2. PHARMACOKINETICS
PK refers to what body does to drug(s) when
administered, i.e. effect of the body on the drug
In other words, it is the kinetics (movement) of
drugs in the body
Consists of four (4) processes
Absorption
Distribution
Metabolism
Excretion
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3. ABSORPTION
Defined as the movement of drug from the site
of administration to the bloodstream
Sites of drug absorption include stomach, small
and large intestines, alveolar surface, skin
The rate and extent of absorption depend on
Environment where the drug is absorbed
Chemical characteristics of the drug, and
Route of administration (which influences
bioavailability)
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4. Mechanisms of Drug Absorption
Simple (Passive) diffusion
From high concentration to low concentration
(along concentration gradient)
Energy and carrier not needed
The driving force is the concentration gradient
Majority of drugs are absorbed by this mechanism
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5. Facilitated diffusion
From high conc. to low concentration (along
concentration gradient)
No energy is needed
Carrier proteins are required
They facilitate the passage or large molecules
These carrier proteins undergo conformational changes,
allowing the passage of drugs into the cell
Transport may be inhibited by compounds that compete
for the same carrier proteins
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6. Active transport
From low concentration to high concentration
(against concentration gradient)
Need specific carrier proteins
Need energy
Endocytosis and Exocytosis
These transport drugs with exceptionally large size
across the cell membrane
Endocytosis: engulfment of drugs by the cell
membrane and transport into the cell by pinching
off the drug-filled vesicle
Exocytosis: is the reverse of endocytosis
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7. Factors Affecting Absorption
Patient-related factors
Routes of administration
Total surface area available for absorption
Increase surface area → increase absorption
Blood flow to the absorption site
Increase blood flow → increase absorption
Contact time at the absorption site
Increase contact time → increase absorption
Presence of other drugs
Ca2+ (from milk) → decrease absorption of tetracycline
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8. Factors Affecting Absorption…
Drug-related factors
Disintegration and dissolution time
Lipid solubility
High lipid soluble drugs → high absorption
Ionization
Unionized drugs → high absorption
Valency
Ferrous iron (Fe2+) absorbed more than ferric iron (Fe3+)
Dosage forms
Solution > suspension > tablet
pH of the medium and pKa of the drug
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9. DISTRIBUTION
Is the transfer of drugs from the bloodstream
into the tissues
The distribution of drugs depends on:
Blood flow
Capillary permeability
Binding of drugs to plasma proteins
Lipophilicity
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10. 10
The conversion of drug from nonpolar (lipid-
soluble) compounds to polar (lipid insoluble) so
that they can be easily excreted
The primary site for drug metabolism is liver;
others are kidney, intestine, lungs and plasma
Objectives
Activation of pro-drugs.
Inactivation and elimination of drugs
METABOLISM
(Biotransformation)
11. Classification
Nonsynthetic/Phase I reactions
Converts lipophilic drugs into more polar molecules
by introducing or unmasking a polar functional
group such as –OH or –NH2
Involves
Oxidation
Reduction
Hydrolysis
Metabolites could be less active, more active or even
toxic
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12. Synthetic/Conjugation/Phase II reactions
This phase consists of conjugation reactions
If the metabolite from phase I metabolism is
sufficiently polar, it can be excreted by the kidneys
However, many phase I metabolites are still too
lipophilic to be excreted
A subsequent conjugation reaction with an
endogenous substrate, such as glucuronic acid,
sulphuric acid, acetic acid, or an amino acid, results
in polar, usually more water-soluble compounds that
are often therapeutically inactive.
Conjugation reactions have high energy requirement
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13. 13
NOTE:
All these reactions are to convert the drug from
lipid soluble (nonpolar, unionized ) to more water
soluble (polar, ionized).
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Drug Excretion
• Process by which drugs and/or metabolites are
irreversibly transferred to the external environ
• Most drugs are excreted in urine either as
unchanged drugs and/or drug metabolites
• Primarily in the kidneys but also takes place in
lungs, biliary system, GIT & skin
16. Types of Excretion
Renal Excretion
Via the kidney
Primary route of drug excretion
Non-renal Excretion
Other routes outside kidney
Biliary excretion
Pulmonary excretion
Salivary excretion
Mammary excretion
Dermal excretion
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18. 18
Pharmacodynamics is the study of drug effects.
It starts with describing what the drugs do, and
goes on to explain how they do it.
Thus, it attempts to elucidate the complete
action-effect sequence and the dose-effect
relationship.
