VET PHARMACOLOGY

INTRO TO PHARMACOLOGY Molecular Pharmacology

Pharmacology - study of basic mechanisms of drug actions
- experimental science dealing with the in the system
properties of drugs and their effects on the Clinical Pharmacology
living system - concerned on the actual observation and
Definition of Terms treatment of patients
 Drug – any article intended to be used in Pharmacogenomics
diagnosis, mitigation, treatment, or prevention - study of genetic variations that causes
of disease differences in drug response among
 Therapeutics – treatments of disease in general individuals
that includes drugs, surgery, radiation, etc.
VETERINARY PHARMACOLOGY
SCOPES OF PHARMACOLOGY - Concerned with the use of drugs in the
Pharmacodynamics – how drugs affect the living diagnosis, treatment, and intentional
system and the response alteration of animal physiology
o Sites which biological effects are HISTORY OF PHARMACOLOGY
produced - Development of Veterinary Pharmacology
o Mechanism by which B.E. are produced parallels Human Pharmacology
o Fate of drugs in the body o Indian military hospitals for horses and
o Factors that influence drugs elephants were found in 5000 BC
Pharmacokinetics - Formal discipline of Vet Pharma started in
- mathematical description of temporal France, Austria, Germany and the
changes in conc. of drugs and/or Netherlands
metabolites in the body - Lyon Veterinary School is the 1st veterinary
Pharmacotherapy school
- use of drugs in the treatment of disease - In early colleges, most teachings were
Chemotherapy essentially materia medica
- deals with drugs that selectively  The Veterinarian’s Vade Mecum
inhibit/destroy specific agents (bacteria, - Mid 19th century; 1st materia medica for
virus, fungi) used, published by John Gamgee
- Use of drugs in the treatment of neoplastic  Veterinary Materia Medica and Therapeutics
disease - By Kenelm Winslow
Toxicology – study of poisons  Book of Veterinary Pharmacology and
- Concerned with the adverse effects of Therapeutics
xenobiotics - By John L. Meyer in 1954
Posology – study of medicine dosage - Shifted from materia medica to actual
- Dose: quantity of medication administered science of drug action
at one time
- Dosage: determination and regulation of
doses DRUG SOURCES
Metrology
- study of weights and measurements applied Drugs are obtained from 6 different sources:
in the preparation of drugs 1) Plants

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 VET PHARMACOLOGY

2) Animals
3) Minerals Synthetic Sources
4) Microbiological sources  Synthetic sources
5) Synthetic sources - When nucleus and chemical structure of
6) Recombinant DNA technology drug from natural source is altered
- Emetine bismuth iodide
Plant Sources  Semi-synthetic sources
- Oldest source (materia medica) - Nucleus is maintained but the chemical
- All parts of the plants are used structure is altered
 Leaves - Apomorphine, methyl testosterone
- Digitalis purpurea – source of digoxin and
digitoxin Microbiological Sources
- Atropa belladona – gives atrophine - From microorganisms
 Flowers  Penicillum notatum = penicillin
- Papaver somniferum – source of morphine  Actinobacteria = streptomycin
- Vinca rosea – gives vincristine and  Streptomyces spp. & Micromonospora spp. =
vinblastine aminoglycosides
 Fruits
- Senna pods give anthracine Recombinant DNA Technology
- Calabar beans give physostigmine - Involves cleavage of DNA by enzyme
 Seeds restriction endonuclease
- Seeds of Nux vomica give strychnine - Desired gene is coupled to a rapidly
 Roots replicating DNA
- Ipecacuanha roots give emetine - New genetic combination is inserted into
 Bark bacterial cultures
 Stem Advantages:
- Huge amounts of drugs produced
- Drugs are obtained in pure form
- Less antigenic
Disadvantages:
Animal Sources - Well-equipped lab is necessary
- Source of insulin for diabetes treatment - High-trained staff required
- Urine of pregnant women contain hGC used - Complex and complicated techniques
to treat infertility
- Sheep thyroid for thyroxine to treat DRUG DEVELOPMENT
hypertension - Process of bringing a novel drug from
“bench to bedside”
Mineral Sources
- Iron used to treat iron deficiency
- Iodine used as antiseptic
- Zinc used as supplement/zinc oxide paste in
wounds or eczema
- Mercurial salts used in syphilis

