Pharmacodynamics

B.A.Z. Chedi
Pharmacology Department
Bayero University, Kano
 Introduction
Pharmacology
is the study of substances that interact with living system especially
by binding to regulatory molecules and activating or inhibiting normal
body processes.

Drug
is any substance or product that is used or intended to be used to
modify or explore physiological or pathological states for the benefit
of the recipient.
Introduction
Pharmacodynamics is derived from Greek
Pharmacon = Drug
Dynamics = Action/Power
Pharmacodynamics covers all the aspects relating to “What a drug does to the
body” Mechanism of action
Action: How and Where the effect is produced is called as Action.
Effect: The type of response producing by drug.
Site of Drug Action
Extra cellular
Cellular
Intracellular
 Mechanism of Drug
Action
 A drug may produce its effect through:

– Direct or Non-receptor mediated action.

– Indirect or Receptor mediated action.

 Non-Receptor Mediated
Mechanisms
 Drugs act on enzymes:
 Inducers
 Inhibitors
Nonspecific e.g heavy metals
Specific
Competitive
o Reversible e.g methyldopa and dopa decaboxylase
o Irreversible e.g methotrexate and DHFR
Noncompetitive e.g NSAIDs and COX

 Drugs Act on Voltage- gated ion channels:

 Calcium channel blockers e.g amlodipine
 Sodiun Channel Blockers e.g lidocaine
 Drugs Act on Subcellular Structures:
 Erythromycin and chloramphenicol inhibit protein synthesis in bacteria by
binding to 50 S ribosomal subunit. Tetracyclines and aminoglycosides bind
30 S ribosomal subunit.
 Drugs Act by Chemical Action:
 Antacids neutralize gastric acid secretion.
 Protamine (alkaline & +ve charge) antagonizes heparin (acid & -ve charge).
 Drugs Act on Plasma Membrane:
 Polymixins and amphotericin B increase the permeability of bacterial plasma
membrane.
 Drugs Act on Transporters:
 SSRIs e.g. fluoxetine
 Inhibitors of Na-2Cl-K Symporter e.g furosemide
Drugs Act by Physical Means:
Osmosis e.g. mannitol.
Lubricant e.g. liquid paraffin.
Adsorbent e.g. kaolin and charcoal.
Chelation:
Chelation is mainly employed in the treatment of heavy metal poisoning. A
chelating agent holds the toxic metal ion to form a drug-metal complex, which is
non-toxic, water-soluble and easily excreted in urine e.g.:
EDTA chelates calcium, lead and digitalis.
Dimercaprol (BAL) chelates mercury and copper.
Desfferioxamine chelates iron in cases of iron toxicity.
 Receptor Mediated Action
 Receptor: receptor is a special molecular component of the cell (protein macro-
molecule or DNA) which is capable of selectively recognizing and binding a drug,
hormone, mediator or neurotransmitter, thereby eliciting a cellular response.
 Functions of a receptor are
 ligand binding and message propagation i.e., signaling
 Receptor Mediated Action involves
Drug receptor binding
Signal transduction mechanism
Second messengers
 Drug Receptor Binding…
 Chemicals (ligands/drugs) must bind to the receptor and remain bound long enough for
the receptor to be activated.
Presynaptic

Synaptic cleft Ligands

Receptor
Postsynaptic
 Receptor - Specificity
 There are a number of specific ligands and a number of associated receptors.

Presynaptic

Synaptic cleft

Postsynaptic
 Signal Transduction
 Four types receptor families

1. Enzyme linked (multiple actions)

e.g. receptors for insulin

2. Ion channel linked (speedy)

e.g. Nicotinic, GABA receptors

3. G protein linked (amplifier)

e.g. Adrenergic, muscarinic receptors
4. Nuclear (gene) linked (long lasting)
e.g. NO, Steroid, hormones receptors
1. Enzyme (Protein kinase)-linked receptors
 Group of receptors with intrinsic enzymatic activity
2. Ligand gated ion channels
3. G protein-coupled receptors (GPCRs)
4. Nuclear Receptors = Gene active receptors:
 are soluble DNA binding proteins that regulate the transcription of
specific genes.
 The signal molecule must be able to pass through plasma membrane.

 These hormones can easily pass the

cell membrane and bind with
cytoplasmic mobile receptors. The
drug-receptor complex enters the
nucleus and bind to DNA response
element, which in turn regulates RNA
transcription with production of
unique protein concerned with the cell
response.
 Cytoplasmic Second Messengers
 Binding of an agonist to a receptor provides the first message in receptor
signal transduction to effector to affect cell physiology.
 The first messenger promotes the cellular production or mobilization of a
second messenger, which initiates cellular signaling through a specific
biochemical pathway.
 Common second messengers include
 cyclic AMP,
 cyclic GMP,
 Ca2+,
 Second messengers influence each other both directly, by altering the other’s
metabolism, and indirectly, by sharing intracellular targets.
• Cyclic AMP
• Prototypical second messenger, is synthesized by adenylyl cyclase (AC) under the control
of many GPCRs;
• A single AC activation produces many molecules of cyclic AMP, which, in turn, can
activate PKA.
• Cyclic AMP is eliminated by a combination of hydrolysis, catalyzed by cyclic nucleotide,
phosphodiesterases, and extrusion by several plasma membrane transport proteins.
• Cyclic GMP
• Cyclic GMP is generated by guanylyl cyclase (GC).
• Pharmacologically important effects of elevated cyclic GMP include modulation of
platelet activation and regulation of smooth muscle contraction.
• Calcium
• The entry of Ca2+ into the cytoplasm is mediated by diverse channels: Ca2+ channels in
endoplasmic reticulum, in excitable cells, Ca2+ stores in the sarcoplasmic reticulum.
• Ca2+ propagates its signals through a much wider range of proteins including metabolic
enzymes, protein kinases, and Ca2+-binding regulatory proteins (e.g., calmodulin) that
regulate still other ultimate and intermediary effectors that regulate cellular processes as
diverse as exocytosis of neurotransmitters and muscle contraction.
 Dose-Response Functions
 Displays the relationship between the dose of a ligand and some biological
response to that ligand.

