PRELIMS

PHARMACOLOGY 1
PHARM 226

UNIT 1 CHAPTER 2: PHARMACOKINETICS

OUTLINE
I. Pharmacokinetics
II. Liberation
A. Pharmacotechnical factors affecting liberation
1. Disintegration
2. Dissolution
III. Absorption
A. Drug Absorption by Passive Diffusion Factors
1. Membrane Concentration Difference Figure 2. Pharmacokinetics – how the drug is being handled
2. Particle Size in the body.
3. Partition Coefficient (PC)
4. Degree of Ionization
B. Physiological Factors
1. Degree of Perfusion
2. Gastric Emptying
3. Gastrointestinal Motility
4. Surface Area of the Absorbing

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Environment
IV. Distribution
A. Factors Affecting Drug Distribution
1. Cardiac Output
2. Regional Blood Flow
3. Blood Brain Barrier (BBB)
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4. Blood Placenta Barrier
5. Plasma Protein Binding Figure 3. Pharmacodynamics – explain how drugs create
6. Tissue Storage pharmacologic or clinical effects
V. Metabolism
A. CYP450 Enzymes LIBERATION >
only
-

dissolved are absorbed

B. Phases of Drug Metabolism •Release of the active drug ingredient and excipients
1. Phase 1 Metabolism from the dosage form to the biological system. disintegration
>
-

2. Phase 2 Metabolism ↓

VI. Excretion
• Concrete biopharmaceutic process deaggregation
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↓

• Highly modifiable process -reduction

of drug's powders
↓
particle Sizz
PHARMACOKINETICS • Orally administered dissolution

• Branch of pharmacology dedicated in determining PHARMACOTECHNICAL FACTORS AFFECTING

the fate and disposition of substances administered LIBERATION
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in living organisms. DISINTEGRATION

• “What the body does to the drug?” • Disintegration of the drug product and subsequent
• Absorption, Distribution, Metabolism and Excretion release of the drug
(ADME) • USP defines complete disintegration as “the state in
which any reside of the unit, except fragments of
insoluble coating or capsule shell, remaining on the
screen of the test apparatus or adhering to the lower
surface of the disk, if used, is a soft mass having no
palpably firm core”
• Physical break-up of an intact dosage form to its
component aggregates (depends on the nature of
the dosage form)
• Happens mostly in tablets (even in capsules but
Figure 1. Drug release and absorption – Liberation and mostly in tablets)
Absorption. Not all drugs undergo absorption. If drug is DISSOLUTION
administered in IV (Intravenous) solution there is NO • Dissolution of the drug in an aqueous environment
ABSOPRTION. Drug in systemic circulation – present in • Solid drug substance becomes dissolved in a solvent
blood stream. Blood is responsible for delivering the • Important prior to systemic absorption, dissolution
substances, nutrients and even drugs to certain regions in tests are used to predict bioavailability
the body. Pharmacologic/Clinical effect – site of action.
Metabolism and Excretion – Drugs will be metabolized and
excreted in the body.

m
plasma conc.

VS .

time

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 UNIT 1 CHAPTER 2: PHARMACOKINETICS

If there is adequate or enough gastrointestinal blood flow,

bloodstream will always be the region of low drug
concentration because if it is properly perfused,
adequately perfused the presence of blood in low drug
concentration will always carry the drug being
transported.
GASTRIC EMPTYING
• Time it takes for the stomach to empty its contents
• Normal gastric emptying time: 2 to 3 hrs.
GASTRIC EMPTYING
High GET (Gastric Low (Gastric Low Absorption
Emptying Time) Emptying Rate) Rate
Low GET (Gastric High (Gastric High Absorption
enters the Emptying Time) Emptying Rate) Rate
Figure 4. Liberation
~ Rate: Amount per time
plasma blood

ABSORPTION
• Rate and extent of drug entry into the systemic
circulation
• Rate and extent of disappearance from the site of
administration
DRUG ABSORPTION BY PASSIVE DIFFUSION FACTORS