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- IND (investigational new drug)

o Investigator
STAGES OF DRUG DEVELOPMENT o Emergency use
i. Early drug discovery o Treatment
ii. Preclinical research - IND can be categorized as “commercial” or
iii. Investigational new drug application ”research”
iv. Clinical research - IND sponsor is required to wait 30 days
v. Regulatory review, approval, and post- before starting clinical trials
marketing surveillance survey
4. Clinical research
1. Early Drug Discovery - Designed to answer specific questions
- Performed in laboratories in vitro using related to IND
animal models - Trials should follow a specific protocol to
- Involves several core steps ensure safety of participants and integrity
- Collaboration between industry scientists of data
and academicians - Involves 3 phases
 Target Identification and Validation
- Target identification: identifying which part Phase 1
of the disease can potentially be interfered - 20-100 healthy or unhealthy participants
by a potential drug compound - Lasts several months
 Hit Identification and Validation - Primary purpose: to determine safety and
- Hit: a compound that interacts with the gather information on dosage
target of interest Phase 2
 Hit-to-lead and lead optimization - Primary purpose: to determine efficacy and
- Refines several of the most promising “hits” adverse effects
to create more potent and selective - Lasts from several months – 2 years
candidates with “optimized” - Several hundred diseased participants
pharmacokinetics properties Phase 3
 Candidate selection - Primary purpose: to determine drug’s
- Identifies which high-quality leads will efficacy and monitor adverse reactions
proceed as clinical candidate - Lasts 1-4 years
o Bind selectively to targets - Greatest proportion of safety info is
o Elicit desired functional response collected
o Must have adequate bioavailability and
biodistribution 5. Regulatory review, approval, and post-
marketing surveillance survey
2. Preclinical research  New Drug Application – needed for marketing
- Tests a candidates’ efficacy and safety authorization
before it is tested to target species  Biologics license application – submitted for
- In vitro/in vivo models therapeutic biological products
o Monoclonal antibodies
3. Investigational new drug application o Cytokines
- Authority groups INDs into 3 types (FDA) o Growth factors

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o Enzymes
 Product launch – carried out after relevant
activities
o Manufacturing scale-up and
serialization
o Printing of final product label
information, packaging and artwork
o Product storage, shipping and
distribution arrangements
o Production staff and quality team
availability
 Post-Marketing Safety Surveillance: monitoring
of a drug after it has received approval and has
reached the market
 Phase IV: conducted after approval of the drug
- several thousand participants diagnosed
with the disease the drug is approved for
use
- purpose of is to obtain additional
information about the long-term risks and
benefits of taking a drug now that it is being
more widely used.

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Drug Passage Across Membranes  Weak acids are better
absorbed from the stomach
Drugs that cross the bilipid-layer than weak bases due to acidic
cellular membrane conditions (e.g aspirin,
pKa=3.5)
Nonpolar, lipid-soluble compounds
 Weak bases are absorbed
Polar, water soluble compounds poorly in an acidic environment
since they exist in the ionized
Factors that affect the ability of drugs
state (thus low lipid solubility)
to cross the membrane
 Weak bases are more
 Lipid solubility absorbed at the small
 Molecular size intestines where pH is more
 Degree of non-ionization alkaline
Reaching the Site of Action - Henderson-Hasselbach equation
calculates the percent of the drug
• Passive diffusion
that exists in ionized form and its
 Movement of solutes (drugs) concentration across a biologic
following a concentration membrane
gradient
pH = pKa + log ([UA]/[IA]) (weak
 Drugs generally are classified
acids)
into weak acids and weak
pH = pKa + log ([IB]/[UB]) (weak
bases
bases)
 Lipid solubility is determined
by their pKa and pH of the
medium containing the drug
- pK = pH at which 50% of the drug is
ionized and 50% is non-ionized

- Monogastric animals: low pH,

KOOKIEDVM3A 1
Filtration Pinocytosis
 Low molecular weight  Small particles suspended in
substances (e.g water, extracellular fluid are brought
urea) cross membranes into the cell through an
through pores / invagination of the cell
channels membrane
 Glomerular filtration  Minor method of drug
provides evidence of absorption
existence of pores large  Important in the absorption of
enough to allow passage polypeptides, antigens, and
of large molecular bacterial toxins by the gut
weight substances but
small enough to retain Routes of Drug Administration
albumin
 (MW = 60,000 g/mol) • Alimentary Routes: Oral

