE 1. THALAMOLAL
• Fentanyl 0.05mg/ml; Droperidol 2.5mg/ml SEDATIVES, HYPNOTICS
• MIXTURE 2. INNOVAR-VET_ and TRANQUILIZERS
• Fentanyl 0.4mg/ml; Droperidol 20mg/ml
CLASSIFICATION
• MIXTURE 3. HYPNORM
• Fentanyl 0.315mg/ml; Droperidol 10mg/ml • TRANQUILIZER SEEDATIVE GROUP
• Phenothiazine derivatives
ETORPHINE AND • Butyrophenone Derivatives
• Benzodiazepenes
PHENOTHIAZINE
• MIXTURE I. (Immobilon L.A.) • SEDATIVE HYPNOTIC GROUP
• Etorphine 2.45mg/ml; Acepromazine • Barbiturates
10mg/ml • Chloral Hydrate
• MIXTURE 2. Immobilon SA) • Xylazine
• Etorphine 0.074mg/ml,
METHOTRIMEPRAZINE PHENOTHIAZINE
18.00mg/ml
SUBJECT
VERNON MARCIANO
TRANQUILIZERS
• most extensively used for preanesthetic
• has central and peripheral effects sedation in
• tranquilization or reduced alertness is the both large and small animals
major cortical effect with a • extremely potent, and the duration is
variable depression of the CNS dependent
• have central emetic effect upon the dose
• CENTRAL ACTION: due to depression of

the Reticular Activating System
(RAS) in the brain stem.RAS normally alerts
or warns the cerebral cortex
as to what stimuli or what information the
cortex is about to receive.
Without this alerting route, stimuli arriving at
the sensory cortex cannot
enter into full consciousness. this is what
Phenothiazine is blocking.
• do not have analgesic action, but the

lowering of alertness make pain
more tolerable
BUTYROPHENONE
PHENOTHIAZINE
TRANQUILIZERS
TRANQUILIZERS
• major side effects of phenothiazine
• HALOPERIDOL
tranquilizers
• first butyrophenone tranquilizers introduced
• alpha adrenergic blockade (beware of
but not
epinephrine reversal
used in vetted
effect)
• important in vetted: DROPERIDOL and
• ganglionic blockade
AZAPERONE
• direct depression of the myocardium
• fall in body temperature
• reduce motor activity, but may produce
• extrapyramidal effect (convulsive seizures)
cataleptic effect,
at high doses.
they may prevent the fatal Cardiovascular
The antidote to this effect is
effects of
DIPHENHYDRAMINE, an
catecholamines and reduce stress and
antihistaminic agent
trauma.
PHENOTHIAZINE
• MOA: blockade of the excitatory central
dopaminergic
TRANQUILIZERS
pathway just like the phenothiazine
tranquilizers
• examples:
• acepromazine
BUTYROPHENONE
• methotrimeprazine
• chlorpromazine
TRANQUILIZERS
• promethazine
• promazine
• DROPERIDOL
• propionylpromazine
• 400 times more potent in dogs than
chlorpromazine
ACEPROMAZINE
SUBJECT
VERNON MARCIANO
• shorts action among the butyrophenone, • MOA: potentiation of the GABA, an indirect
but has the effect and
most potent antiemetic activity which is prefenrentially act on the polysynaptic
about 1000 neuronal
times more active than chlorpromazine. pathways in the CNS, no effects on
monosystemic
• used in combination with fentanyl pathways.
coproduce a state
called NEUROLEPTANALGESIA BENZODIAZEPENES
• dosage: 0.125mg/kg • aka LIBRIUM or CHLORDIEPOXIDE

• first be benzodiazepines introduced
BUTYROPHENONE
BENZODIAZEPENES
TRANQUILIZERS
• DIAZEPAM (VAlium)
• AZAPERONE • most widely used in vetted
• has an anticonvulsants edative, hypnotic
• more suitable for sedation of pigs and tranquilizing effects.
• produces reliable sedation within 15 • in healthy dogs, the hypnotics and
minutes of IM administration; effect lasts for sedatives appear minimal or absent
2-3 hours. • muscle reaction occurs due to the action int
However it causes violent excitement in he spinal cord
horses • used clinically to control convulsion of any
origin, to control behavioral problems in pets
• minimal respiratory effects and to control restlessness during the post
• antagonizes the respiratory depressant of operative state.
the anesthetics • particularly useful when used prior to
• small decrease in BP, leading tom alpha ketamine anesthesia to reduce hallucination
adrenergic blockade which
• does not appreciable affects the piglet, just occur with this drug.
sleepy
• DOSAGE: low: 0.5-1mg/kg • DOSAGE: dog: 5mg/kg/day oral for control
of behavioral problems; 1 mg/kg IV for
• medium: 2mg/kg socializing effect anesthetic and postoperative medication
• high 4mg/kg knock down effect
• HORSES: 0.1-0.8mg/kg • Horse: 0.22mg/kg IV (preanesthetics)
BENZODIAZEPENES BENZODIAZEPENES
• BENZODIAZEPENES • LORAZEPAM (Activan)

