Download INTRODUCTION to Pharmacology

INTRODUCTION
to Pharmacology
What is pharmacology?
• It is the study of the actions, mechanisms,
uses, and adverse effects of drugs
• A Drug is any natural or synthetic substance
that alter the physiologic state of a living
organism
Drugs are divided into:
• Medicinal drugs:
These are used in the prevention, treatment and
diagnosis of disease
• Non-medicinal drugs or social drugs:
These are used for purposes other than treatment
e.g. illegal mood- altering substances such as
cannabis, heroin and cocaine
Drugs name and classification
Factors that are used to classify drugs:
1. Pharmacotherapeutic action
2. Pharmacologic action
3. Molecular action
4. Chemical nature
Definitions
• Pharmacodynamics:
• It is what the drug do to the body i.e. drug
actions on the receptor, tissue, organ or system.
• Pharmacokinetics:
• It is what the body to the drug i.e. absorption,
distribution, metabolism and elimination
Pharmacodynamics
Targets of drugs
•
•
•
•
•
•
Receptors
Enzymes
Ion channels
Carrier molecules
Physical
Chemical
Drug receptors
• Highly specific, highly sensitive binding site
• Found on the surface of the cell membrane,
enzyme molecules on nuclear membranes.
• Receptor Specificity
– There are a number of specific ligands and a number
of associate receptors
• Affinity
• The extent to which the ligand is capable of binding
and remains bound to a receptor
• High affinity: The ligand bind well and remains bound
for long enough to activate the receptor
• Low Affinity: The ligand binds less well and may not
remain bound long enough to activate the receptor
The receptor intrinsic activity
• The extent to which the ligand activates the
receptor
• High intrinsic activity: the ligand produces a large
effect on the post synaptic cell
• Low intrinsic activity: the ligand produces a small
or inconsistent effect on the post synaptic cell
Classes of Ligands
• Agonists
– High affinity
– High intrinsic activity
• Antagonist
– High affinity
– Low intrinsic activity
Agonists
•
An agonist is a drug that binds to a receptor and
activates it to give a response
• There are 2 types of agonists:
1. Full agonist: is a drug when bound to a receptor
produces 100% of the maximum possible
biologic response
2. Partial agonist: a drug that produce less than
100% of the maximum possible biologic
response no matter how high their
concentration
AGONIST
R
R+
Resting state
RESPONSE
Activated state
-ve
-ve
ANTAGONIST
Antagonist
•
An antagonist is a drug that bind to a receptor and
produce no response.
• Type of drug antagonism:
1. Receptor antagonists
a) Competitive: the antagonists competes with the
agonist at the same receptor site of an agonist and
binds to it reversibly. By increasing the concentration
of drug agonist the antagonism is abolished. E.g.
antihistamine competes with histamine at its receptor
site
b) Non competitive: the antagonist binds
irreversibly to a different site on the enzyme
e.g. than the agonist, noncompetitive
agonists can not overcome by increasing the
concentration of the drug agonist. E.g.
succinylcholine is irreversible neuromuscular
blocker.
Continue …
2. Physiological antagonism: e.g. glucagon and
insulin
3. Chemical antagonist: is the type of a drug that
acts by binding chemically to the compounds
and inactivates it. E.g. chelating agents,
charcoal (poisoning with iron)
4. Pharmacokinetic antagonist: by increasing the
metabolism and excretion of a drug, e.g.
enzyme induction to speed metabolism
Antagonist
Reversible: •
Can be unbound from the receptor –
Irreversible: •
Cannot be unbound from the receptor –
Competitive: •
Competes with other ligands for binding to the –
receptor
Non competitive: •
Exerts its antagonist effects without competition for –
occupancy of the receptor
Presynaptic Adrenergic Neurons
(Blue balls = NE)
Yellow Balls = Beta Blocker
Dose- response curve
• The response to increasing doses of an agonist or
antagonist are plotted graphically.
• It can measure the following:
• Efficacy: is the maximum effect (Emax) which can
be obtained from a large dose of the drug.
