BASIC PHARMACODYNAMIC. Pharmacodynamic Pharmacodynamic the study of drug effects and attempts to...

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