Facilitated Diffusion  Safest, most convenient, and

economical
 does not operate against a
- Disadvantages:
concentration gradient
 Drug transport involves  Acidic stomach pH and
attachment to a carrier digestive enzymes may destroy
 Not a major mechanism of the drug
drug transport  Some drugs irritate the GIT
o e.g glucose reabsorption mucosa
by kidneys, intestinal  Food may adversely alter
absorption of Vit. B12 absorption
along with intrinsic  Some drugs are extensively
factor metabolized by the GIT
Active Transport mucosa and liver before it
reaches the systemic
 Requires ATP, operates against circulation (first-pass effect)
a concentration gradient
- Other considerations:
 Chemical structure of the drug
is important in attaching to the  Antimuscarinics and narcotics
carrier molecule delay gastric emptying,
o e.g 5-fluorouracil is prolonging drug absorption
absorbed in the intestine and drug onset
by the same system used  Hyperactive gut shortens the
to absorb uracil transit time, and thus drug-gut
contact and absorption is
reduced

KOOKIEDVM3A 2
• Alimentary Routes: Rectal Inhalation
 Can be used in an unconscious  used for volatile gases
or vomiting animal /gaseous anesthetics
 Response is rapid because of
Parenteral Routes
the large surface area and large
 Circumvent the GIT blood flow of the lungs
 Intravenous (IV), Dosage Forms
 Intramuscular (IM),
 Subcutaneous (SC), Oral dosage forms
 Intraperitoneal (IP),
 Intrathecal (IT),  Powder: simplest mixture, fine
 Intra-arterial (IA) particles
o Compressed tablets,
- Advantages: granules,
 rapid onset (IV>IM>SC) ideal in  Pellets: most commonly used,
an unconscious or vomiting consists of an active drug
patient combined with a binder,
 absorption more uniform and excipient, lubricants, and
 Predictable disintegrants
 Enteric coated tablets: drugs
- Disadvantages: coated with phenylsalicylate or
 asepsis is necessary other substances insoluble in
 causes pain, with a risk of acid but soluble in alkaline
penetrating a blood vessels environments
when doing IM route  Capsules: containers made
 speed of onset is rapid, ofmixture of gelatin and
cardiovascular responses may glycerin for drugs in powdered
occur to drugs that normally and liquid forms
have minimal effects to the  Boluses: large, compressed
cardiovascular system tablets rectangular in shape
 discoloration of meat or used in horses and cattle
 Mixtures: aqueous solutions
abscess formation in food
animals, devaluing the carcass or suspensions of insoluble
solid substances added with
Dermal / Topical preservatives (benzoic acid /
chlorobutanol) to inhibit
Administration
bacterial and mold growth
- Degree of absorption is dependent  Syrups: solutions of medicinal
on lipid solubility agents, flavoring and coloring
agents in 85% sucrose medium
- Abraded / burnt skin may absorb
(usually cough remedies)
more than intact skin
KOOKIEDVM3A 3
  Emulsions: oily substances
dispersed in aqueous solutions
with stabilizers
 Elixirs: hydroalcoholic
solutions, sweetened and
flavored
 Decoctions: syrups from
boiled medicinal plants
Parenteral dosage forms
 Injections: sterile solutions in
Passage of drugs from site of
an aqueous (or oil) vehicle
application into the blood circulation
 Repository forms: drugs
designed to prolong effective  For drugs administered orally,
drug concentration in the body bioavailability may be less than
providing for sustained release 100% due to incomplete extent
(drug chemical nature is of absorption and first-pass
modified todecrease solubility) elimination
 Implants: hard, sterile pellets
inserted under the skin where
it is dissolved very slowly
Dosage form for the respiratory tract
 anesthetic gases,
 vapors,
 fine mist produced by
nebulizations, Absorption from GIT
 aerosols Pharmaceutical factors:
 sprays
 dissolution of solid drugs takes
time and is ratelimiting
Drug Absorption
 dissolution may be hastened
by micronization, preparation
Passage of drugs from site of
as soluble salts, and
application into the blood circulation
incorporation of disintegrants
 Affected by the drug dosage  pH can be manipulated to
form and route of enhance dissolution time (e.g
administration aspirin is taken with food to
 Bioavailability (unchanged buffer the GIT since aspirin
drug fraction reaching dissolves more when the pH of
systemic circulation) limits the environment goes toward
drug absorption alkaline)
KOOKIEDVM3A 4
Physiological factors:  aqueous solutions given IM are
usually absorbed within 10-30
 greater absorptive surface area minutes, provided blood flow
entails great absorption rate, is good and unimpaired
and therefore absorption is  when a drugs is given IM, the
reduced in GIT hypermotility or drug becomes continuous with
GIT epithelial damage ECF and the rate of diffusion
 food may enhance or retard and rate of blood flow will limit
drug absorption the extent of absorption
o (e.g milk/antacids  if blood-flow is rate-limiting,
chelate tetracycline) absorption rate can be altered
 gastrointestinal pH determines and can be prolonged by
absorption rate as it influences application of tourniquet,
lipid solubility immobilization, or local
 weak acids and weak bases cooling
have different sites of  larger volumes injected SC or
absorption IM reduces absorption rate due
 digestive differences: to the increase in distance
stomach type influences between the drug molecule and
absorption, where oral capillary endothelial linings
administration is impractical in
ruminants (due to large volume Absorption from IV administration
of ingesta and presence of  useful if rapid onset of action
microflora), whereas birds may is of paramount importance
not have difficulty  the rate of injection is equal to
disintegrating capsules and the rate of absorption
tablets because of their  adverse responses are more
gizzard readily encountered, and
 first-pass effect (metabolism chances can be reduced by
and partial inactivation of a allowing at least one
drug reaching the liver): drugs circulation time (1-2 min) to
which undergo first-pass effect complete an injection
must be given orally in higher  some drugs may be needed to
doses than what is required be given to effect, or slow
when the drug is given titration of the drug until the
parenterally desired effect is seen (e.g
Absorption from parenteral pentobarbital)
administration  a drug may be injected in bolus
(at once) as when inducing
 usually more rapid and emesis through apomorphine
predictable than PO in dogs

