Pharmacodynamics
description
Transcript of Pharmacodynamics
Dr. Asmah Nasser
Drug DoseAdministration
Drug Effect or Response
Pharmaceutical
Pharmacokinetics
Pharmacodynamics
Pharmacotherapeutics
Disintegrationof Drug
Absorption/distribution
metabolism/excretionDrug/Receptor
Interaction
Introduction
Pharmacodynamics: Study of the biochemical and physiologic effects of drugs and their
mechanisms of action.
Drug actionThe main ways by which drugs act are via
interaction with cell proteins, namely receptors, ion channels, enzymes and transport/carrier proteins.
In addition, drugs can work by themselves mechanically or chemically.
Its useful to know what are the basic principles of drug action.
Principles of Drug actionStimulation: Enhancement of the level of a
specific biological activity (usually already ongoing physiological process). E.g. adrenaline stimulates heart rate.
Depression: Diminution of the level of a specific biological activity (usually already ongoing physiological process). E.g. barbiturate depress the CNS.
Replacement: Replacement of the natural hormones or enzymes (any substance) which are deficient in our body. E.g. insulin for treating diabetes.
Cytotoxic action: Toxic effects on invading micro organisms or cancer cells.
How does all this happen?A drug can produce all the said effects by
virtue of any of the following action1. Through enzymes: a drug can act by either
stimulating or inhibiting an enzymeThrough receptors: this is when a drug
produces its response by attaching itself to a protein called as receptor which in turn regulates the cell function.
Receptor action is the most commonest way of producing action.
Continuation...2. Physical action: The physical property is
responsible for drug action. E.g. radioisotope I131 and other radioisotopes.
3. Chemical action: The drug reacts extracellularly according to simple chemical equations. E.g. antacids neutralising the gastric acid.
4
A deeper look into the receptorThe best-characterized drug receptors are
regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters and hormones.
This class of receptors mediates the effects of many of the most useful therapeutic agents.
Word “Receptor” is used as a loose term
Other Receptors Other classes of proteins that have been
identified as drug receptors include 1. Enzymes, which may be inhibited (or,
less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate)
2. Transport proteins (eg, Na+/K+ ATPase, the membrane receptor for cardioactive digitalis glycosides)
3. Structural proteins (eg, tubulin)
Agonist & AntagonistWhen a drug binds to a receptor the
following can occur and based on this the drugs are classified.
Agonist: when a drug binds to the receptor and activates it to produce an effect
Antagonist: when a drug binds to a receptor and prevents the action of an agonist, but does not have an action on its own.
Tricky
Other termsInverse agonist: when a drug activates a
receptor to produce an effect in the opposite direction to that of the agonist
Partial agonist: when a drug binds to the receptor and activates it but produces a submaximal effect (by antagonising the full effect of the agonist)
Agonist & Inverse Agonist
Affinity & Intrinsic activityAffinity: It is the ability of a drug to bind to
the receptor (just bind)Intrinsic activity: It is the ability of a drug to
activate a receptor following receptor occupation.
AgonistAgonists are the chemicals that interact
with a receptor, thereby initiate a chemical reaction in the cell and produces effect .
Example—ACh is agonist at muscarinic receptor in heart cell.
Will have both Affinity and maximal Intrinsic activity
So, what is a receptor “agonist”?
Any drug that binds to a receptor and stimulates the functional activities
e.g.: Ach
Receptor
Acetylcholine
A Cell
Some Effect
AntagonistA drug that binds to the receptor and
blocks the effect of an agonist for that receptor
Atropine is antagonist of ACh at Muscarinic receptors.
Will have only Affinity but no Intrinsic activity
So, what is a receptor “antagonist”?Any drug that prevents the binding of
an agonisteg: Atropine (an anticholinergic drug)
Acetylcholine
AtropineDude, you’rein my way!
Inverse agonist
Inverse Agonists are the chemicals that interact with a receptor, but produces opposite effect of the well recognized agonist for that receptor
Will have Affinity and negative Intrinsic activity
Example: Flumazenil is an inverse agonist of Benzodiazepine
Inverse agonist
Any drug that binds to a receptor and produces an opposite effect as that of an agonist
Receptor
Inverse agonist
A Cell
Effect opposite to that of the true agonist
Partial agonistPartial agonist activates receptor to
produce an effect. Less response than a full agonist .