It provides fundamental insights into
biochemical and physiological regulation.
Modification of the action of one drug by
another drug is also an aspect of
pharmacodynamics.
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PRINCIPLES OF DRUG ACTION
Drugs (except those gene based) do not impart
new functions to any system, organ or cell; they
only alter the pace of on going activity
However, this alone can have profound
medicinal as well as toxicological impact.
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The basic types of drug action can be broadly
classed as:
Stimulation: It refers to selective enhancement
of the level of activity of specialized cells, e.g.
adrenaline stimulates heart.
Depression: It means selective diminution of
activity of specialized cells, e.g. omeprazole
depresses gastric acid secretion.
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Replacement: This refers to the use of natural
metabolites, hormones or their congeners in
deficiency states, e.g. insulin in diabetes mellitus,
iron in anaemia.
Cytotoxic action: Selective cytotoxic action on
invading parasites or cancer cells, attenuating
them without significantly affecting the host
cells is utilized for cure/palliation of infections
and neoplasms.
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Majority of drugs produce their effects by
interacting with a discrete target biomolecule,
which usually is a protein.
Such mechanism confers selectivity of action to
the drug.
Functional proteins that are targets of drug
action can be grouped into four major
categories, viz. receptors, enzymes, ion channels
and transporters.
MECHANISM OF DRUG ACTION
23. RECEPTORS
Macromolecules that serve to recognize the
signal molecule/drug and initiate the response to
it, but itself has no other function.
May be cell surface or nuclear receptors
Usually protein in nature, specific and have
affinity
Receptors serve two essential functions, viz,
recognition of the specific ligand molecule and
transduction of the signal into a response.
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24. 24
The following terms are used in describing drug-
receptor interaction:
Agonist: An agent which activates a receptor to
produce an effect similar to that of the
physiological signal molecule.
Partial agonist: An agent which activates a
receptor to produce submaximal effect but
antagonizes the action of a full agonist.
Drug – Receptor Interactions
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Inverse agonist: An agent which activates a
receptor to produce an effect in the opposite
direction to that of the agonist.
Antagonist: An agent which prevents the action
of an agonist on a receptor or the subsequent
response, but does not have any effect of its
own.
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ENZYMES
Common drug target, next to receptors
Enzymes are involve in biosynthesis
Some drugs bind to enzymes and inhibit their
activities.
Loss of product due to the inhibition mediates
the effects of the drug
Few drugs also activate enzymes
Nitroglycerin (Guanylyl cyclase)
Pralidoxime (cholinesterase)
29. ION CHANNELS
Proteins which act as ion selective channels
participate in transmembrane signalling and
regulate intracellular ionic composition
Thus, certain drugs modulate opening and
closing of the channels
This makes them a common target of drug
action
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30. 30
Channel Drug
Ca channel blocker Verapamil
Amlodipine
Diltiazem
Na channel blocker Lidocaine
Amiodarone
K Channel activator Minoxidil
Cl channel activator Alprazolam
31. TRANSPORTERS
Several substrates are translocated across
membranes by binding to specific transporters
(carriers) which either facilitate diffusion in the
direction of the concentration gradient or pump
the metabolite/ion against the concentration
gradient
Many drugs produce their action by directly
interacting with the solute carrier (SLC) class of
transporter proteins to inhibit the on going
physiological transport of the metabolite/ion.
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33. Unconventional Mechanisms
Being nutrients e.g. vitamins and minerals
Being antigens e.g. vaccines
Being Enzymes e.g. streptokinase for
thrombolysis
Reacting chemically with small molecules e.g.
antacids
Disruption of structural proteins e.g. vinca
alkaloids for cancer, colchicine for gout.
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Flake A small fragment of something broken off from the whole
Histamine neurotransmitter released by the human immune system during allergic reactions, it cusses dilatation of capillaries and contraction of smooth muscles.
Leukotrienes chemical produced by the body that accompanies inflammation and causes symptom of asthma
Hypertrophy Abnormal enlargement of a body part or organ
Releasing or activated by acetylcholine or a related compound
Cholinergic Releasing or activated by acetylcholine or a related compound
Corticosteroids A steroid hormone produced by the adrenal cortex or synthesized; administered as drugs they reduce swelling and decrease the body's immune response
Corticosteroids A steroid hormone produced by the adrenal cortex or synthesized; administered as drugs they reduce swelling and decrease the body's immune response
Corticosteroids A steroid hormone produced by the adrenal cortex or synthesized; administered as drugs they reduce swelling and decrease the body's immune response