KOOKIEDVM3A 5
Absorption from IP administration
 commonly used in small
rodents, range animals, and
pigs
 drugs may undergo first-pass
effect when they are absorbed
into the hepatic portal
circulation from the peritoneal
cavity
Absorption from the skin
 usually insignificant except
when the skin is extensively
damage due to wounds or
burns
 highly lipid-soluble drugs are
almost completely absorbed
from the skin
 DMSO and polyethylene in
topical preparations can
enhance percutaneous
absorption
Absorption from the respiratory tract
 seldom used except during gas
anesthesia
 gaseous and volatile liquid
agents are absorbed into
systemic circulation by
diffusing across the pulmonary
alveolar epithelium, where
bloodgas partition coefficient
governs absorption
 particle size larger than 0.1 m
may not reach the alveoli

KOOKIEDVM3A 6
VETERINARY PHARMACOLOGY [DRUG ACTION]

ESSENTIALS OF DRUG ACTION  full agonist: produces full cell/tissue response

 Pharmacodynamics  partial agonist: provokes response but maximum
- Focuses on the action and effects of drugs within the response is less than that of full agonist due to a higher
body affinity for receptor but lesser activity than full agonist
- “what the body does to the drug”  inverse agonist: drugs that bind to the receptor and
Terminologies: suppressing the signaling activity
Receptor Affinity - propanol and antihistamines
Ligand Intrinsic activity/efficacy
Drug activity Potency Antagonist
- have affinity for receptor site but with no intrinsic
activity
 RECEPTORS – macromolecular component of body - block/reduce effects of agonists
tissues which interacts with a drug to initiate its effects
- Proteins: receptors on cardiac cells, smooth muscle, - antagonist effect is seen as a DEFICIENCY of normal
exocrine glands physiologic effects of the blocked hormone,
- Enzymes: acetylcholinesterase (AChE) transmitter, substrate
- Others: nucleic acids, ion channels tubulin

Properties of Receptors
- Saturability: finite number of receptors are present
in a cell
- Specificity: binding drugs with receptors is possible
due to complementary structures similar to lock-
and-key
- Reversibility: drugs that binds to a receptor can
dissociate in its non-metabolized form  Competitive antagonist
- Reversible on removal
 Ligand – any drug or substance with specific affinity to a - Degree of antagonism depends on the quantity of
receptor agonist relative to the quantity of agonist
- Receptors binds ligands & transduce signals - Occurs on the same receptor protein such that 2
- Drug binding to receptor uses similar chemical bonds drugs (agonist & antagonist) compete and bind to
with enzyme-substrate interaction the same receptor protein