Partial agonist blocks the agonist action.
Will have Affinity but sub maximal Intrinsic activity
Partial agonistProduces a submaximal response
True agonist
Partial agonistOh!!!, I shouldHave been here
Submaximal effect
Types of ReceptorsAre they specific?
usually, but not always
Are there subtypes?sometimes …example:
there are several types of epinephrine receptors
1 Receptors in Heart
2 Receptors in Bronchioles
Epinephrine
A ProblemEpinephrine is a non-specific drug: it is an
agonist for BOTH 1 and 2 receptors
Why might this be a problem for someone with asthma and hypertension?
A SolutionMore specific agonists have been developed:
eg: terbutaline is a more specific 2 agonist that is used for treating people with asthma
Major Concepts
Drugs often work by binding to a “receptor”
Receptors are found in the cell membrane, in the cytoplasm, and in the nucleus
Anything that binds to a receptor is a “ligand”
Drug-Receptor interactionIn most cases, a drug (D) binds to a receptor (R)
in a reversible bimolecular reaction
Antagonists can bind to the receptor and occupy its binding site and, therefore, participate only in the first equilibrium.
Agonists, on the other hand, have the appropriate structural features to force the bound receptor into an active conformation (DR*).
This conformational change leads to a series of events causing a cellular response.
Assessment of Receptor Occupation Measure of Affinity
kd is a relative measure of affinity of a drug for its receptor.
It varies inversely with the affinity of the drug for its receptor
High-affinity drugs have lower kd values and occupy a greater number of drug receptors than drugs with lower affinities.
Drug-receptor interactionGenerally the intensity of response
increases with doseThe drug receptor interaction obeys the
law of mass action Emax X [D] KD+[D]E=
Law of mass actionE is observed effect at dose [D] of a drugEmax is the maximal responseKD is the dissociation constant of a drug
receptor complexKD is usually equal to the dose of a drug at
which half maximal response is produced
Classification of receptorsG-protein coupled receptorsIon channelsEnzymatic receptorsIntracellular receptors (regulates gene
expression)
Ion channelsThe cell surface enclose ion channels specific
for Ca2+, K+, or Na+
These ion channels are controlled by the receptors
E.g. Gs opens Ca2+ channels in the myocardium and skeletal muscle and Gi opens the K+ channels in heart
Some receptors also modulate the ion channels without the intervention of coupling proteins or 2nd messengers
E.g. benzodiazepines modulating Cl- channels in the brain
Ion channels
Dose Vs Response
Increases in response until it reaches maximum, Later it remains constant despite increase in dose .. Plateau effect
DOSE RESPONSE CURVE
DOSE of drug
% o
f Res
pons
e After this point increase in dose doesn’t increase the response
Log dose response curveThe dose response
curve is a rectangular hyperbola
If the doses are plotted on a logarithmic scale, the curve becomes sigmoid
A linear relationship between log of dose and the response can be seen
Efficacy and PotencyEfficacy is the maximal response
produced by a drugIt depends on the number of drug-
receptor complexes formed Potency is a measure of how much drug is
required to elicit a given responseThe lower the dose required to elicit given
response, the more potent the drug is
ED50
It is the dose of the drug at which it gives 50% of the maximal response
A drug with low ED50 is more potent than a drug with larger ED50
Log drug concentration
% o
f res
pons
e
100%
50%
0%10mg 20mg 30mg 40mg 50mg
75%
25%
200mg
Potency of Drug A >Drug B > Drug CA B C
Efficacy and Potency
C
Potency
Dose of a drug that required to produce 50% of maximal effect (ED 50)
Relative Positions of the DRC on x-axis
More left the DRC, more potent the drug
Efficacy
Maximum effect of the drug
Height of the curve on x-axis indicates the
efficacy of the drugTaller the DRC ,more
efficacious the drug
Probing question A 55-year-old woman with congestive heart
failure is to be treated with a diuretic drug. Drugs X and Y have the same mechanism of diuretic action. Drug X in a dose of 5 mg produces the same magnitude of diuresis as 500 mg of drug Y. This suggests that
Drug Y is less efficacious than drug X Drug X is about 100 times more potent than drug Y Toxicity of drug X is less than that of drug Y Drug X is a safer drug than drug Y Drug X will have a shorter duration of action than
drug Y because less of drug X is present for a given effect
Slope of DRCThe slope of midportion of the DRC varies
from drug to drugA steep slope indicates small increase in dose
produces a large change in response
Drug Dose
Fall
in B
P
Hydralazine.. steep
Thiazides.. Flat
SLOPE STEEP DRC
Moderate increase in dose leads to more increase in response
Dose needs individualization for different patients
Unwanted and Uncommon
FLAT DRCModerate increase in
dose leads to little increase in response
Dose needs no individualization for different patients
Desired and Common
Quantal dose response curvesThe quantal dose-effect curve is often
characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect.
Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50) If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined
Quantal dose-effect curves are used to generate information regarding the margin of safety (Therapeutic index)
Quantal DRC
Therapeutic index
Therapeutic index (TI)Lethal dose (LD50) is estimated only in
preclinical animal studies LD50 is not calculated in humans-OFCOURSESo we use the term “safety margin” of a drug
or “therapeutic window”
Therapeutic windowIt is a more clinically relevant index of
safetyIt describes the dosage range between the
minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose
E.g. theophylline has an average minimum plasma conc of 8 mg/L and the toxic effects are observed at 18 mg/L
The therapeutic window is 8 – 18 mg/L
Therapeutic range
EFFE
CT
Toxic effect
Therapeutic effect
8 mg/L 18mg/L8-18mg/L
Min
imum
ther
apeu
tic e
ffect
Min
imum
tole
rabl
e ad
vers
e ef
fect
Clinical significanceDrugs with a low TI should be used with
caution and needs a periodic monitoring (less safe)
E.g. warfarin, digoxin, theophyllineDrugs with a large TI can be used
relatively safely and does not need close monitoring (highly safe)
E.g. penicillin, paracetamolOther terms used: wide safety margin,
narrow safety margin
Synergism and antagonism When two drugs are given together or in
quick succession 3 things can happen:1. Nothing (indifferent to each other)2. Action of one drug is facilitated by the
other (synergism)3. Action of one drug may decrease or inhibit
the action of other drug (antagonism)
Synergism Two types:1. Additive effect: the effect of two drugs
are in the same direction and simply add up.
Effect of drug A + B = effect of drug A and B
2. Supraadditive effect (potentiation): the effect of combination is greater than the individual effect of the components.
Effect of drug A + B > effect of drug A + effect of drug B
Antagonism Different types of antagonism1. Physical: based on physical property of a
drug. E.g. activated charcoal adsorbs alkaloids
and prevents their absorption (in alkaloid poisoning)
2. Chemical: based on chemical properties resulting in an inactive product.
E.g. chelating agents complex metals (used in heavy metal poisoning)
Contd..3. Physiological antagonism: two drugs act
on different receptors or by different mechanisms, but have opposite effects
E.g. histamine and adrenaline on bronchial smooth muscle and BP
E.g. several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin.
4. Receptor antagonism
Receptor antagonismThis when an antagonist interferes with
the binding of the agonist with its receptor and inhibits the generation of a response
Receptor antagonism is specificE.g. an anticholinergic will decrease the
spasm of intestine induced by cholinergic agonists but not the one induced by histamine
Receptor antagonism can be competitive and noncompetitive
Competitive antagonismCompetitive ---
Surmountable Competes with agonist
in reversible fashion for same receptor site
Necessary to have higher concentration of agonist to achieve same response
Competitive agonist
Noncompetitive antagonismNoncompetitve ---
Insurmountable Antagonist binds to
a site different to that of an agonist
No matter how much agonist -- antagonism cannot be overcome
COMPETITIVE Antagonist binds with
same receptorChemical resemblance
with agonist Parallel rightward
shift of DRCApparently reduces
potency of agonistIntensity of response
depends both on antagonist and agonist concentration
Eg: Acetylcholine and Atropine
NONCOMPETITIVE Another site of receptor
bindingDoes not resemble Flattening of DRC
Apparently reduces efficacy of agonist
Intensity of response depends mainly on antagonist concentration
Eg: phenoxybenzamine (for pheochromocytoma)
Receptor Numbers and ResponsesThe NUMBER and AFFINITY of receptors
may changeAn increase in receptor number is called
UPREGULATIONA decrease in receptor number is called
DOWNREGULATION
Upregulation of ReceptorsUpregulation: An increase
in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another agent.