• very long acting and slow onset of action.
• not generally neuronal depressants, they • maximum effect can be attained at 30-40
do not cause min after IV injection and
true general anesthesia 40-50 min after oral administration
• not painful upon injection
• effects include: muscle relaxation, • 4 times as potent as diazepam.
hypotonia without • maybe used clinically a premedication
interfering with normal locomotion, before ketamine anesthesia, but
anticonvulsant effect diazepam is preferred
and analgesic effect by some.
• ZOLAZEPAM - available in combination
with tiletamine a dissociative
SUBJECT
VERNON MARCIANO
agent • small doses of barbiturates are

HYPERALGESIC (enhance the perception of
BARBITURATES pain, barbiturates cannot be relied upon to
produce sedation sleep in the
• LONG ACTING presence of moderate pain.
• slight depression of cardiovascular, cardiac
• Phenobarbital (Luminal) arrythmias, vasodilation due to
• Barbital (Veronal) histamine secondary release
• SHORT ACTING
• phenobarbital (Nembutal) BARBITURATES
• Secobarbital (Seconal)
• SITE OF ACTION
• ULTRA SHORT ACTING • act at the reticular activating system.
• Thiopental(Pentothal) • Non anesthetic doses preferentially
• Thiamylal (Surital) suppress.
• Methohexital (Brevane) polysynaptic responses.
• Inhibition only occurs at GABA nergic
BARBITURATES synapses
• MOA
• potentiate GABA induced increases in
chloride ion
conductance mimicking the action
benzodiazepines but
acting at a different site
• Pentobarbital is more potent than
Phenobarbital in
producing neuronal depression
• more selective anticonvulsant effects of
phenobarbital
and its higher therapeutic index maybe
explained by its
lower capacity to produce profound
depression of
neuronal functions
BARBITURATES
• PHARMACOLOGICAL EFFECTS
• include selective depression of

transmission in autonomic ganglia and
reduction of nicotinic excitation by choline
esters.
• cause an increase neurotransmitter release
at the NMJ but with the
concurrent decrease in the sensitivity the
post synaptic membrane
• poor analgesic activity, pain perception and
reaction still present until the
moment consciousness is lost.

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SUBJECT

VETERINARY PHARMACOLOGY AND HISTORY

VETERINARY TOXICITY • PHARMACODYNAMICS - what you did to me?

• “science of safety” • PHARMACOKINETIS - what i did to you?

• pharmacology is the study of drugs used at • TOXICOLOGY - am i BI?anung level?

• PHARMACODYNAMICS - how drugs produce

• TOXICOLOGY - study of harmful effects of drugs

• Posology - drug dosage

PHYSIOLOGICAL Maintains normal body

PHARMACOLOGI alteration in the normal body

• A dose of a drug maybe poisonous to one

• basis for chemotherapy.(use of chemicals to kill or

• Drug effect - what is produced by the drug

What is a silent receptor?example?anesthesia

DUALIST - an agonist acting on specific receptors

Example: MEPYRAMINE. brain and

-Determination of the chemical

-Quantitative SARs (QSAR) as a

QSAR -Attempts to find consistent

GENERAL PROCEDURES in SAR STUDY

1. Identification of appropriate biological

2. structural modification of prototype drug

Poorly soluble compounds can reduce

- compound precipitation during serial dilution in

PARTITION COEFFICIENT - extent of distribution

WATER SOLUBILITY OF DRUGS

HOMO - highest occupied molecular orbital

LUMO - Lowest unoccupied molecular orbital

STEREOCHEMISTRY AND DRUG ACTION

composed of member drugs that act on specific

A) functional groups in the molecule

B) spatial arrangements of the groups

EASSON AND STEDMAN HYPOTHESIS

THINK!!!!! if antagonists are not related

NAMING OF DRUG FAMILIES

- typical members of the group

- families of antagonist derive their names from

morphine derivatives ANTAGONIST DERIVE FROM CORRESPONDING

Adrenergic blocking agents (vs adrenaline nor

Barbiturates (derivatives of barbituric acid)

Page 43 part 1B lesson 4

DOSE RESPONSE RELATIONSHIP

systemic description of the magnitude of the

Describes the change in the effect of an

DOSE - amount of a substance administered at

also known as the HILL SLOPE

IMPORTANCE OF DRUG DOSE RELATIONSHIP

GRADED DOSE RESPONSE CURVE

- graph between dose and effect

DRUG RESPONSE STIMULUS factors: The specific effect being measure:

give each group only 1 of increasing dose MEDIAN EFFECTIVE DOSE

3 MECHANISM OF DRUG ACTION the DO NOT

1. Non-specific action and cell membrane

eg. DEANTURANTS - desroy the integrity and

- reversible drug induced state characterized by

d. changes in curvature elasticity

Principles: a) ion gating

MILLER and SMITH Hypothesis “LIPID BILAYER