• Aspirin is a weak acid (pKa 3.4).
• Acidic drugs in an acidic environment (like gastric lumen) are most likely to be in their neutral form ( non-ionized )
• Non-ionized drugs are more lipid soluble. Hence, they can be readily absorbed
• Since aspirin is a weak acid and gastric pH is an acidic environment,  it can be readily absorbed.
• Bloodstream has a pH of around 7.4, therefore aspirin tends to be ionized. This prevents the drug from diffusing back to the stomach.

Source: University of Rhode Island Pharmacy Animations

Now, watch again the video paying attention to the following details.

Non-ionized form a at the gastric lumen. It has 8 white spheres.

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Ionized form of aspirin, in the bloodstream. It has 7 white spheres, this means that it has lost a proton.

Deprotonated form =  ionized = non-lipid soluble.

Now,since the drug is ionized it can’t diffuse back to the stomach and remains in the bloodstream.

This is ion trapping!

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Recommended reading

Watch animation

They approach the following topics related to the neurobiology of drug addiction.

• Methamphetamine actions on dopamine vesicles.
• LSD action on serotonin receptors.
• Heroin effects on opioid receptors .
• How marijuana interacts with the cannabinoid system and its receptors.
• Activation of the GABA-A ionotropic receptor by alcohol.
• Cocaine action on dopamine reuptake.

This blog has a related post that explains nicotine addiction mechanism through a 3-D video animation.

Classification of antiplatelet agents

The figure below shows how antiplatelet drugs can be classified according to their mechanism of action. Drug classes include: ADP antagonists (Thienopyridines), COX-1 inhibitors (the only member of this class is aspirin), phosphodiestherase inhibitors and GPIIb/IIIa antagonists.

Classification of antiplatelet agents

Aspirin

Mechanism of action

As shown in the figure, aspirin inhibits platelet cyclooxygenase, a key enzyme in thromboxane A2 (TXA2) generation. Thromboxane A2 triggers reactions that lead to platelet activation and aggregation, aspirin acts as a potent antiplatelet agent by inhibiting generation of this mediator. These effects last for the life of the anucleate platelet, approximately 7 to 10 days.

Aspirin inhibition of COX-1 decreases TXA2 production. Source: Gasparyan, A. Y. et al. J Am Coll Cardiol 2008;51:1829-1843

Therapeutic considerations

Aspirin is indicated as prophylaxis against transient ischemic attacks, myocardial infarction and thromboembolic disorders. It is also used for the treatment of acute coronary syndromes and in the prevention of reoclusion in coronary revascularization procedures. Since side effects such as GI bleeding and acute renal insufficiency are dose dependent, the recommended antiplatelet dose ranges from 75 mg to 325 mg. A related post in this blog reviews some relevant aspects about aspirin pharmacokinetics.

ADP-receptor blockers: thienopyridines

Mechanism of action

Thienopyridines block ADP receptors. Source:Harvey, R; Champe, P “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Thienopyridines act by inhibiting the ADP-dependent pathway of platelet activation. These drugs have no direct effect on prostaglandin metabolism.

Therapeutics

Ticlopidine is the oldest thienopyridine currently available. It is approved for secondary prevention of thrombotic strokes in patients intolerant of aspirin and for prevention of stent thrombosis in combination with aspirin.  Serious adverse effects of ticlopidine therapy are mainly hematologic and include: neutropenia, thrombocytopenia and thrombotic thrombocytopenic purpura.

Clopidogrel is approved for prevention of atherosclerotic events following recent myocardial infarction, stroke or established peripheral arterial disease. It is also approved for use in acute coronary syndromes that are treated with either PCI  or coronary artery bypass grafting. It has a better safety profile than ticlopidine. Recent studies have shown that PPIs interact with clopidogrel, leading to a reduced effectiveness of the latter.

New antiplatelet drugs: Prasugrel is a recently approved  ( July 2009) agent in this class. Like ticlopidine and clopidogrel, prasugrel requires a loading dose to achieve a maximal antiplatelet effect rapidly.

Phosphodiesterase inhibitors

Dipyridamole is acts as vasodilator and antiplatelet agent. It inhibits adenosine uptake and cyclic GMP phosphodiesterase activity, this decreases platelet aggregability.  Dipyridamole alone has  little antiplatelet effect, it is currently used in combination with aspirin or warfarin in the prophylaxis of thromboembolic disorders.  It is also used in stress testing for myocardial perfusion imaging.

GPIIb/IIIa inhibitors

The glycoprotein IIb/IIIa inhibitors are used parenterally in patients with acute coronary syndromes by specialists, this class of drugs is not used in an outpatient setting by non-specialists.

Mechanism of action

IIb/IIIa receptor binding to fibrinogen. Source: www.integrilin.com

Platelet membrane GPIIb-IIa receptors constitute the final common pathway of platelet aggregation, the  integrin GPIIb/IIIa antagonists prevent cross-linking of platelets. Their action is independent of the aggregation-inducing stimulus.

Therapeutic considerations

Abciximab is a chimeric human-murine monoclonal antibody directed against GPIIb/IIIa, current indications include unstable angina that does not respond to conventional therapy in patients that undergo percutaneous coronary intervention. The peptide derivatives, eptifibatide  and  tirofiban  are  more selective towards the GPIIb/IIIa receptor and have a shorter effect than abciximab.

The most serious adverse effects of GPIIB-IIIa antagonists include major bleeding, intracerebral hemorrhage and thrombocytopenia.

