Module 1
Leesopdracht
I. Introduction
● Pharmacology: the study of the properties of chemicals used as drugs for therapeutic
purposes
○ Pharmacokinetics: the study of drug absorption, distribution,
biotransformation (metabolism), and excretion
○ Pharmacodynamics: the study of cell/tissue responses and selective receptor
effects
II. Drug Absorption and Disposition
A. General Principles
How do drugs reach their site of action?
● Passive diffusion → through membranes
○ Weak acids and weak bases
■ Degree to which drugs are
fat-soluble → regulated by their
pKa and the pH of the medium
containing the drug
■ pKa = pH at which 50% of the drug
is ionized and 50% is nonionized
○ Henderson-Hasselbalch equation
𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑛𝑜𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑎𝑐𝑖𝑑
■ Weak acid: 𝑝𝐾𝑎 = 𝑝𝐻 + 𝑙𝑜𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑎𝑐𝑖𝑑
𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑏𝑎𝑠𝑒
■ Weak base: 𝑝𝐾𝑎 = 𝑝𝐻 + 𝑙𝑜𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑛𝑜𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑏𝑎𝑠𝑒
● Filtration → through pores
● Facilitated diffusion → attached to a carrier
○ No cellular energy needed + not against a concentration gradient
● Active transport → attached to a carrier
○ Cellular energy needed + against a concentration gradient
● Pinocytosis
B. Routes of Administration
● Alimentary routes
○ Oral
■ Advantages
● Safest, convenient, economical
● Drugs can be mixed in the food to facilitate
, ● Food stimulates bile secretion → helps dissolve lipophilic
drugs
■ Disadvantages
● Acidic environment of stomach and digestive enzymes →
destroy drug
● May irritate GI mucosa
● Drugs may be metabolized by GI mucosa and liver before they
reach the systemic circulation
○ First-pass effect
○ Rectal
■ Advantages
● Can be used in unconscious or vomiting animal
● Slower absorption
● Reduces first-pass effect
● Parental routes
○ Examples
■ Intravenous (IV)
■ Intramuscular (IM)
■ Subcutaneous (SC)
■ Intraperitoneal (IP)
■ Spinal and subdural
○ Advantages
■ Rapid onset → absorption is more uniform and predictable
■ Absorption from IM and SC injection sites → determined by the
amount of blood flow
○ Disadvantages
■ Asepsis is necessary
■ Causes pain
■ May penetrate blood vessel during IM injection
■ Rapid onset → cardiovascular responses may occur
■ Food animals → devalues the carcass
● Other routes
○ Dermal or topical
■ Degree of absorption → dependent on lipid solubility
■ Abraded or damaged skin may be expected to absorb more drug than
intact skin
■ Animals with thin skin → absorb drugs readily if applied topically
■ Convenient + allows non-skilled operators to administer the drugs
○ Inhalation
■ Used for volatile or gas anesthetics
■ Rapid response → large surface area of lungs + large blood flow to
lungs
■ Reversible
C. Drug Distribution
● Distribution: the reversible transfer of drug from one site in the body to another site
● Junction between capillary endothelial cells → not tight
, ○ Permits free drug to rapidly reach equilibrium on both sites of the vessel wall
● Distribution into the CNS and CSF is restricted → blood-brain barrier (BBB)
○ Processes that contribute to keeping drug concentration in CNS low
■ Capillary endothelial junctions are tight + glial cells surround the
precapillaries
● Reduces filtration → requires drug to diffuse across cell
membranes to enter CSF
■ CSF production circulates through the ventricles + over the surface of
the brain + spinal cord to flow into the venous drainage system
● Dilutes out the drug’s concentration in the CSF
■ Active transport mechanisms → found for organic acids and bases in
the choroid plexus → transports drug from CSF into the blood
● Plasma protein binding → drug + protein (free) ⇌ drug - protein (bound)
○ Acidic drugs → bound to albumin
○ Basic drugs → bound to ⍺1-acid glycoprotein
○ Steroid + thyroid hormones → bound by globulins
○ Drug-protein binding reaction → reversible
○ Binding slows the rate at which it reaches a concentration sufficient to
produce a pharmacological effect
○ Limits glomerular filtration → bound drugs cannot be filtered
○ Binding to albumin → lowers the free drug concentration
○ Drug interactions may occur when 2 drugs are used that bind at the same site
on the plasma proteins
■ Competition increases
● Drug redistribution → can terminate drug response
○ Biologic response to a drug → terminated by metabolism/biotransformation
and excretion
○ Redistribution of drug → lowers its concentration at its site of action →
terminates drug response
○ Drug exhibiting redistribution phenomenon → highly lipid soluble
● Drug distribution from dam to fetus
○ Drug transfer across the placenta → simple diffusion
○ Drugs cross placenta best if they are lipid soluble