MEMBRANCE CONCENTRATION DIFFERENCE

• High drug concentration to low drug concentration

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(along concentration gradient)
Based on anatomical structure of stomach
• Passive diffusion does not require energy. Hence,
would rely on difference in the concentration
GASTROINTESTINAL MOTILITY
gradient.
Fick’s Law of Diffusion • Peristaltic movement
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• States that the flux of molecules per unit time is • Peristalsis – involuntary movement of GIT in
directly proportional to the concentration gradient, order to transport the food intake.
area and permeability coefficient and inversely • Promotility Drugs speed up absorption
proportional to membrane thickness • Anti-motility Drugs slow down absorption
(𝑪𝟏 − 𝑪𝟐) 𝒙 𝑨𝒓𝒆𝒂 𝒙 𝑷𝒆𝒓𝒎𝒆𝒂𝒃𝒊𝒍𝒊𝒕𝒚 𝒄𝒐𝒆𝒇𝒇𝒊𝒆𝒄𝒊𝒆𝒏𝒕
𝑭𝒍𝒖𝒙 ( 𝒑𝒆𝒓 𝒖𝒏𝒊𝒕 𝒕𝒊𝒎𝒆) = SURFACE AREA OF THE ABSORBING ENVIRONMENT
𝑴𝒆𝒎𝒃𝒓𝒂𝒏𝒆 𝑻𝒉𝒊𝒄𝒌𝒏𝒆𝒔𝒔
I PARTICLE SIZE • Villi and microvilli increase the organ’s surface area.
An increase in surface area facilitates a faster rate
•
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Generally, drugs with larger particle size will have

and greater degree of absorption
slower rate of diffusion (absorption)
.
2 PARTITION COEFFICIENT (PC) Main absorption site in the intestines: Small intestine
• Generally, drugs with higher PC will have better • Because it has the largest surface area for drug
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membrane penetration than drugs with lower PC absorption in the GI tract, and its membranes are
• Pertains to lipophilicity of a drug more permeable than those in the stomach.
• More lipophilic better membrane penetration than
drugs with less lipophilicity DISTRIBUTION
PARTITION COEFFICIENT
High PC Lipophilic
• Drug movement from the site of administration to the
different tissued of the body or site of action
Low PC Lipophobic
non-polar = non-ionized • Delivery of drug via Bloodstream
3 .
DEGREE OF IONIZATION /POLARIZATION polar = ionized
• Main facilitator of distribution: Blood
• Charged or ionized frug molecules easily attracts FACTORS AFFECTING DRUG DISTRIBUTION
water, hence are bulkier (cannot easily penetrate
membrane) CARDIAC OUTPUT
• Drugs are better absorbed in unionized form • Volume of blood plumped out by the heart per minute
PHYSIOLLOGICAL FACTORS REGIONAL BLOOD FLOW
• Fraction of cardiac output delivered to the specific
DEGREE OF PERFUSION organs or tissues
• Increased gastrointestinal blood flow ensure that REGIONAL BLOOD FLOW
more drug molecules are absorbed; more drug will Highly perfused organs are • Heart
be carried to its site of action rich in blood supply • Liver
• Perfusion maintains the systemic circulation as a • Kidneys
region of lower drug concentration • Lungs
• High drug concentration to low drug concentration • Brain
Poorly perfused organs • Bones
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. Lipophilic
have limited blood supple • Adipose tissues
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5

.
6 solubility • Skeletal muscle
.
7 Presence of excipient
A .
disintegrant
B
. Binders

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Affect perfusion • Only lipid-soluble (of small particle size) drugs can
• Cardiac output penetrate and have action on the CNS.
• Regional Blood Flow • Lipophilic drugs have low MW
ENZYMATIC BBB
• do not allow catecholamines, 5HT, Ach, etc. to enter
the brain
Examples:
• MAO (Monoamine oxidase)
• Acetylcholinesterase Inhibitors
• Tolcapone
BLOOD PLACENTA BARRIER
• Drug molecules can penetrate this barrier easier
relative to BBB
• Placenta membranes allow lipid-soluble, non-
ionized drugs to readily enter the fetal bloodstream
from maternal circulation
Figure 5. Absorption – drugs will be present in systemic • That is why there are drugs that should not be given
circulation or in blood stream. Blood – is responsible in to pregnant patients because these drugs may harm
delivering the drug. Tissues – site of action. Distribution the developing fetus, we call them as
possibility: Pre-maturely metabolized, Drugs will be delivered TERATOGENIC DRUGS.
to their site of action exert their therapeutic activity then after
which the drugs will not permanently stay on their site of
actions, eventually they wll dissociate from their site of action
then will go back to the blood then deliver to oragns

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elimination.

