3. pharmacodymics and toxicodynamics 21_09_15.pptx

Pharmacodynamics/Toxicodynamics

Elizabeth Kampira PhD

What is Pharmacodynamics

• Effect of the drug on the biochemical and physiological function of the body.

• The mechanisms of drug action and the relationship between drug concentration and effect.

• L +R LR

• where L=ligand (drug), R=receptor (attachment site)

Toxicodynamics

• Is the study of toxic actions of xenobiotic substances on living systems.

• It is concerned with processes and changes that occur to the drug at the target tissue, including metabolism and binding that results in an adverse effect.

• These effects are result of the interaction of the biologically effective dose of the ultimate (active) form of the toxicant with molecular target

• Simply, TD is concerned with what the toxicant do to the body

Site of ActionDosage Effects

PlasmaConcen.

Pharmacokinetics Pharmacodynamics

DosageExposure

ToxicEffects

PlasmaConc.

Site ofaction

Toxicokinetics Toxicodynamics

Pharmacodynamics/Toxicodynamics

Molecular Targets Concept

• The toxic action of a chemical is a consequence of thephysical/chemical interaction of the active form of

thatchemical

withorganism

a molecular

target

within

the

living

Molecular

Targets

Concept

Examples of Molecular Targets

Proteins––

Arylhydrocarbon(Ah) receptor—DioxinHemoglobin—COLipids—Carbon

tetrachlorideDNA—Aflatoxin

Toxicodynamics

Why concerned with what the drug does to the body

• FDA Approved and Unapproved Uses

• Interactions with Other Drugs

• Adverse Effects and Contraindications

Why concerned with what the drug does to the body

• Better assessment of new modalities for using drugs

• Better assessment of new indications for drugs

• Better assessment of new concerns regarding risk-benefit

AIDS EVALUATION OF MEDICAL LITERATURE:

Why concerned with what the does to the body

• The patient has more respect for and trust in a therapist who can convey to the patient how the drug is affecting the patient’s body.

AIDS PATIENT-DOCTOR RELATIONSHIP:

• A patient who understands his/her therapy is more inclined to become an active participant in the management of the patient’s disease.

Why concerned with what the drug does to the body

• Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately.

PEACE OF MIND!

HOW DO DRUGS WORK?

• Some antagonize, block or inhibit endogenous proteins

• Some activate endogenous proteins

• A few have unconventional mechanisms of action

Most work by interacting with endogenous proteins:

HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors

• Enzyme Inhibitors

• Ion Channel Blockers

• Transport Inhibitors

•Inhibitors of Signal Transduction Proteins

Toxicodynamics

• Determines the no. of receptors that can interact with toxicants

• Binding • Interaction • Induction of toxic effects

Receptor (key element)

• In addition to its usefulness for explaining biology, the receptor concept has important practical consequence for The development of drugs Arriving at therapeutic decisions in clinical

practice.

Macromolecular nature of drug receptors

• Regulatory proteins

• Enzymes

• Transport proteins

• Structural proteins

• The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to Interact with complementary surfaces on the receptor

RECEPTOR:• A macromolecular component of the organism that binds the

drug and initiates its effect.

Cell surface receptor• A receptor that is embedded in the cell membrane and

functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment

In most cases, the chemical nature of the receptor site remains obscure.

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

• Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell.

• Some compounds bind to cell surface receptors, yet do not activate the receptors to trigger a response.

• When cell surface receptors bind the molecule, the endogenous chemical cannot bind to the receptor and cannot trigger a response.

• The compound is said to “antagonize” or “block” the receptor and is referred to as a receptor antagonist.

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Cell Membrane

Bound Endogenous Activator (Agonist) of Receptor

Active Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

Cellular Response

Displaced Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor Upon being Bound

Extracellular Compartment

Intracellular Compartment

Bound Antagonist of Receptor (Drug)

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Inactive Receptor

Cell Membrane

Displaced Endogenous Activator (Agonist) of Receptor

Extracellular Compartment

Intracellular Compartment

Bound Antagonist of Receptor

Allosteric Inhibitor

Active Receptor

•Angiotensin Receptor Blockers (ARBs) for high blood pressure, heart failure, chronic renal insufficiency(losartan [Cozaar®]; valsartan [Diovan®])

Are they clinically useful?

HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors

• Enzyme Inhibitors

• Ion Channel Blockers

• Transport Inhibitors

•Inhibitors of Signal Transduction Proteins

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?

