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BASIC PHARMACODYNAMIC
Pharmacodynamic
Pharmacodynamic the study of drug effects and attempts to elucidate the complete
action-effect sequence and the dose-effect relationship
what the drug does to the body
Pharmacodynamic
Describes the relationship between plasma drug concentration and pharmacological effects, on various
systems of the body CNS, CVS, Resp, GIT, GU, MS etc
Pharmacodynamics - Concept Transduction of biological signals /
Mechanisms of drug action Chemical evaluation of drug effects Variation in drug response
Adverse Drug Reaction Drug Interactions
1. MECHANISM OF DRUG ACTION
Excitable Cell Membrane Proteinseg receptor, ion channels, ion pumps
Activation of chemical cascades
Clinical Effects
Mechanism of Drug Action
1. Receptors:- Ion channel linked (atracurium) - G-protein coupled (adrenaline) - Protein kinase linked (insulin)- Cytosolic or nuclear receptors that
regulate gene transcription (steroids)
2. Direct Ionic Channel Actions (local anaesthetics on Na
channel)
3. Enzyme Inhibition (neostigmine- inhibit antichol)
Mechanism of Drug Action
4. Carrier molecules (digoxin on Na+/K+/ATPase)
5. Colligative properties (mannitol) 6. Structural analogues/counterfeiting (acyclovir chemotherapeutic agents) 7. Chemical reactions (heparin/protamine,
antacids) 8. Chelation (penicillamine, desferrioxamine)
Mechanism of Drug Action
Drug needs to transduce extracellular signals into intracellular messages via
receptor
a. Receptor
Macromolecular complexes with recognition sites That selectively bind and interact with
extracellular drugs To initiate a biochemical change/ a cascade
of biochemical alteration That represent a characteristic biological
effects of the drugs. Consists of at least 2 components;
Recognition site- bind to drugs Effector system- senses & responds to binding of
Drug
Mechanism of Drug Action
5 basic mechanism for transmembrane signaling:
A lipid soluble ligand that crosses the membrane and acts on an intracellular receptor
Transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain
Mechanism of Drug Action
Transmembrane receptor that binds and stimulates a protein tyrosine kinase
A ligand-gated transmembrane ion channel that can be induced to open and close by the binding of a ligand
Transmembrane receptor protein that stimulates a GTP binding signal transducer protein which generate intracellular second messenger
Intracellular receptor
Not all signal receptors are located on the plasma membrane. Some
are proteins located in the cytoplasm or nucleus of target cells.
The signal molecule must be able to pass through plasma membrane.
Examples:
~Nitric oxide (NO)
~Steroid
~ Hormone (estradiol, progesterone, testosterone and thyroid
hormones )
Intracellular receptor
Steriods pass through the plasma membrane
interact with intracellular receptor proteins
The activated receptor complex binds to specific DNA sequences
and acts to regulate the transcription of specific genes.
Ligand regulated transmembrane enzyme:receptor tyrosine kinases
Structure:
•Receptors exist as individual polypeptides
•Each has :
~ an extracellular signal-binding site
~ An intracellular tail with a number of tyrosines and
~ a single å helix spanning the membrane
Ligand regulated transmembrane enzyme:receptor tyrosine kinases
Ion- channel- linked receptor
There are two general classes of ion channels: i. voltage gated ii. ligand gated
i) Voltage gated - activated by alterations in membrane voltage. e.g. voltage-gated sodium (Na+) channels open when the membrane is depolarized to a
threshold potential and contribute to further
membrane depolarization by allowing Na+ influx into
the cell.
Ion- channel- linked receptorii. ligand gated activated after binding to specific
ligands or drugs. Many neurotransmitters and drugs activate membrane- bound ligand
ion – gated channels Eg: Nicotinic Ach R GABA receptor
Ion- channel- linked receptor
G-Protein
• Many ligands acts by increasing
intracellular second
messengers.
• There are three separate components
Ligand binds to receptors
Receptor activate G protein
G protein activate enzyme or ion
channels
G-protein
Is a heterotrimetric nucleotide regulatory proteins that translates a signal
to a biological event inside cells. G proteins : 3 subunits
, and The -subunit is bind
to GDP
G-proteinactivated receptor binds
to G- protein,
it induces the G protein to exchange GDP for a GTP.
Presence of GTP causes the
-subunit to separate.
-subunit then activates the enzyme that initiates a second
messenger response.
G-protein The effectors may be :
phosphodiesterase, phospholipase C, adenylate cyclase, phospholipase A2
The second messengers : inositol triphosphate (IP3), diacylglycerol (DAG) cyclic AMP (cAMP).
