Download Introduction 2 pharma

Introduction
Pharmacology is the science that deals with the
study of therapeutic agents.
What is Pharmacology ?
Pharmacokinetics
Pharmacodynamics
What the body does to drug
What the drug does to body
Pharmacology
Pharmacotherapeutics
The study of the use of drugs
Pharmacocognosy
Identifying crude materials as drugs
Toxicology
Major areas of pharmacology:
• pharmacodynamics: study of the action of drugs on
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living tissue. WHAT DRUG DOES TO BODY.
pharmacokinetics: study of the process of drug
absorption, distribution, metabolism, and excretion.
WHAT BODY DOES TO DRUG.
pharmacotherapeutics: study of the use of drugs in
the treatment of disease
pharmacy: science of preparing and dispensing
medication
posology: study of the amount of drug required to
produce therapeutic effects
toxicology: study of the harmful effects of drugs on
living tissue
How Do We Study
Pharmacology?
Drug
• general definition: Chemical substance that can cause a
change in function when administered to a living organism
• pharmacologically: any medication that is used in treating
a disease or disorder
General Concepts
Drug Dose
Administration
Pharmaceutical
Pharmacokinetics
Pharmacodynamics
Pharmacotherapeutics
Disintegration
of Drug
Absorption/distribution
metabolism/excretion
Drug/Receptor
Interaction
Drug Effect
or Response
How are Drugs Administered?
Routes of Drug Delivery
Parenteral
(IV)
Inhaled
Oral
Transdermal
Topical
Parenteral
(SC, IM)
Rectal
Routes of Administration
• Critical to efficacy
– Rapidity of onset
– Duration of effects
– Magnitude of effects
• Systemic administration
– Drug into circulatory system via ...
• Enteral routes
• Parenteral routes
– Drug effects throughout body ~
Routes of Drug Administration
Enteral
within or by way of the GI tract
Oral (PO), rectal, sublingual
Parenteral
Not within the alimentary canal
Inhalation, IM, SC, IP, topical
Central
Into the brain or spinal cord
Intrathecal, ICV
Routes of Drug Administration
common abbreviations…
PO = per os = oral
IV = intravenous = into the vein
IM = intramuscular = into the muscle
SC = subcutaneous = between the skin and muscle
IP = intraperitoneal = within the peritoneal cavity
icv = intracerebroventricular =
directly into the ventricle of the brain
Oral
• Per Os (PO)
• by mouth
– absorption across
membrane in GI
– most common
– most variable
– 1st pass metabolism
• Cooperation required
• Can recall ~
Oral
• Sublingual
– Absorption:
• mucous membrane
• salivary glands
– e.g., nitroglycerin,
buprenorphine
• Chewing
– absorbed across lining
of mouth ~
Injection
• Intravenous (iv)
– directly into vein
– rapid onset of effects
• Fastest
• Intramuscular (im)
• Location important
– Deltoid - rapid
– Thigh - moderate
– Buttocks - slowest
– Difference in blood supply & distance
Routes of Drug Administration and
Absorption.
• Injecting
(Intravenous):
– Puts drugs
directly into a
vein
– Put drugs into
muscles or under
skin
Intravenous (IV)
Intramuscular (IM)
Subcutaneous
15 – 30 seconds
3 – 5 minutes
3 – 5 minutes
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Inc.
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Injection
• Subcutaneous (sc)
– under skin
– slow, steady absorption
• Disadvantages
– Variable absorption
– limited volume
– skin irritations ~
Routes of Drug Administration and
Absorption
or Transdermal
Contact
Absorption
Absorption through the
skin is the slowest
method of drug use. It
often takes 1–2 days
for effects to begin and
the absorption can
continue for about 7
days. Nicotine,
fentanyl, and heart
medications can also
be absorbed this way
Skin creams & ointments
absorbed through skin
Contact or
Transdermal:
1 to 2 days
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•
Routes of Drug Administration and
Snorting &
Absorption
Mucosal Exposure:
– Drugs can be
snorted and
absorbed through
capillaries in the
nasal passages or
placed on mucosal
tissues in the gums,
cheeks, or even
rectum and
absorbed.
• Cocaine snorter’s nose
showing how cocaine
ate a hole through the
nasal septum
separating the nostrils.
Snorting or Mucosal Exposure: 3 to 5 minutes
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Inc.
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Injection
• Intrathecal
– under sheath of nerve fibers,
spinal
cord, or brain
• Mostly as local anesthesia
– little importance for most psychoactive
drugs ~
Other routes
• Transdermal patches
– absorbed by skin
– slow continuous release
• also liposomes: via injection
• Suppositories - rectal or vaginal
– absorption incomplete & unpredictable
• Pellets - Norplant
• Microcatheter & pump ~
Routes of Drug Administration and Absorption.
