This article will focus on the classification of serotonin receptors, as well as drug classes that act on serotonergic transmission. This includes 5-HT agonists, antagonists and medications that modulate 5-HT at the presynaptic level, all of them of very high clinical relevance. Overdose of a combitation of serotonergic agents can lead to serotonin syndrome.

Outline:

• Serotonin receptors
• Drugs acting on serotonergic transmission: MAO inhibitors, SNRIs, SSRIs
• Serotonin agonists
• Serotonin antagonists

Serotonin receptors

Based on biochemical and pharmacological criteria, serotonin receptors are classified into seven main receptor subtypes, 5-HT1–7. Of major pharmacotherapeutic importance are those designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated ion channel.

5-HT1 receptors are subdivided into 5-HT1A, 5-HT1B, and 5-HT1D receptors; while 5-HT2 subtypes include 5-HT2A, 5-HT2B, and 5-HT2C.

Drugs acting on serotonergic neurotransmission

The figure above depicts how serotonin neurotransmission may be modified at the presynaptic level by inhibiting degradation, storage or reuptake.

MAO inhibitors

Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation. MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of depression (phenelzine, tranylcypromine, selegiline) and Parkinson’s disease (selegiline). Dietary restrictions (because of tyramine toxicity) limit their widespread use.

Inhibitors of serotonin storage

They interfere withe the ability of synaptic vesicles to store monoamines; displace serotonin, dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that share this mechanism of action include amphetamine, methylphenidate and modafinil.

SNRI

SNRIs mechanism involves blockade of 5-HT and norepinephrine reuptake in a concentration-dependent manner. Agents in this class include venlafaxine and duloxetine, they may be effective for the treatment of depression in patients in whom SSRIs are ineffective.

SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and to an enhanced postsynaptic neuronal activity.

TCAs

Tricyclic antidepressants act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters, thereby causing enhancement of postsynaptic response.

Serotonin agonists

Serotonin receptors agonists have wide clinical applications, from treatment of depression to abortive medications for migraine headache. According to the receptor they activate, they can be divided into:

5-HT1A agonists

Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression.

5-HT1B and 5-HT1D agonists

The “triptans” are a drug class useful as abortive medication for the treatment of  acute migraine headaches. They are very effective medications that bind to 5-HT1B and 5-HT1D receptors in cranial vessels, which leads to vasoconstriction and decreased release of neuropeptides involved in “sterile inflammation”.

5-HT2C agonist

Trazodone was previously believed to be a 5-HT2C receptor antagonist. However,  recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as somnorific.

5-HT4 agonists

Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from the U.S. market because of cardiovascular toxicity.

Non-selective agonists

Ergotamine activates a more than one subtype of 5-HT receptor, it binds to  5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks.

LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties.

5-HT2 antagonists

Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its serotonin antagonism, it has affinity for alpha-1 receptors, which may contribute to its antihypertensive effect.

Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors.  It represents a class of atypical antipsychotic drugs, one key advantage of this group is its reduced incidence of extrapyramidal side effects compared to the classical antipsychotics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia.

Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor.

5-HT3 antagonists

This class includes drugs such as ondansetron, palonosetron and others. These agents are particularly useful in the treatment of chemotherapy induced nausea and vomiting (CINV).

References and further reading

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.

General characteristics and pharmacokinetics

All 5-HT3 antagonists are identified by the suffix -setron, according to the WHO’s Anatomical Therapeutic Chemical Classification System.

The following are  5-HT3  antagonists serum half- lives:

• Dolasetron (Anzemet): 7-9 hours.
• Granisetron (Kytril, generic) 9-11 hours.
• Ondansetron (Zofran, generic): 3.9 hours.
• Palonosetron (Aloxi): 40 hours.
• Tropisetron (Navoban):  7.3 hours. Not available in the United States.

At equivalent doses for the prevention of acute emesis, 5-HT3 serotonin receptor antagonists have equivalent safety and efficacy and can be used interchangeably.