BLOOD BRAIN BARRIER (BBB)

• Responsible for the selective entry of substances/
drugs from the blood to the extracellular fluid of the
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brain
• The capillary endothelial cells in the brain have tight
junctions and lack large intracellular pores
• Only drugs that are able to penetrate the BBB can
exert the effect of Central Nervous System. Figure 8. Blood Placenta Barrier
Pregnancy Category
X – Teratogenic drugs; Fetal abnormalities
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A – No risk to fetus; Drugs can be used

B – Adequate Human studies lacking; Drug can be used
in pregnancy
C – No human studies, human fetal risk is unknown;
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Drugs may be used in serious situation despite its

potential risk
D – Evidence of human fetal risk; May be used in serious
diseases
PLASMA PROTEIN BINDING
• Drugs possessing physiochemical affinity for plasma
proteins;
• The formation of drug-protein complex limits
Figure 6. Blood Brain Barrier distribution
3 PLASMA PROTEINS
ALBUMIN Structurally Weak acidic
non-specific drugs
ALPHA-1 ACID Structurally Weak basic
GLYCOPROTEIN non-specific drugs
GLOBULIN Structurally Hormone
specific

Albumin
• most abundant plasma protein in the body
• most probably where weak acidic drug bind to

• Only drug that is not bound to proteins can diffuse

across cell membrane
• Bound fraction is not available for action. However,
Figure 7. Capillary Cross Section it is in equilibrium with the free drug in the plasma
when the bound fraction dissociates.

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• lower affinity (i.e. Phenylbutazone displacing

Warfarin)
• The amount of free drug can be increased by
reduction of plasma protein levels (during diseased
states – liver problems).
TISSUE STORAGE
• Drugs may also accumulate in specific organs by
active transport or get bound to specific tissue
constituents (bone and adipose tissue)
• Drug sequestered in various tissues are differentially
distributed and tend to have larger volume of
distribution and long duration of action.
Figure 9. Reversible Binding of a Drug to Albumin
• Some may exert local toxicity due to high
• If a drug is bound to a plasma protein it will not exert
concentrations.
its therapeutic effect (not active)
Examples:
BOUND DRUG
• Tetracycline on bone and teeth
• If a drug will bind to a plasma protein such as
• Chloroquine in retina
albumin
• Streptomycin in vestibular apparatus
• Inactive
• Can not be excreted, biotransformed or metabolized Streptomycin
FREE DRUG • Ototoxic
• If the drug does not binf to plasma protein • Adverse Effect: Hearing Loss
• Active
• Therapeutically active METABOLISM
• Can be excreted, biotransformed or metabolized • Or Biotransformation is the chemical alteration of the

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drug in the body. (Chemical alteration for it in
excretable form)
I. Inactivation of Drugs
• To terminate biologic effects
• To render their excretable metabolites
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• To make them less toxic or non-toxic
II. Activation of Prodrugs
• Inactive parent molecules, biotransformed
Figure 10. iRetention of Protein—Bound Drug Withi the to become active or;
Vasculature • Active parent molecules, biotransformed to
• If a drug is bound to a plasma protein it can not go become active or more active (inactive to
to its biologic site of action active)
• When a drug is bound to a plasma membrane it
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• The primary site for metabolism is in the liver; others

become “bulkier” are in the kidney, intestine, lungs, and plasma
Prodrugs
• These are inactive but active when undergo
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biotransformed
•
A process in which a drug administered by mouth is
absorbed from the GIT and transported via the portal
vein to the liver, where it is metabolized. As a result,
in some cases, only a small portion of the active drug
reaches the systemic circulation
Drugs that undergo First Pass metabolism:
• Calcium Channel Blockers (CCBs)

Figure 11. Protein Binding Diagram

• If a drug is bound to plasma proteins it is not forever.
Ther would become a time when there would be less
concentration or declining concentration of drug in 3
the blood. The bound drugs will also dissociate from
the plasma proteins to become free drugs.
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Consequences:
• High degree of protein binding generally makes the
drug long-acting (because of bound fractions is not
available for either metabolism or excretion)
• Potential for drug displacement interaction: Drug
with higher affinity will displace that bound drug with Figure 12. First Pass metabolism

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• Drugs are prematurely metabolized before it goes CYP450 ENZYMES

to systemic circulation
• Liver inactivates drug
• 100% dose intake
• 15% of dose enters in bloodstream
If higher dose is needed to enter in bloodstream the dose
intake will adjust
Example:
If 15% dose is not enough for the systemic circulation they
will adjust the 100% to 185% then the dose that will enter
in bloodstream will be enough for the systemic circulation.