• Potency: is the amount (dose) of drug or
concentration in the plasma that can produce a
similar effect by a dose of another drug
• EC50 (Effective concentration): is the
concentration that produce 50% of the
maximum effect.
• ED50 (Effective dose): is the dose that produces
the response of 50% of subjects
• LD50 (Lethal dose): is the dose that cause death
in 50% of subjects
• Non competitive antagonist will bind
irreversibly with the receptor leading to
decrease in number of receptors available
for binding with the agonist
• This will cause the maximum effect of the
agonist to be less than when it is used alone
or with competitive antagonist
Therapeutic index
• Is the ratio between the average maximum
tolerated dose LD50 and the average minimal
effective dose ED50
TI= LD50/ ED50
• It indicates the margin of safety in use of a
drug
• The higher the TI the safer the drug
Type of receptor proteins
A. ligand gated ion cannels:
• Ionotropic receptors
• They are membrane receptors that
compose an ion channel with ligand binding
site (receptor) in the extracellular domain
that stimulate the opening of the channel.
• It increases Na, K permeability and possibly
generates an action potential.
• Typically are these the receptors
which fast neurotransmitters acts
(milliseconds).
• E.g. nicotinic Ach receptor, GABA A
receptor
B. G-protein coupled receptors
• Know as metabotropic receptor, they are
membrane receptors
• They either stimulate an enzyme or a channel
• The receptor is coupled with G protein
• G-proteins comprises 3 subunits; α, β, γ . The
α subunit consists of GTPase, which catalyzes
the conversion of GTP to GDP and break down
the G-proteins releasing the α subunit
• The α-GTP diffuse in the membrane and
associate with various enzymes causing
activation or inactivation.
• This process is terminated when the α subunit
is recombined with the β, γ subunits
Na+
Neuromuscular
Blocking Drugs
Competitive
Tubocurarine
Gallamine
Pancuronium
Vecuronium
Atracurium
Rocuronium
Depolarizing
Suxamethonium
ACh
Na+
α
ACh
δ
γ
α
β
• Classes of G- protein : Gi, Gs, Gq. Gs & Gi either
stimulate or inhibit enzyme Adenylate cyclase. Gq
activates phospholipase C (PLC)
• Example: cholera toxin acts by Gs
pertusis toxin acts by Gi
• Targets of G- proteins:
1- adenylate cyclase (cAMP)
2- Phospholipase C PLC(IP and DAG)
3- Ion channels (Ca+2 and K+)
Cholinergic nerve terminal
Neuromuscular
Blocking Drugs
Action
Potential
Arrives
Acetyl CoA + Choline
Cholineacetyl Transferase
ACh
Ca++
ACh
ACh
Potentiate
Transmission
Pyridostigmine
Neostigmine
Distigmine
edrophonium
Synaptic
Cleft
ACh
ACh
ACh
ACh
Agents that reduce
ACh release
Vesamicol
ACh
ACh
Hemicholinium
Botulinum toxin
Aminoglycosides
Mg2+, Ca2+ ions
ACh
ACh
ACh
ACh
Competitive
Tubocurarine
Gallamine
Pancuronium
Vecuronium
Atracurium
Rocuronium
Depolarizing
Suxamethonium
Na+
Acetate ion + Choline
Acetylcholinesterase
inhhbitors
G
P
C
R
Post-Synaptic
membrane
Receptors)
G-protein coupled receptors
• Membrane bound receptors which are bound
to effector system through G-proteins
• These are hetero trimeric molecules having 3
subunits alpha, beta, and gamma
• Based on alpha subunits they are further
classified into 3 main subtypes Gs, Gi, and Gq
C- Kinase- linked and related receptor:
• They mediate the action of many different
mediators including growth factors, cytokines,
and hormones (insulin)
• They have a common structure, a large
extracellular
(ligandbinding)
domain
connected by an α- helix to an intracellular
domain (effector)
D- Nuclear receptors
• These are ligand for: steroid hormones, thyroid
hormones, vt.D and retinoic acid as well as lipidlowering drugs and antidiabetics
• From its name it is found in the nucleus
(intracellular) so the ligand must enter the cell.
