Pharmacody

namics
Ma. Minda Luz M. Manuguid,
M.D.
 Pharmacodynamics
Pharmacodynamics – deals with the
action of a drug on the body; what the
drug does to the body;
Mechanisms of Drug Action on the
bory:
Receptor interactions
Dose-related phenomena
Therapeutic action
Toxic effects
 Definitions
Agonist – drug that triggers the same events as the
native ligand when it binds to a receptor
Antagonist – drug that prevents binding of the native
ligand to the receptor so that it sannot produce its
normal action
Affinity – ability of a drug to bind to a receptor (how
well a drug & a receptor recognize each other)
Potency – quantity of a drug needed to achieve a
desired effect; more potent, lower EC50
Quality – bioavailability of the drug
Efficacy – maximal effect an Agonist can achieve at
the highest practical concentration ( a measure of
how well a drug produces a response); high Emax
 Definitions
2nd messenger – small nonprotein water-
soluble molecule or ion that readily
spreads a ‘signal’ throughout the cell by
diffusion (e.g. cyclic AMP; Calcium ions)
Signal transduction – process by which
extracellular inputs (e.g. drug-receptor
interactions) lead to intracellular
messages that moderate cell physiology
sequencing
 Mechanisms of Signal
Transduction
 Drug crosses the cell membrane, activates an
intracellular receptor e.g. steroid hormones
 A transmembrane receptor protein with intracellular
enzyme activity is affected by a drug binding to a site
on the enzyme that can alter its activity
 A drug-transmembrane receptor protein complex binds
& stimulates a 2nd protein such as Tyrosine kinase
 A drug binding to a transmembrane ion channel
changes ion conductance, affecting membrane
potentials e.g. nicotinic Ach receptor stimulation
 An agonist drug binds to a transmembrane receptor,
stimulating a G protein, leading to increased
intracellular 2nd messengers that result in many
2ºintracellular responses e.g. adrenergic stimulation
 Benefits of a Signal
Transduction Pathway
Signal amplification
Increased cellular processes
Proteins persist in active form long enough to
process numerous molecules of substrate
Each step activates more products than the
preceding step
Signal specificity
Specific cellular components (& therefore
specific cellular processes) are affected
 Drug Binding
 Covalent bonds – sharing of a pair of electrons
between 2 atoms; very stable, very strong-
requires hundreds of kilojoules to disrupt
 nonCovalent bonds – generally weak –
 Hydrogen bonds
 Van der Waals forces
 Ionic / Electrostatic interactions
 Hydrophobic interactions
 Effects of Binding:
 Conformation – binding locks a mobile flexible
molecule into a restricted conformation
 Configuration / Stereochemistry -
 Targets for Drug Action
“A drug will exert its activity through interactions at one or
more molecular targets – macromolecular species that
control the function of cells: surface-bound receptors & ion
channels or internal structures like enzymes & nucleic
acids”
Targets for Drug action: Processes of Drug Action:
 Receptors *chemical
 Ion channels *enzymatic
 Enzymes *thru receptors
 Carriers * thru ion channels
*thru 2nd messengers
 Receptor targets for Drug
Action
receptor agonist antagonis
t
Nicotinic Ach Acetylcholine; Tubocurarine
receptor Nicotine
β blocker Noradrenalin Propranolol
Opiate Morphine Naloxone
5 HT2 receptor 5 HT Ketanserin

Dopamine2 Dopamine Chlorpromazin

receptor e
Ion channel targets for Drug
Action
Ion channel Effectors: Modulators
blockers
Voltage-gated Na Local Veratridine
channel anaesthetics
Renal tubular Na Amiloride Aldosterone
channel
Voltage-gated Ca Divalent cations Dihydropyridines
channel
GABA-gated Cl Picrotoxin Benzodiazepines
channel
ATP-sensitive K ATP Sulfonylureas
channel
Glutamate-gated Dizoclipine, Glycine
channel Ketamine
 Enzyme targets for Drug
Enzyme
Action
Effectors: False
inhibitors substrates
Acetylcholinester Neostigmine;
ase (AChE) Organophosph
ates
cycloOxygenase Aspirin
Angiotensin- Captopril
converting
enzyme (ACE)
Xanthine oxidase Allopurinol
Choline acetyl hemicholiniu
transferase m
Reverse Didanosine
transcriptase
 Carrier targets for Drug
Carrier
Action
Inhibitors False
substrates
Choline carrier Hemicholinium

