PHARMACODYNAMICS

BY
DR MOHAMMED O.H
 PHARMACODYNAMICS (PD)
• PD is defined as the action of the drug on the body
– (1) How the drugs act on the body?
– (2) The mechanism of action of drug and its effects.

• An interaction usually exist between the

administered drug and biological ligand(receptor)
for a pharmacological response to be elicited, this is
called the ‘mechanism of action’.
• Receptors are macromolecules that mediate a
biological change following ligand (drug) binding
• Most receptors are proteins and are located on the
surface or within the cells
 SITE OF DRUG ACTION
• They can be divided into:
specific and
non-specific

• Specific action;
– It is connected with interaction of the drug with specific
site(s) on the cell membrane or inside the cell.

– Non-specific action;
• osmotic diuretics, osmotic laxatives, antacids
 Main specific targets
for drug actions are
• DNA
• Microbial organelles
• Target macroproteins
  DNA

Alkylating agents bind covalently to

sites within the DNA such as N7 of
guanine and block DNA-replication.
 Microbial organelles

Doxy- Nystatin Rifampicin

Peni-
cyclin cillins
 Target macroproteins
• receptors (> 150 types
with many subtypes)
• ion channels
• enzymes
• carrier molecules
 RECEPTORS
• Paul Erlich “a drug will not work unless it is bound
• Receptors are the regulatory macroproteins – sensitive
elements in the system of chemical communications that
coordinates the function of the different cells in the body.
• Receptors bind to;
• Endogenous ligands (such as):
- neurotransmitters (mediators)
- hormones
- autacoids (tissue mediators)
- grouth factors
- inhibitory factors, etc.
• Exogenous ligands:
- many (but not all) drugs
- some other xenobiotics
 RECEPTORS

• The main receptor

ligands are
 agonists - activate the
receptors
 antagonists - block the
receptors
 RECEPTORS
 The interaction between the ligand and the receptor does
not involve covalent bonds but weaker, reversible forces,
such as:
• Ionic bonding
• Hydrogen bonding
• Hydrophobic bonding
• Van der Waals forces.

 The numbers of receptors may be altered during chronic

drug treatment, with either an increase in receptor
numbers (up-regulation) or a decrease (down-regulation).
 There are pre and postsynaptic receptors.
 Presynaptic receptors may inhibit or increase transmitter
release (feedback mechanism: +/-)
 RECEPTORS
• There are 4 main types of receptors, according to their
molecular structure and the nature of receptor-effector
linkage.
– Ligand-Gated Receptors (ionotropic)
– G-protein Coupled Receptors
– Enzyme Linked Receptors
– Intracellular Receptors

• The location of type 1, 2 and 3 receptors is on (into) the cell

membranes;

• type 4 inside the cell.

 1) Ionotropic receptors
 Otherwise called ligand-gated ion channel receptors
 These receptors are involved mainly in fast synaptic
transmission.
 They are proteins containing several
transmembrane segments arranged around a
central channel.
 Ligand binding and channel opening occur on a
millisecond time-scale.
 ion channel (Ca2+, Na+, K+, Cl–)
 Examples are: nACh-receptors, GABAA-receptors, 5-
HT3-receptors
 Ionotropic receptors
GABA receptor Nicotine receptor
Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels
 2)G-Protein-coupled receptors
• All comprise 7 membrane-spanning segments.
• One of the intracellular loops is larger than the others
and interacts with G-protein.
• The G-protein is a membrane protein comprising 3
subunits (, , ).
• The alpha-subunit possessing GTP-activity.
• When the agonists occupy a receptor, the alpha-subunit
dissociates and is then free to activate a target (effector):
– enzyme (AC, GC, PLC)
– Ca2+ ion channels
b-adrenoceptor (7 sub-units)
 2)G-Protein-coupled receptors
• Adenylyl cyclase(AC) catalyses formation on
the intracellular messenger (cAMP).
• cAMP activates various protein kinases (PKA
and others) which control cell function in
many different ways by causing
phosphorylation of various enzymes, carriers
and other proteins.
•
Adrenaline (b1&b2)
(+)
Ex

Gs AC

In

cAMP ATP

PKA Effects
 2)G-Protein-coupled receptors
 PLC (phospholipase C) catalyses the formation
of two intracellular messengers - InsP3 and
DAG, from membrane phospholipids.
• InsP3 (inositol-triphosphate) increases free
cytosolic calcium by releasing Ca2+ from the
endoplasmic reticulum. Free calcium initiates
contractions, secretion, membrane
hyperpolarization
• DAG activates protein kinase C (PKC).
Noradrenaline (a1)
(+)
Ex

Gs PLC
In
PIP2

IP3 DA
ADP G

Ca2+ ATP PKC

Effector Second Protein kinase
messenger

AC cAMP PKA

PLC IP3 PKC

DAG

cGMP PKG
GC
G-protein-coupled receptors
Effector Enzyme (AC, GC, PLC);
Ca2+ channels
Coupling G-protein
Time scale seconds
Examples AT1-receptors
mACh-receptor
Adrenoceptors (a, b)
H1 – H5-receptors
Opioid receptors (m, k, d)
 3)Tyrosine-kinase receptors
 Incorporate thyrosine kinase in their
intracellular domain.