Biological Effect
 Dose-Response Function
 ED50: The dose at which 50% of the maximal biological response is observed

Pain Relief

ED50
 Dose-Response Function

 TD50: The dose at which 50% of the maximal toxicity is observed

Toxicity

TD50
 Dose-Response Function

 LD50: The dose at which lethality is observed in 50% of subjects.

Lethality

LD50
Therapeutic Index
TI = TD50/ED50

Percentage Responding
ED50 TD50
 DOSE-RESPONSE
RELATIONSHIP
 May be:
Graded (dose dependent)
Quantal (all or none)
 Graded dose-response relationship:
o The effect is directly related to dose
o Such a curve has the following characteristic variables:
 Potency:
o Lies on X-axis
o Relates drug dose
o Potency depends mainly on affinity and to some extent on
intrinsic activity (efficacy)
o Potency also depend on drug’s availability at relevant receptors
(thus, absorption, distribution, biotransformation and excretion)
 DOSE-RESPONSE RELATIONSHIP
 Maximal efficacy (Emax)
 It lies on response (Y) axis
 Represents plateau of the curve
 Efficacy and potency are not identical
 Differences in efficacy:
o Morphine is effective all types of pain
o Aspirin is effective on mild to moderate pain
 DOSE-RESPONSE RELATIONSHIP

 Quantal dose-response relationship

 It occurs in an ALL-OR-NONE fashion
 It is not graded or dose dependent, but QUANTAL
o Examples: Death, hypnosis, analgesia, prevention of
convulsion, increase of heart rate by 20 beat/min
 Characterized by EC50, TD50, LD50, EC99
 Used to determine potency by comparing EC50s
 Used to determine margin of safety by using therapeutic
index.
 Terminology
• Efficacy, Power, Intrinsic Activity: it is the ability of a drug receptor
complex to produce an effect. Maximal effect produced if a maximal dose
is given. It is determined by the graded dose- response curve.
• Affinity: it is the ability of a drug to bind a receptor. It is determined by the
dissociation constant (Kd) (the lower the Kd the higher the affinity).
• Potency: it refers to the concentration (EC50) or dose (ED50) of a drug
producing 50% of the maximum effect. It depends on the Kd which
determines the receptor affinity to bind that drug. The lower the ED50,
the more potent drug.
Efficacy & Potency

A B

Biological Effect
Efficacy: A=B
Potency: A>B
Efficacy & Potency

Biological Effect
B

Efficacy: A>B
Potency: A=B
 General classification
of drugs
 Agonist: These drug trigger the maximal biological response or mimic effect of the
endogenous substance. e.g Methacholine is a cholinomimetic drug which mimics
the effect of Ach on cholinergic receptors.
Agonist
 Partial agonist: a drug has affinity, weak efficacy and moderate association
and dissociation. It produces an effect < the full agonist when it has
saturated the receptors. It acts as antagonist in the presence of full agonist
e.g. nalorphine, ergotamine, succinylcholine and oxprenolol.

Partial Agonist
Types of Agonism
Summation
Two drugs eliciting same response, but with different mechanism and their
combined effect is equal to their summation. e.g. Aspirin + Codiene (1+1=2)
Additive
Two drugs eliciting same response by same mechanism. e.g. Aspirin +
Paracetamol (1+1=2)
Synergism (Supra additive)
The combined effect of two drug effect is higher than either individual effect. e.g.
Sulfamethaxazole + Trimethoprim (1+1>2)
Potentiation
Two drugs (one active and the less or inactive) combined and the combined
effect is higher than the effect of the active drug. e.g. Augmentin + Clavunalic
acid (1+0>2)
Types of antagonism Antagonism:
Effect of two drugs is less than sum of the effects of the individual drugs.
Chemical antagonism e.g. heparin (-ve) protamine +ve, Chelating agents
Physiological /Functional antagonism
Pharmacokinetic antagonism
Pharmacological antagonism
Competitive ( Reversible)
Non competitive (Irreversible)
 Antagonist: a ligand having affinity, but no efficacy and slowly associated and
dissociated from the receptor.

Antagonist
 Reversible or Competitive Antagonist: competes with other ligands for biding
to the receptor.
 Irreversible or Noncompetitive Antagonist: exerts its antagonist effects without
competition for occupancy of the receptor.
 Receptor Regulation
 Receptor down regulation
 Prolonged use of agonist
 receptor number and sensitivity e.g. chronic use of salbutamol down
regulates β2 adrenergic receptors.
 Receptor up regulation
 Prolonged use of antagonist
 Increase receptor number and sensitivity e.g propranolol is stopped after
prolong use, produce withdrawal symptoms rise BP, induce of angina.
Types of Receptors
System Type
Acetylcholinergic Cholinergic receptors
Monoaminergic Adrenergic receptors
Dopamine receptors
Serotonin receptor
Aminoacidergic GABA receptors
Glutamate ionotropic receptors
Glutamate metabotropic receptors
Glycine receptors
Histamine receptors
Peptidergic Opioid receptors
Other peptide receptors
Purinergic Adenosine receptors (P1 purinoceptors)
P2 purinoceptors