The Basics of Pharmacokinetics and Pharmacodynamics

1. INTRODUCTION TO PHARMACOLOGY
(PHARMACOKINETICS AND
PHARMACODYNAMICS)
TAHIR ALBASHIR
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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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 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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NOTE:
All these reactions are to convert the drug from
lipid soluble (nonpolar, unionized ) to more water
soluble (polar, ionized).

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Factors Affecting Drug Metabolism
 Age
 Sex
 Genetic variation
 Drugs
 Disease

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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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17. PHARMACODYNAMICS
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 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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 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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Receptor Agonist Antagonist
Adenoceptors Epinephrine (β and α)
Phenylephrine (α1)
Salbutamol (β2)
Atenolol (β1)
Prazosin (α1)
Phentolamine (α)
Cholinoceptors Acetylcholine (M & N)
Carbachol (M & N)
Nicotine (N)
Atropine (M)
Scopolamine (M)
Tubocurarine (N)
H-receptors - Promethazine (H1)
Cimetidine (H2)
Opioid receptors Morphine, Heroin
Codeine
Naloxone, Naltrexone
5-HT receptors Buspirone (5-HT1A)
Triptans (5-HT1B & 5-HT1D)
Ketanserin,
Oandansetron
D-Receptors Bromocriptine
Pramipexole
Chlorpromazine
Fluphenazine

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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)

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Enzyme Inhibitors (Drugs)
Acetylcholinesterase Neostigmine, Physostigmine
Dihydrofolate reductase Trimethoprim, Methotrexate
Cyclooxygenase (COX) Aspirin, ibuprofen
Angiotensin converting
enzyme
Captopril, enalapril

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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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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Transporter Ligand Drug
SERT Serotonin Fluoxetine
Paroxetine
Na-Cl-K
symporter
Na
Cl
Furosemid
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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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34. THANK YOU
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