For example, there is an increase in uterine oxytocin receptors in the third trimester of pregnancy, promoting the contraction of the smooth muscle of the uterus
Downregulation of ReceptorsEg: Downregulation:
prolonged use of propranolol can DECREASE the number of 1 receptors
Prolonged & frequent use of short acting 2 receptor agonists decrease the number of 2 receptors
Clinical relevance:A patient’s response to drug
therapy may change over time
Rats!Where did they
all go?!?
Tolerance Gradual reduction in response to drugs
is called as tolerance Requirement of higher dose to produce a
given response It occurs over a period of time E.g. tolerance to sedative-hypnotics Many reasons for tolerance1. Pharmacokinetic reasons-chronic use
leads to enhanced clearance-less effective concentration
2. Pharmacodynamic reasons (reduced number and/or affinity of the receptors to the drugs)-downregulation
TachyphylaxisRapid desensitization
to a drug produced by inoculation with a series of small frequent doses.
A rapidly decreasing response to a drug following its initial administration
E.g. ephedrine, tyramine, nicotine.
Spare receptorsIn some cases, the response elicited by a
drug is proportional to the fraction of receptors occupied
More commonly, a maximal response can be achieved when only a small fraction of receptors are occupied by an agonist
Receptors are said to be spare when maximal response can be elicited by an agonist at a conc. that does not result in occupancy of the full complement of available receptors
No qualitative difference form non spare receptors
Graphical representation of a spare receptor (refer to notes section below for explanation)
Spare receptors, KD and EC50KD is the concentration of the agonist at
which 50% of the receptors are occupiedIf the number of receptors increase many
fold (spare receptors) THEN:A much lower concentration of agonist is
sufficient to produce 50% of maximal response (EC50)
Occupation of spare receptors is determined by comparing the EC50 with Kd
If EC50 is less than Kd, spare receptors are said to exist
Factors affecting Drug ActionIt is a rule rather than an exception that
there is a large variation in the drug response for the same dose in different individuals.
Pharmacokinetic handling of the drug
Number or state of receptors
Variations in neurogenic/hormonal tone
Contd..Body Size/Wt.The average adult dose refers to individuals
of medium builtFor exceptionally obese and lean and for
children the dosage should be calculated based on body wt.
Individual Dose = BW (Kg)/70 x average adult dose
Dosage calculation based on surface area more appropriate for children
Contd..Age Extreme care has to be taken while
administering drugs to children and elderlyDrug metabolizing enzymes are very poor
and in case of elderly they might have some other diseases
Reduced doses are ideal for these age groups.
Contd..GeneticsDeficiency of some enzymes may lead to drug
toxicity because of poor or absence of metabolism
Route of drug administrationIV route has quicker and prominent action
when compared to oral routePsychological role is also a major determinant
of drug effect
Contd..
Pathological statesAny underlying pathology may alter the drug
responseSpecial care is taken if the patient has renal or
hepatic impairment as the drugs are not eliminated and it may lead to severe drug toxicity.
Alzheimer’s disease – memory loss- failure to take medications
Contd..Co-administration of other drugsOne drug may affect the drug action of
others, it may be useful or it may be harmful.
Drug interactions play a very important part of therapeutics.
Diet & environmental factors too play a important role in deciding the drug action.
Things to know In pharmacodynamics you SHOULD know by now:
1. Principles of drug action2. Agonist & its types3. Antagonist and its types (on DRC)4. Spare receptors 5. Affinity-intrinsic activity6. Potency-efficacy (explain with DRC)7. Therapeutic index and its calculation8. Classification of receptors9. G-protein coupled receptors10. Second messenger concept (role of cAMP and
IP3 & DAG)11. Downregulation & upregulation of receptors
Practice Question When tested under identical conditions with all
statistical requirements rigidly applied, drug X has the following parameters: LD50=0.5 mg/Kg
Ed50=0.5 µg/Kg. The therapetic index is1. 0.0012. 0.13. 1.04. 105. 1000
Practice Question In the absence of other drugs, pindolol causes
an increase in heart rate by activating beta adrenoceptors. In the presence of highly effective beta stimulants, however, pindolol causes a dose-dependent, reversible decrease in heart rate. Therefore, pindolol is probably
An irreversible antagonist A physiologic antagonist A chemical antagonist A partial agonist A spare receptor agonist
Practice question
Which line is most efficacious?
Which is more potent?