• The compounds are usually lipophilic so they
readily cross the lipid-bilayer.
• They are important for gene expression, alter
protein synthesis and drug metabolizing enzymes.
• They are the slowest
Other GATING mechanisms:
1- voltage- gating channels:
• They open when the membrane is depolarized
(i.e. excitation) in the activation phase
• It is short lasting
• They are either Na+, K+, Ca+2 voltage- gated
channel
2- calcium releasing channels:
• They lie on the membrane of the endoplasmic
reticulum
Functions of receptors
• To propagate signals from outside to inside
• To amplify signals
• To integrate various extracellular and
intracellular regulatory signals
• To adapt to long term changes in
maintaining homeostasis
Undesirable responses to drug therapy
• Toxic effect :
– When too much drug has collected in the
patient.
– It may be due to:
– an acute high dose of a drug
– chronic buildup over time
–or increased sensitivity to the standard
dose of a drug.
• Drug allergy (hypersensitivity):
– The body sees the drug as an antigen and an
immune response is established against the
drug.
– This may be an immediate response or
delayed
• Adverse reaction– undesirable drug effect.
• Side effect– This is similar to the term adverse reaction.
– It is an unwanted but expected responses to a
drug.
Adverse Drug Reaction
• Frequency of adverse drug reaction
• ADRs are common.
• About 2-6% of hospital admissions are for
ADRs.
Types of ADR’s
• A:
– Augmented
– dose related
– Related to pharmacology (toxic effect or
side effect--for example, digoxin toxicity)
• B
– Bizarre
– non-dose related,
– Unrelated to pharmacology (idiosyncratic for
example, malignant hyperthermia, or
immunological--for example, penicillin rash)
• C:
– Continuous or chronic
– Dose and time related,
– Related to cumulative drug use--for or chronic
example, NSAID induced renal failure
• D:
– Delayed,,
– Delayed effect
– Can be seen only some time after use of
drug--for example, ???
• E:
– End of use
– Withdrawal
– Related to discontinuation that is too abrupt-for example, addisonian crisis after steroid
withdrawal
Factors affecting a patient’s response
to a drug
• Age.
– The very young
– The elderly.
• Body weight.
• Pregnancy and lactation.
• Nutritional status.
• Food-drug interactions. For example, orange juice
(vitamin C) will enhance the absorption of iron
sulphate, but dairy products reduce the absorption of
tetracycline..
• Disease processes. Includes:
– Changes in gut motility e.g. diarrhoea
– Loss of absorptive surface in the small intestine, as
occurs in Crohn’s disease will affect absorption.
– Hepatic disease
– Renal disease
– Circulatory diseases
– Mental and emotional factors.
– Genetic and ethnic factors.
PHARMACOKINETICS
Translocation of drug molecules
Drug molecule move around the body in 2 ways:
1. in blood stream (bulk transfer), the chemical
nature of a drug is of no importance to its
transfer.
2. molecule by molecule, over short distance
(diffusional transfer), the chemical nature of a
drug is an important factor especially its ability
to cross hydrophobic barriers. The rate of
diffusion depends also on its molecular size,
large molecules tend to diffuse more slowly
than smaller ones.
Movement of drug molecule across cell barriers
Cell membrane form the barrier between
aqueous compartments of the body
epithelial barrier such as GI mucosa or renal
tubules, consist of a layer of cells tightly
connected to each other
Vascular epithelium: Gabs between endothelial
cells are packed with a loose matrix of proteins
that acts as filters, retaining large molecules and
letting smaller ones through.
In some organs, especially CNS and
placenta, there are tight junctions between
the cells and the endothelium is an
impermeable layer.
These features prevent potentially harmful
molecules from leaking from the blood to
these organs.
In other organs (e.g. liver and spleen), the
endothelium is discontinuous, allowing free
passage between cells.