• Inhaling:
– Allows the vaporized
drug to enter the
lungs, the heart and
then the brain in
about 7-10 seconds
(Most rapid)
Inhaling: 7 to 10 seconds
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Inc.
3
(Pictures)
• Marijuana inhaling tent used by
the Scythians, c. 500 B.C.
• Man in India smokes ganja
(marijuana) in a “chillum” pipe.
Copyright, 2004, CNS Productions,
Inc.
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Every drug produces three effects
• Therapeutic effect - intended
• Side effects - not necessarily harmful
– secondary indication for use
– undesired side effects
• Adverse effects
– may be harmful
– with prolonged use may effect function of vital organs,
e.g. liver and kidneys
– reduction of dosage or switching to other drug may
minimize harmful consequences
• Toxic effects - all drugs will act as poison when taken in excess
– implies drug poisoning
– can be extremely harmful, sometimes even life
threatening
Concepts applicable to any drug
• Site of action - unknown for some drugs but determined
for most
• Mechanism of Action - how the drug produces effects ex
cocaine
• Receptor site - specific location on certain cells - similar to a
lock and key concept
• Agonists and antagonists
– chemical substances that alter a drugs action
• facilitate -- agonist
• interfere with --- antagonist
Agonist vs. Antagonist
Agonist
Antagonist
Receptor
Receptor
Activated receptor
Inactivate receptor
What Happens After Drug
Administration?
Drug at site
of administration
1. Absorption
Drug in plasma
2. Distribution
3. Metabolism
Drug/metabolites
in urine, feces, bile
4. Elimination
Sources of Drugs
Pharmacognosy
Animals
Plants
Minerals
Synthetic
Microbes
Many of these old sources are
still in use today
• Foxglove plant
• Meadow flower
Colchicum autumnale
• Beef or pork pancreas
• Digitalis comes from the
foxglove plant and is used
in the treatment of CHF
• Colchicine is the drug of
choice for treatment of
gout
• Insulin is used today to
treat diabetes and is
derived from the
pancreas of beef or pork
or may be synthetically
produced as well.
Drugs Derived from Plants
• Ephedrine is present in the leaves of a bushy shrub
(species name Ephedra), which, when burned were
used by the ancient Chinese to treat respiratory
ailments. Today, it is a bronchodilator.
• Many estrogen hormone replacement therapy drugs
are derived from yams.
• The belladonna plant – source of atropine, which is
still used to dilate the pupils.
Pharmacokinetics
Pharmacokinetics is the study of the behavior and time
course of the following features of a drug:
· Administration
When the drug is given
· Absorption
· When the drug is taken up by the body
· Distribution
· When the drug spreads through the body
· Metabolism & Elimination
· When the drug is removed from the body
Factors Affecting Drug
Absorption
ATP
• Transport
– active vs. passive
• pH
• Physical factors
– blood flow
– surface area
– contact time
ADP
+ Pi
ABH+
• Oral administration
• The most common route of systemic
administration
• A disadvantage of oral administration is that all
blood from the gut must pass via the portal vein
through the liver first.
• The liver metabolizes many drugs and so they are
inactivated before entering the systemic
circulation.
• This is the first pass effect.
Drug absorption
• In order for a drug to be absorbed, it must be able to
pass through cell membranes (which is a lipid barrier).
• Lipid soluble drugs would be ideal to pass through the
membrane easily, but not all drugs can be lipid soluble
to a great extent.
ways drugs can be absorbed:
• 1. Lipid diffusion
• 2. Aqueous diffusion
• 3. Facilitated diffusion/active transport
• Lipid diffusion
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Highly lipid soluble drugs are able to pass
across cell membranes quite easily.
• The movement is driven by passive diffusion
down a concentration gradient.
• Aqueous diffusion
• special protein channels designed for the
movement of water into and out of cells. Drugs
which are small and easily dissolved in solution
will be able to pass through the cell membrane
via this route, in conjunction with water which
naturally diffuses.
Active transport
All cells have specialized transport systems and
channels which allow the active (requiring
energy) uptake of materials from the ECF into
the cell.
Features of drugs which affect their
absorption
• Molecular weight
Drugs with a small size are absorbed well
• Chemical and enzymatic stability
The drug must be able to withstand the acid conditions in the
stomach and also the gut enzymes. E.g. Penicillin G ( b
lactam antibiotic) is highly acid labile, which means that it
is not stable to acid.
• pH and lipid solubility
• Most drugs are either weak acids or weak bases and can
exist in either the ionised (less lipid soluble) or unionised.
• If an acid drug lives in an acid environment, then the
proton which it has (the H+) will be retained and it will
exist preferably in its unionised form.
