Chapter 1 Introduction

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Chapter 1 Introduction
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What is Pharmacology
From the Greek pharmakon (drug), logos (study)
Pharmacology is the science that deals with the
mechanisms of action, uses, adverse effects and
fate of drugs in animals and humans
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Definition of drug

• Substance that when taken into living organism
  brings about a change in biologic function
  through its chemical actions.
• Activation
• Inhibition

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Properties of an ideal drug

• Safety
• Fewer side effects or lower toxicity
• Effectiveness
• Better therapeutic effects
• Selectivity
• Target to desired sites or molecules

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Names of drug

• Each drug has at least three names
• Chemical
• Description of the drug using chemical
  nomenclature
• Generic
• Non-proprietary name
• Simpler than chemical name
• Trade
• Proprietary or brand names
• Created by companies to sell drugs

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Principles of Drug Action

• Drugs do not produce new function
• No drug has a single action
• have both therapeutic and adverse actions
• Or have multiple therapeutic effects
• Drug vs poison
• dose related

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Principles of Drug Action

• Therapeutic actions are interchangeable
• Actions can be considered therapeutic in one
  case and adverse in another
• e.g. viagra

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Principles of Drug Action
Drugs effects are variable?

• It depends
• Many sources of variability
• Disease state, age and sex
• route of drug administration, dose, drug
  interactions
• Deciding to use a drug
• weigh benefits vs. risks
• there are always risks

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Pharmacology deals with two aspects
what the drug does to the body drug action/effect
what the body does to the drug metabolism
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Introduction to Pharmacology-I

• Drug administration and absorption

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Pharmacokinetics
Locus of actionreceptorsBound Free
TissuereservoirsBound Free
Systemiccirculation
Absorption
Excretion
Free drug
Bound drug
Metabolites
Biotransformation
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Pharmacokinetic Process-ADME

• Absorption
• Distribution
• Metabolism
• Excretion
• It is also called ADME process
• Elimination is the sum of M and E

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Drug administration

• Route and form in which drug is delivered to body

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Oral administration-most common route

• Governed by
• surface area for absorption, blood flow, physical
  state of drug, concentration.
• occurs via passive process.
• In theory weak acids optimally absorbed in
  stomach, weak bases in intestine.
• In reality the overall rate of absorption of
  drugs is always greater in the intestine

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Subject to First Pass Effect

• pass through liver before reaching circulation
• undergo metabolism by liver

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Rate of Appearance in Blood

• Dependent on rate of dissolution
• Rate of absorption from GI tract
• timed release
• dissolve at different rates
• what about crushing?

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• enteric coating
• dissolve in alkaline fluid
• what about crushing?

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Forms of Oral Drugs

• liquids syrups, elixirs
• suspensions
• powders
• pills capsules, tablets

Fastest Slowest
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Buccal/Sublingual

• absorbed though oral mucus membranes in mouth
• buccal cheek

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Buccal/Sublingual

• sublingual (SL) under tongue

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Sublingual Administration

• Absorption from the oral mucosa has special
  significance for certain drugs despite the small
  surface area.Nitroglycerin - nonionic, very
  lipid soluble.Because of venous drainage into
  the superior vena cava, this route protects it
  from first-pass liver metabolism.

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Parenteral

• Route other than alimentary canal
• intradermal (ID)
• subcutaneous (SC or SQ)
• intramuscular (IM)
• intravenous (IV)
• How quick is onset?

Slow
Fast
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Parenteral

• Intravenous (IV)
• directly into vein
• rapid onset of drug actions
• Fastest

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Intramuscular

• Rapid rate of absorption from aqueous solution,
  depending on the muscle.
• Perfusion of particular muscle influences the
  rate of absorption gluteus vs. deltoid.
• Slow constant absorption of drug when injected
  in an oil solution or suspension.

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Subcutaneous

• Slow and constant absorption.
• Slow-release pellet may be implanted.
• Drug must not be irritating.

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Topical on the skin

• not absorbed in appreciable amounts
• have local effects(keep in mind large surface
  area)
• absorbed
• transdermal usually slowly over a day

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Example not absorbed
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Example absorbed
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Example Nitroglycerin

• Onset
• .. immediate
• . . 1-3 min
• . 40-60 min

• Route
• IV
• SL
• Transdermal

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Inhalation

• systemic drugs intended to absorbed into blood

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Inhalation

• local drugs designed to act on lung tissue

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Intraarterial Administration

• Occasionally a drug is injected directly into an
  artery to localize its effect to a particular
  organ, e.g., for liver tumors, head/neck cancers.
  
• Requires great care and should be reserved for
  experts.

