HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses...
-
Upload
lisbeth-tutt -
Category
Documents
-
view
220 -
download
0
Transcript of HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses...
![Page 1: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/1.jpg)
HOW DO DRUGS WORK?
![Page 2: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/2.jpg)
WHY BE CONCERNED ABOUT HOW DRUGS WORK?
• FDA Approved and Unapproved Uses
• Interactions with Other Drugs
• Adverse Effects and Contraindications
AIDS MEMORIZATION OF:
![Page 3: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/3.jpg)
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:
![Page 4: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/4.jpg)
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.
![Page 5: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/5.jpg)
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!
![Page 6: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/6.jpg)
HOW DO DRUGS WORK?
• Some drugs antagonize, block or inhibit endogenous proteins
• Some drugs activate endogenous proteins
• A few drugs have unconventional mechanisms of action
Most drugs work by interacting withendogenous proteins:
![Page 7: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/7.jpg)
HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBITENDOGENOUS PROTEINS?
• Antagonists of Cell Surface Receptors
• Antagonists of Nuclear Receptors
• Enzyme Inhibitors
• Ion Channel Blockers
• Transport Inhibitors
• Inhibitors of Signal Transduction Proteins
![Page 8: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/8.jpg)
HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
A macromolecular component of the organism that binds the drug and initiates the drug’s effect.
Definition of RECEPTOR:
Most receptors are proteins that have undergone various post-translational modifications such as covalent
attachments of carbohydrate, lipid and phosphate.
![Page 9: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/9.jpg)
HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
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:
![Page 10: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/10.jpg)
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
![Page 11: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/11.jpg)
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
![Page 12: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/12.jpg)
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)
![Page 13: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/13.jpg)
Footnote:
Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent
endogenous agonist from binding.
However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist
or prevent endogenous agonist from activating receptor.
HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?
![Page 14: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/14.jpg)
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 drugs bind to cell surface receptors, yet do not activatethe receptors to trigger a response.
• When cell surface receptors bind the drug molecule,the endogenous chemical cannot bind to the
receptor and cannot trigger a response.
• The drug is said to “antagonize” or “block” the receptor andis referred to as a receptor antagonist.
![Page 15: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/15.jpg)
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®])
![Page 16: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/16.jpg)
HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?
A receptor that exists in the intracellular compartment and uponactivation binds to regulator regions in
the DNA and modulatesgene expression.
Definition of NUCLEAR RECEPTOR:
![Page 17: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/17.jpg)
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
![Page 18: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/18.jpg)
HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?
Intracellular Compartment
Nucleus
DNA
Modulation ofTranscription
Active Nuclear Receptor
Bound Endogenous Activator (Agonist) of Nuclear Receptor
![Page 19: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/19.jpg)
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
![Page 20: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/20.jpg)
HOW DO DRUGS WORK BY ANTAGONIZINGNUCLEAR RECEPTORS?
Footnote:
Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent
endogenous agonist from binding.
However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist
or prevent endogenous agonist from activating receptor.
![Page 21: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/21.jpg)
HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?
KEY CONCEPTS:
• Nuclear receptors exist to mediate the effects of intracellular,endogenous chemicals on gene expression.
• Some drugs bind to nuclear receptors, yet do not activatethe receptors to translocate to the nucleus, bind DNA
and alter gene expression.
• When nuclear receptors bind the drug molecule,the endogenous chemical cannot bind to the receptor and cannot alter gene expression.
• The drug is said to “antagonize” or “block” the receptor andis referred to as a receptor antagonist.
![Page 22: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/22.jpg)
ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORS
CLINICAL 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 treatmentof breast cancer (tamoxifen [Nolvadex®])
![Page 23: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/23.jpg)
HOW DO DRUGS WORK BY INHIBITING ENZYMES?
Active Enzyme
Substrate Product
Cellular Function
![Page 24: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/24.jpg)
HOW DO DRUGS WORK BY INHIBITING ENZYMES?
