Contents:

- Structure and general characteristics
- Location and physiology of Beta 1 Adrenergic Receptors
- Location and physiology of Beta 2 Adrenergic Receptors
- Weight control Beta 3 Adrenergic Receptors

Structure and general characteristics

Beta receptors are G-protein coupled receptors, they act by activating a Gs protein. Gs activates adenylyl cyclase, leading to an increase in levels of intracellular cAMP. Increased cAMP activates protein kinase A, which phosphorylates cellular proteins.

Beta receptors are characterized by a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine. The rank order in terms of potency is the following:

isoproterenol > epinephrine > norepinephrine

Beta receptors are subdivided into three subgroups, beta 1, 2, and 3. This division is mainly based on their affinities to adrenergic agonists and antagonists.

Beta 1 receptors

Beta 1 receptors are located mainly at the heart and the kidney, their main effects are depicted below.

Heart

- Increase in chronotropy (heart rate)  and inotropy (force of contraction)

Tachycardia results from a Beta 1 mediated increase in the rate of phase 4 depolarization of sinoatrial node pacemaker cells. The inotropic effect is mediated by increased phosphorylation of Ca ++ channels, including calcium channels in the sarcolemma and phospholamban in the sarcoplasmatic reticulum

- Increase in AV- node conduction velocity

Beta 1 stimulated increase in Ca entry increases the rate of despolarization of AV node cells.

Kidney

Beta 1 receptors are present mainly on yuxtaglomerular cells, where receptor activation causes renin release.

Beta 2 receptors

In this section Beta 2 receptors will be studied in two diagrams. The first highlights effects after Beta 2 activation in two systems (respiratory and reproductive), this is viewed separately because of the clinical relevance of Beta 2 agonists in clinical practice. The second figure shows the remaining sympathomimetic effects elicited by Beta 2 receptor activation in other systems.

Bronchial smooth muscle

Beta 2 receptor activation promotes bronchodilation, this physiological property is enhanced by inhaled Beta 2 agonists used in the treatment of asthma and COPD. Some drugs under this category include: salbutamol (albuterol in the US), salmeterol, formoterol and terbutaline.

Uterine contraction

Drugs that bind to Beta 2 receptors (Beta 2 agonists) are used in the treatment of premature labour, this clinical application illustrates how Beta 2 receptors mediate tocolysis on the uterine muscle. Ritodrine is an example of a tocolytic drug.

Bladder detrusor muscle: adrenergic activation of Beta 2 receptors at the bladder promotes relaxation. Bladder constriction is activated by the parasympathetic system, therefore drugs that activate muscarinic receptors such as bethanechol are used in the treatment of urinary retention.

Eye ciliary muscle: this muscle controls eye accomodation and regulates the flow of aqueous humour. Its sympathetic innervation is mediated by Beta 2 receptors.

GI tract: adrenergic activation of the gastrointestinal tract produces a slowing of peristaltic movements (decreased motility) and secretions. These changes are mediated by Beta 2 receptors.

Liver: hyperglycemia and lipolysis occur when Beta 2 receptors are activated. Glucose metabolism is potentiated through gluconeogenesis and glycogenolysis.

Vascular smooth muscle: while Alpha 1 receptors mediate vasoconstriction, Beta 2 receptors induce vasodilation in muscle and liver.

Beta 3 receptors

It has been recently proposed that Beta 3 receptors are linked to the regulation of body weight. Located mainly in adipose tissue, Beta 3 receptors promote lipolysis.

References and further reading

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

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

This articles overviews the key concepts on the pharmacology of acetylcholine receptors, such as:

What happens after acetylcholine is released?

Classification of acetylcholine receptors

Location

Acetylcholine receptors and the autonomic nervous system

Muscarinic receptors

Nicotinic receptors

What happens after acetylcholine is released?

Acetylcholine is released from a presynaptic neuron into the synaptic cleft. Once in the synaptic gap, acetylcholine can:

- Bind to presynaptic receptors: presynaptic activation or inhibition leads to automodulation of the presynaptic cholinergic neuron.

- Be degradated by acetylcholinesterase:  activity of this enzime on acetylcholine triggers its degradation into choline and acetyl coenzime A, thus terminating its effect.

- Bind to postsynaptic receptors: activation of these receptors by acetylcholine leads to cholinergic response.

Classification of acetylcholine receptors

The figure below shows the two main families of acetylcholine receptors: muscarinic and nicotinic. In structural terms, muscarinic receptors are G-coupled protein receptors, while nicotinic receptors are ligand-gated ion channels. They can be found on both sides of the synaptic cleft (presynaptic and postsynaptic).  However, for clinical purposes, we are focusing only on postsynaptic receptors.

Location of acetylcholine receptors

Acetylcholine is a key neurotransmitter acting on a wide number of functions and tissues. This figure shows the three main locations of acetylcholine receptors:

CNS receptors (muscarinic and nicotinic): cholinergic neurotransmission at the CNS level is thought to regulate sleep, wakefulness, and memory.  Two clinical situations depict the role of acetylcholine in CNS:

- Acetylcholinesterase inhibitors are used in the treament of Alzheimer’s disease and other dementias. Inhibition of the enzime that catalyzes acetylcholine degradation (acetylcholinesterase) produces an increased concentration of acetylcholine at the synaptic cleft, thus potentiating cholinergic neurotransmission.  Examples of these drugs include donepezil and rivastigmine.

