This is the first edition of a series  entitled ” Pharmacotherapy updates for your medical education”. The intention is to provide readers a selection of links that are relevant to healthcare professionals interested in keeping up to date with the latest news on drug therapy.

Prescribing advice for GP’s

• Sibutramine cardiovascular concerns

The Annals of Pharmacotherapy

• Colchicine for the Primary and Secondary Prevention of Pericarditis: An Update
• Beta Adrenergic Antagonists in Hypertension: A Review of the Evidence
• Does Simvastatin Cause More Myotoxicity Compared with Other Statins?

NEJM

• Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism
• Ticagrelor versus Clopidogrel in Acute Coronary Syndromes
• When to Consider the Use of Antibiotics in the Treatment of 2009 H1N1 Influenza-Associated Pneumonia

BMJ and BMJ’s Evidence Based Medicine

• Medical students are to be tested on prescribing
• Rosiglitazone was non-inferior to metformin plus sulphonylurea for CV events but increased risk of HF and fractures in type 2 diabetes
• Review: aspirin reduces vascular events but increases bleeding in primary and secondary prevention

An important notice

Like all posts, this new feature takes time and effort;  this is why this time I’m asking for your feedback. I’ve decided that I will make this a real newsletter only if readers find it useful. For that purpose I’ve set up a threshold of comments or e-mail replies, this means that:

This newsletter will continue only if 50 or more readers reply to this e-mail or comment on the post.

I would really appreciate if you could answer some questions, like:

• Did you like it?
• Did you find it relevant?
• What other sources would you add?
• Would you like future updates oriented to updates from the blogosphere or from classic medical journals?

Thanks for your feedback!

Flavio Guzmán, M.D.

Please use the comment form to post your opinion about the article.

Pathophysiology of chemotherapy induced nausea and vomiting

CINV Pathophysiology

Chemotherapeutic drugs can trigger emesis by two ways:

• Direct activation of the medullary chemoreceptor trigger zone. 5-HT3 (serotonin 3), D2 (dopamine) and NK-1 receptors play a critical role as neurotransmitters.
• Cell damage of the GI tract. This causes serotonin release from the enterochromaffin cells, this molecule activates 5-HT3 receptors on vagal and splanchnic afferent fibers that send impulses to the medulla, activating the CTZ which stimulates the vomiting center.

Drugs used for CINV treatment and prophylaxis

The rational therapeutic approach to the pathophysiology of CINV includes blockade of the neurotransmitters involved in the triggering of emesis. The image below shows the main pharmacological groups, organized by mechanism of action.

Serotonin 5-HT3-receptor antagonists

5-HT3 antagonists play a key role in the management of CINV.They act through selective blockade of 5-HT receptors in visceral vagal afferent fibers and in the chemoreceptor trigger zone. They are efficacious against all grades of emetogenic therapy. Drugs in this class include: ondansetron, granisetron, palonosetron and dolasetron.

NK-1 receptor blocker

Aprepitant is the first drug in this new family of antiemetic agents. It targets the neurokinin receptor and blocks the actions of the natural substance P. Aprepitant is recommended before chemotherapy of high emetic risk (combined with 5-HT3 blocker and dexamethasone) and moderate emetic risk (combined only with dexamethasone).

Antipsychotics

Phenothiazines. Prochlorperazine: its main mechanism of action is dopamine D₂ receptor antagonism at the chemoreceptor trigger zone. It is effective against low emetogenic chemotherapy, but side effects (hypotension, restlessness, sedation, extrapyramidal symptoms) are dose limiting.

Atypical. Olanzapine  has potential antiemetic properties because of its action at multiple receptor sites implicated in the control of nausea and vomiting. MASCC and NCCN guidelines recommend a dose of 2.5–5 mg olanzapine for the treatment of refractory and breakthrough emesis.

Metoclopramide

Metoclopramide is no longer supported as a first-line agent by the MASCC, ASCO, and NCCN guidelines.  Besides, antidopaminergic side effects (sedation, diarrhea, extrapyramidal symptoms)  limit use of metoclopramide at high doses. However, metoclopramide has been proven to be as effective as 5-HT3 receptor antagonists when combined with steroids in the prevention of delayed CINV.

Corticosteroids

Dexamethasone plays a major role in the prevention of acute and delayed CINV and it is an integral component of almost all antiemetic regimens.  Corticosteroid antiemetic mechanism remains to be elucidated, it is believed that it may involve blockade of prostaglandins synthesis. Dexamethasone can be administered P.O or IV , and is recommended in combination with aprepitant before highly emetogenic chemotherapy.

Cannabinoids

Dronabinol and nabilone are effective against moderately emetogenic chemotherapy. Side effects include dysphoria, hallucinations, sedation, vertigo and disorientation. This number of adverse reactions places them as second line agents.

