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Pharmokinetics
CHAPTER 3 - 3
Dr. Dipa Brahmbhatt VMD MpH
[email protected]
Drug Absorption
• Drug absorption is the movement of a drug from
the site of administration into the fluids of the
body that will carry it to its site(s) of action (IV is
directly in blood)
• Drug factors include bioavailability, route of
administration, lipophilic/ hydrophilic, pH of the
environment, ion trapping, dissolution, first pass
effect, perfusion
• Patient factors include the animal’s age, health,
metabolic rate, genetic factors, sex, and species
pH and Ionization
• pH – the measurement of the acidity or alkalinity
of a substance and environment (scale 0-14)
• # of available hydrogen ion
• More hydrogen ions lower the pH
– Lower numbers (1-3) = acid/acidic
– Higher numbers (10-12) = alkaline/basic (fewer
hydrogen ions available)
– Neutral = 7
– Relative: pH 6 is more acidic than pH 9
0
100
1
10–1
2
10–2
3
10–3
pH
value
10–4
5
10–5
H+
6
10–6
7
10–7
8
10–8
increasingly acidic
(H+ > OH–)
10–9
10
10–10
11
10–11
neutral
(H+ = OH–)
(H+ < OH–)
12
13
10–12
10–13
drain cleaner (14.0)
1 molar sodium
hydroxide (NaOH)
oven cleaner (13.0)
household ammonia (11.9)
washing soda (12)
phosphate detergents
chlorine bleach (12.6)
toothpaste (9.9)
seawater (7.8–8.3)
baking soda (8.4)
water from faucet
milk (6.4)
pure water (7.0)
blood, sweat (7.4)
normal rain (5.6)
urine (5.7)
black coffee (5.0)
orange (3.5)
tomatoes
beer (4.1)
vinegar, cola (3.0)
stomach acid (2)
lemon juice (2.3)
1 molar
hydrochloric
acid (HCl)
• The pH scale
4
9
14
10–14
increasingly basic
concentration in moles/liter
Fig. 2-11
Comparison of I/NI for 3 drugs at
Different pHs
ASPIRIN (acidic)
SULFADIMETHOXINE
(acidic)
LIDOCAINE (basic)
pH
I/NI
pH
I/NI
pH
I/NI
1
1:100
1
1:100000
1
100:1
2
1:10
2
1:10000
2
10:1
3
1:1
3
1:1000
3
1:1
4
10:1
4
1:100
4
1:10
5
100:1
5
1:10
5
1:100
6
1000:1
6
1:1
6
1:1000
7
10000:1
7
10:1
7
1:10000
8
100000:1
8
100:1
8
1:100000
RATIO
• Hydrophilic (ionized) molecules : lipophilic (nonionized) molecules, pH of the liquid
environment
• Depended on drug’s acid/base nature and pKa
pH and Ionization
• Aspirin: weak acid
– Stomach (pH 2): Acidic environment ,
mostly nonionized/uncharged,
lipophilic (1:10)
– Duodenum (pH 6): : More alkaline
environment, mostly ionized/charged
form, hydrophilic (1000:1)
– Absorbed better in stomach than SI to
go through plasma membrane
Acid/ Alkali Drug and pKa
• Nature of the drug: pH of drug
– Weakly acid drugs = hydrophilic form in alkaline
environment, ionized e.g. aspirin and sulfamethoxine
– Weakly alkaline drugs = hydrophilic form in acid
environment, ionized e.g. lidocaine
Increasing acidic
environmental pH
Increasing alkaline
(basic) environmental
pH
Acidic drug
Becomes more
Becomes more ionized
nonionized (lipophilic)
(hydrophilic)
Alkaline (basic) drug
Becomes more ionized
Becomes more
(hydrophilic)
nonionized (lipophilic)
pKa
• pH at which drug has 1:1 ratio of ionized drug:
nonionized drug e.g. aspirin pH 3 and
sulfadimethoxin pH 6.
