text:
The Committee marked up and passed 11 bipartisan regulatory relief bills this week. The bills are designed to help strengthen the economy, preserve consumer choice and allow more Americans an opportunity to achieve financial independence.
As the Committee began debate on the bills, Chairman Jeb Hensarling (R-TX) said "it is difficult, perhaps even impossible, to be more bipartisan or less controversial than these 11 bills that we consider today -- which means because they are bipartisan, they are modest. Although they are modest, they are not insignificant to our fellow citizens back home or to the community banks and credits unions that our fellow citizens depend on," he said.
Financial Institutions and Consumer Credit Subcommittee Chairman Randy Neugebauer (R-TX) said, "Today, the Financial Services Committee has begun to move the pendulum closer to the direction of reasonable regulation by taking the first step to address much-needed regulatory relief for our Main Street financial institutions and the consumers they serve."
This week the Committee also approved a resolution to create the bipartisan Task Force to Investigate Terrorism Financing. The resolution passed unanimously by voice vote. Serving as the Chairman and Co-Chairman of the Task Force are Rep. Michael Fitzpatrick (R-PA) and Rep. Robert Pittenger (R-NC). Rep. Stephen Lynch (R-CT) will serve as the Ranking Member on the Task Force.
"As the United States pushes back against the tide of terror and extremism that is the enemy of freedom and peace everywhere, it must do so with every tool available – including within the financial system," said Rep. Fitzpatrick.
Rep. Pittenger said, "America remains the primary target of radical Islamist jihadists, who seek to destroy our way of life and the freedoms we cherish. We must do all we can to mitigate that threat."Subcommittee Examines FDIC's Role in Operation Choke Point
Bloomberg | House Panel Passes Banking Relief Bills; Legislation Is Repeat of Old Congress
The Hill | House panel advances Dodd-Frank tweaksThe Hill | House Republicans demand FDIC punish 'Operation Choke Point' operators
Washington Times | Small business owners victimized by Operation Choke Point decry government overreach
American Banker | House Banking Panel to Take Up Slate of Dodd-Frank Changes
The Hill | Republicans grill SEC chief over financial adviser regs
Washington Examiner | Operation Choke Point claims more victims, ignores due process
The Hill | House panel advances Dodd-Frank tweaks
Credit Union Times | Credit Union Reg Relief Bills Approved
American Banker | House Panel Passes Reg Tweaks
Daily Signal | Republicans to Government Official: Why Has No One Been Fired Over Choke Point?Green Bay Gazette | Duffy pushes FDIC on 'Operation Chokepoint'
The explosive growth of regulation following the enactment of the Dodd-Frank Act has made it significantly harder for community banks and credit unions to survive and serve customers. New regulations and higher compliance costs have accelerated the pace of industry consolidation and forced many small banks and credit unions to close their doors. Since the passage of Dodd-Frank nearly five years ago, big financial institutions have gotten bigger and small financial institutions have become fewer.
As a result, consumers are finding they have less access to affordable credit and that their local financial institution can no longer provide them with the products and services they want and need, such as free checking or affordable home mortgages.
This is why Chairman Jeb Hensarling (R-TX) has said the committee has no more "urgent priority" than passing regulatory relief legislation for hometown banks and credit unions.
"It is not an exaggeration to say that community banks and credit unions are withering on the vine. We are losing, on average, more than one a day and they are not perishing of natural causes," said Chairman Hensarling. "The sheer weight, volume, cost, complexity and uncertainty of federal regulation is a burden that is killing them off. And as they die, unfortunately, so do the dreams of millions of our fellow citizens who rely upon these community financial institutions to achieve their American dream of financial independence."
The 11 bills passed by the committee have bipartisan support. All 11 bills had also previously been approved by either the Financial Services Committee or the House of Representatives during the 113th Congress. However, none of the bills came up for a vote in the Senate, which was then under Democratic control.
A list and summary of the bills passed today follows:
H.R. 299, the Capital Access for Small Community Financial Institutions Act
Sponsor: Rep. Steve Stivers (R-OH)
Summary: Allows privately insured state chartered credit unions to apply for membership in the Federal Home Loan Bank System, which would help them better serve the financial needs of consumers. The bill passed the House by a vote of 395-0 during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 56-1.
H.R. 601, the Eliminate Privacy Notice Confusion Act
Sponsor: Rep. Blaine Luetkemeyer (R-MO)
Summary: Reduces confusion among consumers by clarifying that they will receive privacy notices after opening a new account when their financial institution's privacy policies change rather than an annual notice. The House passed a similar bill by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 57-0.
H.R. 650, the Preserving Access to Manufactured Housing Act
Sponsor: Rep. Stephen Fincher (R-TN)
Summary: Amends the Truth in Lending Act, as modified by the Dodd-Frank Act, to ensure that consumers can continue to have access to manufactured housing by altering the definition of a "high-cost mortgage." The bill passed the committee by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 43-15.
H.R. 685, the "the Mortgage Choice Act
Sponsor: Rep. Bill Huizenga (R-MI)
Summary: Provides clarity to the calculation of points and fees, allowing more loans to qualify as Qualified Mortgages and increasing options for borrowers. The bill passed the House by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 43-12.
H.R. 1195, the Bureau of Consumer Financial Protection Advisory Boards Act
Sponsor: Rep. Robert Pittenger (R-NC)
Summary: Creates a small business advisory board to advise the Consumer Financial Protection Bureau (CFPB). This advisory board will provide small businesses the opportunity to weigh in on matters of concern, and for the CFPB to learn about market conditions affecting these businesses. The bill also codifies two other advisory committees created by CFPB Director Cordray, the Credit Union Advisory Council and the Community Bank Advisory Council. The committee passed the bill by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 53-5.
H.R. 1259, the Helping Expand Lending Practices in Rural Communities Act
Sponsor: Rep. Andy Barr (R-KY)
Summary: Provides an appeals process for areas to be designated as rural for the purpose of exempting certain loans from the CFPB's Qualified Mortgage rule. The bill passed the House by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 56-2.
H.R. 1265, the Bureau Advisory Commission Transparency Act
Sponsor: Rep. Sean Duffy (R-WI)
Summary: Brings greater transparency and accountability to the CFPB by subjecting it to the Federal Advisory Committee Act. Only three agencies are exempted from the Federal Advisory Committee Act – the CIA, the Directorate of National Intelligence and the Federal Reserve. The CFPB is not involved in intelligence collection, covert operations, or the formation of monetary policy, so there is no reason that it cannot hold its committee and subcommittee meetings in public. This bill passed the committee by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 56-2.
H.R. 1367, clarifying the Expedited Funds Availability Act's application to U.S. territories
Sponsor: Rep. Amata Radewagen (R-American Samoa)
Summary: Improves check-clearing wait times in American Samoa and the Northern Mariana Islands by extending the application of the Expedited Funds Availability Act. The bill passed the House by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 58-0.
H.R. 1408 the Mortgage Servicing Asset Capital Requirements Act
Sponsor: Rep. Ed Perlmutter (D-CO)
Summary: Directs federal banking agencies to conduct a study to determine the appropriate capital requirements for mortgage servicing assets for community financial institutions. The bill passed the committee 44-9 during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 49-9.
H.R. 1480, the SAFE Act Confidentiality and Privilege Enhancement Act
Sponsor: Rep. Robert Dold (R-IL)
Summary: Provides assurance for financial institutions that privileged information shared between federal banking regulators and state regulatory agencies will be protected and remain confidential. The bill passed the House by voice vote during the 113th Congress.
The Financial Services Committee approved the bill today by a vote of 58-0.
H.R. 1529, the Community Institution Mortgage Relief Act
Sponsor: Rep. Brad Sherman (D-CA)
Summary: Ensures that consumers continue to have various credit choices by allowing smaller community financial institutions to enter the mortgage market without being deterred by the high cost of regulatory compliance. The bill amends the Real Estate Settlement Procedures Act to direct the CFPB to provide exemptions from the mortgage escrow account requirements of Dodd-Frank and for small servicers that annually service 20,000 or fewer mortgage loans. The bill passed the committee 43-16 during the 113th Congress.The Financial Services Committee approved the bill today by a vote of 48-10. Read More
House Financial Services Committee Chairman Jeb Hensarling (R-TX) released the following statement after the House passed the Fiscal Year 2016 budget resolution (H. Con. Res. 27):
"Budgets are about priorities, and the House Republican budget resolution passed today by the House of Representatives advances several important priorities. To give hardworking, middle income families the opportunity to achieve economic success, our budget calls for comprehensive, pro-growth tax reform that lowers tax rates on American families and businesses, and broadens the tax base by getting rid of loopholes and special interest provisions. To keep our promise to current and future seniors, we save, strengthen, and secure Medicare and Social Security by getting these important programs off the path to certain bankruptcy. To get our nation's fiscal house in order and off the path to national bankruptcy, our budget stops spending money we don't have, will balance in less than 10 years, and will allow us to begin paying down our nation's debt. To empower patients and doctors to make their own health care decisions, our budget fully repeals Obamacare. To stop future bailouts enshrined into law by the Dodd-Frank Act, our budget ends Washington's regime for officially designating certain financial firms as 'too big to fail' and envisions the eventual elimination of Fannie Mae and Freddie Mac, the government-controlled mortgage giants that received the largest taxpayer-funded bailout in history. Our budget also brings needed accountability to the Consumer Financial Protection Bureau to make sure it doesn't engage in wasteful spending but instead uses its resources to actually help protect American consumers.
"At a time when the threats to our national security are on the rise, this budget ensures that our nation's military has the resources needed to defend our nation and allow our men and women in uniform to carry out the mission we've tasked them with. In a perfect world, it would have been my preference to provide increased spending for our nation's defense without using the 'off-budget' Overseas Contingency Operations (OCO) account. But this would have opened the door for the President to enter this process seeking dramatic increases for his priorities, ultimately threatening to undo the spending caps established by the Budget Control Act.