PowerPoint presentation on CINV pharmacology

Download PPT

References and further reading

Navari, R. “Chemotherapy induced Nausea and Vomiting”, 1st edition. Oxford University Press: 2010

Guidelines on CINV management

Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009

Guidelines for Antiemetic Treatment of Chemotherapy-Induced Nausea and Vomiting

Download PDF

Outline:

• Introduction
• Classification of CINV
• Emetogenicity of chemotherapeutic agents
• Patient-Related Risk Factors
• Antiemetics
• Prevention of CINV
• Management of Breakthrough and Refractory CINV
• Multiple-Day Chemotherapy
• Other Antiemetics

What’s new in ASCO Guidelines?

Download PDF

Further reading

Navari, R. “Chemotherapy induced Nausea and Vomiting”, 1st edition. Oxford University Press: 2010

Hypertension management

This PDF file on the pharmacological management of hypertension was written by the Pharmacology OpenCourseWare initiative at Harvard Medical School – MIT.

Hypertension: Pharmacological management

Download PDF

Lecture notes outline:

• Rational pharmacotherapy of hypertension
• Major Antihypertensive Drug Classes
• Diuretics (thiazide, loop, and potassium-sparing diuretics).
• Sympatholytics
• Beta adrenergic blockers
• Alpha-1 adrenergic blockers
• Central sympatholytics
• Vasodilators (calcium-channel blockers, direct arterial vasodilators, and sodium nitroprusside).
• Renin-angiotensin system (RAS) blockers
• Have certain drugs been shown to reduce the morbidity and mortality due to hypertension?
• What is the best initial therapy for the newly diagnosed hypertensive patient?

]]> http://pharmamotion.com.ar/hypertension-management-pdf/feed/ 0 http://pharmamotion.com.ar/ppt-cephalosporins-pharmacology-overview/ http://pharmamotion.com.ar/ppt-cephalosporins-pharmacology-overview/#comments Thu, 17 Dec 2009 16:26:56 +0000 Flavio Guzmán, MD http://pharmamotion.com.ar/?p=2919 This presentation is focused on the core characteristics of cephalosporins as a group. It highlights the differences in terms of bacterial coverage between different generations, using some clinical uses as examples.

PowerPoint: cephalosporins pharmacology

Download PPT

Lecture outline:

• Chemical characteristics of beta-lactams.
• Mechanism of action.
• First, second, third and fourth  generation cephalosporins drug list.
• Bacterial coverage of first, second, third and fourth generation cephalosporins.
• Clinical uses.
• Adverse effects.
• Ceftriaxone and meningitis.

Further reading

Gilbert, D; Moellering R (editors) “Sanford Guide to Antimicrobial Therapy”, 39th edition. Antimicrobial therapy: 2009

Hauser, A. “Antibiotic Basics for Clinicians: Choosing the Right Antibacterial Agent”.1st edition. LWW:2007

Gallagher, J. “Antibiotics Simplified“. 1st edition. Jones & Bartlett Publishers: 2008

Clopidogrel interaction with PPIs

This page will be constantly updated on the latest news about the possible interaction between the antiplatelet drug clopidogrel (Plavix) and PPIs.

News on this interaction are be posted in a timeline style:

• 10 December 2009. NPCi blog: Cardiovascular outcomes and mortality in patients using clopidogrel with a PPI: more data
• 17 November, 2009. FDA: Drug interaction between Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole.
• 06 October, 2009. NeLM – News. Review: Potential interaction between clopidogrel and proton pump inhibitors.
• 11 September, 2009. NPCi blog. Clopidogrel plus PPIs: doubts about clinical relevance of interaction.
• 29 May, 2009. EMEA statement on possible interaction between clopidogrel and proton pump inhibitors

NRTIs mechanism

Nucleoside analog reverse transcriptase inhibitors (NRTIs) are nucleoside analogues that act as competitive inhibitors of HIV-1 reverse transcriptase. As shown in the animation, these drugs compete with nucleoside triphosphates for access to reverse transcriptase.

All NRTIs lack a 3-hydroxyl group; thus, their incorporation into a growing DNA chain results in its termination. They require intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1.

NRTIs mechanism of action

List of NRTIs

• Zidovudine or azidothymidine (AZT) (also called ZDV): first approved drug in its class.
• Didanosine (ddI): second FDA-approved drug for the treatment of HIV infection.
• Tenofovir (TDF): first nucleotide analog. It has significant drug interactions.
• Lamivudine (3TC): also used in the treatment of HBV infection.
• Emtricitabine (FTC): acts as an inhibitor of HBV and HIV transcriptase.
• Abacavir (ABC): a guanosine analog.