• If a basic drug lives in a basic environment, then it will
not want to accept a H+ and so it will exist preferably in
its unionised form
• REMEMBER THAT A DRUG IS ABSORBED BETTER
IN THE UNIONISED FORM
• e.g. Aspirin is an acidic drug. In the stomach, the pH is from 1 - 3,
which means that it is an acidic environment. Hence most of the
drug will exist in the uinionised form and be better at passing
through the lipid membranes (i.e. better absorbed)
• Most drugs are weak organic acids or bases, existing
in un-ionized and ionized forms in an aqueous
environment.
• The un-ionized form is usually lipid soluble and
diffuses readily across cell membranes.
• The ionized form cannot penetrate the cell membrane
easily because of its low lipid solubility and high
electrical resistance, resulting from its charge and the
charged groups on the cell membrane surface.
• Thus, drug penetration may be attributed mostly to
the un-ionized form.
• Bioavailabilty
• The amount of drug reaching its site of action
• If a drug is administered intravenously, then
the bioavailability will be 100%
– Fraction of a drug
that reaches systemic
circulation after a
particular route of
admin’n
• Affected by:
Serum Concentration
• Def’n:
An Important Concept:
BIOAVAILABIITY
Injected Dose
– 1st pass metabolism
(eg: Lidocaine,
propranolol)
– Solubility
– Instability
Oral Dose
(eg: Penicillin G,
insulin
If a drug
is )administered intravenously, then the bioavailability
Time
will be 100%
Drug Metabolism
• First pass
– metabolism of drugs may occur as they
cross the intestine or transit the liver
• eg: nitroglycerin
• Other drugs may be destroyed before
absorption
• eg: penicillin
Volume of Drug Distribution
• Drugs may distribute into
any or all of the following
compartments:
– Plasma
– Interstitial Fluid
– Intracellular Fluid
Plasma
(4 litres)
Interstitial Fluid
(10 litres)
Intracellular Fluid
(28 litres)
Serum Concentration
• It takes time for a drug to distribute in the body
• Drug distribution is affected by elimination
1.5
Drug is not eliminated
1.0
Elimination Phase
0.5
Distribution Phase
0
0
Time
Drug is eliminated
• Volume of distribution
• “Volume of body water in which a drug appears to be
dissolved in after it has distributed throughout the
body”
Vd =
X
C
amount of drug in whole body
concentration in plasma
• Apparent volume of the distribution of a drug
can be estimated by dividing the amt of the
drug in the body by the plasma concentration
of the drug.
• Half –Life of a drug is the time
required for the amt of drug in
the plasma to decrease to 50% of
the level determined at an earlier
time.
• This is a reflection of the rate of clearance and
the rate of metabolism of the drug.
• It mainly depends on the volume of the
distribution and the clearance rate.
• The half-life of a drug can be determined using the
following equation:
• t1/2 = (0.693 x Vd)/CL
• In the simplest cases, the half-life does not
change with dose (this is always true for
first-order elimination).
• first-order kinetics, which implies that a constant
fraction of drug is eliminated per unit time, so that
drug elimination is dependent on the plasma
concentration.
• Few drugs exhibiting zero-order kinetics, also
known as saturation kinetics. This means that a
constant amount of drug is eliminated per unit
time, regardless of the plasma concentration.
• Very few drugs actually exhibit zero-order
kinetics; notable examples are ethanol, phenytoin
and salicylate.
• Drugs with zero-order kinetics and first-order kinetics
can be distinguished from each other by examining a
graph depicting the time course of the disappearance
of the drug from the plasma.
• With zero-order kinetics, the drug concentration falls
linearly.
• With first-order kinetics, the drug declines in an
exponential fashion.
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Drug metabolism:
Reduces the drugs effect
Often inactivates the drug
Makes the drug more polar so that it can be
readily excreted
• Occurs mainly in the SER of the liver hepatocytes.
• Can also occur in other sites: Kidney
• Occurs in 2 phases:
• · Phase I reaction
• · Phase II reaction
• Phase I reactions
• Phase I reaction usually, but not always occur
before phase II reactions.
• It involves the addition of some reactive functional
group to the drug.
• This reactive site on the drug serves as a point of
attack by a conjugating system which occurs in
phase II.
• 3 main types of phase I reactions:
• Oxidation
• Reduction
• Hydrolysis
• Phase II reactions
• Combines some endogenous substrate which is
added to the phase I product (conjugation).
• Phase II reactions are usually the
detoxification step.
• Sometimes, phase II reactions occur before
phase I.
e.g. Isoniazid undergoes acetylation first
(conjugation of the drug with Acetyl CoA) and
then Hydrolysis.
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Phase I reaction – Processes
· The main phase I reactions involve:
· Oxidation
· Reduction
· Hydrolysis
· The most important phase I reaction is
oxidation involving the mixed function oxidase
system.