Inactive Enzyme
Substrate
Bound Enzyme Inhibitor (Drug)
![Page 25: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/25.jpg)
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.
![Page 26: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/26.jpg)
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®])
![Page 27: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/27.jpg)
HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
Open Ion Channel
Intracellular Compartment
Ions (e.g., Ca++, Na+, K+)
[Ions]
Cellular Response
![Page 28: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/28.jpg)
HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
Blocked Ion Channel
Intracellular Compartment
Ions (e.g., Ca++, Na+)
Drug that Blocks Ion Channels
Ions (e.g., K+)
![Page 29: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/29.jpg)
HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? KEY CONCEPTS:
• Ion channels allow ions to transverse the cell membranethrough a pore and down an electrochemical gradient.
• Some drugs bind to ion channels and physicallyblock the pore or cause an allosteric change
that closes the pore.
• Changes in the intracellular concentration of ions mediatesthe effects of inhibitors of ion channels.
![Page 30: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/30.jpg)
ARE DRUGS THAT BLOCK ION CHANNELSCLINICALLY 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®])
![Page 31: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/31.jpg)
HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Active Transporter
Intracellular Compartment
Membrane Impermeable Solute
Cellular Response
Membrane Impermeable Solute
![Page 32: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/32.jpg)
HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Inactive Transporter
Intracellular Compartment
Membrane Impermeable Solute
Membrane Impermeable Solute
Drug that Inhibits Transporters
![Page 33: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/33.jpg)
HOW DO DRUGS WORK BY INHIBITING TRANSPROTERS?KEY CONCEPTS:
• Transporters bind to and shuttle membrane impermeablesolutes across the cell membrane.
• Some drugs bind to transporters and cause allosteric changesthat prevent proper functioning of the transporters.
• Changes in the intracellular concentration of specific solutes mediatesthe effects of inhibitors of transporters.
![Page 34: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/34.jpg)
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®])
![Page 35: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/35.jpg)
HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS?
(Some overlap with enzyme inhibitors)
Cell Membrane
Bound Endogenous Activator (Agonist) of Receptor
Active Cell Surface Receptor
Extracellular Compartment
Intracellular Compartment
Cellular Response
Multiple Signal Transduction Proteins(each is a potential drug target)
![Page 36: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/36.jpg)
HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS?
(Some overlap with enzyme inhibitors)
Cell Membrane
Bound Endogenous Activator (Agonist) of Receptor
Active Cell Surface Receptor
Extracellular Compartment
Intracellular Compartment
Blockade or Augmentation of Signal Transduction Pathway by Drug
![Page 37: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/37.jpg)
HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS?
KEY CONCEPTS:
• Signal transduction proteins transmit a chemical signalfrom a receptor to the final biological target.
• Some drugs bind to and inhibit key signal transduction proteins.
• Inhibition of key signal transduction proteins may block oraugment the signal transduction pathway and this
mediates the effects of the drug.
![Page 38: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/38.jpg)
• 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?
![Page 39: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/39.jpg)
HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS?
• Agonists of Cell Surface Receptors
• Agonists of Nuclear Receptors
• Enzyme Activators
• Ion Channel Openers
![Page 40: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/40.jpg)
HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?
Cell Membrane Inactive Cell Surface Receptor
Extracellular Compartment
Intracellular Compartment
![Page 41: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/41.jpg)
HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?
Cell Membrane Active Cell Surface Receptor
Extracellular Compartment
Intracellular Compartment
Bound Exogenous Agonist of Receptor (Drug)
Cellular Response
![Page 42: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/42.jpg)
Footnote:
Most agonists attach to binding site on receptor for endogenous agonist and trigger a response.
However, agonists may bind to remote site on receptor and cause
allosteric effects that increase the ability of an endogenousagonist to bind to or activate the receptor.
HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?