Noradrenalin TCA; Cocaine Amphetamine;

uptake Methyldopa
Noradrenalin Reserpin
uptake (vesicular)

Weak acid carrierProbenecid

Na-K pump Cardiac

glycoside
 Drug Receptors
Drug receptor – macromolecular component of a
cell with which a drug interacts to produce a
response; usually a protein, a drug interacts with it
in a “lock-&-key” fashion, initiating a chain of
events that leads to a pharmacologic response.
Types of Receptors:
Type I : Ionotropic /Ligand-gated ion channels
Type II : Metabotropic / coupled to G-protein
Type III: Tyrosine Kinase-linked (e.g. Insulin
receptor)
Type IV: Steroid receptors (e.g. Thyroxine; Cortisol)
 Protein Receptors
Receptors for endogenous regulatory
ligands – hormones, growth factors,
neurotransmitters;
Enzymes of crucial metabolic or
regulatory pathways –
Acetylcholinesterase,
Enzymes in transport processes – Na/K
pump;
Structural proteins – Tubulin;
Drug – Receptor Interactions
 The binding of a drug to a specific receptor causes some
event which leads to a response
 Response to a drug is graded or dose-dependent
 Drug-Receptor interactions follow simple mass-action
relationships:
 Only one drug molecule occupies each receptor site
 Binding is reversible
 For a given drug, the magnitude of response is directly
proportional to the number of receptor sites occupied by
drug molecules
 The number of drug molecules is assumed to be much
greater than the number of receptor sites
Drug – Receptor Interactions
 Receptor – specific macromolecule ( Proteins –
90% - membrane, cytoplasmic or extracellular
enzyme, nucleic acid; Lipids; Carbohydrates)
which is the site of action of most drugs: Only
around 10% of drug actions & effects are NOT
mediated thru receptors.
 For most drugs, the magnitude of the
pharmacological response increases as the
dose (drug concentration) increases
 Only one drug molecule occupies each receptor
site, & binding is reversible
 The Dissociation Constant
The Dissociation Constant – KD –
drug concentration at which half
maximal binding occurs: the smaller
the KD, the greater the affinity of the
drug to the receptor; the smaller the
KD for a reaction, the lower the
concentration of drug required in
order to produce half maximal
binding
Log dose – Response curve
characteristics:
Maximal effect (plateau)
Potency – the location of the drug response curve
along the horizontal axis: drug effect with respect to
dose (vs. Efficacy – maximal ceiling effect)
Slope
 Standing curve – minute changes in dose result in large
effects
 Inclining curve – large changes in dose needed for an effect
Variability – the curve is different from drug to drug,
from patient to patient, & from time to time in the
same patient. So if you want to fix the pharmacologic
response at a certain level, you have to use a Range
of Dose
Log dose – Response Curve