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Intrathecal

• Necessary if the blood-brain barrier and
  blood-CSF barrier impede entrance into the CNS.
  Used for local or rapid effects of drugs on the
  meninges or cerebrospinal axis, as in spinal
  anesthesia or acute CNS infections.

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Rectal/Vaginal

• Suppositories
• Vaginal usually not absorbed

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Rectal/Vaginal

• Rectal absorbed
• May be useful when oral administration is
  precluded by vomiting or when the patient is
  unconscious.
• some first pass effect,
• approximately 50 of
• the drug that is
• absorbed from the
• rectum will bypass
• the liver.

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Choice of route of drug administration

• Consider factors
• Concentration in blood
• Rapidity of onset
• Duration of effects
• Magnitude of effects
• Amount delivered
• Patient characteristics

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Absorption

• Process of drug leaving site of administration

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Important Properties AffectingDrug Absorption

• Chemical properties
• acid or base
• degree of ionization
• polarity
• molecular weight
• lipid solubility or...
• partition coefficient

• Physiologic variables
• gastric motility
• pH at the absorption site
• area of absorbing surface
• blood flow
• Pre-systemic elimination
• ingestion w/wo food

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Absorption

• Influenced by
• size thickness of absorbing surface
• GI tract
• large with single cell layer
• small bowel gt large bowel

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Surface

• Lung
• Large with single cell layer
• Mucus membranes
• Surface small with multiple cell layers
• Skin
• Surface large with multiple cell layers

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Surface

• blood supply to surface
• GI, lung, mucus membranes
• good blood supply
• skin variable

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Factors Influencing Absorption

• interaction of drug with surface characteristics
• e.g. skin
• low in water and lipid

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Factors Influencing Absorption

• amount of time in contact with surface
• concentration gradient

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Physicochemical Factors In Transfer of Drugs
Across Membranes

• Cell Membranes
• Passive Properties
• Carrier-Mediated Transport

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Cell Membranes
The character of biological membrane
Be composed of phospholipids and
proteins -----lipid soluble molecule can cross it
easily Has aqueous channel -----water and liquid
soluble molecule with little molecule weight can
cross it easily
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Membranes and Absorption
Lipid Bilayer
Small, uncharged
H2O, urea, CO2, O2, N2
Swoosh!
Large, uncharged
Glucose Sucrose
DENIED!
Small charged ions
H, Na, K, Ca2, Cl-, HCO3-
DENIED!
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Passive difusion

• Passive diffusion depends on movement down a
  concentration gradient.

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1. Aqueous diffusion

• Water-soluble, small molecular mass drugs
• The force of it is the liquid static pressure or
  osmotic pressure across the membrane
• Through aqueous channels

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Molecular Size

• In general, smaller molecules diffuse more
  readily across membranes than larger ones
  (because the diffusion coefficient is inversely
  related to the sq. root of the MW). This applies
  to passive diffusion but NOT to specialized
  transport mechanisms (active transport,
  pinocytosis).
• tight junction MW lt200 for diffusion.
• large fenestrations in capillaries MW 20K-30K.

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2. Lipid diffusion

• The lipid-soluble drug molecule penetrates along
  a concentration gradient by virtue of its
  solubility in the lipid membrane

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Lipid-SolubilityOilWater Partition Coefficient

• The greater the partition coefficient, the
  higher the lipid-solubility of the drug, and the
  greater its diffusion across membranes.A
  non-ionizable compound (or the non-ionized form
  of an acid or a base) will reach an equilibrium
  across the membrane that is proportional to its
  concentration gradient.

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Absorbed fromstomach in1 hour( of dose)
50
580
40
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30
20
1
10
Other things (MW, pKa) being equal, absorption
of these drugs is proportional to lipid
solubility.
0
barbital(pKa 7.8)
secobarbital(pKa 7.9)
thiopental(pKa 7.6)
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3. Inization

• Most drugs are small (MW lt 1000) weak
  electrolytes (acids/bases). This influences
  passive diffusion since cell membranes are
  hydrophobic lipid bilayers that are much more
  permeable to the non-ionized forms of drugs.The
  fraction of drug that is non-ionized depends on
  its pKa, and the local biophase pH...

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• ionized polar water-soluble
• non-ionized less polar more lipid-soluble
• Think of an acid as having a carboxyl COOH /
  COO_
• Think of a base as having an amino NH3 / NH2
• For both acids and bases, pKa acid
  dissociation constant, the pH at which 50 of the
  molecules are ionized.
• Exampleweak acid aspirin (pKa 3.5)
• weak base morphine (pKa 8.0)

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Weak acid
Weak base
H
extracellular pH
H
BH
B
A-
HA
B
BH
HA
A-
intracellular pH
H
H
The pH on each side of the membrane determines
the equilibrium on each side
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A Useful Concept...