Displaced Endogenous Activator (Agonist) of Nuclear Receptor

Intracellular Compartment

Nucleus

DNA

Bound Antagonist of Receptor (Drug)

Inactive Nuclear ReceptorIn Cytosolic Compartment

Inactive Nuclear ReceptorIn Nuclear Compartment

Estrogen Receptor Antagonists for the prevention and treatment of breast cancer (tamoxifen [Nolvadex®])

HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors

• Enzyme Inhibitors

• Ion Channel Blockers

• Transport Inhibitors

•Inhibitors of Signal Transduction Proteins

HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

Inactive Enzyme

Substrate

Bound Enzyme Inhibitor (Drug)

•Enzymes catalyze the biosynthesis of products from substrates.

• Some drugs bind to enzymes and inhibit enzymatic activity.

• Loss of product due to enzyme inhibition mediates theeffects of enzyme inhibitors.

e.g Cyclooxygenase Inhibitors for pain relief,particularly due to arthritis (aspirin; ibuprofen [Motrin®])/ ACE

HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors

• Enzyme Inhibitors

• Ion Channel Blockers

• Transport Inhibitors

•Inhibitors of Signal Transduction Proteins

ARE DRUGS THAT BLOCK IONCHANNELS CLINICALLY USEFUL?

• Calcium Channel Blockers (CCBs) for angina and high blood pressure (amlodipine [Norvasc®]; diltiazem [Cardizem®])

Some important examples:

• Sodium Channel Blockers to suppress cardiac arrhythmias (lidocaine [Xylocaine®]; amiodarone [Cordarone®])

ARE DRUGS THAT INHIBIT TRANSPORTERSCLINICALLY USEFUL?

• Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression (fluoxetine [Prozac®]; fluvoxamine [Luvox®])

Some important examples:

• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in renal epithelial cells to increase urine and sodium output for the treatment of edema (furosemide [Lasix®]; bumetanide [Bumex®])

•Tyrosine Kinase Inhibitors for chronic myelocytic leukemia (imatinib [Gleevec®])•Type 5 Phosphodiesterase Inhibitors for erectile dysfunction (sildenafil [Viagra®])• This is a major focus of drug development

Some important examples:

ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINSCLINICALLY USEFUL?

HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS?

• Agonists of Cell Surface Receptors(e.g. alpha-agonists, morphine agonists)

• Agonists of Nuclear Receptors(e.g. HRT for menopause, steroids for inflammation)

• Enzyme Activators(e.g. nitroglycerine (guanylyl cyclase), pralidoxime)

• Ion Channel Openers(e.g. minoxidil (K) and alprazolam (Cl))

HOW DO CHEMICALS WORK BY ACTIVATING CELL SURFACE RECEPTORS?KEY CONCEPTS:

•Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell.

• Some chemicals bind to cell surface receptors and trigger a response.

• Chemicals in this group are called receptor agonists.

• Some agonists are actually the endogenous chemical signal, whereas other agonists mimic endogenous chemical signals.

HOW DO CHEMICALS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION?

•Disrupting of Structural Proteins e.g. vinca alkaloids for cancer, colchicine for gout

• Being Enzymese.g. streptokinase for thrombolysis

• Covalently Linking to Macromoleculese.g. cyclophosphamide for cancer

• Reacting Chemically with Small Moleculese.g. antacids for increased acidity

• Binding Free Molecules or Atomse.g. drugs for heavy metal poisoning, infliximab (anti-TNF)

HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION (Continued)?

•Being Nutrientse.g. vitamins, minerals

• Exerting Actions Due to Physical Propertiese.g. mannitol (osmotic diuretic), laxatives

• Working Via an Antisense Actione.g. fomivirsen for CMV retininitis in AIDS

• Being Antigens e.g. vaccines

•Having Unknown Mechanisms of Actione.g. general anesthetics

Characteristics of Drug-Receptor Interactions

• Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent.

• Saturable• Competitive• Specific and Selective • Structure-activity relationships• Transduction mechanisms

Receptor Transduction Mechanisms

• Neurotransmitter and peptide signaling requires receptor‐mediated responses to affect the target cell.

• Ion channel linked receptors e.g. Ach nicotinic (Na+) and GABA (Cl-)

• Second messenger generation, adenylate cyclase stimulation or inhibition - cAMP,

guanylate cyclase - cGMP, phospholipase C - IP3, DAG

• Some receptors are themselves protein kinases• Intracellular receptors (e.g. corticosteroids,

thyroid hormone)

Drug-Receptor Interactions Obey the Law Of Mass Action

effectDRRDk

k

1

2

2].[1].].[[ kDRkRD By law of mass action:

At equilibrium

][

]].[[

1

2

DR

RDK

k

kD

Therefore:

Quantitative aspects of drug-receptor interaction

K1 rate constant for combination

K2 rate constant for dissociation

KD equilibrium dissociation constant

Occupancy Theory• Single-occupancy theory – The intensity of the body’s response to the drug is directly related to the number of receptors occupied by the drug. – The maximum response occurs when all of the receptors have drug molecules attached. • Modified occupancy theory – Different drugs have different strengths of attractions, or affinity, for receptor sites. – Once a drug is attached to a receptor, it has different abilities to stimulate the receptor