"When you compare this budget with the President's budget, his hurts the economic and job opportunities of current and future generations of Americans by continuing to spend money we don't have. By completely blowing up the bipartisan spending caps that Republicans and Democrats agreed to just over three years ago in the Budget Control Act, increasing taxes on hard working Americans, and failing to reform Social Security and Medicare – all the president has really done is step on the accelerator, hurdling us that much faster towards financial oblivion and leaving American families with a downsized American Dream.
"Simply put, President Obama's budget prioritizes big government and even bigger taxes. The House Republican Budget prioritizes economic growth and opportunity for all Americans and gives them the opportunity to pursue their version of the American dream."
Financial Services Committee Chairman Jeb Hensarling (R-TX) delivered the following opening statement at today's full committee hearing to examine the Securities and Exchange Commission's FY2016 budget request and agenda:
This morning we welcome Securities and Exchange Commission Chair Mary Jo White back to the Committee.
This Committee is indeed committed to conducting vigorous oversight to make certain the SEC is accountable in fulfilling its three-part mission of protecting investors, maintaining fair, orderly and efficient markets, and promoting capital formation.
By holding today's hearing, we hope to better understand the progress the Commission is making and its priorities for the remainder of the year.
I have no doubt the hearing will serve as déjà vu all over again for Members who argue that the SEC has inadequate resources within with which to carry on its mission. However, the facts are that the SEC's budget has grown tremendously over the years. In fact, the SEC's current budget of $1.5 billion represents an increase of almost 35% since the passage of the Dodd-Frank Act not yet five years ago. In fact, over a twenty year period since 1995, the SEC's budget has increased by nearly 400%. That is three times greater than our national defense budget has grown at a time when we have to fight the international war on terror. This growth in the SEC's budget considerably outstrips most other government agencies over the similar time period.
Furthermore, as I look to the monitors on my left and right which shows the rapidly rising and unsustainable red ink of our national debt; a debt that threatens to bankrupt our nation, I am reminded that hard-working Texans of the Fifth District that represent, they have not had the privilege of seeing their family budgets increase four-fold. They are the ones who ultimately will have to pay for this unsustainable debt.
Which again underscores that in Washington, it is not always how much money you spend that counts; it's how you spend money. And that leads to the SEC's priorities and agenda for 2015.
The bipartisan JOBS Act should be a priority but, regrettably, it does not appear the SEC treats it as such. At a time when the American people continue to struggle with the slowest, weakest recovery of the post-war era, the SEC's neglect of this makes no sense. Even President Obama, with whom I rarely agree, has called the JOBS Act "a big deal" and a "potential game changer" that will help smaller companies take "a major step towards expanding and hiring more workers." Surely, we want companies on Main Street to hire more workers. So if the SEC will not finish the work on the JOBS Act, it is incumbent that Congress do it for them.
Likewise, the SEC's delay in completing its Dodd-Frank mandates, particularly in the derivatives area, has caused unnecessary uncertainty and allowed the CFTC to dictate outcomes that I believe most Members of Congress did not intend.
So as we discuss the SEC's budget request today, our goal as always is accountability. It is this committee's duty to ensure SEC resources are used wisely and efficiently and for the benefit of the American people.
Tuesday, March 24 at 10:00 A.M.- A full committee hearing to review the Securities and Exchange Commission's (SEC) agenda, operations, and Fiscal Year 2016 budget request. SEC Chair Mary Jo White will testify.
The hearing will take place in room HVC-210 of the Capitol Visitor Center.
Tuesday, March 24 at 2:00 P.M.- An Oversight and Investigations Subcommittee hearing to examine the Federal Deposit Insurance Corporation's (FDIC) role in Operation Choke Point. FDIC Chairman Martin Gruenberg will testify.
The hearing will take place in room HVC-210 of the Capitol Visitor Center.
Wednesday, March 25 at 9:00 A.M.- A full committee markup of bipartisan legislation to preserve consumer choice and financial independence. A list of the legislation to be considered during the markup can be found here. The committee will also formally approve the creation of the bipartisan Task Force to Investigate Terrorist Financing.
###Read More
"We are committed to making sure our government is doing everything possible to stop the Islamic State and other terrorists from using the global financial system to finance their acts of evil," said Chairman Hensarling. "Fighting the financial war against terror demands constant innovation and vigilance."
The committee is scheduled to consider a resolution creating the task force on Wednesday.
Task Force Membership
Rep. Mike Fitzpatrick (R-PA) (Chairman)
Rep. Robert Pittenger (R-NC) (Vice Chairman)
Rep. Peter King (R-NY)
Rep. Steve Stivers (R-OH)
Rep. Dennis Ross (R-FL)
Rep. Ann Wagner (R-MO)
Rep. Andy Barr (R-KY)
Rep. Keith Rothfus (R-PA)
Rep. David Schweikert (R-AZ)
Rep. Robert Dold (R-IL)
Rep. Bruce Poliquin (R-ME)
Rep. French Hill (R-AR)
Rep. Stephen Lynch (D-MA) (Ranking Member)
Rep. Brad Sherman (D-CA)
Rep. Gregory Meeks (D-NY)
Rep. Al Green (D-TX)
Rep. Keith Ellison (D-MN)
Rep. James Himes (D-CT)
Rep. Bill Foster (D-IL)
Rep. Daniel Kildee (D-MI)
Rep. Kyrsten Sinema (D-AZ)
###Read More
Witnesses told the Committee on Wednesday that Washington's growing regulatory burden doesn't just affect a bank or credit union's bottom line, it also restricts consumers' choices and access to affordable credit.
This is especially true for Americans with low and moderate incomes.
"It's not an exaggeration to say that every single week we hear from another financial institution that is having trouble meeting the needs of their customers," said Chairman Jeb Hensarling (R-TX). I have one message here from a bank in Arkansas that says due to the Qualified Mortgage rule that they have had to cease funding mobile homes 'which have long been a source of homeownership for low to moderate income consumers in our markets.' Here is one from a credit union in California who says due to federal regulation that one of their members can no longer wire funds to a family member in Ukraine. Here is one from a bank in Massachusetts -- 'we have experienced a spike in loan declines to women,' for their investigation identified that women attempting to buy the family home to settle their divorce and stabilize their family were being declined at a high rate due to the Dodd-Frank Qualified Mortgage rules and the ability to pay rules."
In its coverage of the hearing, the Mobile Press-Register quoted witness Tyrone Fenderson. "This job has been made much more difficult by the avalanche of new rules, guidance and seemingly ever-changing expectation of regulators,' Fenderson said. 'It is this regulatory burden and the fear of even more regulation that often pushes small banks to sell to banks many times their size.'"
Witness Peggy Bosma-LaMascus urged Congress to require "realistic and robust cost-benefit analyses of proposed regulations," the American Banker reported, "so the result would be smarter regulation."
The Committee's hearing on Tuesday gave Members the opportunity to question Treasury Secretary Jacob Lew on a variety of important issues ranging from the international financial system to the growing regulatory burden to the ongoing transparency controversy surrounding former Secretary of State Hillary Clinton.
Monetary Policy and Trade Subcommittee Chairman Bill Huizenga (R-MI) questioned the Obama Administration's plans for the IMF, asking "why should hardworking, middle-income American taxpayer dollars be used to bail out other countries, especially after suffering from bailout fatigue in our own backyard dealing with Fannie Mae, Freddie Mac, FHA and a number of others?"
Others voiced concerns that the Financial Stability Oversight Council (FSOC) has ignored the harmful consequences the Dodd-Frank Act has had on community financial institutions and their customers. "The administration's insistence on defending the Dodd-Frank brand at all costs is made all the more mystifying by the fact that the primary author of the law, our former colleague Barney Frank, has identified a number of provisions that he believes should be revisited. What's more, then-Fed Chairman Bernanke, in his last hearing with us, listed multiple bipartisan legislative reforms that policy makers could unite around to improve our financial regulatory system," said Rep. Randy Hultgren (R-IL). "They both recognized that a law that runs to 2,300 pages and imposes at least 400 mandates cannot possibly be perfect, and that changes are, therefore, warranted."
The Durango Herald reported that Rep. Scott Tipton (R-CO) questioned why FSOC "has not reviewed the effects of these regulations on the local banks in the over 40 FSOC meetings since 2010, despite being legally required to do" under Dodd-Frank.
Committee Members also sought answers from Secretary Lew regarding former Secretary Clinton's use of a personal email address for official business. For much of the first two years of the Obama Administration, Secretary Lew served as Deputy Secretary of State for Management and Resources, making him the department's chief operating officer.
However, Secretary Lew failed to shed any light on the issue, saying he had "no recollection" if he ever had any conversations with anyone about the State Department's email policy and the he "didn't pay a lot of attention to what e-mail" Secretary Clinton was using.Subcommittee Calls for Fairness and Protection of Shareholders in the SEC's Use of Enforcement
March 24, 2015 10:00 a.m.
Full Committee Hearing
"Examining the SEC's Agenda, Operations, and FY 2016 Budget Request"
March 24, 2015 2:00 p.m.
Oversight and Investigations Subcommittee Hearing
"The Federal Deposit Insurance Corporation's Role in Operation Choke Point"
Wall Street Journal | Treasury Secretary Lew: No Recollection of Clinton Email System
Durango Herald | Tipton questions impact of rules on local banks
Mobile Press-Register | Mobile community banker calls for relief from 'avalanche of new rules' created by Dodd-Frank
Wall Street Journal | How Foreigners Became America's Financial Regulators
Wall Street Journal | Ending Federal Loan Fraud
American Banker | 'Time Is of the Essence' to Save Small Institutions, Lawmakers Warn
Lubbock Avalanche-Journal | Local banker to speak on behalf of community banks at Congressional hearing
Bloomberg | Lew Says He Didn't Pay Attention to Clinton's E-Mail Account
Reuters | U.S. Treasury Secretary Jack Lew dodges Clinton email questions
Weekly Standard | Former State Department Official Refuses to Testify About Hillary's Emails
American Banker | Treasury's Lew on Volcker, Systemic Threshold and the State of Regulation
CNN | GOP hits Fed on leaks
Bloomberg | House Financial Services Chairman Says Criminal Probe Opened Into 2012 Fed Leak
"We are committed to making sure our government is doing everything possible to stop the Islamic State and other terrorists from using the global financial system to finance their acts of evil," said Chairman Hensarling. "Fighting the financial war against terror demands constant innovation and vigilance. The Task Force to Investigate Terrorist Financing will examine what, if any, changes are needed to upgrade and improve our nation's ability to starve terrorists of the money they need to carry out their attacks."