METABOLIZING ENZYMES
PHASES OF DRUG METABOLISM
MICROSOMAL ENZYMES • Located on the
PHASE I METABOLISM
smooth
endoplasmic • Functionalization or asynthetic reaction
reticulum primarily • Introduction of polar functional groups (replaces
on the liver, polar functional group - increase water solubility)
kidney, intestinal • Absorb – non-polar (water insoluble)
mucosa, and • Inactivate and excrete – polar (water soluble)
lungs. 1. Oxidation
• CYP450 a. Cytochrome mediated
NON-MICROSOMAL • Located in the • CYP450 enzymes are essential for the
ENSYMES cytoplasm metabolism of many drugs

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andmitochondrial • has more than 50 enzymes (6 of them
liver cells. metabolize 90% of the drugs present in
• Flavoprotein the market)
oxidase, esterase, • Genetic variability in these enzymes
amidase, and may influence patient response.
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conjugase • CYP450 enzymes can be inhibited and
induced by drugs, resulting in clinically
significant drug-drug interactions
ENZYME INHIBITION & INDUCTION OR DRUG TO thatcan cause unanticipated adverse
DRUG INTERACTION reactions or therapeutic failure – both
ENZYME INHIBITION • Inhibition or potent inhibitors and potent inducers
reduction of b. Non-cytochrome mediated
metabolizing • MAO, COMT, Acetylcholinesterase
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enzyme activity • Alcohol and aldehyde dehydrogenase

• Enzyme inhibitor + 2. Reduction
Object Drug • Nitroreduction
• If the object drug • Carbonyl reduction
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is:
• Azo reduction
(1) Prodrug → ___ biologic
3. Hydrolysis
effect
• Hydrolysis of ester bonds
(2) Active Drug → ___
PHASE II METABOLISM
biologic effect
• Conjugation or synthetic reactions
ENZYME INDUCTION • Enhancement of
• Conjugation of large polar groups – add large
metabolizing
polar groups (total loss of biologic activity; high
enzyme activity
polarity - excreted)
• Enzyme inducer +
(1). Glucuronidation
Object Drug
(2). Acetylation
• If the object drug (3). Glycine conjugation
is: (4). Methylation
(1) Prodrug → ___ biologic (5). Sulfate conjugation
effect EXCRETION
(2) Active Drug → ___
• Removal of a drug (or its metabolite) from the body
biologic effect
• Elimination is a collective term for the processes of
Example: drug metabolism and excretion
Enzyme Inhibitors: Drug and their metabolites are excreted via:
• Cimetidine (enzyme inhibitor) + Carvedilol (will A. Urine
not metabolized; consequence: high biologic • Through the kidney; is the most important
effects/intensified action) channel of excretion for majority of drugs
Enzyme Induction • Responsible for excreting all water-soluble
• Phenobarbital (enzyme inducer) + Glipizide substances
(faster metabolized; consequence: low biologic effect) Major Processes:
1. Glomerular filtration
2. Active tubular secretion

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3. Tubular reabsorption
*Net renal excretion = (1+2)-3

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Figure 13. Urine
pH Dependence of Renal Excretion
• pH affects ionization and therefore also affects the
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polarity of a drug.
• Weak acids in alkaline urine
• Weak bases in acidic urine
Weakly acidic (Drug) + Alkaline → enhance excretion
Acid + Base = Promote ionized → polar
Example:
Metamphetamine + Acidic urine → enhance excretion
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• Metamphetamine – weakly basic (amine –

basic)
• Acidic urine – Urinary acidifiers (e.g. NH4Cl)
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B. Feces or Biliary excretion

• Apart from the unabsorbed fraction, most of the drug
present in feces is derived from bile
C. Exhaled air
• Gases and volatile liquids are eliminated through the
lungs, irrespective of their solubility
D. Saliva and Sweat
E. Breast Milk
• Most drug enter the breast milk via passive
diffusion (contraindicated to nursing mothers)
Reference(s):
APA Format
Handout & Discussion: Sir Christopherson P. Mata
RPhMSPharm©2021

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