Receptors and their relationship to transmembrane signaling pathways
Ion Pumps
Pharmacological agent acting on ion pumps, altering intracellular / extracellular cation ratios, resulting in altered membrane potential Digitalis- inhibit Na/K ATPase in
myocardial cells, replaced by slower Na/Ca xchange
Loop diuretics- inhibit Na/K/Cl co- transporter at luminal membrane of loop of Henle
CLINICAL EVALUATION OF DRUG EFFECTS
Relation between drug concentration & response
Dose- response curve - hyperbolic Generally the response increase
with the increase of concentration at the receptor
Eventually, increments in dose produce no
further change in effect i.e. maximal effect for that drug is obtained Difficult to analyze mathematically
Principle of clinical pharmacology – Elsevier 2007
Log dose-response curve Sigmoid curve
This has the advantage of:- Wide range of drug can
be easily displayed Comparison easier
displayed Easier to analysed
mathematically
Relation between drug concentration & response
Log-dose response curve
Position of DRC on the dose axis shows potency
Upper limit of the DRC show efficacy
The DRC slope steeper requires dose individualization
Dose Response Curve
Potency Quantity of drug, that must be
administered to produce a maximum effect
Range of concentration over which a drug produces increasing response
Related to affinity tendency of a drug to form a stable
complex with the receptor Related to ‘position of the curve’
potency Leftward shift of the curve
Dose Response Curve
Efficacy Measure of the intrinsic ability of a drug to produce a given effect Intrinsic ability;
ability to produce a response by interacting with receptor
Related to the maximum effect that can be produced by a given drug
Dose Response Curve
Slope
The slope of DCR is influence by the number of receptors that
must be occupied before the effect occurs.
A steep slope on DCR means majority of the receptors must be occupied
before an effect occurs. small increase in dose evoke intense
increase in drug effect.
Slope
Dose response curve Individual variability ~ pharmacokinetics - transport proteins binding &
metabolism - bioavailability - liver function - renal function - cardiac function - age ~ pharmacodynamics - receptors and sensitivity - drug interactions ~ genetic variability - missing enzymes - disease unmasked by drugs
Binding Characteristic of Drugs Agonist
a drug that acts on receptors to elicit a response
Partial Agonist a drug that acts on receptors to elicit a
response but cannot produce the maximal response have low intrinsic activity able to antagonise the effect of large doses
of full agonist. Inverse Agonist
drug act at same receptor as agonist but produce opposite pharmacological effect
Also called negative antagonists, Eg: BDZ receptor inverse agonist: propyl carboline-3-carboxylate
Binding Characteristic of DrugsAntagonist: The drug that interact with the receptor but do
NOT change the receptor they have affinity but NO efficacy drug that binds to receptors does not elicit a
response
Types of antagonism:1.Competitive reversible antagonism
2.Competitive irreversible antagonism
3.Non-competitive or functional antagonism
4.Physiological antagonism
5.Chemical antagonism
Competitive reversible antagonism drug that bind to the receptor
in a reversible way without activating the effector system for that receptor
compete with agonists for the receptor
the antagonism can be overcome by increasing the agonist concentration
displace the agonist dose-effect curve to the right
do not change the maximal efficacy
Competitive irreversible antagonism drug that bind to the
receptor in an irreversible way
reduce the number of receptors available to produce a response
effects are not reversed by increasing concentrations of the agonist.
decreases maximal efficacy.
e.g. pralidoxime in OP poisoning
Non-competitive or functional antagonism
Irreversible non-competitive antagonist – functional antagonism
drug that bind to the receptor in an irreversible way and reduce the number of receptors available to produce a response
Not compete wt agonist for receptor Drug binds to receptor & stays
bound The effects are not reverse by
increasing the concentration of the agonist.