There are 4 main ways by which molecules
cross the cell membrane:
1) by diffusion directly through lipids
2) by diffusion through aqueous pores
formed by special aquaprotiens that
traverse the lipids
3) by combination with transmembrane
carrier protein that binds a molecule on
one side of the membrane then changes
configuration and release it to the other
side.
4) by pinocytosis
PH ionization of weak acids and weak
bases, the Handersons-Hasselbakh
equation
The electrical charge of an ionized molecule
attracts water dipoles and results in polar,
relatively water soluble compound.
Since lipid diffusion depends on relatively
high lipid solubility, ionization of drugs may
markedly reduce their ability to permeate
membranes.
Weak acid is best defined as a neutral
molecule that can reversibly dissociate into an
anion and a proton.
The protonated form is neutral and more lipid
soluble
HA↔H+ +AWeak base is defined as neutral molecule that
can form a cation by combining, with a
proton,
the un-protonated form is the neutral form
B H+↔H+ +B
The HHE relates the ratio of protonated to
unprotonated weak acids and weak bases to the
molecules PKa and PH of the medium as follows:
Log 10 protonated = PKa _ PH
unprotonated
For bases:
PKa = PH + Log 10 [BH+]
[B]
For acids:
PKa = PH + Log 10 [AH]
[A-]
PKa: (ionization constant), is PH at which 50% of the
drug is ionized.
Because the uncharged form is the more lipid
soluble, more of weak acids will be lipid
soluble in acidic medium and more weak
bases will be lipid soluble in alkaline medium.
Ionization increases renal
clearance of drugs
• Both ionized and non-ionized forms of a drug are
filtered
• Only free unbound drug is filtered
• Only non-ionized forms undergo secretion and
active or passive reabsorption
• Ionized forms of drugs are trapped in the filtrate
Fick’s law of diffusion
The passive flux of molecules down a concentration
gradient is given by fick’s law
Flux (molecule per unit time)=
(C1-C2) × area × permeability coefficient
× Thickness
C1: the higher concentration
C2: the lower concentration
Area: is the area across which the diffusion is occurring
Permeability coefficient: is a measure of the mobility of the
drug molecule in the medium of the diffusion bath
Thickness: is the thickness (length) of the diffusion bath
DRUG DISPOSION
DIVIDED INTO:
– Absorption
– Distribution
– Metabolism
– Excretion
Drug forms
1.
2.
3.
4.
5.
Tablets
Capsules
Solution: for injections, either IM, IV, SC
Solution to drink
Preparation to apply to skin or mucus
membranes
6. Vaginal tablets
7. Rectal preparation
Routes of drug administration
•
•
•
•
•
•
Oral
Sublingual
Rectal
Application to other epithelial surfaces
(cornea, skin, vagina and nasal mucosa)
Injections (SC, IM, IV, intra-thecal)
Inhalation
ORAL ROUTE
• Taken by mouth
• Drugs are absorbed by:
• Passive Diffusion:
o Determined by the lipophilcity of the drug
compound
o Ionized drugs are poorly absorbed (strong base
or acid)
• Active Diffusion:
o By carrier proteins
o Example: ca+2 is carried by V.t-D dependent
carrier system
Factors affecting GI absorption
1- Altered gastric motility e.g. diarrhea
2- Splanchnic blood flow (it decreases in shock)
3- Particle size and formulation
4- Physiochemical Factors: i.e. ions that affect
the absorption of some drugs. e.g.
Tetracycline: it binds to ca and ca containing
food
SUBLINGUAL ROUTE
• It is useful when rapid response is required
specially if the drug is unstable or has an
increase first pass.
• The drug by pass the portal circulation
• Example: Glyceryl trinitrate
RECTAL ROUTE:
• Used for either local effect (anti-inflammatory
drugs used for ulcerative colitis) or to produce a
systemic effect like Diazepam in children who
present with epilepsy.
