Article review: Preparing for clinical clerkships during medical school
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Do you remember the sheer terror you felt, when you first started your medical school clinical rotations? Your first two years were probably spent in classrooms and small-group labs discussing anatomy, pharmacology, pathology, etc.

Then BAM! You are thrown into the deep end of the pool. You are now on a clinical team of medical professionals taking care of actual patients!

Some students fare better than others during this abrupt transition period. This commentary in Academic Medicine provides a framework to help students adapt to this change, by understanding adult learning literature. Specifically, the authors review the concept of Kolb's learning cycle.

Kolb initially proposed that learning occurs in a 4-stage cycle. This consists of:
  1. Concrete Experience (experiencing an event)
  2. Reflective Observation (reflection on that concrete experience)
  3. Abstract Conceptualization (generation of new approach or style based on reflection)
  4. Active Experimentation (test the new approach or style in reality)
The authors of this article propose a 5-stage modified Kolb cycle to adapt to the new challenges of the clinical years of medical school:
  1. Prepare for the clinical setting
  2. Experience the clinical setting
  3. Reflect on the experience
  4. Conceptualize new approaches
  5. Testing new approaches
1. Preparing for the Clinical Setting
  • As a student, identify what your roles and responsibilities are on the team. The clerkship director should tell you this, but if not, seek out the answer. What should your presentations be like for new and established patients? Do you write notes in the chart, and if so, what is the format preferred?
  • Remember to do no harm. As a student, be sure not to give definitive answers to patients or families if you are not sure of the answers. Tell them that you will find out the answer. Also, do not perform procedures with which you are unfamiliar. Let the resident or attending know that you are uncomfortable with the new procedure and would like to observe at this time.
2. Experiencing the Clinical Setting
  • Keep a log of patient encounters, framed within goals and objectives in the medical school curriculum. Such objectives might include: communication with a consultant, dealing with a difficult patient, practicing cost-effective viagra cialis online pharmacy pharmacy when deciding on prescribing discharge medications.
  • Learning should be driven by the student. Read more about conditions or symptoms from your patient encounters. For me personally, I retain information more when it's contextually based.
  • Share what you have learned by teaching your fellow team members. Teaching reinforces what you've learned.
  • Move beyond "reporter" status. Medical students are traditionally perceived as data gatherers. Go one step further and think about a broad differential diagnosis list, based on your gathered data, without prompting from your resident or attending.
  • Build collaborative relationships with your team members. In team-based clinical work, it is crucial to understand the importance of collaboration. Unit secretaries, mid-level providers, nurses, and other professionals in the health care system are all part of the greater team.
  • Set a high professionalism standard. Sometimes students may witness unprofessional behavior. Think about how you would have handled the scenario differently, so that you don't fall into that trap in the future. Emulate those who exhibit humanistic behavior towards their patients and colleagues.
  • Develop habits that promote mental health and physical and social well-being.

3. Reflecting on Experience
  • A critical component in the "learning cycle" is the reflective piece. For self-reflection to improve your learning, seek out frequent feedback on how you are performing from residents and faculty. Be specific in what you are seeking feedback on -- "Can you tell me how I did in taking this patient's history?" or "Any feedback about my venipuncture procedure?"
  • During your reflection of your clerkship experiences, think about what you like and don't like about that specialty. Start developing a pros/cons list of factors which will play into your decision-making about selecting a career choice. Clearly, the specialty of Emergency Medicine is the best, but I suppose I'll let you come to that decision yourself.

4 and 5. Conceptualizing and Testing New Approaches
  • Based on self-reflection, think of how you might improve upon yourself or what you are doing. This might be how you approach a difficult patient, how you ask sensitive questions, troubleshooting a procedure, or present your differential diagnosis list.
  • Test your new approaches.
  • Repeat as new experiences arise.

Reference
Greenberg L, & Blatt B (2010). Perspective: successfully negotiating the clerkship years of medical school: a guide for medical students, implications for residents and faculty. Academic medicine : journal of the Association of American Medical Colleges, 85 (4), 706-9 PMID: 20354392

Drug Plans
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Prescription Drugs are the most expensive part of any benefits plan. Prescription Drugs typically account for 60-70% of all health care expenses, and account for the majority of cost increases. In order to combat the explosive growth in drug costs carriers have come up with several strategies, most of which, revolve around controlling which drugs are covered and which are not.