 These receptors are involved mainly in events

controlling phosphorilation, cell growth and
differentiation.
Kinase-linked receptors

Effector thyrosine kinase

Coupling direct
Time scale minutes (to hours)
Examples Insulin receptor
ANP receptor
growth factors rec.
 4) Intracellular receptors
 They are nuclear proteins, so ligands must first
enter cells.

 Receptors have DNA-binding domain.

 Stimulation of these receptors increase

protein synthesis by the activation of DNA
transcription
 Intracellular
(steroid/thyroid) receptors
Effector gene transcription
Coupling via DNA
Time scale hours
Examples steroid receptors
thyroid receptors
vitamin D receptors
 4a) Cytoplasmic receptor
Steroid hormone diffuse into the cell. When activated, the receptors translocate to the
nucleus where they can upregulate gene transcription by action on specific DNA response
element and recruiting co-activator proteins.
 4b) Nuclear receptor
(thyroid hormones T3,T4)
• T3 or T4 penetrate the nucleus

• Combine with their receptors

• Alters DNA-RNA mediated

protein synthesis
Types of receptor-effector linkage (R = receptor; G = G-protein; E = enzyme)
B) ION
CHANNELS
LAH+ (local
anaesthetics) block
Na+
channels.
C. Enzymes
Drug Action on enzyme

Galantamine (-) ACh-esterase

Digoxin (-) Na+/K+-ATP-ase
Aspirin (-) COX-1/COX-2
Obidoxim (+) ACh-esterase
Ex 3Na+
In

Na+/K+ (–)
DIGOXIN
АТФ-аза
2K+

3Na+

Na+/Ca2+
обмен
Ca2+
D. Carrier
molecules
 DOSE-RESPONSE RELATIONSHIPS
• Most drug produce graded dose-related effects, which
can be plotted as a dose response curve.
• Such curves are often hyperbolic (a), but they can be
conveniently plotted on semi-logarithmic paper to give
sigmoidal shape (b).
• The method of plotting dose-response curves facilitates
quantitative analysis of:
– full agonists, which produce graded responses up to
maximum value;
– antagonists, which produce no response on their own but
antagonize the response to an agonist;
– Partial agonists, which produce some response but to a lower
maximum than that of a full agonist and antagonize its effect
Plotted
dose-
response
curves:
(a) arith-
metically
(b) semi-
logarith-
mically
Hyperbolic Sigmoidal
shape (a) shape (b)
 PD terms
• AFFINITY: This is the ability of a drug to bind to a
receptor, the better the affinity, the better the drug-
receptor response.
• EFFICACY: This is the ability of a drug to produce an
effect(response) at a receptor. This is the maximum
effect of which the drug is capable. Also called
maximal efficacy or intrinsic activity
• POTENCY: The potency of a drug refers to the dose
required to produce a specific intensity of effect. If the
ED50 of drug A and B are 5 and 10 mg, respectively, the
Relative Potency of A is twice that of B
• The selectivity of a drug is the extent to which it acts
preferentially on particular receptor types
EC50
 Affinity Intrinsic Efficacy Selec-
Drugs activity tivity