The committee is expected to adopt a resolution that formally creates the task force next week.
"As the United States pushes back against the tide of terror and extremism that is the enemy of freedom and peace everywhere, it must do so with every tool available – including within the financial system," said Rep. Mike Fitzpatrick (R-PA) who will serve as Chairman of the task force. "It is my hope that this new task force will encourage and produce true bipartisan measures to devastate and disrupt the ability of terror groups to finance and fund their warped ideologies. I thank Chairman Hensarling and Ranking Member Waters for their leadership in taking the first step toward addressing this important issue, and look forward to working with Rep. Lynch on efforts to expand this committee's role in the fight against terrorism," Fitzpatrick added.
"Deterring terrorist activity is not a Democratic or Republican issue, it's an American issue," said Maxine Waters (D-CA), the Committee's Ranking Member. "I hope that this task force is able to embrace our common goal of making America more secure by working together in a non-partisan manner to prevent banks and other financial institutions from supporting terrorist groups."
"Detecting and disrupting the flow of funding to terrorist groups is critical in our fight against terrorism. While it has proven to be difficult work, it is also worthwhile. I am honored by Ranking Member Maxine Waters' recommendation to serve as the Democratic lead on this new bipartisan Task Force as we join with Chairman Hensarling and Rep. Mike Fitzpatrick to improve our efforts to halt terrorist financing. The rise of ISIS, and the organization's ability to finance an extensive enterprise requires us to continually meet new challenges in this critical counterterrorism area," said Congressman Lynch.
Under House rules, committee task forces can exist for no longer than six months, so the Task Force to Investigate Terrorist Financing will complete its work by the end of September.
###Read More
Financial Services Committee Chairman Jeb Hensarling (R-TX) delivered the following opening statement at today's full committee hearing to examine the regulatory burden facing community banks and credit unions and the detrimental effect this burden has on consumers:
I would say of all the priorities of our committee I know of not one that is more urgent than providing some regulatory relief for our community financial institutions. It is not an exaggeration to say that they are literally withering on the vine. We are losing more than one a day and they are not perishing of natural causes. The sheer weight, volume, cost, complexity and uncertainty of federal regulation is a burden that is killing them off. And as they die, unfortunately, so do the dreams of millions and millions of our fellow citizens, hardworking taxpayers, who rely upon these community financial institutions to help buy a pickup truck to to drive to work, maybe help fund the first kid in their family to ever to go to college, to start a small business and achieve their American dream of financial independence.
It's not an exaggeration to say that every single week we hear from another financial institution that is having trouble meeting the needs of their customers. I have one message here from a bank in Arkansas that says due to the Qualified Mortgage rule that they have had to cease funding mobile homes "which have long been a source of homeownership for low to moderate income consumers in our markets." Here is one from a credit union in California who says due to federal regulation that one of their members can no longer wire funds to a family member in Ukraine. Here is one from a bank in Massachusetts -- "we have experienced a spike in loan declines to women" for their investigation identified that women attempting to buy the family home to settle their divorce and stabilize their family were being declined at a high rate due to the Dodd-Frank Qualified Mortgage rules and the ability to pay rules.
Regrettably, these are not exceptions. We hear from these banks and credit unions every day and we understand how federal regulation can adversely impact low and moderate income Americans.
Now some, particularly those on the other side of the Capitol, have said community financial institutions are doing just fine. In fact they have said"regulators have done a pretty good job protecting community banks." I suspect many of our witnesses will disagree with their statement. I believe that assertion is just wrong, dangerously wrong and out of touch with low and moderate income Americans.
Much, but certainly not all, of this regulatory burden has emanated from Dodd-Frank. I am not a fan of Dodd-Frank but even I can find some good in it. What Dodd-Frank attempted to do on 13(3) of the Fed, what it's done to help eliminate the credit rating agencies' monopoly, what it's done to make balance sheets less opaque. So if I can find some good in it I hope my friends on the other side of the aisle can admit it has done some harm. I know Barney Frank has found at least half a dozen different areas where we he would amend his own law. He said it right before us back in July.
And so I would ask all of my Democratic colleagues to have an open mind as we enter into this and I invite all Members to engage in in the bipartisan effort of regulatory relief for our community financial institutions and find some common ground. I will reserve the right to have an exception to the rule but the rule is going to be any Member who brings a legitimate, bipartisan piece of legislation to provide needed regulatory relief to community financial institutions, we will mark it up. Time is of the essence; let's get started.
2129 Rayburn HOB
Washington, DC 20515
Phone 202-225-7502
Fax 202-226-0471


text:
Welcome to the St. Nicholas Greek Orthodox Church Website
"Welcome one another, therefore, just as Christ has welcomed you, for the glory of God." - Romans 15:7
Through this web site, we are pleased to be able to introduce you to that same worship and fellowship as it is expressed in the life of our St. Nicholas Parish. If you are a new member of our St. Nicholas Parish, or are considering membership, these web pages will acquaint you with what our parish offers to those who give it support and sustenance; to those who already belong to the church, we hope they will provide you with the assurance that your sacrificial offerings are received with profound respect, and are utilized to maximum effectiveness. They will, in any case, enable you to make the informed decisions that are necessary for a meaningful relationship with your church!
Services Schedule
Sundays: Orthros (Matins): 8:00 AM | Divine Liturgy: 10:00 AM
Weekdays: Orthros (Matins): 8:00 AM | Divine Liturgy: 9:00 AM
For information on our Lenten and Holy Week services please contact the Church office at (201) 652-4774 between the hours of 9:00 AM - 5:00 PM, Monday through Friday.
Lenten Services Schedule
Saints, Feasts, and Readings for 3/31/2015
The Holy Hieromartyr Hypatius, Bishop of Gangra; Innocent, Enlightener of Siberia & Alaska; Akakios the Confessor

subset: commoncrawl


text:
unicredit spa (UCG:BrsaItaliana)
Last €6.41 EUR
Change Today +0.075 / 1.18%
Volume 44.7M
As of 9:25 AM 04/1/15 All times are local (Market data is delayed by at least 15 minutes).
BOARD MEMBERS AFFILIATED WITH Candido Fois *
Deputy Vice Chairman, Member of Internal Controls Sub-Committee, Member of Risks Sub-Committee and Member of Remuneration Committee
*Data is at least as current as the most recent Definitive Proxy.
|Recently Viewed
MOST CONNECTED PEOPLE TO Candido Fois
|Luca Cordero di Montezemolo
|98 Relationships
|Mohamed Ali Ali Ismaeil Al Fahim
|98 Relationships
|Enrico Laghi
|94 Relationships
|Giovanni Quaglia
|88 Relationships
|Alessandro Caltagirone
|67 Relationships
Sponsored Financial Commentaries
Sponsored Links
Report Data Issue
To contact UNICREDIT SPA, please visit . Company data is provided by Capital IQ. Please use this form to report any data issues.
Please enter your information in the following field(s):
Your requested update has been submitted
Our data partners will research the update request and update the information on this page if necessary. Research and follow-up could take several weeks. If you have questions, you can contact them at firstname.lastname@example.com.


text:
I enjoy buying sets that have all the basic necessities in one. This is not the longest lasting lip color (not a stain) but definitely above par. It's not the type of color that drys and that's why it's not extra long lasting. The color is very feminine and classy and I like being able to wear a lipstick or gloss or both and the matching lip liner. Great set for the money for certain.
This item is not returnable unless the problem you experience is the result of our error.
More details
Our standard shipping method is ground shipping. We also offer expedited shipping for most items. Your final shipping cost and estimated delivery timeframe will be available at checkout.
Standard shipping details
Expedited shipping details
* For your protection, all orders are screened for security purposes. If your order is selected for review, our Loss Prevention Team may contact you by phone or email. There may be a two business day delay to process your order.