Maximal
effect
intensity of effect

variability

slope

potency

Log dose
 Dose – Response
Relationship
 No drug can create a new effect: a drug only
modulates a pre-existing function
 Drug-receptor interaction leads to
enhancement, inhibition, or blockade of
molecular signals, which is then amplified thru
biochemical & physiologic events to produce
the pharmacological (clinical) effect
 The magnitude of a response is graded, i.e.
increases continuously as the concentration of
unbound drug increases at the receptor site
 Definitions
GRADED-RESPONSE CURVE: A plot of efficacy
(some measured value, such as blood pressure) -vs-
drug concentration.
 EC50 = drug concentration at which 50% efficacy is
attained. The lower the EC50, the more potent the drug.
 Emax = the maximum attained biological response out of
the drug.
QUANTAL DOSE-RESPONSE CURVE: A graph of
discrete (yes-or-no) values, plotting the number of
subjects attaining the condition (such as death, or
cure from disease) -vs- drug concentration.
 ED50: dosage at which 50% of the population attains the
desired effect
 LD50: dose at which 50% of the population is killed from a
drug.
 Agonists & Antagonists
 Agonists – drugs that interact with &
activate receptors
 Full agonists – maximal efficacy (Emax)
 Partial agonists – less than maximal efficacy - At
low concentrations, it increases the overall
biological response from the receptor. At high
concentrations, as all receptors are occupied, it
acts as a competitive inhibitor and decreases
the overall biological response from the receptor.
 Antagonists – drugs that prevent the
agonists from having an effect by binding to
the receptor or to part of the effector
mechanism; have no effect themselves
 AGONIST ANTAGONIST
Agonist has affinity Antagonist has affinity
plus intrinsic activity but NO intrinsic
activity
Partial agonist has Competitive
affinity & (less) antagonists may be
intrinsic activity overcome
(surmountable)
Agonists tend to Antagonists tend to
desensitize receptors up-regulate receptors
 Inhibition
 COMPETITIVE INHIBITORS: They bind to the same site as
the endogenous molecule, preventing the endogenous
molecule from binding.
 The Dose-Response Curve SHIFTS TO THE RIGHT in the
presence of a competitive inhibitor. EC50 is increased: more of
a drug would be required to achieve same effect. Emax does
not change: maximum efficacy is the same, as long as you have
enough of the endogenous molecules around.
 The effect of a competitive inhibitor is REVERSIBLE and can be
overcome by a higher dose of the endogenous substance.
 The intrinsic activity of a competitive inhibitor is 0. It has no
activity in itself, but only prevents the endogenous substance
from having activity.
 Inhibition
NON-COMPETITIVE INHIBITORS: They either (1)
bind to a different (allosteric) site, or (2) they bind
irreversibly to the primary site.
 The Dose Response Curve SHIFTS DOWN in the presence of
a non-competitive inhibitor. EC50 is increased: more of a
drug would be required for same effect. Emax decreases:
The non-competitive inhibitor permanently occupies some
of the receptors. The maximal attainable response is
therefore less.
 The intrinsic activity of the non-competitive inhibitor is
actually a negative number, as the number of functional
receptors, and therefore the maximum attainable biological
response, is decreased.
 Properties of a Drug
 Safety:
Therapeutic Index (TI) = LD50 / ED50
 The ratio of median lethal dose to median effective dose.
 The higher the therapeutic index, the better. That means that a
higher dose is required for lethality, compared to the dose
required to be effective.
 minimum dose that produces toxicity over the minimum dose
that produces an effective therapeutic response; TI < 4
=relatively greater potential for toxicity
Margin of Safety = LD1 / ED99
 The ratio of the dosage required to kill 1% of population,
compared to the dosage that is effective in 99% of population.
 The higher the margin of safety, the better. greater difference
between therapeutic effective dose (ED) & toxic dose (TD)
 Drug interactions
Synergism/Potentiation – concomitant
administration of another drug will increase the
clinical effect e.g. multi-regimen TB treatment
Addition – effects of two drugs administered at the
same time will be added to each other e.g. DOLCET
Inhibition – simultaneous administration of another
drug will decrease the effects of the first e.g. Warfarin
& vitamin K
Pharmacokinetic interaction – giving of another drug
will affect the first’s absorption, distribution,
metabolism, &/or excretion
 Adverse Effects & Drug
Interactions
Side effect - part of the pharmacologic action of
the drug but not the effect the drug is being used
for; may be undesirable (adverse) e.g. gastric
irritation from NSAIDS
Hypersensitivity reactions / Drug Allergy: An
exaggerated, immune-mediated response to a
drug.
 TYPE-I: Immediate IgE-mediated anaphylaxis.
e.g.Penicillin anaphylaxis.