![Page 43: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/43.jpg)
HOW DO DRUGS 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 drugs bind to cell surface receptors and trigger a response.
• Drugs in this group are called receptor agonists.
• Some drug agonists are actually the endogenous chemical signal,whereas other drug agonists mimic endogenous chemical signals.
![Page 44: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/44.jpg)
•Alpha1-Adrenoceptor Agonists for nasal congestion (oxymetazoline [Afrin®]; phenylephrine [Neosynephrine®])
Some important examples:
• Opioid Receptor Agonists for analgesia(morphine; meperidine [Demerol®])
ARE DRUGS THAT ACTIVATE CELL SURFACE RECEPTORS
CLINICALLY USEFUL?
![Page 45: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/45.jpg)
HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?
Inactive Nuclear ReceptorIn Cytosolic Compartment
Intracellular Compartment
Nucleus
DNA
Inactive Nuclear ReceptorIn Nuclear Compartment
![Page 46: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/46.jpg)
HOW DO DRUGS WORK BY ACTIVATINGNUCLEAR RECEPTORS?
Intracellular Compartment
Nucleus
DNA
Modulation ofTranscription
Active Nuclear Receptor
Bound Exogenous Agonist of Receptor (Drug)
![Page 47: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/47.jpg)
HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?
Footnote:
Most agonists attach to binding site on receptor for endogenous agonist and trigger a response.
However, agonists may bind to remote site on receptor and cause
allosteric effects that increase the ability of an endogenousagonist to bind to or activate the receptor.
![Page 48: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/48.jpg)
HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?
KEY CONCEPTS:
• Nuclear receptors exist to mediate the effects of intracellular,endogenous chemicals on gene expression.
• Some drugs bind to nuclear receptors and trigger a response.
• Drugs in this group are called receptor agonists.
• Some drug agonists are actually an endogenous chemical,whereas other drug agonists mimic an endogenous chemical.
![Page 49: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/49.jpg)
ARE DRUGS THAT ACTIVATENUCLEAR RECEPTORSCLINICALLY USEFUL?
• Estrogen Receptor Agonists for hormone replacement therapy in postmenopausal
women (conjugated equine estrogens [Premarin®])
Some important examples:
• Glucocorticoid Receptor Agonist for inflammation (hydrocortisone[Cortef®]; dexamethasone [Decadron®])
![Page 50: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/50.jpg)
HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Inactive Enzyme
Substrate
![Page 51: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/51.jpg)
HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Active Enzyme
Substrate Product
Cellular Function
Enzyme Activator (Drug)
![Page 52: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/52.jpg)
HOW DO DRUGS WORK BY ACTIVATING ENZYMES? KEY CONCEPTS:
• Enzymes catalyze the biosynthesis of products from substrates.
• Some drugs bind to enzymes and increase their enzymatic activity.
• Increased biosynthesis of product mediates theeffects of enzyme activators.
![Page 53: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/53.jpg)
ARE DRUGS THAT ACTIVATE ENZYMESCLINICALLY USEFUL?
• Activators of Guanylyl Cyclase for angina (nitroglycerin; isosorbide dinitrate [Isordil®])
Some important examples:
• Reactivators of Cholinesterase after poisoning with nerve gasor organophosphate pesticide
(pralidoxime [Protopam®])
![Page 54: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/54.jpg)
HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Closed Ion Channel
Intracellular Compartment
Ions (e.g., Ca++, Na+)
Ions (e.g., K+)
Binding Site on Ion Channel
![Page 55: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/55.jpg)
HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Open Ion Channel
Intracellular Compartment
Ions (e.g., Ca++, Na+, K+)
[Ions]
Cellular Response
Drug That Opens Ion Channel
![Page 56: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/56.jpg)
HOW DO DRUGS WORK BY OPENING ION CHANNELS? KEY CONCEPTS:
• Ion channels allow ions to transverse the cell membranethrough a pore and down an electrochemical gradient.