Other local applications:
•
•
•
•
Cutaneous administration
Nasal spray (ADH, GnRH, Calcitonin)
Eye drops
Inhalation (Ipratropium, salbutamol)
PARENTRAL ADMINSTRATION
Intravenous injection:
• Fast and most effective
• Directly enter the venous circulation then to
the right side of the heart then to the lungs
the to the systemic circulation.
Intramuscular injection:
• They fastest than the oral route.
• The rate of absorption depends on the site of
inj. And the blood flow.
• Increase the blood flow: exercise, rubbing,
hot bath
• decrease the blood flow: cooling
Intra- thecal injection:
• The injection in the subarachnoid space
Example:
• Methotrexate: given for treatment of
leukemia
• Regional anesthesia
BIOAVAILABILITY
• Defined as the proportion of drug conc that
reach the systemic circulation following
administration.
• This is measured by the area under the curve
AUC
AUC= A / Ke
• A: the point or concentration where the drug
reach max plasma concentrated
• Ke: elimination rate constant (0.7/ t½)
f = AUC PO/AUC IV
A
DRUG CONCENTRATION
DRUG CONCENTRATION
A
Ke
AUC
IV
0
TIME
AUC
ORAL
0
Ke
TIME
Ke= 0.7/ t½
• Ke: the time were the concentration of the drug in
plasma drop by 50% (elimination constant)
• IV doses have 100% bioavailability, f = 1
Factors affecting Bioavailability
A- Extent of absorption:
• Usually any drug taken by oral administration is
incompletely absorbed
B- First- pass metabolism:
• After absorption of a drug it goes to the liver
through portal circulation were it is metabolized
to active or inactive compounds (can occur in
the gut).
• Some of these compounds are excreted in bile.
VOLUME OF DISTRIBUTION
• Vd: relates to the amount of drug in the body to
the concentration of the drug in blood or plasma
Vd= amount of drug in body
C
• It is affected by protein binding.
• Only unbound drug (free fraction) exerts
pharmacolological effects
Special Barriers to Distribution
Placental
• Most drugs cross the placental barrier, but fetal blood
level is usually lower than maternal
Blood-Brain
• Permeable to lipid soluble or very small drug molecules
Redistribution
• Lipid-soluble drugs redistribute into fat tissues prior to
elimination - repeated doses cause saturation – may
prolong duration of action
• The higher the Vd, the lower the plasma
concentration and vice versa
• Vd is low when a high % of drug is bound to
plasma proteins
Hepatic Extraction ratio (ER)
• It is affected by: rate of hepatic clearance of
the drug and hepatic blood flow
ER= CL liver/ Q
• CL liver: liver clearance of the drug
• Q: hepatic blood flow
Systemic Bioavailability (F)
F= f(1-ER)
• f: the extent of absorption of the drug
Example:
A drug like morphine if taken orally almost
completely absorbed f=1 hepatic ER=0.67 so
F=(1-ER)=1-0.67=0.33
F= 0.33×100=33%
DRUG ELIMINATION
• It involves the following:
1- Drug metabolism: which include enzymatic
conversion of one chemical entity to another
2- Drug excretion: includes the elimination of
drugs either unchanged or metabolized
• It occurs through the kidney, hepato-billiary
and lung systems
Drug Metabolism
• Lipophilic compound are not excreted by the
kidney and they need to become more soluble or
polar to be excreted.
• Metabolism occurs mainly in the liver (CYP450
system)
• Metabolism may result in formation of active
metabolites (diazepam – nordiazepam)
• Prodrugs lack activity until they undergo
bioactivation (clorazepate – nordiazepam)
Metabolism involves two phases:
Phase -1 reaction: (catabolic)
• it includes: oxidation, reduction, and hydrolysis
reaction.
• It is called “the microsomal mixed function
oxidase system”.