• pKa bridges the drug with the location in which it
is best absorbed
• Acid drugs > lipophilic > more readily absorbed
across the membrane : pH more acidic than pKa
• Alkaline drugs > lipophilic: pH more alkaline
than pKa
pKa
• Henderson – Hasselbalch equation
– pH = pKa + log ([I/NI])
– E.g. aspirin has pKa = 3 at what pH 10:1
– pH = 3 + log ([10/1]) = 4
E.g True or False
• An alkaline drug with pKa of 9 is mostly nonionized after being placed in a medium with
pH of 8
Ion Trapping
• Definition – when a drug changes from an ionized to nonionized form as it moves from one body compartment to
another
• Shift between nonionized and ionized forms traps and moves
drug around the body
• e.g aspirin
– Stomach lumen - pH 2: nonionized > stomach wall: pH 7.4
(most fluids and body cells): ionized in stomach cell
membrane, some nonionized > blood: other ionozed >
nonionized to maintain ratio
– Net effect: slower absorption of drug and mild GI upset as
it accumulates in stomach cells
Ion Trapping
• This process is important in overdose of drug/
toxic agents
– Change in urine pH: urinary acidifiers and
alkalizers > change nonionophilic lipophilic drug/
toxin to hydrophilic molecules: kidney cannot
reabsorb > renal tubules > urine
“Alkalization of the urine with intravenously administered sodium
bicarbonate will enhance renal excretion of salicylate (aspirin) by
decreasing tubular reabsorption of the drug. This effect may be
enhanced by instituting an osmotic diuresis with mannitol solution.
Peritoneal dialysis is effective in removing salicylate from the plasma “
Dissolution - PO
• PO: lipophilic and broken to smaller particles:
dissolution e.g. tablets, granules, powders
• Solutions and elixirs: Don’t need dissolution
– E.g. digoxin elixir more rapidly absorbed and
higher bioavailability than tablet
• SR medication:
– Adv: sustained release over time
– DisAdv: lower peak conc
– Harder to get to target tissue from blood pg 64 Fig
3-9
Oral vs. Parenteral
• ORALLY ADMINISTERED DRUGS
– Must be disintegrated and dissolve before they are absorbed
• Inert substances: size/shape and dissolution of drug
• K / Na add to drug increase absorption of drug: penicillin
• This may be sped up by administering fluids with solid drugs
– Speed may be hindered by decreased gastric motility,
large drug size, and they must be lipophilic in form
• PARENTERAL DRUGS
– Tissue blood flow affects drug absorption
• Also, drugs must by hydrophilic
First pass effect
• First-pass effect: Intestinal
lumen > hepatic portal v. >
liver: xenobiotics e.g.
diazepam not effective PO
– Liver:
Metabolized/biotransformed to
inactive form for excretion
– Reduces bioavailability
– Lidocaine and nitroglycerine
are not given orally due to firstpass effect
Getting in: DRUG ABSORPTION
Patient Factors
• Affect drug absorption
– Blood flow
– Pain/Stress/Food: slow gastric emptying, increases
absorption
– Hunger
– Fasting
– pH
Perfusion
• Few capillaries/ further
away than absorbed slowly
• Perfusion: IM > SC > fat
• Inactivity
– Atrophy, sedation/
anesthesia > absorbed at
slower rate
• Hypothermia:
vasoconstriction > dec.
absorption of drug
• Inc. temp: hyperthermia,
exercise > inc. absorption
Exception SNS vasodilation but
vasoconstriction in SC so dec. absorption of
drug
GI motility – PO
Patient factor
• Stomach contractions/ GI motility: mix;
stomach > SI
– Condition/ dz. That decrease > delay absorption
– Spasm of pylorus > dec gastric emptying > delay
absorption
– Inc > drug absorbed faster
• Intestinal motility
– Hypermotile diarrhea > dec. absorption most in
feces
– Constipation/ antidiarrheal drugs: inc. absorption
Drug Absorption
• Age
– Young animals may not have well developed
gastrointestinal tracts/ liver and less active enzyme
systems
• Health
– Sickness will affect
the rate of absorption of
certain drugs
Drug Absorption
• Metabolic rate
– Animals with a high
metabolic rate may
eliminate drugs from
their system quicker
• Genetic factors
– Individual variation in
response to drugs may
occur because of genetic
differences between
animals
Drug Absorption
• Sex
– Male and females have
different body
compositions
– These specific
compositions may affect
the action and distribution
of the drug
• Species
– Cats have a reduced ability
to biotransform certain
drugs and thus eliminate
certain drugs slowly
DRUG MOVEMENT
• PHARMACOKINETICS is the physiological movement of drugs.