If RT = total # of receptors, then RT = [R] + [DR]

Replace [R] by (RT -[DR]) and rearrange:

OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS

[DR] [D]

RT Kd + [DR]Max. effect==

EFFECTDR complex D+R

Fractional occupancy = DR = DR RT R + DR

But from KD = KD DRD

R

KD

When [D] = KD

[DR] RT

= 0.5

[D]

[DR]

/Rt

0 5 10 15 200.00

0.25

0.50

0.75

1.00

][

][][

DK

D

R

DR

Dt

effect [DR] [D]

Max. effect RT Kd + [D]=

Notice how the drug effect reaches a plateau or maximum. This is because there are a finite number of receptors.

=

Dose-Response Concept

The magnitude of the toxic effect will be a function of the

concentration of altered molecular targets, which in turnis related to the

concentration of the active form of thetoxicant( biologically effective

dose)at th

esite

where

themolecul

artargets

are

located.

12

Receptor Binding

The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).

% B

ound

Concentration of Ligand

Kd

The log-dose response curve is dependent on the affinity of the ligand for the receptor and its intrinsic activity. Affinity determines the position of the dose-response curve on the X-axis, while intrinsic activity affects the magnitude of the response.

[D] (concentration units)

[DR

]/RT

0.01 0.10 1.00 10.00 100.000.00

0.25

0.50

0.75

1.00

Kd=1

kd=5

Kd=0.5

Compounds Have Different Affinities for the Same Receptor

Competitive Noncompetitive

Types of Receptor Antagonists

[D] (concentration units)

% M

axim

al E

ffect

0.01 0.10 1.00 10.00 100.00 1000.000.0

0.2

0.4

0.6

0.8

1.0

Partial agonist

Full Agonist

Partial agonist

PARTIAL AGONISTS - EFFICACYEven though drugs may occupy the same # of receptors, the magnitude of their effects may differ.

Receptor Sensitivity

• Changes in receptor sensitivity – Receptors are not static. – Continual stimulation from an agonist usually makes the drug less effective. – Continual blockage from an antagonist usually makes the drug more likely to react. • Nonreceptor responses – Drugs exert their effect by reacting physically or chemically with other molecules in the body

Drug (D)

Ri

DRi DRa

Ra

CONFORMATIONAL SELECTION

HOW TO EXPLAIN EFFICACY?

The relative affinityof the drug to either conformation will determine the effect of the drug

Factors Governing Drug Action1. Affinity A measure of the tightness that a drug binds to the receptor.

2.Intrinsic activity.Is a measure of the ability of a drug once bound to the receptor to generate an effect activating stimulus and producing a change in cellular activity.

Spare Receptors

Receptor Regulation

• Sensitization or Up-regulation1. Prolonged/continuous use of receptor blocker2. Inhibition of synthesis or release of hormone/neurotransmitter - Denervation

• Desensitization or Down-regulation1. Prolonged/continuous use of agonist2. Inhibition of degradation or uptake of agonist

Homologous vs. HeterologousUncoupling vs. Decreased Numbers

GRADED DOSE-RESPONSE CURVE

ED50

ED50

QUANTAL DOSE-RESPONSE CURVE

Frequency Distribution

CumulativeFrequency Distribution

Morphine

Aspirin

THERAPEUTIC INDEX – AN INDEX OF SAFETY

Hypnosis Death

The Therapeutic Index (TI) is used to compare the therapeutically effective dose to the toxic dose

Therapeutic index• The use of the ED50 and LD50 doses to derive the TI

may be misleading as to safety, depending on the slope of the dose-response curves for therapeutic and lethal effects.

• To overcome this deficiency, toxicologists often use another term to denote the safety of a drug – the Margin of Safety (MOS).

• The MOS is usually calculated as the ratio of the dose that is just within the lethal range (LD01) to the dose that is 99% effective (ED99).• The MOS = LD01/ED99. A physician must use caution in prescribing a drug in which the MOS is less than 1.

Margin of Safety = LD1

ED99

ED50AED99A

LD1A

Causes of Variability in Drug Response

Those related to the biological system1. Body weight and size2. Age and Sex3. Genetics - pharmacogenetics4. Condition of health5. Placebo effect

Causes of Variability in Drug Response

• Those related to the conditions of administration1. Dose, formulation, route of administration.2. Resulting from repeated administration of drug:

drug resistance; drug tolerance-tachyphylaxis; drug allergy3. Drug interactions:

chemical or physical; GI absorption; protein binding/distribution; metabolism (stimulation/inhibition); excretion (pH/transport processes); receptor (potentiation/antagonism); changes in pH or electrolytes.