Brand Name Drugs



Just like the name implies these are drugs made by big name pharmaceutical companies. They fall under brand names like Viagra, online pharmacy and Levitra. We see ads on TV, brochures in doctors’ offices and generally know what they are called but not what they do. (ask your doctor if is right for you! )

Because of the marketing blitz and patent periods (the time when no other company can produce a similar chemical agent) the big drug companies can charge whatever they want. Brand name drugs tend to be very expensive, not necessarily because they work any better but because they are SOLD better.

Most cost saving measures have targeted Brand Name Drugs. By avoiding brand names plans can avoid the cost of all that marketing and hype, reducing costs substantially.



















Generic Alternatives



Often made in the very same factory as brand name drugs, generics are typically bough in huge bulk orders by either provincial or federal agencies. Because the generics lack the little logo stamp and occasionally use less expensive fillers they can cost up to a half as much as the same brand name drug. Generics are mandated by law, to provide the exact same medicinal ingredients, in the exact same dosages and of the exact same quality as the brand name. Generics, for all intents and purposes ARE the brand name drug, for only half the cost.



While the medicinal ingredients are mandated by law the fillers and binders aren’t; occasionally people will find they are sensitive to side effects from the generic when they are not sensitive to the brand name. This can usually be traced to a difference in fillers or psychosomatic response. For these people drug plans typically allow for a “no substitutions” clause. If the doctor writes “No substitutions” on the script the drug plan will cover the cost of the brand name drug.
















Lowest Cost Alternative (LCA)



A newer and more aggressive plan of attack on drug costs, LCA goes beyond substituting brand for generic form, and actually replaces the whole ingredient with another designed to do the same job. LCA looks not at the drug being prescribed but the ailment being treated. Take depression as an example, Prozac has been around for years, it is inexpensive and effective at the treatment of depression. Wellbutrin is another drug designed to treat depression, however, it is about 5 times the cost of Prozac. Wellbutrin has the added benefits of reduced side effects, fewer drug interactions and less complications, so doctors will often prescribe Wellbutrin over Prozac. A Lowest Cost Alternative plan will look at the problem of depression, and determine that while Wellbutrin is indeed a method of solving the problem it is substantially more expensive than good old Prozac. The LCA plan will decline the claim for Wellburtin, and prompt the pharmacist to dispense one of the less expensive alternatives which are covered by the plan.



LCA plans receive a substantial rate reduction, as well as a huge amount of flack from members. I have on several occasions had employees screaming at me over an LCA drug plan. The fact that they cannot receive the drug prescribed by their physician drives them crazy. Again for these people a plan can have a No Substitutions clause which allows the generic or Brand name drug to be claimed.
















Formulary



 Most plans work on a formulary basis, a formulary is just a list of drugs to be covered. Simple examples of active formularies are drug plans that do not cover lifestyle drugs such as: anti-smoking drugs, fertility drugs, or prescription weight loss medication. More aggressive formularies resemble the Lowest Cost Alternative plans but are even more restrictive, they also tend not to allow a “no-substitutions” clause. That is, if a drug isn’t covered, no amount of fuss from your doctor will get it covered.



Formulary plans are designed to use the cheapest drug possible to treat any one given malady. Typically there is ONE single drug for each medical condition. Members are allowed to purchase a non-formulary drug, however, they tend to either be reimbursed at a lower level, or only the cost of the listed drug is covered, any additional cost is born by the plan member.







A new, kinder, gentler formulary plan is referred to as a Conditional Formulary. Pioneered by Green Shield of Canada this is a very restrictive formulary which has several hoops plan members can jump through to get their drug of choice. You have to play the insurance companies game to get the drugs. The plan starts off very restrictive, most claims occur without incident; however, once a member has a problem with a formulary drug, they can apply for an alternative. Once approved, the more expensive alternative is covered and hopefully fixes the problem with the first drug, perhaps there are lesser side effects. If this second drug still is unsatisfactory a second application can be made for a higher tier of coverage. More expensive drugs are made available at this tier and again the process is repeated until a satisfactory drug of the lowest cost is found. The core idea is to cover the cheapest drug that works. If it doesn’t work you can try a more expensive one until either a working drug is found or you reach the top tier where the most expensive drugs are covered.