Video review on antiplatelet drugs

Dr. Paul, from www.usmlevideos.net reviews antiplatelet therapy, focusing on ticlopidine and clopidogrel.

References and further reading on antiplatelet therapy

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

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

Brunton, L.B., Lazo, J.S., & Parker, K.L. (Eds.). “Goodman & Gilman’s the pharmacological basis of therapeutics“, 11th edition. New York: McGraw-Hill:2005.

Transcript of the video narration:

“Although nicotine can interact with a variety of receptor at numerous tissues, it is its interaction with specific receptors in the brain that creates the dependence associated with smoking.

Within the midbrain, nicotine interacts with the alpha 4 beta 2 nicotinic acetylcholine receptor. Acetylcholine is the natural ligand for this receptors. However, nicotine also an acetylcholine receptor agonist, has a higher affinity for the α4β2 (alpha 4 beta 2) receptors. Located on postsynaptic neurons, these receptors are comprised by two α4 and three β2 subunits that form a channel for transporting ions through the membrane.

When two molecules of nicotine or another ligand engage binding sites within the ionotropic receptor, the ion channel is activated. Looking into the receptor, we see that it is closed, but activation by ligand triggers channel opening for the passage of calcium, sodium and potassium ions.This generates action potentials to the reward area of the brain. Here, the impulse stimulates the release of neurotransmitters including dopamine. Dopamine triggers additional signaling events that stimulate the reward circuit generating short feelings of well-being, increased attention and improved mood. Every time tobacco is used, dopamine levels surge. However, nicotine is eliminated rather rapidly, causing dopamine levels to decline. The result: a craving for more nicotine.

With continued use, α4β2 (alpha 4 beta 2) nicotinic receptors undergo complex adaptive changes including up regulation and desensitization. Over time, these and other downstream changes contribute to a stronger need for nicotine stimulation to achieve the rewards of smoking.”

Lecture outline:

• Minimal Inhibitory concentration.
• Drug resistance.
• Overview of Drug targets.
• Inhibition of cell wall synthesis (beta lactams).
• Inhibition of protein synthesis (macrolides, aminoglycosides, tetracyclines).
• Inhibition of nucleic acid synthesis.
• Adverse drug reactions.
• Antiviral agents

Pharmamotion also has posts that show animations on:

• Linezolid mechanism.
• Vancomycin mechanism.

Anti-microbial drugs

Simponi is a recently approved human monoclonal antibody for the treatment of rheumatic diseases. Its indications include:

• Moderately to severely active Rheumatoid Arthritis (RA) in adults, in combination with methotrexate.
• Active Psoriatic Arthritis (PsA) in adults, alone or in combination with methotrexate.
• Active Ankylosing Spondylitis in adults (AS).

According to the FDA, histoplasmosis and other invasive fungal infections are not consistently recognized in patients under other TNF-α blockers such as Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). This has resulted in delays in appropriate antifungal treatment, which in some cases has lead to death. The agency also added  a Boxed Warning to this group of medications,  alerting about an increased risk of  lymphoma.

Also, the UK’s National Institute for Health and Clinical Excellence (NICE) issued in February 2009 an update of the rheumatoid arthritis clinical guidelines.

Source

MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Simponi (golimumab)

• Become aware of the NCEP ATP III guidelines for cholesterol management.
• Discuss the mechanisms of action of the 5 classes of lipid-lowering agents.
• Indentify medications that belong in each class of lipid-lowering agents.

Lecture outline:

Inhibitors of cholesterol synthesis: statins (check an animation on their mechanism of action).

Inhibitors of bile acid absorption.

Cholesterol absorption inhibitors.

Fibrates.

Niacin (vitamin B3 or nicotinic acid)

In addition to the alert, the FDA requested the manufacturer (Roche) to conduct in vitro studies to assess the potential of precipitation of ceftriaxone and calcium  when ceftriaxone and calcium-containing products are mixed in vials and infusion lines.

The updated recommendations include the following:
Concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates (<28 days of age). Ceftriaxone should not be used in neonates (<28 days of age) if they are receiving (or are expected to receive) calcium-containing intravenous products.

In patients >28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid.

Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via a Y-site in any age group.

FDA now recommends that ceftriaxone and calcium-containing products may be used concomitantly in patients >28 days of age, using the precautionary steps above because the risk of precipitation is low in this population.

FDA had previously recommended, but no longer recommends, that in all age groups ceftriaxone and calcium-containing products should not be administered within 48 hours of one another.

In addition, the agency repeats three of the 2007 recommendations:

Do not reconstitute or mix ceftriaxone with a calcium-containing product, such as Ringer’s or Hartmann’s solution or parenteral nutrition containing calcium, because particulate formation can result.

There are no data on interactions between intravenous ceftriaxone and oral calcium-containing products or between intramuscular ceftriaxone and intravenous or oral calcium-containing products.

Report patients who have adverse events following ceftriaxone administration to the FDA’s MedWatch program.

Lecture outline:

• FDA-approved drugs for the treatment of neuropathic pain.
• Pregabalin (EMEA did not approve it for fibromyalgia).
• Duloxetine (read about its mechanism of action in pain).
• Lidocaine patch 5% (FDA warned about its potential side effects).
• Gabapentin.
• Carbamazepine.
• Principles of opiod therapy (see related PowerPoint presentations on opioids).
• Mu opioid receptor polymorphisms.
• Epidural steroid injections rationale, safety and complications.
• Celiac plexus block.
• Spinal drug delivery.
• Neurostimulation delivery.

Lecture: An update on pharmacologic and non-pharmacologic management of neuropathic and cancer pain