 Immunologic Reactions
 TYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG
or IgM mediated attack against a specific cell type, usually
blood cells (e.g.Hemolytic anemia: induced by Penicillin or
Methyldopa; Thrombocytopenia: induced by Quinidine;
Drug-induced SLE caused by Hydralazine or Procainamide.
 TYPE-III: Immune-complex drug reaction Serum Sickness:
Urticaria, arthralgia, lymphadenopathy, fever. Steven-
Johnson Syndrome: Form of immune vasculitis induced by
sulfonamides. May be fatal. Symptoms: Erythema multiforme,
arthritis, nephritis, CNS abnormalities, myocarditis.
 TYPE-IV: Contact dermatitis caused by topically-applied drugs
or by poison ivy.
 Drug Toxicity
 Drug Toxicity: dose-dependent adverse response to a
drug.
 Organ-Directed Toxicity: Aspirin induced GI toxicity (due to
prostaglandin blockade); Epinephrine induced arrhythmias (due
to beta-agonist); Propanolol induced heart-block (due to beta-
antagonist); Aminoglycoside-induced renal toxicity;
Chloramphenicol-induced aplastic anemia.
 Neonatal Toxicity: Drugs that are toxic to the fetus or
newborn. Sulfonamide-induced kernicterus;Chloramphenicol-
induced Grey-Baby Syndrome; Tetracycline-induced teeth
discoloration and retardation of bone growth.
 Teratogens
TERATOGENS: Drugs that adversely affect the
development of the fetus: especially dangerous
during organogenesis (3rd to 8th week)
• Thalidomide:
• Antifolates such as Methotrexate.
• Phenytoin: Malformation of fingers, cleft palate.
• Warfarin: Hypoplastic nasal structures.
• Diethylstilbestrol: Oral contraceptive is no longer
used because it causes reproductive cancers in
daughters born to mothers taking the drug.
• Aminoglycosides, Chloroquine: Deafness
 Idiosyncrasy
 Drug Idiosyncrasies: An unusual response to a drug due to
genetic polymorphisms, or for unexplained reasons.
 Isoniazid: N-Acetylation affects the metabolism of isoniazid
• Slow N-Acetylation: Isoniazid is more likely to cause peripheral neuritis.
• Fast N-Acetylation: Some evidence says that Isoniazid is more likely to cause
hepatotoxicity in this group. However, other evidence says that age (above 35 yrs
old) is the most important determinant of hepatotoxicity.
 Alcohol can lead to facial flushing, or Tolbutamide can lead to
cardiotoxicity, in people with an oxidation polymorphism.
 Drug Idiosyncrasies
 Succinylcholine can produce apnea in people with abnormal serum
cholinesterase. Their cholinesterase is incapable of degrading the
succinylcholine, thus it builds up and depolarization blockade results.
 Primaquine, Sulfonamides induce acute hemolytic anemia in
patients with Glucose-6-Phosphate Dehydrogenase deficiency.
• They have an inability to regenerate NADPH in RBC's ------> all reductive
processes that require NADPH are impaired.
• Note that this is Acute Hemolytic Anemia, yet it is not classified as an
allergic reaction -- it is an idiosyncrasy when caused by sulfonamides or
primaquine. Other anemias are Type-II hypersensitivity reactions.
• G6PD deficiency is most prevalent in blacks and semitics. It is rare in
caucasians and asians.
 Barbiturates induce porphyria (urine turns dark red on standing) in
people with abnormal heme biosynthesis.
• Psychosis, peripheral neuritis, and abdominal pain may be found.
 Tolerance
 Pharmacokinetic Tolerance: Increase in the
enzymes responsible for metabolizing the drug.
e.g.Warfarin doses must be increased in patients
taking barbiturates or phenytoin, because these
drugs induce the enzymes responsible for
metabolizing warfarin.
Pharmacodynamic Tolerance: Cellular tolerance,
due to down-regulation of receptors, or down-
regulation of the intracellular response to a drug.
Physiologic Tolerance: Two agents yield
opposite physiologic effects.
 Tolerance
Competitive Tolerance: Occurs when an agonist
is administered with an antagonist. Example:
Naloxone and Morphine are chemical antagonists,
and one induces tolerance to the other.
Tachyphylaxis (Refractoriness /
Desensitization) – progressive reduction in drug
effect due to receptor desensitization
 Homologous – decrease in number of receptors
 Heterologous – decreased signal transduction
e.g.Tyramine can cause depletion of all NE stores if you
use it long enough, resulting in tachyphylaxis.
 Habituation & Addiction
Habituation – getting used to a
drug such that one becomes
emotionally dependent on the drug
Addiction – true physical as well as
emotional dependence on a drug; will
need pharmacologic support during
withdrawal
 to be
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