By starting at the bottom price wise, and moving up only when necessary, huge costs savings can be found. Administration, paperwork and frustration are the trade off for these savings.







Summary

Which plan is best for your group depends on your budget, your drug claims history and your benefits philosophy. Obviously not everyone wants to put their members into a position of jumping through hoops with a conditional formulary, then again having conditional coverage is better than none at all.



Other than Brand Name drugs, all of these strategies require a drug card. Drug cards are where the plan design and formulary are held. While a drug card increases the cost of a benefits plan due to an increase in claims, the cost savings from drug control are starting to offset the cost.



TL;DR you might be able to lower your drug costs by using generic, lowest cost alternative, or conditional formularies.




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Latest New Drug Approvals
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Bystolic (nebivolol)
Date of Approval: December 17, 2007
Company: Mylan Laboratories Inc. and Forest Laboratories
Treatment for: Hypertension
Bystolic (nebivolol) is a once daily beta blocker approved for the treatment of hypertension.
Bystolic, a Novel Beta Blocker, is Now Approved by the FDA for the Treatment of Hypertension - December 18, 2007
FDA Issues Approvable Letter for Bystolic (nebivolol) for the Treatment of Hypertension - December 3, 2007
Response Submitted to FDA Approvable Letter for Hypertension Compound Nebivolol - May 1, 2007
Mylan Laboratories Receives Approvable Letter For Its Next Generation Beta-Blocker Nebivolol - June 1, 2005
FDA Extends PDUFA Action Date for Nebivolol Tablets to May 31, 2005 - February 25, 2005
Mylan's NDA for Nebivolol Accepted for FDA Review - July 1, 2004
Mylan Submits New Drug Application for Nebivolol - May 5, 2004

Kuvan (sapropterin dihydrochloride) Tablets
Date of Approval: December 13, 2007
Company: BioMarin Pharmaceutical Inc.
Treatment for: Phenylketonuria
Kuvan is the synthetic form of 6R-BH4 (tetrahydrobiopterin), a naturally occurring enzyme cofactor that works in conjunction with phenylalanine hydroxylase to metabolize phenylalanine (Phe). Kuvan is indicated for the treatment of phenylketonuria, an inherited metabolic disease caused by a deficiency of the enzyme phenylalanine hydroxylase.
BioMarin Announces FDA Approval for Kuvan - December 13, 2007
Kuvan Receives Priority Review Status from FDA - July 26, 2007
BioMarin Submits New Drug Application for U.S. Marketing Authorization of Kuvan for
Phenylketonuria (PKU) - May 24, 2007

Triesence (triamcinolone acetonide) Injectable Suspension
Date of Approval: November 29, 2007
Company: Alcon, Inc.
Treatment for: Use in Eye Surgery
Triesence is a synthetic corticosteroid indicated for visualization during vitrectomy and treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids.
Alcon Receives FDA Approval of Triesence Injectable Triamcinolone Suspension for Use in Eye Surgery - December 3, 2007

Cymbalta (duloxetine) Delayed-Release Capsules
Date of Approval: August 3, 2004
Company: Eli Lilly and Company
Treatment for: Depression, Anxiety
Cymbalta is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Cymbalta was first approved in August 2004 for the acute treatment of major depressive disorder and has since been approved for the management of neuropathic pain associated with diabetic peripheral neuropathy and for the acute treatment of generalized anxiety disorder.New Indication Approved: November 28, 2007Treatment for: Maintenance Treatment of Major Depressive DisorderCymbalta is now also approved for the maintenance treatment of major depressive disorder (MDD) in adults.
FDA Approves Cymbalta for Maintenance Treatment of Major Depressive Disorder - November 30, 2007
FDA Approves Cymbalta for Treatment of Generalized Anxiety Disorder - February 26, 2007
Cymbalta Eli Lilly and Company - Treatment for Depression - August 4, 2004
FDA Extends Action Date for Cymbalta for Continued Analysis of Already-Submitted Data - June 24, 2004

Mircera (methoxy polyethylene glycol-epoetin beta) Injection
Date of Approval: November 14, 2007
Company: Roche
Treatment for: Anemia Associated with Chronic Renal Failure
Mircera is an erythropoiesis-stimulating agent indicated for the treatment of anemia associated with chronic renal failure.
FDA Approves Mircera: First Renal Anemia Treatment in the US with Monthly Maintenance Dosing - November 15, 2007
Roche Receives Approvable Letter for Mircera in the United States - May 21, 2007
Roche Offers the FDA Additional Mircera Data - December 15, 2006
Roche Submits Application with FDA to Market C.E.R.A. - April 20, 2006