These drugs are metabolized in the liver and are eliminated by renal and hepatic excretion. In spite of this, dose adjustment is not  required in geriatric patients or patients with renal insufficiency.  Dose reduction may be required when giving ondansetron to patients with hepatic insufficiency.

Mechanism of Action

Chemotherapy causes emesis through effects at a number of sites. When antineoplastic agents are administered, 5-hydroxytryptamine (5-HT) is released from the upper small intestine enterochromaffin cells,  5-HT activates 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. These afferent fibers have projections to the  nucleus tractus solitarius (NTS) and the area postrema (AP).

Source: Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008 358: 2482-2494

Selective 5-HT3-receptor antagonists antiemetic properties are mediated through central (vomiting center, chemoreceptor trigger zone) and peripheral (intestinal and spinal) 5-HT3 receptor blockade.  This mechanism explains why their clinical use is limited to situations that produce vagal stimulation (eg. surgery) and chemotherapy.

Indications

Chemotherapy-induced nausea and vomiting  (CINV)

According to the 2006 update of the American Society of Clinical Oncology Guideline for Antiemetics in Oncology,  5-HT3-receptor antagonists are considered one of the classes of drugs with highest therapeutic index.  When used alone, these drugs have little or no efficacy for the prevention of delayed nausea and vomiting (ie, occurring  24 hours after chemotherapy).

These drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy in the following schedules:

Dose and Schedule of Antiemetics to Prevent Emesis Induced by Antineoplastic Therapy

Post-operative nausea and post-radiation nausea and vomiting

According to a recent meta-analysis, 5HT3 antagonists are superior to metoclopramide, droperidol, and dimenhydrinate in the pharmacologic prophylaxis of postoperative nausea and vomiting. Recently, the FDA added a boxed warning to metoclopramide because of an increased risk of tardive dyskinesia. Due to this and other restrictions on antiemetic agents, 5-HT3-receptor antagonists are gaining more acceptance for this clinical use.

Adverse effects

These drugs are generally very well tolerated, frequent adverse effects are: constipation or diarrhea, headache, and light-headedness. According to experimental data, these agents have shown to induce minor electrocardiographic changes. It is recommended not to administer dolasetron to patients with prolonged QT or with drugs that may prolong the QT interval.

References and further reading

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

Kris MG, Hesketh PJ, Somerfield MR, Petra F, Clark-Snow R, Koeller JM, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol (2006) 24:2932–47

Gregory E, Ettinger D. 5-HT3 Receptor Antagonists for the Prevention of Chemotherapy-Induced Nausea and Vomiting. Drugs 1998 Feb; 55 (2): 173-189.

Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008 358: 2482-2494

Martin J, Kim M. Meta-analysis of pharmacologic prophylaxis of postoperative nausea and vomiting in adults: 5HT3 antagonists, dexamethasone, droperidol, metoclopramide, dimenhydrinate, or combinations? Ital J Public Health 2005; 2: 273.

The panel experts were charged with answering the following critical questions about the management of hepatitis B:

What is the current burden of hepatitis B?

What is the natural history of hepatitis B?

What are the benefits and risks of the current therapeutic options for hepatitis B?

Which persons with hepatitis B should be treated?

What measures are appropriate to monitor therapy and assess outcomes?

What are the greatest needs and opportunities for future research on hepatitis B?

The panel  also considered oral and written comments  from conference attendees while developing the following statement.

Download PDF file: 2009 Clinical practice guidelines on the management of hepatitis B infection

Pharmamotion has now a new page containing updates on  clopidogrel – PPI interactions.

The latest edition of the monthly newsletter from the Medicines and Healthcare products Regulatory Agency has issued a drug safety advice on the interaction between the antiplatelet drug clopidogrel (Plavix) and PPIs.

They conclude that available data supports a clinically significant interaction that makes clopidogrel less effective when given with these drugs.

