boundfree bound locus of action “receptors ” tissue reservoirs systemic circulation free drug...
TRANSCRIPT
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Site of ActionDosage Effects
PlasmaConcen.
Pharmacokinetics Pharmacodynamics
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Bound Free Free Bound
LOCUS OF ACTION
“RECEPTORS”TISSUE
RESERVOIRS
SYSTEMIC CIRCULATION
Free Drug
Bound Drug
ABSORPTION EXCRETION
BIOTRANSFORMATION
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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
• FDA Approved and Unapproved Uses
• Interactions with Other Drugs
• Adverse Effects and Contraindications
AIDS MEMORIZATION OF:
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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
• 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:
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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
The patient has more respect for and trust in a therapist whocan 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.
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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately.
PEACE OF MIND!
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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 withendogenous proteins:
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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
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A macromolecular component of the organism that binds the drug and initiates its effect.
Definition of RECEPTOR:
Most receptors are proteins that have undergone various post-translational modifications such as covalent
attachments of carbohydrate, lipid and phosphate.
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A receptor that is embedded in the cell membrane and functionsto receive chemical information from the extracellular
compartment and to transmit that information to the intracellular compartment.
Definition of CELL SURFACE RECEPTOR:
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
KEY CONCEPTS:
• 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.
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
Cell Membrane
Unbound Endogenous Activator (Agonist) of Receptor
Inactive Cell Surface Receptor
Extracellular Compartment
Intracellular Compartment
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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
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
Cell Membrane
Displaced Endogenous Activator (Agonist) of Receptor
Inactive Cell Surface Receptor
Extracellular Compartment
Intracellular Compartment
Bound Antagonist of Receptor (Drug)
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Footnote:
Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent
endogenous agonist from binding. If binding is reversible - Competitive antagonists
If binding is irreversible - Noncompetitive antagonists
However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist
or prevent endogenous agonist from activating receptor. (Noncompetitive antagonists)
HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
Cell Membrane
Displaced Endogenous Activator (Agonist) of Receptor
Inactive Receptor
Extracellular Compartment
Intracellular Compartment
Bound Antagonist of Receptor
Allosteric Inhibitor
Active Receptor
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ARE DRUGS THAT ANTAGONIZE CELL SURFACE RECEPTORS
CLINICALLY USEFUL?
• Angiotensin Receptor Blockers (ARBs) for high blood pressure, heart failure, chronic renal insufficiency(losartan [Cozaar®]; valsartan [Diovan®])
Some important examples:
• Beta-Adrenoceptor Blockers for angina, myocardial infarction, heart failure, high blood pressure, performance anxiety
(propranolol [Inderal®]; atenolol [Tenormin®])
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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?
Unbound Endogenous Activator (Agonist) of Nuclear Receptor
Inactive Nuclear ReceptorIn Cytosolic Compartment
Intracellular Compartment
Nucleus
DNA
Inactive Nuclear ReceptorIn Nuclear Compartment
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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?
Intracellular Compartment
Nucleus
DNA
Modulation ofTranscription
Active Nuclear Receptor
Bound Endogenous Activator (Agonist) of Nuclear Receptor
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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
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ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORSCLINICALLY USEFUL?
• Mineralocorticoid Receptor Antagonists for edema due toliver cirrhosis and for heart failure
(spironolactone [Aldactone®])
Some important examples:
• Estrogen Receptor Antagonists for the prevention and treatment
of breast cancer (tamoxifen [Nolvadex®])
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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
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HOW DO DRUGS WORK BY INHIBITING ENZYMES?
Active Enzyme
Substrate Product
Cellular Function
Inactive Enzyme
Substrate
Bound Enzyme Inhibitor (Drug)
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HOW DO DRUGS WORK BY INHIBITING ENZYMES?
KEY CONCEPTS:
• 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.
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ARE DRUGS THAT INHIBIT ENZYMESCLINICALLY USEFUL?
• Cyclooxygenase Inhibitors for pain relief,particularly due to arthritis (aspirin; ibuprofen [Motrin®])
Some important examples:
• Angiotensin Converting Enzyme (ACE) Inhibitors for high blood pressure, heart failure, and
chronic renal insufficiency(captopril [Capoten®]; ramipril [Altace®])
• HMG-CoA Reductase Inhibitors for hypercholesterolemia(atorvastatin [Lipitor®]; pravastatin [Pravachol®])
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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
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ARE DRUGS THAT BLOCK ION CHANNELS
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®])
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ARE DRUGS THAT INHIBIT TRANSPORTERSCLINICALLY USEFUL?
• Selective Serotonin Reuptake Inhibitors (SSRIs) for thetreatment of depression
(fluoxetine [Prozac®]; fluvoxamine [Luvox®])
Some important examples:
• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) inrenal epithelial cells to increase urine and sodium
output for the treatment of edema (furosemide [Lasix®]; bumetanide [Bumex®])
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• Tyrosine Kinase Inhibitors for chronic myelocytic leukemia(imatinib [Gleevec®])
Some important examples:
• Type 5 Phosphodiesterase Inhibitors for erectile dysfunction(sildenafil [Viagra®])
• This is a major focus of drug development
ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINS
CLINICALLY USEFUL?
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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 Activatorse.g. nitroglycerine (guanylyl cyclase), pralidoxime
• Ion Channel Openerse.g. minoxidil (K) and alprazolam (Cl)
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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.
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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)
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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
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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
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NH4+-CH2(n)-NH4
+
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Receptor Transduction Mechanisms
• 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)
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k1
D + R <=> DR k2
By Law of Mass Action: [D]•[R]•K1= [DR]•K2
Therefore K2 /K1= Kd = [D]•[R]/[DR]
If RT = total # of receptors, thenRT = [R] + [DR]
Replace [R] by (RT-[DR]) and rearrange: [DR] [D]
RT Kd + [D]=
OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS
EFFECT
effect
Max. effect=
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Kd
effect [DR] [D]
Max. effect RT Kd + [D]
==When [D] = Kd
[DR] RT
= 0.5
[D]
[DR
]/R
T
0 5 10 15 200.00
0.25
0.50
0.75
1.00
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Receptor Binding
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
% B
oun
d
Concentration of Ligand
Kd
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[D] (concentration units)
[DR
]/R
T
0.01 0.10 1.00 10.00 100.000.00
0.25
0.50
0.75
1.00
Kd=1kd=5
Kd=0.5
Compounds Have Different Affinities for the Same Receptor
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Competitive Noncompetitive
Types of Receptor Antagonists
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[D] (concentration units)
% M
axim
al E
ffec
t
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.
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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
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R
R1*
R2*
R3*
R R
R1*
R1*
R2*
R2*
R3*
R3*
From Kenakin, T. Receptor conformational induction versus selection: all part of the same energy landscape. TiPS 1996;17:190-191.
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Spare Receptors
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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
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From Nies A and Speilberg SP. Principles of Therapeutics. in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th edition, 1996. Pages 43-62.McGraw Hill,
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GRADED DOSE-RESPONSE CURVE
ED50
ED50
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QUANTAL DOSE-RESPONSE CURVE
Frequency Distribution
CumulativeFrequency
Distribution
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Morphine
Aspirin
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THERAPEUTIC INDEX – AN INDEX OF SAFETY
Hypnosis Death
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Margin of Safety = LD1
ED99
ED50AED99A
LD1A
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Causes of Variability in Drug Response
Those related to the biological system
1. Body weight and size
2. Age and Sex
3. Genetics - pharmacogenetics
4. Condition of health
5. Placebo effect
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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 allergy
3. 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.