Combigan (brimonidine tartrate and timolol maleate) Ophthalmic Solution
Date of Approval: October 30, 2007
Company: Allergan Inc.
Treatment for: Intraocular Hypertension, Glaucoma
Combigan is an alpha adrenergic receptor agonist and beta adrenergic receptor inhibitor combination ophthalmic solution for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP.
Allergan, Inc. Receives FDA Approval for Combigan (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% - October 31, 2007
Allergan Announces FDA Issues Approvable Letter for Combigan 0.2%/0.5% - December 21, 2006

Tasigna (nilotinib) Capsules
Date of Approval: October 29, 2007
Company: Novartis
Treatment for: Chronic Myelogenous Leukemia
Tasigna is a kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included imatinib.
Tasigna Receives US Approval Providing New Hope to Chronic Myeloid Leukemia Patients with Resistance or Intolerance to Existing Therapies - October 29, 2007

Renvela (sevelamer carbonate) Tablets
Date of Approval: October 19, 2007
Company: Genzyme Corporation
Treatment for: Hyperphosphatemia of Renal Failure
Renvela (sevelamer carbonate) is a calcium-free, metal-free, non-absorbed phosphate binder indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis.
FDA Approves Genzyme's Renvela for Dialysis Patients - October 22, 2007
Genzyme Files for Approval of Sevelamer Carbonate for Patients on Dialysis - December 21, 2006

Voltaren Gel (diclofenac sodium) Topical Gel
Date of Approval: October 17, 2007
Company: Novartis AG
Treatment for: Osteoarthritis
Voltaren Gel (diclofenac sodium) is a topical gel non-steroidal anti-inflammatory (NSAID) cheap cialis indicated for the pain of osteoarthritis in joints amenable to topical treatment, such as the knees and those of the hands.
Voltaren Gel Receives US Regulatory Approval as the First Approved Topical Prescription Treatment for Pain Associated with Osteoarthritis - October 22, 2007

Ixempra (ixabepilone) Injection
Date of Approval: October 16, 2007
Company: Bristol-Myers Squibb
Treatment for: Breast Cancer
Ixempra (ixabepilone) is a semisynthetic analog of epothilone B indicated for the treatment of patients with metastatic or locally advanced breast cancer.
FDA Approves Ixempra (ixabepilone), a Semi-Synthetic Analog of Epothilone B, for the Treatment of Advanced Breast Cancer - October 17, 2007
FDA Grants Priority Review for Bristol-Myers Squibb's Investigational Oncology Treatment Ixabepilone - June 19, 2007

Doribax (doripenem) Injection - formerly Doripenem
Date of Approval: October 12, 2007
Company: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Treatment for: Intraabdominal Infection, Urinary Tract Infection
Doribax is a penem antibacterial indicated for the treatment of complicated intra-abdominal and complicated urinary tract infections, including pyelonephritis.
FDA Approves Doribax for the Treatment of Complicated Intra-Abdominal and Complicated Urinary Tract Infections - October 15, 2007
New Drug Application Submitted for Investigational Antibiotic Doripenem - June 6, 2007
New Drug Application Submitted for Investigational Antibiotic Doripenem - December 15, 2006

Isentress (raltegravir) Tablets
Date of Approval: October 12, 2007
Company: Merck & Co., Inc.
Treatment for: HIV Infection
Isentress is an integrase inhibitor indicated for the treatment of Human Immunodeficiency Virus (HIV)-1 infection in combination with other antiretroviral agents.
FDA Approves of Isentress (raltegravir) - October 12, 2007
Impending FDA Approval Decision on the First HIV Integrase Inhibitor Isentress Can Have Significant Impact for Patients - October 12, 2007
FDA Advisory Committee Unanimously Recommends Accelerated Approval of Isentress (raltegravir), Merck's Investigational Oral Integrase Inhibitor, for Treatment of HIV - September 6, 2007
FDA Priority Review Granted for Isentress (raltegravir), Merck's Investigational Integrase Inhibitor for HIV - June 27, 2007