○ Fetus → exposed to some extent to drugs with low lipid solubility when given
to dam
○ General rule: drugs with an effect on the maternal CNS have the
physical-chemical characteristics to freely cross the placenta and affect the
fetus
D. Drug metabolism/biotransformation
● Drug metabolism/biotransformation: the chemical alteration of drugs and normally
found substances in the body
● Principles
○ After filtration at renal glomerulus → most lipophilic drugs are reabsorbed
from the filtrate
○ Biotransformation of drugs to more water-soluble chemicals → reduces ability
to be reabsorbed once filtered by the kidney
, ■ Enhances excretion + reduces volume of distribution
○ Liver → most important organ for biotransformation
○ Frequently reduces the biological activity of the drug
○ Not synonymous with drug inactivation
■ Parent chemical may be transformed to a chemical with greater
activity
● 2 phases of biotransformation
○ Phase I → biotransformation
enzymes are found in the SER
of hepatic cells (microsomal
enzymes)
■ Oxidation → carried out
by cytochrome P450s
■ Mixed function oxidase
→ 1 O atom is incorporated in the drug molecule + other O atom
combines with H to form water
● Side chain and aromatic hydroxylation
● O-dealkylation
● N-oxidation
● S-oxidation
● Deamination or N-dealkylation
● Desulfuration
■ Nonmicrosomal oxidation → a few chemicals are oxidized by cytosol
or mitochondrial enzymes
● Alcohol dehydrogenase + aldehyde dehydrogenase
● Monoamine oxidase
● Xanthine oxidase
■ Oxidative metabolism
■ Reduction biotransformation reactions → less frequent than
oxidation-type reactions
■ Hydrolysis reactions → occur with ester or amide linked chemicals
● Esterases → occur in nonmicrosomal systems → found in
plasma, liver + other tissues
● Amidases → nonmicrosomal enzymes → found in liver
○ Phase II → occurs to a phase I metabolite/parent drug → involves the
coupling of an endogenous chemical → enzyme systems are present in the
microsomes, cytosol, and mitochondria
■ Products of phase II biotransformation → greater water solubility +
more readily excreted via the kidney
■ Species variation in phase II metabolism
● Cat
○ Glucuronide synthesis where the target is -OH, -COOH,
-NH2, =NH, -SH → present at a low rate
○ Cats have longer plasma t1/2 for many drugs
● Dog
○ Acetylation of aromatic -NH2 groups → absent
○ Affects the metabolism of sulfonamides and other drugs
● Pig
Leesopdracht
I. Introduction
● Pharmacology: the study of the properties of chemicals used as drugs for therapeutic
purposes
○ Pharmacokinetics: the study of drug absorption, distribution,
biotransformation (metabolism), and excretion
○ Pharmacodynamics: the study of cell/tissue responses and selective receptor
effects
II. Drug Absorption and Disposition
A. General Principles
How do drugs reach their site of action?
● Passive diffusion → through membranes
○ Weak acids and weak bases
■ Degree to which drugs are
fat-soluble → regulated by their
pKa and the pH of the medium
containing the drug
■ pKa = pH at which 50% of the drug
is ionized and 50% is nonionized
○ Henderson-Hasselbalch equation
𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑛𝑜𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑎𝑐𝑖𝑑
■ Weak acid: 𝑝𝐾𝑎 = 𝑝𝐻 + 𝑙𝑜𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑎𝑐𝑖𝑑
𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑏𝑎𝑠𝑒
■ Weak base: 𝑝𝐾𝑎 = 𝑝𝐻 + 𝑙𝑜𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑛𝑜𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑏𝑎𝑠𝑒
● Filtration → through pores
● Facilitated diffusion → attached to a carrier
○ No cellular energy needed + not against a concentration gradient
● Active transport → attached to a carrier
○ Cellular energy needed + against a concentration gradient
● Pinocytosis
B. Routes of Administration
● Alimentary routes
○ Oral
■ Advantages
● Safest, convenient, economical
● Drugs can be mixed in the food to facilitate
, ● Food stimulates bile secretion → helps dissolve lipophilic
drugs
■ Disadvantages
● Acidic environment of stomach and digestive enzymes →
destroy drug
● May irritate GI mucosa
● Drugs may be metabolized by GI mucosa and liver before they
reach the systemic circulation
○ First-pass effect
○ Rectal
■ Advantages
● Can be used in unconscious or vomiting animal
● Slower absorption
● Reduces first-pass effect
● Parental routes
○ Examples
■ Intravenous (IV)
■ Intramuscular (IM)
■ Subcutaneous (SC)
■ Intraperitoneal (IP)
■ Spinal and subdural
○ Advantages
■ Rapid onset → absorption is more uniform and predictable
■ Absorption from IM and SC injection sites → determined by the
amount of blood flow
○ Disadvantages
■ Asepsis is necessary
■ Causes pain
■ May penetrate blood vessel during IM injection
■ Rapid onset → cardiovascular responses may occur
■ Food animals → devalues the carcass