Agonists + + ++ + +
(Morphine)
Antagonists + - - +
(Naloxon)
Partial
agonists
(Pentazocine) + + - +
Dose-response curve of two full agonists (A, B) of different
potency, and a partial agonist (C).
Dose-response Curve
Full, Partial and Inverse Agonist
Competitive/non-competitive antagonist
Antagonism vs Potentiation
 CONT’D
• AGONIST: This are chemical agents(drugs) that
have both affinity and intrinsic activity(produce a
response). Agonist could be endogenous or
exogenous (adrenaline vs dobutamine….. Both
increases heart rate
• ANTAGONIST: These are agents that has affinity
but not efficacy or intrinsic activity. Antagonist
binds to the receptors but do not elicit any
response , or they block the response of
endogenous ligands
 Dose-Response Relationship
• The exact relationship between the dose and the
response depends on the biological object under
observation and the drug employed.
• When a logarithm of dose as abscissa and
responses as ordinate are constructed
graphically, the “S” shaped or sigmoid type curve
is obtained.
• The lowest concentration of a drug that elicits a
response is minimal dose, and the largest
concentration after which further increase in
concentration will not change the response is the
maximal dose.
 CONT’D
1. Graded dose effect: As the dose administered to
a single subject or tissue increases, the
pharmacological response also increases in graded
fashion up to ceiling effect.
• It is used for characterization of the action of
drugs. The concentration that is required to
produce 50 % of the maximum effect is termed as
EC50 or ED50.
2. Median lethal dose or LD50: This is the dose
(mg/kg), which would be expected to kill one half
(50%) of a population of the same species and
strain.
 CONT’D
• Median effective dose or ED50: This is the dose (mg/kg),
which produces a desired response in 50% of test population.
• Therapeutic index: It is an approximate assessment of the
safety of the drug. It is the ratio of the median lethal dose
and the median effective dose. Also called as therapeutic
window or safety.
• Therapeutic index (T. I) = LD50/ED50

• The larger the therapeutic index, the safer is the drug.

Penicillin has a very high therapeutic index, while it is much
smaller for the digitalis preparation
Therapeutic window
 CONT’D
• Narrow TI Drugs
Digoxin
Lithium
Phenobarbital
Vancomycin
Warfarin
 PHARMACODYNAMIC INTERACTIONS
• (i) Drug Synergism: When the therapeutic effect of two drugs are
greater than the effect of individual drugs, it is said to be drug
synergism.I t is of two types.
(a) Additive effect: When the total pharmacological action of two or
more drugs administered together is equivalent to the summation
of their individual pharmacological actions is called additive effect.
• i.e A + B = AB
• e.g. Combination of ephedrine and aminophyllin in the
treatment of bronchial asthma.
(b) Potentiation effect: When the net effect of two drugs used
together is greater than the sum of individual effects, the drugs are
said to have potentiation effect.
• i.e AB > A + B
• e.g. Trimethoprim+sulfamethoxazole
 CONT’D
• (ii)Drug Antagonism: The phenomenon of opposing actions of two drugs on the
same physiological system is called drug antagonism. Types of drug antagonism
includes
a) Chemical antagonism: In this the biological activity of a drug can be reduced or
abolished by a chemical reaction with another agent. e.g. Antagonism between acids
and alkalis.
b) Competitive or reversible antagonism: In this the agonist and antagonist compete
for the same receptors and the extent to which the antagonist opposes the
pharmacological action of the agonist. Competitive antagonism can be overcome by
increasing the concentration of the agonist at the receptor site.
• e.g. Acetylcholine and atropine antagonism at muscarinic receptors.
c) Non competitive antagonism: In this type of the antagonism an antagonist
inactivates the receptor (R) so that the effective complex with the agonist cannot be
formed, irrespective of the agonist concentration.
• e.g. Acetylcholine and papaverine on smooth muscle.
• Acetyl choline and decamethonium on neuromuscular junction.
d) Physiological antagonism: When the physiological effect of a drug is antagonized by
another drug by acting on two different types of receptors
• e.g. Acetyl choline causes constriction where as adrenaline causes dilatation of
pupil.
 Importance of Antagonism
• (i) Correcting adverse effects of drugs
• (ii) Treating drug poisoning. e.g. Morphine
with naloxone, organophosphate compounds
with atropine.
• (iii) Predicting drug combinations which would
reduce drug efficacy.
 ADVERSE DRUG REACTIONS
• The drugs that produce useful therapeutic effect may
also produce unwanted or toxic effects.
• It has been estimated that about 0.5% of patients who
die in hospitals do so as a result of their treatment rather
than the condition for which they were treated.
• Serious systemic drug toxicity may result from overdoses.
If is always an exaggeration of its pharmacological actions
and some times it is predictable. e.g. Hypotension
following antihypertensive drugs. Hypoglycaemia
following insulin.
• An adverse drug reaction is defined as any response to a
drug that is noxious and unintended and that occurs at
doses used in man for prophylaxis, diagnosis or therapy
(WHO).
 CONT’D
• The adverse effects are 1)Side effects 2)Untoward effects 3)Allergic reactions
4)Idiosyncratic reactions and 5) Teratogenic effects.