Afluria (influenza virus vaccine)
Date of Approval: September 28, 2007
Company: CSL Biotherapies
Treatment for: Influenza Prophylaxis
Afluria is an inactivated influenza virus vaccine, indicated for active immunization of persons ages 18 years and older against influenza disease.
CSL Biotherapies Announces FDA Marketing Approval of Afluria - September 28, 2007

Azor (amlodipine and olmesartan) Tablets - formerly amlodipine and olmesartan
Date of Approval: September 26, 2007
Company: Daiichi Sankyo, Inc.
Treatment for: Hypertension
Azor is a fixed-dose combination of two antihypertensives, the calcium channel blocker amlodipine besylate and the angiotensin receptor blocker olmesartan medoxomil. Azor is indicated for the treatment of hypertension.
Azor Receives FDA Approval for Treatment of High Blood Pressure - September 27, 2007
Daiichi Sankyo and Forest Laboratories Sign Letter of Intent for Co-Promotion of Azor - August 21, 2007
Daiichi Sankyo, Inc. Announces Filing of NDA for Amlodipine Besylate / Olmesartan Medoxomil Combination for the Treatment of Hypertension - November 28, 2006

Totect (dexrazoxane)
Date of Approval: September 6, 2007
Company: TopoTarget A/S
Treatment for: Anthracycline Extravasation
Totect is a topoisomerase inhibitor used as a detoxifying agent for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.
Totect Approved in the United States - September 7, 2007
TopoTarget elaborates on the specific initiatives to obtain FDA approval of Totect - May 31, 2007

ACAM2000 (Smallpox (Vaccinia) Vaccine, Live)
Date of Approval: August 31, 2007
Company: Acambis Inc.
Treatment for: Smallpox Prophylaxis
ACAM2000 is live vaccinia virus smallpox vaccine intended for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection. ACAM2000 is the first biodefense vaccine to be approved as part of the US response to the 2001 bioterrorism attacks.
FDA Approves ACAM2000 Vaccine for Protection Against Smallpox - September 4, 2007

Somatuline Depot (lanreotide acetate) Injection - formerly Somatuline Autogel
Date of Approval: August 30, 2007
Company: Tercica, Inc.
Treatment for: Acromegaly
Somatuline Depot is a sustained-release injection formulation of lanreotide, a somatostatin analogue indicated for the long-term treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.
Ipsen: Somatuline Depot Receives Marketing Approval in the United States for the Treatment of Acromegaly - August 31, 2007
FDA Accepts for Filing a New Drug Application (NDA) for Somatuline Autogel - January 15, 2007
Tercica Reports Somatuline Autogel NDA for Acromegaly Submitted to FDA - November 2, 2006

Evithrom (human thrombin)
Date of Approval: August 27, 2007
Company: Omrix Biopharmaceuticals, Ltd,
Treatment for: Bleeding
Evithrom is a highly purified human thrombin used as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.
FDA Approves Evithrom (human thrombin) for Topical Use in Surgery - August 28, 2007
Zingo (lidocaine hydrochloride monohydrate) Dermal PowderJect
Date of Approval: August 16, 2007
Company: Anesiva, Inc.
Treatment for: Local Anesthesia
Zingo is a needle-free, local anesthetic intradermal injection system, which provides rapid, topical, local analgesia to reduce the pain associated with venous access procedures, such as IV insertions or blood draws, in children three to 18 years of age.
Anesiva Receives FDA Approval for Zingo, a New, Innovative Product to Reduce Pain Associated with Needle Insertion Procedures in Children - August 17, 2007
Endo Comments on Notices Received From Anesiva Regarding Zingo - April 10, 2007
Anesiva Announces FDA Acceptance for Filing of Zingo New Drug Application to Reduce Pain Associated With Needle Insertion Procedures in Children - February 7, 2007
Anesiva Announces Filing of New Drug Application for Zingo to Reduce Pain Associated with Needle Insertion Procedures in Children - November 27, 2006

Selzentry (maraviroc) Tablets
Date of Approval: August 6, 2007
Company: Pfizer Inc.
Treatment for: HIV Infection
Selzentry (maraviroc) is the first in a class of drugs known as CCR5 antagonists, approved for use in combination with other antiretroviral drugs for the treatment of adults with CCR5-tropic HIV-1, who have been treated with other HIV medications and who have evidence of elevated levels of HIV in their blood (viral load).
Pfizer's Selzentry (Maraviroc) Tablets, Novel Treatment for HIV, Approved by FDA - August 6, 2007
Pfizer Receives Approvable Letter From FDA For Maraviroc - June 21, 2007
FDA Advisory Committee Recommends Accelerated Approval of Pfizer’s Maraviroc for Treatment-Experienced Patients - April 25, 2007
Pfizer's Maraviroc to Receive Accelerated Regulatory Reviews in the U.S. and Europe - February 13, 2007More...