• 4 Steps:
– Absorption
– Distribution
– Biotransformation
(drug metabolism)
– Excretion
– Drug properties
determine this:
hydrophilic
Drug Absorption: Distribution
Drug Distribution
• Drug distribution is the physiological movement of drugs
from the systemic circulation to the tissues
• Goal of distribution is for the drug to reach the target tissue or
intended site of action
• Factors affecting drug distribution:
–
–
–
–
Membrane permeability
Tissue perfusion
Protein binding
Volume of distribution
Barriers to drug distribution
• Capillary fenestrations
• Places hard to reach
– Blood- brain barrier
– Prostate
– Eye globe
• Placenta
Membrane Permeability
• Capillary fenestrations (holes between cells) allow
movement of small molecules in and out of them
• Large molecules usually cannot pass through them
-Exception: Only lipophilic drugs can pass through the bloodbrain barrier because capillaries have no fenestrations and
it has an extra layer of cells surrounding them (astrocytes
and glial cells). However, fever/inflammation can make the
membrane more permeable to other drugs
- Exception: The placenta has the ability to block
SOME drugs from affecting the fetus with its
barrier. Capillary has fenestrations.
Tissue Perfusion
• Definition – the relative amount of blood supply to an area or
body system. It affects how rapidly drugs will be distributed
• Well perfused: exercised skeletal m., liver, kidney, brains
• Poorly perfused: non exercised skeletal m., adipose
– Thiopental : barbiturate, short acting, lipophilic, not in sighthounds
• Drugs travel rapidly to well perfused tissues (brain) if given IV. May initially have
high levels of drug and cause sedation.
• Few minutes of injection animal recovers because of distribution of drug.
• IV > brain > fat and inactive muscle : low blood levels hence more leaves from the
brain
• REDISTRIBUTION: blood > tissue (brain) > 2nd tissue (fat)
• Can also be affected by blood flow rates that are altered via
vasoconstriction or vasodilation
• Decreased rates decrease the amount and rate of the drug that’s
delivered to the tissues.
Protein Binding
• Proteins are large in size and many drugs bind to them when they are in
the body. This makes them too large to pass through capillary
fenestrations and stuck in the circulatory system.
– INCREASED PROTEIN BINDING = less free drug available to the tissues
– DECREASED PROTEIN BINDING = more free drug available to the
tissues
• Albumin is the main protein in circulation and is made in the LIVER.
• Animals with either liver disease or protein-losing
enteropathies/nephropathies will have less protein in their body, thus
more drug will be UNBOUND and available to the tissues.
– DECREASED dosages or different medications should be chosen as the patient may be
exposed to high levels of the drug in it’s tissues. Also important because most drugs will
be metabolized by the liver.
– E.g. barbiturate case on pg. 69 terrier –X with chronic diarrhea
Volume of Distribution = Vd
• How well a drug is distributed throughout the body based on
the concentration of drug in the blood (penetrability and
distribution of drug)
• Assumes that the drug concentration in the blood is equal to
the drug concentration throughout the rest of the body
• Obese dog: less drug in tissue and more in blood > lower Vd
> use lower [drug]
• Dose may need to be increased in cases of larger volumes of
distribution e.g. dog with ascites
• Exception: drug is clustered/ sequestered/ accumulated:
digoxin
• Vd is misleading. Vd high hence well distributed.
• Highly bound to proteins in skeltal m. and heart most is distributed
Volume of Distribution
References
• Romich, J.A. Pharmacology for Veterinary
Technicians, 2nd edition. 2010.
• Bill, R.L. Clinical Pharmacology and
Therapeutics for the Veterinary Technician, 3rd
edition. 2006.
• Ahearn Gregory, Life on Earth, 5th edition,
2008.
• http://vetmed.tamu.edu/common/docs/publi
c/aavpt/aspirin.pdf