** Most Oversize orders are delivered within 1-4 weeks. Some orders may take 6 weeks to be delivered.


text:
Cholinergic Drugs Chapter 5: Autonomic Pharmacology: Cholinergic Drugs http://www.pharmacology2000.com/Autonomics/Cholinergics/Cholin1.htm Table of Contents Cholinergic Spectrum of Indirect-acting Cholinomimetic Drugs Action o Acetylcholinesterase Inhibitors Cholinergic Receptors Overview o Muscarinic Coupling "Reversible", short- o Nicotinic Muscle acting Receptor "Reversible", o Nicotinic Neuronal intermediate-acting Receptor "Irreversible", long- o Muscarinic Receptors acting Type M1 Indirect Acting Agents-Table Type M2 Pharmacokinetics Differences between Clinical use in anesthesia muscarinic and nicotinic Parathion & Malathion receptors: signal transduction Inhibition Mechanisms mechanisms ACHE Locations Differences between "direct" o Organ Systems and "indirect" cholinoceptor Eye: Ophthalmological Uses agonists Gastrointestinal and Urinary Choline esters: Comparisons Bladder and Contrasts Myasthenia Gravis o Potentiation by Alzheimer's Disease Acetylcholinesterases Conditions Resembling Pharmacological Effects of Myasthenia Gravis Cholinergic Agonists Cholinergic Antagonists o Cardiovascular Effects o Antimuscarinics Vasodilation o Clinical Applications Negative CNS Overview Chronotropic Preoperative medications Decreased SA Management of reflex and AV nodal bradycardia conduction Combinations with velocity anticholinesterase agents Negative during pharmacological inotropism antagonism of (decreased nondepolarizing contractility) neuromuscular-blocking Effect on ionic agents currents Bronchodilation o Gastrointestinal and Sedation Page 1 of 27 RSBhati Cholinergic Drugs Urinary Tracts Management of gastric or Cellular Events following intestinal hypersensitivity or Cholinergic Receptor secretion Activation Respiratory Tract Effects Second Messenger Systems Ophthalmological Effects Nitric Oxide and Muscarinic o Adverse Effects Receptor Activation Ganglionic Blocking Agents Some Cholinergic Agents Antimuscarinic drug effects on various organ systems Clinical Uses-Agonists o Gastrointestinal & Genitourinary o Opthalmological o Contraindications Adverse Effects: Muscarinic Agonists . Spectrum of Action of Choline Esters Location of cholinergic synapses mainly determine the spectrum of action of acetycholine and choline esters. Cholinergic Synaptic Sites o autonomic effector sites: innervated by post-ganglionic parasympathetic fibers o some CNS synapses o autonomic ganglia and the adrenal medulla o skeletal muscle motor endplates (motor nerves) Systemic administration of acetylcholine (ACh) may theoretically act at these sites, but poor CNS penetration (ACh is a charged, quaternary nitrogen compound) and plasma butyrylcholinesterase which hydrolysizes ACh limit systemic effects. Acetylcholine (and other choline esters) effects are initiated by interaction with cholinergic receptors, designated either as muscarinic or nicotinic. o Muscarinic receptors (so defined based of their response to muscarine) are found not only at post-ganglionic parasympathetic effector sites but also at autonomic ganglion cells and adrenal medulla where they modulate nicotinic receptor- mediated effects. o Nicotinic receptors are the primary cholinergic receptors at autonomic ganglia and skeletal muscle neuromuscular junctions. These receptors were named because of their responsiveness to the alkaloid nicotine. Cholinergic influences are prominent in many organ systems: Page 2 of 27 RSBhati Cholinergic Drugs Choline Sensitivit Cardiovascul Gastrointestin Urinar Eye Atropin Activity Ester y to ar al y (Topica e at ACHE Bladd l) Sensitiv Nicotini er e c Sites Acetylcholi ne Methacholi ne Carbachol No Bethanecho No ? ? No l 1. Modified from Table 7-1: Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p 143 2. Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 142- 143. Return to Table of Contents. Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms Muscarinic Receptor Coupling Mechanisms Five types of cholinergic receptors have been identified by molecular cloning methods. The possibility of multiple forms was suggested by the pharmacology of piprenzipine which is an effective antimuscarinic in blocking gastric acid secretion, but was not effective in blocking other responses to muscarinic agonists. The five muscarinic receptor subtypes, M1 - M5, are associated with specific anatomical sites. For example: o M1 -ganglia; secretory glands o M2 - myocardium, smooth muscle o M3 , M4 :smooth muscle, secretory glands Nicotinic Muscle Receptor Antagonists Tissue Responses Molecular Aspects Tubocurarine Neuromuscular Membrane Nicotinic (muscle) Junction Depolarization receptor's cation alpha- leading to muscle ion channel bungarotoxin contraction opening Page 3 of 27 RSBhati Cholinergic Drugs Nicotinic Neuronal Receptor Antagonists Tissue Responses Molecular Aspects Mecamylamine Autonomic Ganglia Depolarization: Nicotinic (muscle) (Inversine) postsynaptic cell receptor's cation ion activation channel opening Adrenal Medulla Catecholamine secretion CNS unknown Muscarinic Type M1 Antagonist Tissue Responses Molecular Aspects Atropine Autonomic Ganglia Depolarization (late Stimulation of EPSP) Phospholipase C Pirenzepine (more CNS Unknown (PLC): activation of selective) inositol-1,4,5 triphosphate (IP3 ) and diacylglycerol (DAG) leading to increased cytosolic Ca2+ Muscarinic Type M2 Tissue (Heart) Responses Molecular Aspects SA node decreased phase 4 K+ channel activation depolarization; through ß-gamma Gi hyperpolarization subunits; Atrium decreased contractility; decreased AP duration Gi -mediated inhibition of AV node decreased conduction adenylyl cyclase which velocity decreases intracellular Ca2+ Ventricle decreased contractility levels. (Gi can inhibit directly Ca2+ channel opening) Return to Table of Contents. Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Page 4 of 27 RSBhati Cholinergic Drugs Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p119. Signal Transduction: Comparison of Muscarinic and Nicotinc Receptors o Nicotinic Receptors Ligand-gated ion channels Agonist effects blocked by tubocurarine Receptor activation results in: + 2+ rapid increases of Na and Ca conductance deplorization excitation Subtypes based on differing subunit composition: Muscle and Neuronal Classification o Muscarinic Receptors G-protein coupled receptor system Slower responses Agonist effects blocked by atropine At least five receptor subtypes have been described by molecular cloning. Variants have distinct anatomical locations and differing molecular specificities Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.112-137. Direct vs. Indirect-Acting Cholinomimetics o A direct-acting cholinomimetic drug produces its pharmacological effect by receptor activation. o An indirect-acting drug inhibits acetylcholinesterase, thereby increasing endogenous acetylcholine levels, resulting in increased cholinergic response. Return to Table of Contents. Choline esters: Comparisons and Contrasts Choline Ester Sensitivity Cardiovascular Gastrointestinal Urinary Atropine Activity to ACHE Bladder Sensitive at Nicotinic Sites Acetylcholine Methacholine Carbachol No Page 5 of 27 RSBhati Cholinergic Drugs Bethanechol No ? ? No (Urecholine) Potentiation by Acetylcholinesterases Choline Ester Agent Sensitivity to ACHE Acetylcholine (potentiated by AchE inhibitors) Methacholine (potentiated by AchE inhibitors) Carbachol (AchE inhibitors No have no effect) Bethanechol (Urecholine) No (AchE inhibitiors have no effect) Pharmacological Effects of Cholinomimetics Cardiovascular: Four major effects Vasodilation: This effect is mediated by muscarinic receptor activation and is especially prominent in the salivary gland and intestines. 1. The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptors. 2. Increased NO activates guanylate cyclase which increases cyclic GMP concentrations. 3. Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+. 4. Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation. 5. Ca2+ complexes with calmodulin activating light-chain myosin kinase o Increased cGMP promotes dephosphorylation of myosin light-chains. o Smooth-muscle myosin must be phosphorylated in order to interact with actin and cause muscle contraction. Vasodilation may also occur due to ACh inhibition of N.E. release from post-ganglionic sympathetic fibers. Damaged endothelium can result in ACh causing vasoconstriction by direct action on vascular smooth muscle. Negative chronotropic effect (Decrease in heart rate) o Decreases phase 4 (diastolic depolarization) As a result, it takes longer for the membrane potential to reach threshold. o Mediated by M2 muscarinic receptors Page 6 of 27 RSBhati Cholinergic Drugs Decreased SA nodal and AV nodal conduction velocity o Excessive vagal tone may induce bradyarrhythmias including partial or total heart block (impulses cannot pass through the AV node to drive the ventricular rate; in this case, the idioventricular or intrinsic ventricular rate must maintain adequate cardiac output) + o Transmission through the AV node is especially dependent on Ca2 currents. ACh decreases calcium currents in the atrioventricular node. Negative inotropism (decreased myocardial contractility) o more prominent in atrial than ventricular tissue. o due to a decrease in ICa2+ inward current o in the ventricle, adrenergic tone dominates; at higher levels of sympathetic tone, a reduction in contractility due to muscarinic stimulation is noted. Muscarinic stimulation reduces the response to norepinephrine by opposing increases in cAMP in addition to reducing norepinephrine release from adrenergic terminals Effect of muscarinic receptor activation on cardiac currents o increase in I K (Ach) in atrial muscle and in SA and AV nodal tissue o decrease in slow, inward calcium (ICa2+) current (decreased atrial contractility; decreased AV nodal conduction) o decrease in diastolic depolarizing current (If)--decreases heart rate, because it takes longer for the membrane potential to reach threshold (less depolarizing If current) Gastrointestinal and Urinary Tracts o Muscarinic agonists increase intestinal peristalsis, tone, and contraction amplitude. o Carbachol and bethanecol (not ACh or methacholine) stimulate the urinary tract by increasing ureteral peristalsis and by contraction of the urinary bladder detrusor muscle. o Return to Table of Contents. Cellular Events following Cholinergic Receptor Activation Nicotinic Muscle Receptor o Response: Membrane Depolarization leading to muscle contraction o Molecular Aspects: Nicotinic (muscle) receptor's cation ion channel opening Nicotinic Neuronal Receptor o Responses: Depolarization: postsynaptic cell activation Catecholamine secretion Page 7 of 27 RSBhati Cholinergic Drugs o Molecular Aspects Nicotinic (muscle) receptor's cation ion channel opening Muscarinic Type M1 o Response: Depolarization (late EPSP) o Molecular Aspects Stimulation of Phospholipase C (PLC) with formation of inositol-1,4,5 triphosphate (IP3 ) and diacylglycerol (DAG)resulting in increased cytosolic Ca2+ Muscarinic Type M2 o SA node Responses: decreased phase 4 depolarization; hyperpolarization + Molecular Aspects: K channel activation through ß-gamma Gi subunits. o Atrium Responses: decreased contractility; decreased AP duration Molecular Aspects: Gi -mediated inhibition of adenylyl cyclase which decreases intracellular Ca2+ levels (reduces contractility);(Gi can inhibit directly Ca2+ channel opening) o AV node Responses: decreased conduction velocity o Ventricle: Responses: decreased contractility Molecular Aspects: Gi -mediated inhibition of adenylyl cyclase which decreases intracellular Ca2+ levels (reduces contractility);(Gi can inhibit directly Ca2+ channel opening) Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p119 Muscarinic Receptors: Second Messenger Systems Activation of IP3, DAG cascade 2+ o DAG may activate smooth muscle Ca channels 2+ o IP3 releases Ca from endoplasmic and sarcoplasmic reticulum Increase in cGMP Increase in intracellular K+ by cGMP-K+ channel binding inhibition of adenylyl cyclase activity (heart) Pappano, A.J. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs, In Basic and Clinical Pharmacology, 7th Edition, (Katzung, B.G.,ed) Appleton & Lange, 1998, p. 93-94 Page 8 of 27 RSBhati Cholinergic Drugs Nitric Oxide and Muscarinic Receptor Activation o Activation of salivary gland and intestinal parasympathetic systems produce significant vasodilation. o This effect depends on nitric oxide (EDRF) release and subsequent guanylate cyclase activation. (NO binding to the heme group of guanylate cyclase). o Increased levels of cGMP results in stimulation of ion pumps which lower intracellular Ca2+ promoting relaxation. o Increased nitric oxide production may be mediated by: acetylcholine substance P bradykinin direct mechanical (shear forces) on endothelial membranes. Nitric oxide synthase2 o Nitric oxide synthase catalyzes the conversion of L-arginine and molecular oxygen to nitric oxide. o Three forms of nitric oxide synthase form 1 (constitutive): release nitric oxide over short time periods in response to increase in intracellular Ca2+ . 2+ form 2: responsible for Ca - dependent nitric oxide neuronal release. Page 9 of 27 RSBhati Cholinergic Drugs form 3: induced following cytokine or endotoxin cellular activation. This form catalyzes nitric oxide synthesis for an extended time. This form is Ca2+ - independent and is responsible for some pathophysiological responses to endotoxin (hypotension, e.g.). 1 Granger,D.N., Regulation of Regional Blood Flow, In Essential Physiology,(Johnson, L.,ed) Lippincott-Ravin,1998, p. 231. 2 Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.136-137 Cholinergic Agents o Choline Esters Acetylcholine Bethanechol (Urecholine) Carbachol Methacholine (Provocholine) o Alkaloids Muscarine Pilocarpine (Pilocar) Clinical Uses Gastrointestinal & Genitourinary o Bethanechol (Urecholine) GI smooth muscle stimulant postoperative abdominal distention paralytic ileus esophageal reflux; promotes increased esophageal motility (other drugs are more effective, e.g. dopamine antagonist (metoclopramide) or serotonin agonists (cisapride) Urinary bladder stimulant post-operative; post-partum urinary retention alternative to pilocarpine to treat diminished salivation secondary e.g. to radiation Carbachol not used due to more prominent nicotinic receptor activation o Methacholine used for diagnostic purposes. testing for bronchial hyperreactivity and asthma Opthalmological Uses Page 10 of 27 RSBhati Cholinergic Drugs o Acetylcholine and Carbachol may be used for intraocular use as a miotic in surgery o Carbachol may be used also in treatment of glaucoma. o Pilocarpine is used in management of glaucoma and has become the standard initial drug for treating the open-angle form. o Sequential adminstration of atropine (mydriatic) and pilocarpine (miotic) is used to break iris-lens adhesions. Major contraindication to the use of muscarinic agonists o Asthma: Choline esters (muscarinic agonists) can produce bronchoconstriction. In the predisposed patient, an asthmatic attack may be induced. o Hyperthyroidism: Choline esters (muscarinic agonists) can induce atrial fibrillation in hyperthyroid patients. o Peptic ulcer: Choline esters (muscarinic agonists), by increasing gastric acid secretion, may exacerbate ulcer symptoms. o Coronary vascular disease: Choline esters (muscarinic agonists), as a result of their hypotensive effects, can further compromise coronary blood flow. Adverse Effects: Muscarinic Agonists o salivation o diaphoresis o colic o GI hyperactivity o headache o loss of accommodation Return to Table of Contents. Indirect-acting Cholinomimetic Drugs Acetylcholinesterase Inhibitors o Overview Three domains describe the acetylcholinesterase active site: an acyl binding region, the choline binding region, and a peripheral anionic site. There are three classes of anticholinesterase agents o Reversible, Short-Acting Anticholinesterases Reversible inhibitors, edrophonium (Tensilon) and tacrine (Cognex), associate with the choline binding domain. The short duration of edrophonium (Tensilon) action is due to its binding reversibility and rapid renal clearance. Tacrine (Cognex), being more lipophillic, has a longer duration. Some reversible inhibitors, propidium and fasiculin, a toxic peptide, bind at the peripheral anionic site. o Carbamylating Agents: Intermediate-Duration Acetylcholinesterase Inhibitors Page 11 of 27 RSBhati Cholinergic Drugs Physostigmine and Neostigmine are acetylcholinesterase inhibitors that form a moderately stable carbamyl-enzyme derivative. The carbamyl-ester linkage is hydrolyzed by the esterase, but much more slowly compared to acetylcholine. As a result, enzyme inhibition by these drugs last about 3 - 4 h (t ½ = 15 - 30 min). Neostigmine possesses a quaternary nitrogen and thus has a permanent positive charge. By contrast, physostigmine is a tertiary amine o Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors Organophosphate acetylcholinesterase inhibitors, such as diisopropyl fluorophosphate (DFP) form stable phosphorylated serine derivatives. For DFP the enzyme effectively does not regenerate following inhibition. Furthermore, in the case of DFP, the loss, termed "aging", of an isopropyl group, further stabilizes the phosphylated enzyme. The application of the terms "reversible" and "irreversible" depends on the duration of enzyme inhibition rather than strictly based on mechanism. (see above) Examples of "reversible" acetylcholinesterase inhibitors that may be used clinically include both carbamylating agents and those that associate only with the choline binding domain. o "Reversible" Anticholinesterases Used Clinically edrophonium pyridostigmine-Used in treatment of myasthenia gravis neostigmine physostigmine demecarium ambenonium-Used in treatment of myasthenia gravis Pharmacokinetics of Acetylcholinesterase Inhibitors o Duration of Action: Principles Anticholinesterase duration of action: based on rate of disappearance from plasma. Clinical Anesthesia Context: Anticholinesterase drugs are administered when effects of nondepolarizing neuromuscular-blocking agents are diminishing Note: duration of action of edrophonium is approximately the same compared to that of neostigmine in anesthetized patients. (edrophonium had been usually considered a short-acting agent) o Renal Clearance:anticholinesterase drugs Actively secreted into renal tubule lumen Renal clearance: 50% for neostigmine elimination 75% for edrophonium and pyridostigmine elimination Elimination halftimes -- significantly prolonged in renal failure In renal failure, plasma clearance of anticholinesterase drugs is prolonged more substantially than plasma Page 12 of 27 RSBhati Cholinergic Drugs clearance of neuromuscular-blocking agents-- making recurarization In the absence of renal clearance (renal insufficiency), hepatic metabolism is involved to the following extents:: Neostigmine -- 50% Edrophonium -- 30% Pyridostigmine -- 25% o Carbamates Physostigmine, a tertiary amine, is readily absorbed following systemic administration and may be absorbed systemically after conjunctival use. Neostigmine, also a carbamylating inhibitor, is a quaternary nitrogen compound and, as a result, is poorly absorbed. Neostigmine is hydrolyzed by plasma esterases with metabolites excreted in the urine. o Organophosphates Most organophosphorous acetylcholinesterase inhibitors are well- absorbed lipophillic agents. Organophosphates are generally hydrolyzed by serum and tissue esterases and hydrolytic products are renally excreted. Some organophosphorus chemicals are substrates for mixed-function oxidases that convert phosphorothioates (P=S) to phorphorates (P=O). Organophosphate anticholinesterases are themselves hydrolyzed by liver esterases also called A-esterases or paraoxonases. The extent of paraoxon toxicity in humans is dependent on an A-esterase genetic polymorphism. Lipophillicity and intrinsic reactivity (phosophorylation rate constant) are two important factors in determining the lethality of human exposure to organophosphate inhibitors. Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 224-237; Taylor, P. Anticholinesterase Agents, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.161-174. Differences between Parathion & Malathion o Parathion Parathion, a low volatility and aqueous-stable, organophosphate is used as an agriculural insecticide. Parathion is converted to paraoxon by mixed function oxidases. Both the parent compound and its metabolite are effective acetylcholinesterase inhibitors (P=S to P=O). Parathion probably is the most common cause of accidental organophosphate poisoning and death. The phosphothioate structure is present in other common insecticides: dimpylate, fenthion, and chlorpyrifos. o Malathion Page 13 of 27 RSBhati Cholinergic Drugs Malathion is converted to the oxygen form (P=S to P=O). Inactivation rates (hydrolysis) vary between species. Inactivation rates are much higher in mammals and birds than insects. Accidental poisoning and death is not observed with malathion with acute toxicity seen in suicide or deliberate poisoning. (lethal dose in man is about 1g/kg) Spraying over populated areas with malathion has been used in control of Medierranean fruit flies and mosquitoes. Malathion is used in treatment of lice infestations. Taylor, P. Anticholinesterase Agents, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p. 167. Inhibition Mechanisms o Overview: o Inactivation of acetylcholinesterase by organophosphates or carbamates requires either carbamylation or phosphorylation of an active-site reactive serine. o Phosphorylation of this serine leads to a very stable acyl-enzyme complex. o Deacylation (dephosphorylations) reactions may occur very slowly, thus effective inhibiting enzyme activity for long periods. o Reactivation of phosphorylated enzyme may be possible using a nucleophile such as pyridine-2-aldoxime (2-PAM). o 2-PAM reactivation may be not be possible, depending on the stability of the phosphoryl enzyme derivative. Acetylcholinesterase Locations o Acetylcholinesterase: post-synaptic cholinergic membranes. o Inhibition of acetylcholinesterase with subsequent acetylcholine accumulation causes: 1. enhanced muscarinic responses at parasympathetic effector sites. 2. nicotinic receptor stimulation and then paralysis (depolarization block) at autonomic ganglia and skeletal muscle. 