· This is an enzyme complex requiring:
· A reducing agent (NADPH)
· Molecular oxygen
· NADPH cytochrome p450 oxidase
· Cytochrome p450
• Many drugs can act to induce or inhibit the
cytochrome p450 enzyme.
• Drugs which inhibit cytochrome p450 will prevent
the metabolism of other drugs which rely on this
enzyme.
• Inducers• Barbiturates, phenytoin, griseofulvin
carbamazipine, rifampin,
• Inhibitorsquinidine, INH, Sulphonamides,
Erythromycin, cimetidine, Fluoroquinolones
• Routes of drug excretion
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· Kidney
· Biliary system
· Lungs
· External secretions
· Sweat
By far the most important route of drug elimination
from the body is via the kidney
• Elimination by the kidney
• · Drugs which are not metabolized by the liver rely on
the kidney as the major way of removal of the drug
from the blood.
clearance of a drug
• Clearance is: “The volume (of plasma
presumably) from which all the drug is
completely removed per unit time.”
Albumin Affects Distribution
• Drugs bind
differentially to albumin
• 2 drug classifications:
– Class I: dose less
than available
binding sites (eg:
most drugs)
– Class II: dose greater
than binding sites
(eg: sulfonamide)
• The problem:
– one drug may out-
Albumin
Drug X
Sulfonamide
Therapeutic Index (TI) or Margin of safety
• Therapeutic index – is the ratio between the toxic
dose and the effective dose of a drug.
• A drug with a high therapeutic index is effective at
a low dose and has few, if any toxic side effects
at this dose.
How do we denote the clinical
effectiveness of a drug?
• Potency: Concentration of a drug required to elicit
a biologic effect.
– ED50: Dose required to elicit 50% of the
maximal effect.
100
50
ED50
Dose
How do we denote the clinical
effectiveness of a drug?
• Efficacy: The ability of the drug to elicit an
effect.
Log Dose
DRUG RECEPTOR
INTERACTIONS
• Most drugs bind to receptors—specialized
macromolecules present on cell surface or
intracellularly.
• Receptors bind drugs and mediate their
actions.
• Drug +receptor---drug-receptor complex
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Types of receptors
Ligand gated ion channels
G protein coupled receptors
Enzyme linked receptors
intracellular receptors
Spare receptors
• Ligand gated
• Ligand gated ion channels –control regulation of
flow of ions across cell membranes
• Ex—nicotinic receptor, GABA receptor
• Nicotinic recptr—acetyl choline—sodium influx
• GABA RCPTR—benzodiazepine—chloride influx
• G protein coupled
• these receptors are linked to a G protein
havin 3 sub units – alfa, beta & gamma
• Binding of g protein causes replacement of
GDP by GTP.
• Enzyme linked
• These have a cytosolic enzyme activity
• Binding of ligand activates or inhibits this
cytosolic enzyme activity
• Intracellular receptors
• The receptors are entirely intracellular
• Constraints on physical-chemical properties
on ligand—it must have sufficient lipid
solubility to move across target cell
membrane
• Ex—steroid hormones
• Spare receptors
• Two phenomena
• First –single ligand recptor complex
interacting with G proteins
• Second—activated G protein persist for
longer duration.
• ex.. Action of albuterol
Drug Nomenclature
• Drugs may have at least three names
– chemical name - (usually) long and
complicated chemical name
– nonproprietary name
• usually contraction of chemical name
• also referred to as generic name
– trade name
Example
• CHEMICAL:
DIETHYLAMINOETHYL pAMINO-BENZOATE
• GENERIC:
PROCAINE
• TRADE NAME: NOVOCAIN (WINTHROP)
• Prescription
• a legal document
• contains instructions for pharmacist to dispense
drug
• prescription can only be issued under direction of
individual licensed to prescribe. Ex : physician
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Nonprescription drugs
over the counter (OTC)
can be purchased anywhere
do not require services of a licensed health care
professional
• still carry certain risks
OTC- DISADVANTAGES
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EASY AVAILABILITY?
MISUSE
OVERDOSAGE
DRUG INTERACTIONS
Evaluating Drugs in Humans
The Food and Drug Administration (FDA)
Drug evaluation process
Grants approval for marketing of drugs
Phases of a Clinical Trials
Phase I
Phase II
Phase III
Phase IV
Evaluating Drugs in Humans
Phase I – Healthy adult volunteers
• Evaluation of safety, Pharmacokinetics (PK), side effects???
Phase II - Patients
• Evaluation of efficacy, safety, PK, and side effects
• Single-blind placebo controlled
Phase III – Specific patient subpopulations
• Determine efficacy for specific indications
• Large sample of specific patients (1,000)
• Randomized double-blind placebo controlled
Phase IV – Post FDA Approval
• Determine efficacy for specific indication
• Determine drug utilization patterns and additional efficacy
• Monitor rare, severe side effects/toxicity