• Major phase 1 enzymes – localized in smooth ER
of liver, GI tract, lungs, and kidneys
• It includes two enzymes:
1) NADPH cytochrome reductase
2) CYP450 system
• Require O2 and NADPH
• Multiple CYP families vary by substrate
specificity and sensitivity to inhibitors &
inducing agents
CYP3A4
• Major isoform with wide substrate range
• Inhibited by cimetidine, macrolides, azoles &
ethanol (acute)
• Induced by carbamazepine, phenobarbital,
phenytoin, rifampicin, & ethanol (chronic)
CYP2D6
• Genotypic variations in hydroxylation (fast /
slow)
• Substrates include codeine, debrisoquin &
metoprolol
• Inhibited by haloperidol & quinidine; not
inducible
Other Phase 1 metabolism
Non-microsomal oxidations
• Monoamine oxidases metabolize NE, 5HT,
and tyramine
• Alcohols
metabolized
via
alcohol
dehydrogenase (ADH) to aldehydes then
aldehyde dehydrogenoase (inhibited by
disulfram)
Phase -2 reaction:
• It include conjugation with other groups to
make it more soluble.
• Groups used in conjugation:
 glucoronyl,
 sulfate,
 methyl,
 acetyl,
 glycyl
 glutathione
• This phase can occur in the kidneys
• Acetylation is genetically determined. Fast
acetylators and slow acetylators (develop SLE
like syndrome when given INH, hydralazine,
procainamid or INH
• Transferases: usually inactivate drugs, but may
activate (e.g. morphine, minoxidil). May follow a
phase I hydroxylation, but also occur directly
• Glucuronidation – inducible; reduced activity in
neonate
RENAL EXCRETION
There are 3 main process for Renal excretion of a
drug:
1- Glumerular filtration rate: (GFR)
• This depends on the molecular weight of the drug
and the extents of binding to plasma proteins.
2- Tubular secretion:
• Here drug molecules are transferred by two
independent and non-selective carrier systems
i.e. Transport of acidic compounds or basic
compounds
• They transport drug molecules against conc.
gradient so can reduce the plasma conc. of the
drug to zero.
• E.g. penicillin
3- Diffusion across the renal tubules:
• Renal tubes can be freely permeable (the drug
concentration in the plasma and in the renal
tube is equal)
DRUG ELIMINATION (CLEARANCE)
• Defined as the volume of plasma containing the
amount of substance that is removed by the
kidney in unite time
CL= Cu Vu
Cp
CL: Clearance
Cu: Urine Concentration
Cp: Plasma Concentration
Vu: Volume of Urine
CLEARANCE
•
•
•
•
Equals rate of elimination divided by plasma level
Constant for 1st order elimination
Total body clearance CL = CLR + CLER (extra renal)
With no secretion or reabsorption renal clearance is
the same as glomerular filtration rate, CLR = GFR
• If drug is protein bound then CLR = GFR x free fraction
There are two ways for
drug elimination:
1- First Order Kinetic
2- Zero Order Kinetic
First Order Kinetic (un- saturable)
• Defined as the amount of drug removed
is direct proportion to its concentration in
plasma.
ZERO- ORDER KINETICS (SATURABLE)
• Her drugs are removed at a constant rate
regardless the plasma concentration levels
because it is an enzyme dependant process so
it has limited capacity.
Example:
• Ethanol
• Phenytoin
• Salicylates
Blood Alcohol concentration
t½
10.9
7.6
4.3
TIME
Dose Administration
Alcohol is eliminated
at a rate of 4mmol/l
regard less the
plasma concentration
t½ HALF LIFE OF A DRUG
• Is the time required by the body to eliminate 50% of
the drug concentration
t½= Vd x 0.7
CL
It is important to indicate the time required to attain
50% of the steady state
• This helps in the setting up of a dosage regime which
produces:
– stable plasma drug concentrations
– keeps the level of drug below toxic levels but above
the minimum effective level
• Loading Dose
– This is given when an effective plasma level of
drug must be reached quickly.
– This requires a dose of the drug which is larger
than is normally given.
– This dose is given as a one off.
• Maintenance dose:
– This is the dose given when the required
plasma level of drug has been reached.
– It is the normal recommended dose.
– This is then continued at regular intervals to
maintain a stable plasma level .