3. CNS cholinergic neuronal stimulation o Effects of increased acetylcholine levels can be blocked or reduced by atropine (muscarinic antagonist) at: parasympathetic effector sites autonomic ganglia (muscarinic receptor population) subcortical CNS sites. Organ Systems Affected by Anticholinesterase Agents o Opthalmological Uses of Anticholinesterase Drugs When applied to the conjunctiva, acetylcholinesterase inhibitors produce: constriction of the pupillary sphincter muscle (miosis) contraction of the ciliary muscle (paralysis of accommodation or loss of far vision). Loss of accommodation disappears first, while the miotic effect is longer lasting. Page 14 of 27 RSBhati Cholinergic Drugs During miosis, elevated intraocular pressure (glaucoma) declines due to enhanced flow of aqueous humor. In glaucoma, elevation of intraocular pressure can cause damage to the optic disc and blindness. There are three types of glaucoma: primary secondary (aphakic (no lens) glaucoma, following cataract removal) congenital. Of the three, primary glaucoma responds to anticholinesterase treatment. Primary glaucoma may either be narrow angle (acute, congestive) or wide- angle (chronic, simple) depending on the angle configuration of the anterior chamber. Narrow angle glaucoma, a medical emergency, may rely on drug treatment to control the attack, although surgery may be required for long-term management (iridectomy, peripheral or complete). Anticholinesterase used for management of glaucoma or accommodative esotropia (esotropia (eso- (inward) + Gr. trepein to turn) [Deviation of visual axis toward that of the other other when fusion is possible] Anticholinesterases Used in Treating Glaucoma 1. Physostigmine (eserine) 2. Demecarium (Humorsol) 3. Echothiophate (Phospholine) 4. Isoflurophate (Floropryl) o Gastrointestinal and Urinary Bladder Neostigmine is the anticholinesterase agent of choice for treatment of paralytic ileus or urinary bladder atony. Direct acting cholinomimetic drugs are also useful. o Myasthenia Gravis Myasthenia Gravis appears to be caused by the binding of anti-nicotinic receptor antibodies to the nicotinic cholinergic receptor. Binding studies using snake alpha-neurotoxins determined a 70% to 90% reduction of nicotinic receptors per motor endplate in myasthenic patients. Receptor number is reduced by: increased receptor turnover (rapid endocytosis) blockade of the receptor binding domain antibody damage of postsynaptic muscle membrane A related disease, Lambert-Eaton syndrome, is a presynaptic disorder in which acetylcholine release is impaired due to autoantibodies against P/Q type calcium channels. Most patients with this syndrome have a malignancy, usually small cell lung carcinoma. Treatment includes immunosuppression and plasmapheresis. Anticholinesterase, edrophonium (Tensilon), is useful in differential diagnosis for myasthenia gravis. Page 15 of 27 RSBhati Cholinergic Drugs In this use, edrophonium (Tensilon) with its rapid onset (30 s) and short duration (5 min) may cause an increase in muscle strength. This change is due to the transient increase in acetylcholine concentration at the end plate. Edrophonium (Tensilon) may also be used to differentiate between muscle weakness due to excessive acetylcholine (cholinergic crisis) and inadequate drug dosing. Anticholinesterase drugs provide partial improvement in myasthenia gravis by increasing the amount of acetylcholine available at neuromuscular junctions. Of the anticholinesterases listed below, pyridostigmine (oral) is the one most widely used in the U.S. Anticholinesterases Used in Treating Myasthenia Gravis Neostigmine (Prostigmin) Pyridostigmine (Mestinon) Ambenonium Conditions that resemble myasthenia gravis include: Lambert-Eaton myasthenic syndrome, a presynaptic disorder. (NEJM 332: 1467, 1995 review) Patients with Lambert-Eaton disorder have depressed or absent reflexes, show autonomic changes such as xerostomia and impotence and incremetal responses to repetitive nerve stimulation. Treatment includes plamapheresis and immunosupression. Neurasthenia muscle testing indicates a nonorganic disorder, characterized by feelings of fatigue rather than by a loss of muscle power. Thyroid abnormalities (either hyper or hypo- thyroidism) can increase myasthenic weakness. Thyroid testing is definitive. Associated Disorders: Myasthenia gravis patients often have associated disorders including: thymic abnormalities: >70% hyperthyroidism 3% - 8% other autoimmune disorders--test for rheumatoid factor and antinuclear antibody ventilatory dysfunction Thymic abnormalities: about 35% of patients with epithelial thymoma have myasthenia gravis; furthermore, acetylcholine receptor autoantibody secretion by thymocytes have been reported {Yoshikawa, H and Lennon, V.A. Acetylcholine receptor autoantibody secretion by thymocytes: Relationship to myasthenia gravis, Neurology, 49:562-567,1997} Page 16 of 27 RSBhati Cholinergic Drugs Of the patients who do not have thymomas, most of the rest have thymic hyperplasia (germinal follicles in the thymus) Most thymomas express acetylcholine receptor epitopes on the surfaces of the neoplastic cells (Lancet 339: 707, 1992; Am. J. Path. 148: 1359 & 1839, 1996). This expression may trigger the disease. Seronegative myasthenia gravis patients do not have thymoma: Neurology 42: 586, 1992. Extended thymectomy is the procedure of choice (Ann. Thoracic Surg. 62: 853, 1996). Sites of Drug Intervention in Management of Myasthenia Gravis Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472.: Figure adapted from Figure 382-2, p. 2471 Page 17 of 27 RSBhati Cholinergic Drugs Alzheimer's Disease o Tacrine (Cognex) or other cholinesterase inhibitiors are useful in treating mild to moderate Alzheimer's dementias. 1. Taylor, P. Anticholinesterase Agents, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 172-173.; 2. Moroi, S.E. and Lichter, P.R. Ocular Pharmacology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p. 1634; 3. Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472 Adverse Effects: Overstimulation of Muscarinic and Nicotinic Receptors miosis salivation sweating bronchial constriction vomiting and diarrhea myasthenia gravis neuromuscular blockade (nicotinic effect) CNS effects: high doses Indirect Cholinomimetic Agents Acetylcholinesterase Acetylcholinesterase Inhibitors ("Irreversible") Inhibitors ("Reversible") Neostigmine Soman (Prostigmin) Parathion Physostigmine Malathion (Antilirium) Isoflurophate Edrophonium (Diisopropylflurorphosphate DFP) (Tensilon) Echothiophate Page 18 of 27 RSBhati Cholinergic Drugs Return to Table of Contents Cholinoceptor-Blocking Drugs Introduction: Muscarinic Receptor Antagonists o Antimuscarinic agents were of plant origin. o Belladonna (beautiful woman, a reference to the drug's mydriatic effects,) are found in many plants. o Atropa belladonna (Solanaceae) or the deadly nightshade contains atropine (dl- hyoscyamine) as does Datura stramonium (Jamestown or jimsonweed, thorn- apple, etc.) o Scopolamine, also an alkaloid, is found in the shrub Hyosyamus niger and Scopolia carniolica. An alkaloid is one of a large group of organic, basic plant substances. They are usually pharmacologically active and bitter in taste Alkaloids atropine caffeine morphine nicotine quinine strychnine o Tertiary and Quaternary Antimuscarinic Agents Atropine, scopolamine, and the semisynthetic agent homatropine (Isopto Homatropine) are tertiary amines, generally well-absorbed and able to penetrate the CNS. Each drug can be converted to a quaternary form by addition of a methyl group to the nitrogen, resulting in methylatropine nitrate, methscopolamine bromide and homatropine methybromide. Quaternary muscarinic receptor antagonists tend to be more potent as muscarinic blockers and have increased ganglionic blocking action. Quaternary (permanently charged) antagonists do not penetrate the CNS to a significant extent. Therefore, CNS activity is limited. Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.149-150 Page 19 of 27 RSBhati Cholinergic Drugs Clinical Applications of Cholinergic Receptor Blockers Return to Table of Contents Anticholinergic Drugs -- Anesthesia Applications/Issues o Overview: o Preoperative medication o Management of reflex bradycardia o Use in antagonism of nondepolarizing neuromuscular-blocking agents Common Applications-- anesthesia related (anticholinergic agents) o Preoperative medications o Management of reflex bradycardia o Combinations with anticholinesterase agents during pharmacological antagonism of nondepolarizing neuromuscular-blocking agents Other Applications of anticholinergic drugs: 1. bronchodilation (e.g.,asthma) 2. biliary/ureteral smooth muscle relaxation 3. to cause mydriasis/cycloplegia 4. inhibition of parietal cells acid secretion 5. prevention of motion sickness (nausea) 6. component in cold remedies Central Nervous System Effects of Antimuscarinic Agents o In normal doses, atropine produces little CNS effect. In toxic doses, CNS excitation results in restlessness, hallucinations, and disorientation. o At very high doses, atropine can lead to CNS depression which causes circulatory and respiratory collapse. o By contrast, scopolamine at normal therapeutic doses causes CNS depression, including drowsiness, fatigue and amnesia. Scopolamine also may produce euphoria, a basis for some abuse potential. o Scopolamine may exhibit more CNS activity than atropine because scopolamine crosses the blood brain barrier more readily. o Antimuscarinics are used clinically as preanesthetic medication to reduce vagal effects secondary to visceral manipulation during surgery. o Antimuscarinics with L-DOPA are used in Parkinson's disease. o Extrapyramidal effects induced by some antipsychotic drugs may be treated with antimuscarinic agents. o Scopolamine (transdermal) is effective in preventing motion sickness. o Atropine is also an effective antidote to excessive cholinergic stimulation following organophosphate intoxication. By blocking muscarinic receptors, the consequences of cholinesterase inhibition is attentuated. Atropine may be used in conjunction with 2-PAM which may reactivate phosphorylated, inhibited acetylcholinesterase by nucleophilic displacement. Preoperative Medication Page 20 of 27 RSBhati Cholinergic Drugs o Primary current therapeutic rationale: Sedation Antisialagogue o Historical: IM atropine was used prior to anesthesia induction to limit excessive salivary secretion and reduce vagal reflex influence on the heart current inhaled/injected anesthetic agents are not consistently associated with these effects Anticholinergic drugs are not mandatory as part of preoperative medication o Gastrointestinal effects: Usual anticholinergic drug doses for preoperative medication (and adults) does not affect either gastric volume or pH o Special considerations: Patients with glaucoma: mydriatic effects of scopolamine > atropine; caution with scopolamine use in patients with glaucoma atropine + anticholinesterase causes little/no change in pupil size, therefore appearing apparently safe Glycopyrrolate (Robinul): least effect on pupil size of all anticholinergic drugs used in preoperative medication Parturients: atropine & scopolamine: crosses the placenta; fetal heart rate-- not significantly changed following atropine or glycopyrrolate IV administration Sedation o Scopolamine is preferred when sedation is the objective for including anticholinergic drug in preoperative medication o Atropine: less sedation compared to scopolamine associated with increased incidence of memory deficit associated with anesthesia, compared to glycopyrrolate delayed arousal in the first 30 minutes after anesthesia if atropine- neostigmine mixtures were used to antagonize nondepolarizing neuromuscular-blocking drug effects {compared to glycopyrrolate- neostigmine mixtures} o Scopolamine enhances significantly sedative effects of other drugs administered at the same time, i.e. benzodiazepines and opioids o Scopolamine plus morphine: reliable preanesthetic sedation o Glycopyrrolate (Robinul): does not readily cross the blood-brain barrier; no sedative effects o CNS effects of anticholinergic drugs -- particularly scopolamine: restlessness or somnolence such symptoms more likely to occur in the elderly inhaled anesthetics may potentiate anticholinergic CNS drug effects®increased postoperative restlessness/somnolence incidence Page 21 of 27 RSBhati Cholinergic Drugs Return to Table of Contents o Treatment of Reflex-Mediated Bradycardia Anticholinergic drugs: drugs of choice for management of intraoperative bradycardia --especially if due to increased vagal tone First Degree Heart Block P Wave PR Interval QRS (sec.) Characteristics Before each QRS > 0.20 < 0.12 Regular (identical) Marquette Medical Systems, Inc (http://www.mei.com) Second Degree AV Block (Mobitz Type I) P Wave PR Interval QRS (sec.) Characteristics Conduction Increasingly < 0.12 QRS dropped in a Intermittent Prolonged repeating pattern Marquette Medical Systems, Inc (http://www.mei.com) Third Degree (Complete) Block o Atropine increases heart rate (by blocking acetylcholine effects on the SA node) o Young adults are most sensitive to atropine effects on heart rate {higher vagal tone} compared to infants or elderly patients Page 22 of 27 RSBhati Cholinergic Drugs in the elderly: atropine may have no effect on heart rate o During anesthesia with a volatile agent, atropine dosage required to raise the heart rate may be less than that required in an awake patient -- suggesting vagal center depression during anesthesia P Wave PR Interval QRS (sec.) Characteristics Normal but not none N/A No relationship related to QRS between P & QRS complex Marquette Medical Systems, Inc (http://www.mei.com) Halothane (Fluothane) (like opioids) probably increases central vagal tone, explaining why atropine administration is more likely to result in an increase in heart rate compared to patients anesthetize with enflurane (Ethrane). Antagonist-assisted neuromuscular-blockade reversal o Edrophonium (Tensilon), neostigmine (Prostigmin), or pyridostigmine (Mestinon)-- effective by increasing acetylcholine availability of neuromuscular junction {secondary to acetylcholinesterase inhibition} o Physostigmine (Antilirium): not used because dosage requirement is excessive o Anticholinesterase agents are usually administered during spontaneous neuromuscular-blockade recovery Recovery rate is the sum of: (1) spontaneous recovery from the blocking drug and (2) the activity of the pharmacologic antagonist (anticholinesterase drugs) Therefore: pharmacologic antagonism is more effective for short-or intermediate-acting neuromuscular-blocking drugs (undergoing plasma hydrolysis or Hoffmann elimination) compared to long-acting nondepolarizing neuromuscular-blocking agents o Special Considerations: use of muscarinic antagonists with anticholinesterases in Reversal of Neuromuscular Blockade Reversal of nondepolarizing neuromuscular-blockade: necessitates only nicotinic cholinergic effects of anticholinesterases agents Page 23 of 27 RSBhati Cholinergic Drugs Minimizing muscarinic receptor-mediated effects of anticholinesterase drugs is beneficial an accomplished by a concurrent administration of atropine or glycopyrrolate (antimuscarinics) The antimuscarinic agent should have a more rapid onset than the anticholinesterase drugs -- reducing drug-induced bradycardia if edrophonium (Tensilon)(0.5 mg/kg) is used; atropine 7 µg/kg is appropriate a higher dose atropine (10-15 µg/kg) has been recommended, particularly if nonopioid-based maintenance anesthetic has been used if neostigmine is used (slower onset of action compared edrophonium (Tensilon)), then atropine or glycopyrrolate (Robinul) may be administered as the antimuscarinic agent; concurrent administration of these drugs results in an initial tachycardia because of atropine's more rapid onset o Factors influencing the speed and extent of neuromuscular blockade reversal by anticholinesterase agents intensity neuromuscular-blockade when reversal is initiated (train-of-four visible twitches) which nondepolarizing neuromuscular-blocking drug is being reversed Edrophonium (Tensilon): less effective than neostigmine in reversing deep neuromuscular blockade (twitch height < 10% of control) produced by continuous atracurium (Tracrium), vecuronium (Norcuron), or pancuronium (Pavulon) infusions. Edrophonium (Tensilon), probably better than neostigmine (Prostigmin)for reversing atracurium (Tracrium)blockade Neostigmine (Prostigmin), probably better than edrophonium (Tensilon) for reversing vecuronium (Norcuron) blockade Prevention/inhibition of anticholinesterase-mediated antagonism of neuromuscular-blockade -- Possible factors certain antibiotics hypothermia respiratory acidosis (PaCO2 >50 mm Hg hypokalemia/metabolic acidosis Reversal of phase II block (following prolonged/repeated succinylcholine (Anectine)): may be reversed with edrophonium (Tensilon) or neostigmine (Prostigmin) in patients with normal plasma cholinesterase in patients with atypical plasma cholinesterase, phase II block reversal may not be reliable, requiring mechanical ventilation until blockade subsides. Bronchodilation o Bronchodilation following anticholinergic drug administration is due to blockade of acetylcholine effects on airway smooth muscle muscarinic receptors. o Extent of the response depends on vagal tone (pre-existing bronchomotor tone) e.g. a clinical dose of scopolamine may decrease airway resistance and increase dead space by about 1/3 Page 24 of 27 RSBhati Cholinergic Drugs o Preferred Route of Administration for bronchodilation: aerosol o Ipratropium (Atrovent):anticholinergic drug most commonly used for aerosol administration -- synthetic quaternary ammonium atropine congener most effective in preventing/treating bronchospasm due to ß-adrenergic antagonists more effective than ß-adrenergic agonists in producing bronchodilation in patients with chronic bronchitis or emphysema (high cholinergic tone) Patients with bronchial asthma: usually respond better to beta-agonist because of direct smooth muscle relaxation through beta-receptor activation and by inhibition of histamine & leukotriene release (chemical mediators of smooth muscle contraction) Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 241-244 Gastrointestinal Tract o Vagal effects on the gut are mediated not only by acetylcholine but also by actions on intramural serotonergic and dopaminergic neurons. o Atropine can block Ach effects while having no effect on non-cholinergic modulation of GI motility. o Vagal input affects gastrin release and may be blocked by atropine; however, gastric acid release is more effectively prevented by M1 specific antimuscarinic drugs (pirenzapine) and H2-selective histamine receptor blockers. Brown, J.H and Taylor, P. Muscarinic Receptor Agonists and Antagonists In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.149- 159. Respiratory Tract o Parasympathetic activity produces bronchoconstriction. o Activation of nicotinic and M1-muscarinic receptors is parasympathetic ganglia which lie in the airway wall then activate postganglionic fibers. o These postganglionic fibers release acetylcholine which activate M3 muscarinic receptors which produce bronchiolar smooth muscle contraction. M2 receptors may also be present. o Muscarinic antagonists attenuate pulmonary smooth muscle constriction, often resulting in bronchodilation. The magnitude of the effect depends on the basal parasympathetic tone. Ipratropium bromide has been prominent in treating respiratory disease. Muscarinic Type M3 Agonists Antagonists Tissue Responses Molecular Aspects acetylcholine, atropine Smooth Contraction Phospholipase muscle C (PLC) Page 25 of 27 RSBhati Cholinergic Drugs Secretory Increased stimulation methacholine glands Secretion through Gq/11 formation: (IP3 ) + diacylglycerol (DAG): increased cytosolic Ca2+ Atropine and other antimuscarinic inhibit mouth, bronchial, and pharyngeal secretion which reduce reflex laryngospasm during general anesthesia. o Also, atropine or other antimuscarinics are given during general anesthesia to blunt increases in vagal tone due to mechanical effects on viscera during abdominal surgeries. Antimuscarinics, especially ipratropium, along with sympathomimetics, are useful in management of asthma. Ipratropium (Atrovent) has an advantage in asthma compared to atropine because: o ipratropium does not inhibit mucociliary clearance (atropine does) o ipratropium has no significant CNS effects. o Inhaled ipratropium (a quaternary, charge molecule) has limited or no systemic effects. o ipratropium is more effective that beta-adrenergic agonists in COPD (cholinergic tone may be the only component that may be attenuated) Ophthalmological o Muscarinic receptor antagonists block parasympathetic responses of the ciliary muscle and iris sphincter muscle, resulting in paralysis of accommodation (cycloplegia) and mydriasis (pupillary dilation). o Mydriasis results in photophobia, whereas cycloplegia fixes the lens for far vision only (near objects appear blurred). o Systemic atropine at usual doses does not produce significant ophthalmic effect. o By contrast, systemic scopolamine results in both mydriasis and cycloplegia. o Note that sympathomimetic-induced mydriasis occurs without loss of accommodation. o Atropine-like drugs can increase intraocular pressure, sometimes dangerously, in patients with narrow-angle glaucoma. o Increases in intraocular pressure is not typical in wide-angle glaucoma. Cholinergic Blockers:Adverse effects o Dry mouth (xerostromia) o Blurred vision (cycloplegia) o Photophobia (mydriasis) Ganglion Blocking Drugs o Ganglionic blockers act mainly at the primary nicotinic-type cholinergic receptor at sympathetic and parasympathetic autonomic ganglia. Agents which are classified as ganglionic blockers are not included among those drugs which block neuromuscular junctions. Page 26 of 27 RSBhati Cholinergic Drugs o One class of blocker produces a depolarization block: Nicotine could produce this effect. o The second class of agents include hexamethonium & trimethaphan These agents either competitively block the receptor or block the open channel configuration. o For essential hypertension, ganglionic blockers have been replaced by better drugs. Ganglionic blockers may be used for initial blood pressure control in patients with dissecting aortic aneurysm because, in addition to reducing blood pressure, blunting of sympathetic responses reduce sheer forces at the tear. Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.193-195 Predominary Sympathetic or Parasympathetic Tone Antatomical Site Predominant Autonomic Effect of Ganglionic Tone Blockade Arterioles Sympathetic-adrenergic vasodilatation; increased peripheral blood flow; hypotension Veins Sympathetic-adrenergic dilatation; blood pooling; decreased venous return; decreased cardiac output Heart Parasympathetic- tachycardia cholinergic Ciliary Muscle Parasympathetic- cycloplegia (loss of cholinergic accommodation) Gastrointestinal Tract Parasympathetic- reduced tone and motility; cholinergic constipation; decreased secretions Salivary Glands Parasympathetic- Xerostomia (dry mouth) cholinergic Sweat Glands Sympathetic-cholinergic Anhidrosis (lack of sweating) Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.193-195. Adapted from Table 9-3. Page 27 of 27 RSBhati
Pages to are hidden for
"CHOLINERGIC DRUGA"Please download to view full document


text:
Leafs vs Habs: Game Day Preview
Steve Dangle
January 19 2013 12:29PM
It's back!