Their advice for healthcare professionals:

• The need for PPI therapy in patients who are also taking clopidogrel should be reviewed at their next appointment: avoid concomitant use of these medicines unless considered essential.

• Prescribe PPIs in line with their licensed indications where possible.

• Check whether patients who are taking clopidogrel are buying over-the-counter omeprazole and consider whether another gastrointestinal therapy would be more suitable.

The bottom line message is clear:

Concomitant use of a PPI with clopidogrel should be avoided unless considered essential.

Source: Drug Safety Update: Volume 2 Issue 12, July 2009

Further reading

Pezalla E, et al. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol 2008; 52: 1038.

Ho M, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009; 301: 937.

Juurlink D, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009; 180: 713–18.

Society for Cardiovascular Angiography and Interventions statement on “A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: The Clopidogrel Medco Outcomes Study”.

The U.S. Food and Drug Administration announced today that manufacturers of metoclopramide, a drug used to treat gastrointestinal disorders, must add a boxed warning to their drug labels about the risk of its long-term or high-dose use. Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body, even after the drugs are no longer taken.

Current product labeling warns of the risk of tardive dyskinesia with chronic metoclopramide treatment. The development of this condition is directly related to the length of time a patient is taking metoclopramide and the number of doses taken. Those at greatest risk include the elderly, especially older women, and people who have been on the drug for a long time.

Tardive dyskinesia is characterized by involuntary, repetitive movements of the extremities, or lip smacking, grimacing, tongue protrusion, rapid eye movements or blinking, puckering and pursing of the lips, or impaired movement of the fingers. These symptoms are rarely reversible and there is no known treatment. However, in some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.

Recently published analyses suggest that metoclopramide is the most common cause of drug-induced movement disorders. Another analysis of study data by the FDA showed that about 20 percent of patients in that study who used metoclopramide took it for longer than three months. The FDA has also become aware of continued spontaneous reports of tardive dyskinesia in patients who used metoclopramide, the majority of whom had taken the drug for more than three months.

In 2004, an interesting article was published in the Journal of the American Pharmacists Association: Tardive dyskinesia risks and metoclopramide use before and after US market withdrawal of cisapride. The conclusions of the retrospective and observational analysis were:

Well-described TD risk factors were common in metoclopramide-associated TD reports. Given the cisapride market withdrawal and associated increased metoclopramide utilization, the incidence of TD may increase accordingly. TD risk factors relative to the intended benefit and duration of use should be considered in metoclopramide prescribing.

Two independent organizations have recently published updated clinical information on this drug:

• Australian Prescriber. New drugs: Methylnaltrexone

• Health Canada. Summary Basis of Decision (SBD) RELISTOR

The Scottish Medicines Consortium also reviewed Relistor in January 2009.

1. Drugs affecting GI secretions

2. Laxatives

3. Anti-diarrheals

4. Emetics and anti-emetics

More on nursing pharmacology

Technorati : Anti-diarrheals, Anti-emetics, Laxatives, NCLEX, Nurses & nursing students, PPI, pharmacology for nurses

Mechanism of action of PPI’s. Source: Wikipedia

Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more commonly just gastric proton pump) of the gastric parietal cell. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. (“Irreversibility” refers to the effect on a single copy of the enzyme; the effect on the overall human digestive system is reversible, as the enzymes are naturally destroyed and replaced with new copies.)

Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, result in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%.

The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. However, lack of stomach acid is also called hypochlorhydria, the lack of sufficient hydrochloric acid, or HCl. Hydrochloric acid is required for the digestion of proteins and for the absorption of nutrients, particularly of vitamin B12 and of calcium.

The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) that have acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.

Some agents in this group include: Omeprazole (Losec, Prilosec, Zegerid, ocid); Lansoprazole (Prevacid, Zoton, Inhibitol); Esomeprazole (Nexium); Pantoprazole ( Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan); Rabeprazole ( Rabecid, Aciphex, Pariet, Rabeloc)