• Drugs tend to exist in the ionized form when
  exposed to their pH-opposite chemical
  environment.
• Acids are increasingly ionized with increasing pH
  (basic environment), whereas
• Bases are increasingly ionized with decreasing pH
  (acidic environment).

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basediazepam (3.3)chlordiazepaxide
(4.8)triamterene (6.1)cimetidine
(6.8)morphine (8.0)amantadine (10.1)
HB
acidcromolyn sodium (2.0)furosemide
(3.9)sulfamethoxazole (6.0)phenobarbital
(7.4)phenytoin (8.3)chlorthalidone (9.4)
HA
pH2467.4810
B
A-
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• Henderson-Hasselbalch Eqn.
• protonated log
  pKa - pH
• unprotonated

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Problem What percentage of phenobarbital (weak
acid, pKa 7.4)exists in the ionized form in
urine at pH 6.4?
take antilog of 1 to get the ratio between
non-ionized (HA) and ionized (A-) forms of the
drug
pKa - pH 7.4 - 6.4 1
antilog of 1 10
if pH pKa then HA A- if pH lt pKa, acid form
(HA) will always predominateif pH gt pKa, the
basic form (A-) will always predominate
Ratio of HA/A- 10/1 ionized A- / A-
HA X100 1 / (1 10) X 100 9 ionized
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Problem What percentage of cocaine (weak base,
pKa 8 .5)exists in the non-ionized form in the
stomach at pH 2.5?
pKa - pH 8.5 - 2.5 6
take antilog of 6 to get the ratio between
ionized (BH) and non-ionized (B) formsof the
drug
antilog of 6 1,000,000
if pH pKa then BH B if pH lt pKa, acid form
(BH) will always predominateif pH gt pKa, the
basic form (B) will always predominate
Ratio of BH/B 1,000,000/1 non-ionized
B/ (B BH) X100 1 X 10-4
non-ionized or 0.0001
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Moral of the story...

• Acidic drugs are best absorbed from acidic
  environments

Basic drugs are best absorbed from basic
environments
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Other aspects.

• amphetamine (weak base, pKa 10)
• its actions can be prolonged by ingesting
  bicarbonate to alkalinize the urine...
• this will increase the fraction of amphetamine in
  non-ionized form, which is readily reabsorbed
  across the luminal surface of the kidney
  nephron...
• in overdose, you may acidify the urine to
  increase kidney clearance of amphetamine.

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• Certain compounds may exist as strong
  electrolytes. This means they are ionized at all
  body pH values. They are poorly lipid soluble.
• Ex
• strong acid glucuronic acid derivatives of
  drugs.
• strong base quarternary ammonium compounds
  such as acetylcholine.

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Membrane Transfer
Passive diffusion
endocytosis
carrier-mediated
active
passive
ATP
ADP-Pi
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Special carriers

• Substances that are important for cell function
  and too large or too insoluble in lipid to
  diffuse passively through membranes, eg,
  peptides, amino acids, glucose.
• These kind of transport, unlike passive
  diffusion, is saturable and inhibitable.

• Active transport is characterized by a
  requirement for energy
• Facilitated diffusion needs no energy

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Special carriers

• Carrier-mediated transport is important for some
  drugs that are chemically related to endogenous
  substances
• The transporter proteins also mediate drug efflux
• P-glycoprotein /MDR1
• MRP transporters
• Function as a barrier system
• to protect cells

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P-glycoprotein
Epithelial cell in GI tract

• GI tract limit the absorption
• Kidney promote the renal excretion
• Liver promote the biliary excretion
• Brain limit entry to brain

Function as a barrier system to protect cells
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Facilitated Diffusion

• This is a carrier-mediated process that does NOT
  require energy. In this process, movement of the
  substance can NOT be against its concentration
  gradient.Necessary for the transport of
  endogenous compounds whose rate of movement
  across membranes by simple diffusion would be too
  slow.

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Active Transport

• Occurrence- neuronal membranes, choroid plexus,
  renal tubule cells, hepatocytes
• Characteristics
• - carrier-mediated- selectivity-
  competitive inhibition by congeners- energy
  requirement- saturable- movement against
  concentration gradient
• differences from facilitated diffusion

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Endocytosis, Exocytosis, Internalization

• Endocytosis (or pinocytosis) a portion of the
  plasma membrane invaginates and then pinches off
  from the surface to form an intracellular
  vesicle.
• Ex This is the mechanism by which thyroid
  follicular cells, in response to TSH, take up
  thyroglobulin (MW gt 500,000).