Properties of Drugs
 Intrinsic Activity/Efficacy – property of drug that permits
it to initiate post-receptor processes which leads to a
response
 Affinity – tendency of a drug to combine with a
particular receptor

 Noncompetitive antagonist
- Irreversible
- Removes the receptor from the system where
agonist has no influence upon the degree of
antagonism/reversibility
 Physiologic antagonism
- Occurs as the result of activating receptors with
opposite physiological effects

CLASSIFICATION OF LIGANDS (drugs)

Agonist
- ligands (drugs) with both affinity and efficacy

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VETERINARY PHARMACOLOGY [DRUG ACTION]

 E.g. aspirin blocks synthesis of prostaglandins which

mediates the raising of the body temp by the
hypothalamus (Drug Action), reducing fever (Drug Effect)

Categories of Drug Action

 Stimulation/Depression
- Acts to increase or decrease activity of physiological
function
 Replacement
- In therapy for deficiencies
 Chemical antagonism - E.g. diabetes mellitus
- Occurs as the result of a drug combining with 2 or  Inhibition/killing organisms
more molecules via formation of chemical bonds - Antibiotics, antifungals, antiparasitics
- Often does not require animal tissue to be  Irritation
demonstrated; used to treat heavy metal - Antiparasitics, anthelminthics
intoxication
- Dimercaprol chelates Hg and As, penicillamine Categories of Drug Effect
chelates Cu, Pb, Hg
 Physiologic effect
- Retains the normal function of the biologic system
SIGNAL TRANSDUCTION
 Pharmacologic effect
 Ligand-gated ion channels (Type 1) - Aka “side effects”
- regulates flow of ions through the cellular - Resulting from the lack of specific action while
plasma membrane channels binding to other tissues
- rapid response o Antihistamines causes drowsiness and dizziness
- e.g Ach at nicotinic receptors  Drug toxicity
 GTP-binding proteins (type 2) - Predicable adverse effect of the drug related to the
- couple the binding of the ligand on the cell surface dose given
receptor to intracellular second messengers - Drug safety: range between therapeutic and toxic
- catecholamines cause displacement of GDP from G dose
protein and its replacement by GTP  Allergic reactions
 Kinase-linked receptors (type 3) - Unpredictable adverse effects due to the response
- Signal transduction occurs thru activation of enzyme of the immune system
associated with intracellular domain of receptor  Idiosyncratic reactions
- Tyrosine kinase - Due to genetic differences of the patient occurring at
 Intracellular receptors (type 4) the 1st exposure of the drug
- activated receptor proteins form dimer and move to
the promoter region of the DNA, altering Drug Effects Enhancements
Transcription processes
 Additive Effects
- steroid and thyroid hormones
- If 2 drug with the same effect produces an effect
equal in magnitude to the sum of individual effects
- 1+1 = 2
POTENCY
 Synergism
- refers to the dosage of a drug that must be given to
- If 2 drug with the same effect produces an effect
produce a particular effect of a given intensity
greater in magnitude the sum of individual effects
 influence by affinity & pharmacokinetic processes
- 1+1=3
 not necessarily correlated with efficacy or safety
 Potentiation
 most potent drug in a series is not necessarily clinically - Occurs if a drug is lacking an effect of its own,
superior increases the effects of a 2nd active drug
- 0+1=3
DRUG ACTION vs. DRUG EFFECT
Drug Action DOSE RESPONSE RELATIONSHIP
- where and how the effect is produced (MOA) - Parameter that characterizes drug activity
Drug Effects
 Describes the nature of drug action, potency of drug,
- what is produced by the drug
presence of competitive or non-competitive antagonism
- consequence of the drug-receptor interaction
 2 types:

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VETERINARY PHARMACOLOGY [DRUG ACTION]

- Graded dose response SSM =

100−10
𝑥100
10
- Quantal dose-response relationship

Graded dose relationship

- Refers to rate of change in the intensity of response
proportional to the rate of change of drug conc.
- Higher dose = greater response

Characteristic variables
a. Potency: dose needed to produce an effect
- Smaller dose = greater potency
b. Slope of the Curve
- Indicates range of dosage to which drugs acts

c. Variability in response: depends on physiological,

pathological or drug-induced problem
d. Maximal effect: peak response possible for the
effector