Animations depicting mechanisms of other antiretrovirals

• HIV protease inhibitors
• HIV fusion inhibitors

References and further reading

Katzung, B. “Basic & Clinical Pharmacology”, 11th Edition. Mc Graw Hill Medical: 2009

About the animation author

.Dr. Gary Kaiser is a Professor of Microbiology at The Community College of Baltimore County, Catonsville Campus located in Baltimore, Maryland. Make sure you visit his excellent microbiology website: The Grapes of Staph.

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Classification of agents

Classification of calcium channel blockers

Calcium channel blockers comprise three chemical groups, all of them bind the L-type Ca++ channel, but each class binds to different binding sites of the same channel:

• Phenilalkylamines: verapamil is the only drug in this group, it binds to the V binding site.

• Benzothiazepines: diltiazem binds to the D binding site in the L-type Ca++ channel. It shows cardiovascular effects similar to those of verapamil.

• Dihydropyridines: the prototype agent in this group is nifedipine, a first generation dihydropyridine that binds to the N binding site. Second generation agents include isradipine, nicardipine, and felodipine. Amlodipine is considered a third generation dihydropyridine.

Mechanism of action and pharmacological effects

Calcium channel antagonists block the inward movement of calcium by binding to the L-type calcium channels in the heart and in smooth muscle of the peripheral vasculature. CCB’s dilate coronary arteries and peripheral arterioles, but not veins. They also decrease cardiac contractility (negative inotropic effect) ,automaticity at the SA node and conduction at the AV node. Dilation of the coronary arteries increases myocardial oxigen supply.

As the following table shows, there are differences in terms of tissue selectivity between dihydropiridines (nifedipine and others), diltiazem and verapamil:

Effects of CCBs on heart contraction and conduction

Dihydropiridines have minimal effect on cardiac conduction or heart rate, while they have potent actions as arteriolar vasodilators. This class of drugs can cause reflex tachycardia when peripheral vasodilation is marked.

On the other hand, verapamil and diltiazem slow AV conduction and decrease SA node automaticity, they also decrease heart rate. Diltiazem is used in the treatment of variant angina because of its coronary antispasmodic properties.

Indications

Dihydropiridines indications

Hypertension

CCB’s  effectiveness in the treatment of hypertension is  related to a decrease in peripheral resistance accompanied by increases in cardiac index.

CCB are also useful in the treatment of hypertensive patients with comorbidities such as: asthma, diabetes, angina, ond or peripheral vascular disease.

Angina pectoris

Calcium channel blockers act as coronary vasodilators, producing variable and dose-dependent reductions in myocardial oxygen demand, contractility, and arterial pressure. These combined pharmacologic effects are advantageous and make these agents as effective as beta blockers in the treatment of angina pectoris. They are indicated when beta blockers are contraindicated, poorly tolerated, or ineffective.

In the presence of heart failure, the use of calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect.

Supraventricular tachyarrhythmias

Verapamil and diltiazem indications

Verapamil and diltiazem are class IV antiarrhythmics, according to Vaughan and Williams’ classification of antiarrhythmic drugs. This is based on their depressant action at the SA and AV nodes. Their ability to inhibit the AV node is employed in the management of supraventricular tachyarrhythmias, such as: atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia.

Video review on calcium channel blockers

The following video summarizes most of the concepts above discussed:

References and further reading

Lullmann, Heinz; Mohr Klaus. “Color Atlas of Pharmacology”, 3rd edition. Thieme: 2005.

Fauci AS, Kasper DL, Braunwald E, Hauser SL, Longo DL, Jameson JL, LOscalzo J: “Harrison’s Principles of Internal Medicine”, 17th edition. Mc Graw Hill Medical: 2008.

Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.

Katzung, B. “Basic & Clinical Pharmacology”, 10th Edition. Mc Graw Hill Medical: 2007

Combined Oral Contraceptive Pill mechanism of action, or “How the pill works”

Mechanism of action of oral contraceptives or "How the pill works"

This animation depicts inhibition of ovulation as the primary mechanism of the contraceptive action of sequential and combination birth control preparations. Ovulation is prevented by the suppression of the midcycle surge of FSH and LH.

Estrogens are most active in inhibiting FSH release, but at high enough doses, they also inhibit LH release. In low-dose combination products, the progestin causes LH suppression.The progestin component is also important in causing withdrawal bleeding at the end of the cycle.

This post features two clinical guidelines on the management of community acquired pneumonia.

The British Thoracic Society updated this year many recommendations,  including: when to order a chest X-ray, antibiotic management, among others.

The guidelines issued by the Infectious Diseases Society of America and the AmericanThoracic Society have relevant recommendations concerning empirical antimicrobial therapy and its duration.

British Thoracic Society; 2009 Update of the Guidelines for the Management of Community Acquired Pneumonia in Adults.

Download PDF

Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community‐Acquired Pneumonia in Adults

Download PDF

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