● Other routes
○ Dermal or topical
■ Degree of absorption → dependent on lipid solubility
■ Abraded or damaged skin may be expected to absorb more drug than
intact skin
■ Animals with thin skin → absorb drugs readily if applied topically
■ Convenient + allows non-skilled operators to administer the drugs
○ Inhalation
■ Used for volatile or gas anesthetics
■ Rapid response → large surface area of lungs + large blood flow to
lungs
■ Reversible
C. Drug Distribution
● Distribution: the reversible transfer of drug from one site in the body to another site
● Junction between capillary endothelial cells → not tight
, ○ Permits free drug to rapidly reach equilibrium on both sites of the vessel wall
● Distribution into the CNS and CSF is restricted → blood-brain barrier (BBB)
○ Processes that contribute to keeping drug concentration in CNS low
■ Capillary endothelial junctions are tight + glial cells surround the
precapillaries
● Reduces filtration → requires drug to diffuse across cell
membranes to enter CSF
■ CSF production circulates through the ventricles + over the surface of
the brain + spinal cord to flow into the venous drainage system
● Dilutes out the drug’s concentration in the CSF
■ Active transport mechanisms → found for organic acids and bases in
the choroid plexus → transports drug from CSF into the blood
● Plasma protein binding → drug + protein (free) ⇌ drug - protein (bound)
○ Acidic drugs → bound to albumin
○ Basic drugs → bound to ⍺1-acid glycoprotein
○ Steroid + thyroid hormones → bound by globulins
○ Drug-protein binding reaction → reversible
○ Binding slows the rate at which it reaches a concentration sufficient to
produce a pharmacological effect
○ Limits glomerular filtration → bound drugs cannot be filtered
○ Binding to albumin → lowers the free drug concentration
○ Drug interactions may occur when 2 drugs are used that bind at the same site
on the plasma proteins
■ Competition increases
● Drug redistribution → can terminate drug response
○ Biologic response to a drug → terminated by metabolism/biotransformation
and excretion
○ Redistribution of drug → lowers its concentration at its site of action →
terminates drug response
○ Drug exhibiting redistribution phenomenon → highly lipid soluble
● Drug distribution from dam to fetus
○ Drug transfer across the placenta → simple diffusion
○ Drugs cross placenta best if they are lipid soluble
○ Fetus → exposed to some extent to drugs with low lipid solubility when given
to dam
○ General rule: drugs with an effect on the maternal CNS have the
physical-chemical characteristics to freely cross the placenta and affect the
fetus
D. Drug metabolism/biotransformation
● Drug metabolism/biotransformation: the chemical alteration of drugs and normally
found substances in the body
● Principles
○ After filtration at renal glomerulus → most lipophilic drugs are reabsorbed
from the filtrate
○ Biotransformation of drugs to more water-soluble chemicals → reduces ability
to be reabsorbed once filtered by the kidney
, ■ Enhances excretion + reduces volume of distribution
○ Liver → most important organ for biotransformation
○ Frequently reduces the biological activity of the drug
○ Not synonymous with drug inactivation
■ Parent chemical may be transformed to a chemical with greater
activity
● 2 phases of biotransformation
○ Phase I → biotransformation
enzymes are found in the SER
of hepatic cells (microsomal
enzymes)
■ Oxidation → carried out
by cytochrome P450s
■ Mixed function oxidase
→ 1 O atom is incorporated in the drug molecule + other O atom
combines with H to form water
● Side chain and aromatic hydroxylation
● O-dealkylation
● N-oxidation
● S-oxidation
● Deamination or N-dealkylation
● Desulfuration
■ Nonmicrosomal oxidation → a few chemicals are oxidized by cytosol
or mitochondrial enzymes
● Alcohol dehydrogenase + aldehyde dehydrogenase
● Monoamine oxidase
● Xanthine oxidase
■ Oxidative metabolism
■ Reduction biotransformation reactions → less frequent than
oxidation-type reactions
■ Hydrolysis reactions → occur with ester or amide linked chemicals
● Esterases → occur in nonmicrosomal systems → found in
plasma, liver + other tissues
● Amidases → nonmicrosomal enzymes → found in liver
○ Phase II → occurs to a phase I metabolite/parent drug → involves the
coupling of an endogenous chemical → enzyme systems are present in the
microsomes, cytosol, and mitochondria
■ Products of phase II biotransformation → greater water solubility +
more readily excreted via the kidney
■ Species variation in phase II metabolism
● Cat
○ Glucuronide synthesis where the target is -OH, -COOH,
-NH2, =NH, -SH → present at a low rate
○ Cats have longer plasma t1/2 for many drugs
● Dog
○ Acetylation of aromatic -NH2 groups → absent
○ Affects the metabolism of sulfonamides and other drugs
● Pig