Quantal dose-response relationship

- All-or-none response
- Measures the frequency in which a dose of a drug
produces a pharmacological effect in a population
 Assumes that an individual responds to their maximum
capability or none at all
- Used in clinical trials before drug is marketed for use

Parameters that can be derived:

 Median dose
- midpoint of the curve
- Smallest dose required to produce effect on 50% of
population
 Standard deviation
- Determines the spread of the pop’n around the
mean
 Therapeutic index
- Ratio of LD50 to ED50
- Higher TI means a more safer drug
 Standard safety margin
- More conservative measure of a drug’s safety than
TI
- Relate the therapeutic effect in all animals without
the risk of producing adverse effects

Assume that 10mg/kg of a drug is effective in 99% of animal

pop’n and that a dose of 100 mg/kg will cause toxicity in 1%
of the same pop’n

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VETERINARY PHARMACOLOGY [DRUG DISTRIBUTION]

DRUG DISTRIBUTION
- Movement of drug from the plasma compartment Binding to plasma proteins
into the various fluid and tissue compartments and
sites of action - Only the unbound drug is able to cross the cell
membranes
- Acidic drugs
primarily bind to
albumin
- Basic drugs bind to
a1-acid
glycoprotein
- Binding slows the
rate to which the
drug reaches a
conc. sufficient to produce a pharmacologic effect
- Binding DOES NOT produce an effect but can be
classified as a silent receptor

Redistribution (sequestration)
- Redistribution of a drug from its site of action to
Factors that affect Drug Distribution other tissues lowers its conc. at its site of action,
- Dose and route administration terminating the response
- Blood flow into different organs - Drugs exhibiting redistribution are highly lipid-
- Physiochemical properties of drugs soluble
 Lipid solubility, pK, pH, and molecular size determine
the rate of distribution of a drug to various body fluid
compartments
 Ion-trapping also influences drug distribution; lipid-
soluble drugs distributes more widely in the body than
less lipid-soluble ones

Concentration Gradient
Drug Interactions
- Drugs are more transported - May occur when 2 drugs are used that bind at the
from compartments where same site on the plasma protein
they are more concentrated - Where competition for the same site increases the
to areas where they are less percent of the drug in free-form
concentrated (simple - Thereby increasing the pharmacologic-toxicologic
diffusion) until equilibrium is response to the displaced drug
attained
- Rate of drug diffusion across DISTRIBUTION OF DRUGS INTO SPECIALIZED
the lipid-bilayer is dictated by COMPARTMENTS
the drug’s lipid solubility
CNS Distribution
- Blood-brain barrier is a continuous layer of tight
Binding to tissue constituent junction between capillary endothelial cells in CNS
- Some drugs bind to cell membrane and to soluble IC  Drugs must be highly soluble to cross this barrier
components  Latentiation: process of incorporating lipophilic groups
- Binding restricted = distribution is limited to a drug; allows passage to the BBB
- Binding of drugs to animal tissues for human food is  Encephalitis opens the BBB; allowing passage of drugs
a major consideration thus need for instituting like penicillin (which doesn’t normally pass thru)
withdrawal periods - Active transport exists for organic acids in the
Withdrawal period – minimum period of time from choroid plexus
administration of the last dose and the drug residues in  Allows transport of drugs from CSF  blood
animal by-products

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VETERINARY PHARMACOLOGY [DRUG DISTRIBUTION]

CSF dilutes a drug concentration

- CSF produced circulates thru the ventricles and over
the brain surface and spinal cord to flow directly into
the venous drainage system of the brain

Transplacental Distribution
- Placenta mediates gas exchange between the
maternal and fetal circulation (fetal lung)
 Forms a partial barrier to the transfer of cells from
mother  fetus

- All drugs can cross the placenta thru simple

diffusion and reach the fetus
 Rate of transfer varies with the physiochemical
properties of the drug

- charged molecules rapidly penetrate placenta

depending upon the concentration gradient of the
drug between the maternal and fetal circulation
- only free drugs cross the placenta
 Sink effect – occurs when the free drug crossed the
placenta will become protein bound again in fetal
circulation, establishing a conc. gradient between
maternal and fetal circulation

- Drugs with an effect on the maternal CNS have

physical-chemical characteristics to freely cross the
placenta and affect the fetus

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