- Drugs that possess anticholinergic properties may cause acute encephalopathy, such as delirium or a confusional state. Some over-the-counter medications such as diphenidramine (an antihistamine) can cause cholinergic blockade that may lead to a decompensation of underlying cognitive, functional and behavioral deficits (particularly in patients with Alzheimer’s disease).

Autonomic receptors: they are present both in adrenergic and cholinergic transmission. They are discussed in the next section.

Neuromuscular junction: acetylcholine receptors at the neuromuscular junction are exclusively nicotinic, they belong to the N_N subtype.

Acetylcholine receptors  and the autonomic nervous system

Acethylcholine acts on central and peripheral nervous systems ( the latter is divided into somatic and autonomic). The autonomic nervous system (ANS)  exerts its actions through its two antagonic branches: sympathetic ( adrenergic) and parasympathetic (cholinergic).

Looking the diagram below we can see that both sympathetic and parasympathetic branches are modulated at the preganglionic level by the neurotransmitter acetylcholine. This molecule binds nicotinic receptors at the autonomic ganglia to trigger the release of norepinephrine (if a sympathetic synapse is stimulated) or acetylcholine that binds to tissue muscarinic receptors, which will produce a parasympathetic or cholinergic response.

Muscarinic receptors

Muscarinic receptors bind both acetylcholine and muscarine, an alkaloid present in certain poisonous mushrooms (it was first isolated in Amanita muscaria).  Cholinergic transmission (acetylcholine-mediated) that activates muscarinic receptors occurs mainly at autonomic ganglia, organs innervated by the parasympathetic division of the autonomic nervous system and in the central nervous system.

All muscarinic receptors are G-protein coupled receptors. Binding studies have identified five subclasses of muscarinic receptors: M_1,M_2, M₃, M₄, and M_5. The image below shows their locations:

M1, M4 and M5 receptors: CNS. These receptors are involved in complex CNS responses such as memory, arousal, attention and analgesia. M1 receptors are also found at gastric parietal cells and autonomic ganglia.

M2 receptors: heart. Activation of M2 receptors lowers conduction velocity at sinoatrial and atrioventricular nodes, thus lowering heart rate.

M3 receptors: smooth muscle. Activation of M3 receptors at the smooth muscle level produces responses on a variety of organs that include: bronchial tissue, bladder, exocrine glands, among others.

Nicotinic receptors

Unlike muscarinic receptors (which are G-protein coupled receptors), nicotinic receptors are ligand-gated ion channels. When bound to acetylcholine , these receptors  undergo a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell.

Nicotinic receptors can be divided as the diagram shows:

N₁ or N_M receptors: these receptors are located at the neuromuscular junction, acetylcholine receptors of the N_M subtype are the only acetylcholine receptors that can be found at the neuromuscular junction.

N₂ or N_N receptors: as mentioned before, nicotinic receptors play a key role in the transmission of cholinergic signals in the autonomic nervous systems. Nicotinic receptors of the N_N subtipe can be found both at cholinergic and adrenergic ganglia, but not at the target tissues (e.g, heart, bladder, etc). These receptors are also present in the CNS and adrenal medulla.

References and further reading

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

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

The animation below depicts the Jak-Stat signalling pathway mechanism:

As mentioned above, there are some expectations on the future of JAK STAT pathway in pharmacology:

JAK2 Inhibitors

Despite the success of imatinib mesylate in the treatment of CML, the genetic basis of the other major myeloproliferative disorders (polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis) has, until recently, remained obscure. It is now apparent that a common activating mutation in JAK2 (V617F) underlies the aberrant signaling and proliferation in most cases, although how one mutation leads to this spectrum of disorders remains unclear. The V617F mutation is found in the pseudokinase domain of JAK2, and disruption of this autoinhibitory region leads to unchecked activity of the kinase. Cells containing the JAK2 V617F mutation are growth inhibited and undergo apoptosis in response to specific JAK2 inhibitors in vitro. Thus, JAK2 inhibitors are under development for the treatment of polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

Source: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy: D. Golan et al. LWW. 2007

Related links

Series Introduction: JAK-STAT signaling in human disease. Christian W. Schindler. J. Clin. Invest. 109(9): 1133-1137 (2002)

JAK-STAT signaling in asthma. Alessandra B. Pernis and Paul B. Rothman. J. Clin. Invest. 109(10): 1279-1283 (2002)

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://pharmacologycorner.com/hypertension-management-pdf/feed/ 1 http://pharmacologycorner.com/ppt-cephalosporins-pharmacology-overview/ http://pharmacologycorner.com/ppt-cephalosporins-pharmacology-overview/#comments Thu, 17 Dec 2009 16:26:56 +0000 Flavio Guzmán, MD http://pharmacologycorner.com/?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

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

Recommended reading

• The Sanford Guide to HIV/AIDS Therapy 2010
• Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases (2009)
• HIV Essentials 2010
• HIV Diversity and Antiretroviral Resistance: Epidemiology, Recombination, HAART

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.

.

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