• Some drugs bind to ion channels and allosterically openthe ion channel or allosterically render the
channel more readily opened by other endogenous chemicals.
• Changes in the intracellular concentration of ions mediatesthe effects of drugs that open ion channels.
![Page 57: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/57.jpg)
ARE DRUGS THAT OPEN ION CHANNELSCLINICALLY USEFUL?
• Potassium Channel Openers for hair regrowth(minoxidil [Rogaine®])
Some important examples:
• GABAAChloride Channel Openers for anxiety(alprazolam[Xanax®]; midazolam [Versed®])
![Page 58: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/58.jpg)
HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION?
• Disrupters of Structural Proteins
• Drugs that Are Enzymes
• Drugs that Covalently Link to Macromolecules
• Drugs that React Chemically with Small Molecules
• Drugs that Bind Free Molecules or Atoms
![Page 59: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/59.jpg)
HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION (Continued)?
• Drugs that Are Nutrients
• Drugs that Exert Actions Due to Physical Properties
• Drugs that Work Via an Antisense Action
• Drugs that Are Antigens
• Drugs with Unknown Mechanisms of Action
![Page 60: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/60.jpg)
• Vinca Alkaloids for cancer(vincristine [Oncovin®]; vinblastine [Velban®])
Some important examples:
• Colchicine for gout
DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS?
![Page 61: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/61.jpg)
ARE SOME DRUGS ENZYMES?
• Thrombolytic therapy for acute myocardial infarction(alteplase [Activase®])
Some important examples:
![Page 62: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/62.jpg)
DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES?
• DNA alkylating agents for the treatment of cancer(cyclophosphamide [Cytoxan®]; chlorambucil [Leukeran®])
Some important examples:
![Page 63: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/63.jpg)
DO SOME DRUGS REACT CHEMICALLY WITH SMALL MOLECULES?
• Antacids that neutralize gastric acid(various preparations containing Al(OH)3, Mg(OH)2 or CaCO3)
Some important examples:
![Page 64: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/64.jpg)
DO SOME DRUGS BIND FREE MOLECULES OR ATOMS?
• Bile-Acid Sequestrants for hypercholesterolemia(cholestyramine [Questran®])
Some important examples:
• Chelating Agents for heavy metal poisoning(dimercaprol; penicillamine)
• Proteins that bind TNF-α for rheumatoid arthritis(infliximab [Remicade®]; etanercept [Enbrel®])
![Page 65: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/65.jpg)
ARE SOME DRUGS NUTRIENTS?
• Vitamins, minerals, lipids, carbohydrates, aminoacids
Some important examples:
![Page 66: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/66.jpg)
DO SOME DRUGS EXERT ACTIONSDUE TO PHYSICAL PROPERTIES?
• Bulk Laxatives for constipation(psyllium [Metamucil®]; polycarbophil [Fibercon®]
Some important examples:
• Osmotic Diuretics for edema(mannitol)
![Page 67: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/67.jpg)
DO SOME DRUGS WORK VIA AN ANTISENSE ACTION?
• Antisense Deoxyoligonucleotides for cytomegalovirus retinitisin patients with AIDS
(fomivirsen [Vitravene®]
An important example:
• This is a major focus of drug development
![Page 68: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/68.jpg)
ARE SOME DRUGS ANTIGENS?
Some important examples:
• Vaccines
![Page 69: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/69.jpg)
IS THE MECHANISM OF ACTIONOF SOME DRUGS UNKNOWN?
• Inhalation Anesthetics for general anesthesia(Isoflurane [Forane®]; Sevoflurane [Ultane®]
Some important examples:
![Page 70: HOW DO DRUGS WORK?. WHY BE CONCERNED ABOUT HOW DRUGS WORK? FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications.](https://reader035.fdocuments.net/reader035/viewer/2022062619/5516a9dc550346f0208b4f82/html5/thumbnails/70.jpg)
HOW DO DRUGS WORK?
Now you know!!