Decrease the max. efficacy
Types of Antagonism
Physiological Antagonism Drug that bind to a different receptor producing an effect opposite to that
produced by the drug eg : parasympathetic and sympathetic
nervous sys ACh & Adr
Chemical Antagonism Drug that interact directly with the drug
being antagonized to remove it or to prevent it from
reaching its target eg Protamine & Heparin
3. VARIATION IN DRUG RESPONSE
Variation in drug response Individual variation in response to an
identical dose of administered drug can occur as a result of differences in
Pharmacokinetic parameters ADME
Pharmacodynamic parameters Age, Genetic variability, Disease states,
Receptor Desensitisation/ Increased sensitivity
Adverse Drug Reaction
any responses to a drug which is noxious and unintended,
occurs at doses used for prophylaxis, diagnosis or treatment
i) Type A reaction : Dose related, predictable reaction
Side effects; known pharmacological effect/lack of specificity
Extension of the usual therapeutic response
Adverse drug reaction
Quantal Response Refers to one where specified
response/effect is either present or absent All or none response eg death, sleep, convulsion
Graded Response Refers to one where the magnitude of
response varies over a range depending on the dose of a drug
eg muscle contraction
Drug safety
Therapeutic Index (TI) Margin of safety
Difference between dose producing desired effects and
undesired effects
In animal studies, TI = LD50 (lethal dose in 50%)
ED50 (effective dose in 50%)
Certain Safety Factor (CSF)
In human studies, TI = TD1 (toxic dose in 1%)
ED99 (effective dose in 99%)
Quantification of drug safety
• ED50 (effective dose 50) :
- dose of a drug required to produce a specific effect in 50% of
individuals to whom it is administered
• LD50 (lethal dose 50) :
- dose of a drug required to produce death in 50% of individuals (or
animals) to whom it is administered
Therapeutic Index
- margin of safety
-differences btwn dose producing desired effect & undesired effect
Therapeutic Window
- plasma concentration that prod therapeutic effect in large % of pt, while prod. adverse effect in few
Adverse Drug Reaction
ii) Type B reaction : Non-dose related, unpredictable reaction
Drug allergy Idiosyncratic effects Immunologic effects Carcinogenic effects Teratogenic effects Photosensitive reactions
Adverse drug reactionDrug Allergy Immunologically mediated Hypersensitivity reactions
Type 1: Anaphylaxis vs Anaphylactoid Type 2: Cytotoxic Reaction Type 3: Serum Sickness Type 4: Delayed Hypersensitivity
Type B reactionAnaphylaxis vs anaphylactoid
Anaphylaxis Anaphylactoid
previous exposure No previous exposure
immune responseRelease of histamine
Non immune mediated pharmacological release of
histamine
Increased IgE,Ag+Ab reaction
No increase IgEFibrinolytic system and complements changes
CF: bronchospasm, vasodilatation,oedema,urticaria,hypotension
CF: same, but not severe resolve faster
Type B reactionCytotoxic reaction involves IgG or IgM Ab on cell surface leading to complement activation e.g. Autoimmune haemolytic anemia with -methyldopa
Serum sickness Ag + Ab Immune Complex
deposited in small vessels leading to vasculitis
deposited in lymph nodes leading to lymphadenopathy
deposited in joints leading to arthritis e.g. reaction to horse sera
Delayed hypersensitivity Ag interact with sensitised lymphocytes leading to
inflammation Circulating antibody is not required
Responses
Acute Tolerance (Tachyphylaxis) Progressive reduction in the response upon
repeated presentation of the agonist Chronic Tolerance
Hyporeactivity acquired from chronic exposure to drug
Usual dose is ineffective and must be increased
Mechanisms involved:- P/kinetics: enzyme induction, local
changes- P/dynamics: R downregulation, neuronal/
phys adaptation, mediators, immune tolerance
Responses
Idiosyncrasy Genetically determined Unusual effect of drug in small % of
individual Altered drug metabolism
Abnormal pseudocholinesterase Defective bilirubin conj; Gilbert, Crigler-Najjar Slow acetylators
Atypical response to drugs Red cell enz def; G6PD def, MetHb def ALA synthetase; Acute Intermittent Porphyria MH
Responses
Hyporeactivity People in whom an unusually low dose of
dug produce its expected pharmacological effect
Hypereactivity People in whom require an exceptionally
large dose to produce its expected pharmacological effect
Hypersensitivity Individual who are allergic to the drug
Responses
Additive 2 drugs effect equal to algebraic
summation Synergistic
2 drugs effect > algebraic summation Antagonistic
2 drugs effect < algebraic summation
DRUG INTERACTIONS
the modification of the effects of one drug (object drug) by the prior or concomittant administration of another (the precipitant drug) Physicochemical Interactions Pharmacokinetic Interactions Pharmacodynamic Interactions
Physicochemical Interaction Outside the body Pharmaceutical Incompatibility eg
Thiopentone & Suxamethonium GTN & plastic syringe
Pharmacokinetic Interactions Site of Absorption eg GIT
Motility, pH, chelation, direct toxicity, interference, gut flora
Protein Binding Interaction Sites of Metabolism
Enzyme induction/ inhibition Excretion eg renal
Acute tubular secretion, urine pH
Pharmacodynamic Interaction Receptor sites Uptake & transport mechanism Changes of fluid & electrolytes
balance Synergism Antagonism Potentiation