How Viagra Works
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Mondays Molecule was sildenofil (5-[2-ethoxy-5- (4-methylpiperazin-1- ylsulfonyl) phenyl]-1- methyl-3-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one) better known as its citrate salt, Viagra®.

Viagra® is most often used in the treatment of erectile disfunction. The way it works is to inhibit a specific enzyme called phosphodiesterase-5 located in the smooth muscle of the arteries that supply blood to the penis. In order to understand the significnace of this inhibition, we need a little background.

Nitric oxide (NO) is a chemical produced by special nerve cells called NANC nerve cells. (NANC stands for nonadrenergic-noncholinergic.) Under certain, rather special, conditions the brain sends a signal down the axon of a NANC nerve cell located in the penis. This causes NO to be released into the blood stream in the arteries of the penis.

One of the main roles of NO is to trigger the relaxation of the smooth muscle that lines the arteries. This leads to vasodilation and the lowering of blood pressure. In the penis this causes engorgement as the arteries expand and fill up with blood. The result is an erection that's stimulated by NO.

Nitric oxide acts locally. It diffuses into adjacent cells and binds to an enzyme called guanylyl cyclase. The binding of NO activates the enzyme, stimulating it to produce cyclic guanosine monophosphate or cGMP. The substrate for this reaction is guanosine triphosphate (GTP), a molecule that's similar to ATP except that the base is guanine instead of adenine.

ATP can be also be cyclized to form cAMP—a compound analogous to cGMP. cAMP is a common signal in many hormone-induced signal transduction pathways (and in creating a sense of smell). Like cAMP, cGMP is a signalling molecule. It activates specific enzymes that add phosphate to various proteins causing them to become more, or perhaps less, active. During an erection, the cGMP signal leads to changes in phosphorylation of muscle proteins causing the muscles to relax and the arteries to expand.

As you might expect, cGMP is not infinitely stable; otherwise a man might have an erection forever. cGMP is removed by the action of cGMP phosphodiesterase, which converts it to GMP. The turnover of cGMP in the penis is quite rapid leading to lack of signal unless NO is continually produced by the NANC nerve cells in order to replenish the supply of cGMP by reactivating guanylyl cyclase. This production of NO requires the attention of the brain, which has to keep focused on the task at hand.

The smooth muscle cells in the penis contain a special cGMP phosphodiesterase called phosphodiesterase-5 (PDE5). Sometimes the degradation of cGMP by PDE5 outpaces the production of cGMP by guanylyl cyclase. In such cases, the steady-state levels of cGMP aren't sufficient to signal muscle relaxation and no erection occurs. This is a common cause of erectile disfunction.

Viagra® works by inhibiting PDE5 thus blocking the breakdown of cGMP. This causes levels of cGMP to increase and an erection is prolonged. The structure of the PDE5 enzyme has been solved by Sung et al. (2003) in the presence of bound sildenafil (Viagra®) and two other inhibitors, tadalafil (Cialis®) and vardenafil (Levitra®). The structures are shown as stereo images in the figure below.

The upper image is the PDE5 proetin with overlapping molecules of sildenafil (red) and tadalfil (green) bound to the enzyme. The bottom images shown the structures of the three inhibitors. Viagra® binds to the site where cGMP would normally bind, thus blocking the degradation of cGMP. The structure of Viagra® is similar to cGMP and this exlains why it is such a potent inhibitor.

Sung B-J., Hwang, K.Y., Jeon, Y.H., Lee, J.I., Heo, Y.S., Kim, J.H., Moon, J., Yoon, J.M., Hyun, Y.L., Kim, E., Eum, S.J., Park, S.Y., Lee, J.O., Lee, T.G., Ro, S., and Cho, J.M. (2003) Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 425:98-102.


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