1) Side effects: Side effects are infact pharmacological effects produced with
therapeutic dose of the drug. e.g: Dryness of mouth with atropine which is
troublesome in peptic ulcer patients and useful when used as a preanaesthetic
medication.
2) Untoward effects: Untoward effects develop with therapeutic dose of a drug.
They are undesirable and if very severe, may necessitate the cessation of
treatment. e.g: Diarrhoea with ampicillin and potassium loss with diuretics.
3) Allergic reactions: Most of the drugs and sera used in therapeutics are capable
of causing allergic or hypersensitive reactions. These reactions may be mild or
very severe like anaphylaxis. When an individual has been sensitized to an
antigen (allergen) further contact with that antigen can some times lead to tissue
damaging reactions. These allergic reactions are 4 types.
• Type-I reactions or anaphylactic reactions (Immediate hypersensitive reaction).
• Type-II reactions or cytotoxic reactions.
• Type-III reactions or immune complex mediated reactions.
• Type-IV reactions or cell mediated reactions (Delayed hypersensitive reactions).
 CONT’D
4) Idiosyncratic reactions: The term idiosyncrasy means one’s
peculiar response to drugs. With the increasing knowledge of
pharmacogenetics, many idiosyncratic reactions have been found
to be genetically determined.
• e.g: Drugs like primaquine, sulfonamides and dapsone may
cause haemolysis in patients with glucose -6 phosphate
dehydrogenase defeciency.
5) Teratogenic effect: Some drugs given in the first three months
of pregnancy may cause congenital abnormalities and are said to
be teratogenic. The best known example is thalidomide which
results in early easily recognizable abnormalities such as absent
or grossly abnormal limbs.
• Other drugs with teratogenic potential are androgens, steroids,
anti convulsants, anti neoplastic drugs, cortisone, lithium,
pencillamine, tricyclic antidepressants and warfarin.
The “Five Rights” of Drug Administration
• There are five traditional right actions that
should be followed when giving medication.
• These are to determine the right patient, right
drug, right dose, right time, and right route.
• Five additional rights include the right
assessment, documentation, education,
evaluation, and the right to refuse.
 The Right patient
• The right patient means that the healthcare
provider gives the drug to the right patient.
• Each time a drug is administered, the
healthcare provider must verify who the patient
is by the patient’s identification(NASOMART).
• NB: Some patients are not mentally alert and
do not remember their name. Again, check the
patient’s identification every time medication is
administered.
 The Right Drug
• Healthcare providers must be sure that the drug is
the correct medication for the patient. This too
leads to errors. Healthcare providers ask: Was this
the drug prescribed on the medication order? Is
the medication order legible and complete?
• Why is the patient receiving this medication? Is the
medication consistent with the patient’s condition?
Does the patient have any food or drug allergies?
• Providers check the expiration date and return the
medication to the pharmacy if it has expired. If the
medication is used past the expiration date, the
effect on the patient can be unpredictable.
 The Right Dose
• The dose on the medication order must be within
recommended guidelines.
• The healthcare provider should have a general
idea of the dose before performing any drug
calculations. If the calculated dose varies too
much from this estimated dose, check with a
pharmacist or another appropriate healthcare
provider.
• Some drug calculations should always be checked
by two individuals if the calculation is
complicated or the drug has the potential to be
harmful if the dose is too large or too small.
 The Right Time
• Is it the correct time to administer the drug? The time is
specified in the drug order and may be given a half hour
before or after the stated time depending on the policy
of the hospital or healthcare facility.
• How often a drug is given is dependent on the half life
of the drug. A drug’s half life is the amount of time for 1⁄2
of the drug to be eliminated from the body.
• A drug with a short half life must be administered more
frequently than a drug with a long half-life in order to
maintain a therapeutic level of the drug in plasma.
• Healthcare providers should also make sure that
medication is given in coordination with meals. Some
drugs must be given with meals while other drugs are
given a specific period before or after a meal.
 The Right Route
• The healthcare provider determines the proper routine
to administer the drug so the patient’s body properly
absorbs it.
• Make sure that the patient can swallow if the route of
the medication is by mouth and stay with the patient
until the medication is swallowed.
• Caution should be used when administering intravenous
medications because the body quickly absorbs these
drugs.
• Therefore, healthcare providers need to know expected
side effects, effects that occur when the drug is first
given, effects the drug has during its therapeutic peak,
and duration of the drug’s action.
 Other Drug Administration Rights
• RIGHT TO REFUSE MEDICATION: A mentally
competent patient has the right to refuse
medication. Refusal is documented on the
patient record. Patients should be advised of
the consequences of the refusal to take the
medication such as a worsening of the
condition.
• As a general rule, every effort is made to
encourage the patient to take the medication.
• However, no one should physically force a
patient to take medication.
 CONT’D
• RIGHT TO EDUCATION: The patient has the
right to be told about the medication that is
about to be administered. The patient is told:
• The name of the medication
• Why the medication is given
• What the medication looks like
• How much of the medication to take
• When to take the medication
• When not to take the medication
• What are the side effects, adverse effects, and
toxic effects
THANK YOU