Howdy, folks! Cam locked himself out of his house (I suspect Bettman did it) so I'll be giving you your Leafs pre-game blog. Here's a quick run-down of the essentials.
2013 Maple Leafs "Stars and Goats"
Cam Charron
January 18 2013 04:54PM
It's been so long since we watched a hockey game together.
For too many months, we were caught up in the discussion involving collective bargaining agreements, standard player contracts, hockey-related revenue, defined benefit pension plan, federal mediation, entry-level contract, arbitration and so on and all of a sudden you needed a few credits in 100-level business courses to be qualified to call in to a radio show.
Tomorrow we get to start loving and hating hockey players again.
"Stars" and "Goats" have been a Nations Network tradition. You can edit your Nations profile (you should sign up for an account if you haven't) to modify the players you will love no matter what, and hate no matter what. Last season, The Leafs Nation had players like Mikhail Grabovski and Nik Kulemin listed as "stars", while defensively-liable Joffrey Lupul and Colton Orr were selected as goats.
Below are this year's picks by our contributor staff. Add your own in the comments, and to your profile page.
Grabovski, Kulemin, Komarov: Since you been gone.
Steve Dangle
January 18 2013 04:12PM
Let's stop pretending like that's not a catchy song, Ok?
I've spent the last few months covering the KHL. I've been following all of the locked-out NHL players that were over there, and followed the Leafs over there with the most interest.
Many of you have asked "How did Mikhail Grabovski look with Datsyuk?" "How did Nikolai Kulemin look with Malkin?" and "Who the hell is Leo Komarov?" Allow me to try to answer.
Worst to First Jerseys: The Toronto Maple Leafs
Jonathan Willis
January 18 2013 01:41PM
By John van der Woude
Worst to First Jerseys:This installment of the Worst to First Jerseys features the Toronto Maple Leafs, and much thanks to Leafs Nation for letting me guest post on their blog. On my own blog, I talk about about graphic design in hockey and I'll be doing the jerseys for the rest of the league over time, so come by Hockey By Design to check it out.
I started this series with the Vancouver Canucks, who in just 40 years have produced 8 very distinct jersey designs. Now, with the Maple Leafs, here's a team that in 85 years (since renaming themselves the Leafs from the St. Pats in 1927) have essentially had one jersey design with slight modifications over the years. It makes things slightly more difficult in ranking the Leafs' jerseys – or even in clearly defining different jersey designs that they've had – but I'll have a go at it anyway, because there's definitely still some winners and losers here.
Leafs cut Morgan Rielly, Matt Frattin, set 23-man roster
Cam Charron
January 18 2013 10:36AM
The Toronto Maple Leafs have finalized their 23-man roster, cutting Morgan Rielly and Matt Frattin Friday to trim their roster and set the lineup they'll likely run with tomorrow in Montreal. (Meanwhile, Tim Connolly cleared waivers, and Dave Nonis says he'll report to the Toronto Marlies)
The moves aren't particularly surprising. Frattin is waiver-exempt, and as a player in his scoring peak he barely moved the needle at the NHL-level. He fits better with the Toronto Marlies and as the first-injury call-up for the Leafs. Morgan Rielly will be sent back to junior in Moose Jaw, impressive as he is as an 18-year-old, the reality of the situation is that he's too chaotic in his own end to benefit the hockey team, and it doesn't benefit Rielly as a player to play 15 minutes a night of panicky hockey.
Rielly will get his chance some day, but clearly that is not today.


text:
Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome
1 Department of Biomedicine, Aarhus University, Aarhus, Denmark
2 INSERM UMR S968, Institut de la Vision, Paris, 75012, France
3 UPMC Univ Paris 06, UMR_S 968, Institute de la Vision, Paris, F-75012, France
4 CNRS, UMR_7210, Paris, F-75012, France
5 Service de Biochimie B, Hôpital Saint-Antoine, Paris, France
6 Laboratoire de Biochimie, Hôpital Robert Debré, Paris, France
7 Service de Génétique, Hôpital Robert Debré, Paris, France
8 Inserm U676, Hôpital Robert Debré, Paris, France
9 Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
10 Department of Nephrology and Urology, Division of Nephrology and Dialysis, Ospedale Bambino Gesù, IRCCS, Rome, Italy
11 Centre for Insoluble Protein Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University, Aarhus, Denmark
12 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
BMC Medical Genetics 2013, 14:111 doi:10.1186/1471-2350-14-111Published: 24 October 2013
Imerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B12 receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria.
Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype.
Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B12 binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed.
In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria.


text:
Hiring? Post a Job
Refine Results
Your search Chief Mine Engineer Jobs in Blue Mountain, MS did not match any jobs.
Search Suggestions:
- Make sure all words are spelled correctly
- Try changing filters on the left
- Try more general keywords
- Replace abbreviations with the entire word


text:
All Items > Knives > Fixed Blade Knives > Fixed Knife by Brand > Kershaw Knives (Fixed)
Kershaw Roughneck Fixed Blade Knife - Satin Plain
- Overall Length:11.375"
- Blade Length:6.25"
- Cutting Edge:5.50"
- Blade Thickness:0.13"
- Blade Material:AUS-6
- Blade Style:Clip Point
- Blade Grind:Hollow
- Finish:Satin
- Edge Type:Plain
- Handle Length:5.00"
- Handle Thickness:0.95"
- Handle Material:Polymer
- Color:Black
- Weight:5.40 oz.
- Sheath:Leather
- Knife Type:Fixed Blade
- Brand:Kershaw
- Model:Roughneck
- Model Number:1010
- Country of Origin:Japan
- Best Use:Hunting
- Product Type:Knife
The Kershaw Roughneck is a great knife for your outdoors needs. This knife features a stainless AUS6A steel full-tang blade with a plain primary cutting edge and a 2.5" serrated spine. The co-polymer handles are double injection molded for strength and a secure grip. The Roughneck comes in a black sheath.
Customer ReviewsWrite a review for this item
Filter By Category
Copyright ©2015 Blade Play. All rights reserved


text:
Singer ce 100 help!
bearyhotmomJuly 3, 2007
Can anyone tell me what it means when the machine just stops after the design has been printed and the red power lights just starts flashimg. Also, the bar will not return to the standby position. I cant go any further because of this. I am a beginner and have found the manual and online support useless. I really would like to learn how to do this but I am to the point of frustration and ready to return the machine and choose another brand.


text:
Easter Craft Idea: Table Topiaries Video
This easy craft will make the perfect centerpiece for your Easter dinner. Get the step-by-step instructions in this Good Housekeeping report.
What Do You Think?
The Easiest (and Prettiest) Chocolate Bark for Easter
This is almost too cute to eat. Almost!
DIY All-Natural Easter Egg Dyes
Who needs artificial coloring? A few common foods can create eggs that look rustic and fun.
Marbleize Your Easter Eggs With Nail Polish
Raid your beauty stash to recreate these cuties.
Passover Cookbooks to Inspire You
If you find the word "Seder" to be synonymous with "stress," enlist one of these books for some guidance.
More From Holidays


text: US to suspend most military aid to Egypt, reports say Politics Politics Conflict Americas Egypt Middle East United States Sarah Wolfe on Dec 31, 1969 @ 7:33 PM US President Barack Obama makes a statement on Egypt August 15, 2013, in Chilmark, Massachusetts. Obama said Thursday the United States has canceled military exercises with Egypt to protest the killing of hundreds of protesters. Obama warned that Egypt had entered a 'more dangerous path' but stopped short of sending $1.3 billion in annual military aid. The Obama administration is set to suspend most military aid to Egypt in the wake of this summer's overthrow of President Mohamed Morsi and resulting turmoil, according to several reports. The news was reported late Tuesday by CNN, the Washington Post and Wall Street Journal. More from GlobalPost: Egypt warned after Obama cancels joint military exercises; aid to continue US officials spoke to all three media outlets on condition of anonymity. CNN reported the US planned to cut off all military aid to Egypt, a report White House officials were quick to deny. "The reports that we are halting all military assistance to Egypt are false," Caitlin Hayden, spokeswoman for the White House National Security Council, told Reuters. "We will announce the future of our assistance relationship with Egypt in the coming days, but as the president made clear at [the United Nations General Assembly], that assistance relationship will continue," she said. More from GlobalPost: Obama to meet with top aides on Egypt aid The Post and Wall Street Journal reported that most "nonessential aid" would be suspended. No numbers were immediately available, but a US official told the Washington Post the action is likely to cover most of America's $1.2 billion in military assistance to the Middle Eastern nation. US officials want to halt deliveries of military hardware that could be used by the Egyptian military against protesters, yet not compromise counterterrorism efforts or the defense of Israel, according to the Post. Egypt has not yet been notified of the decision, according to the officials. An announcement could come as early as Friday, according to the Wall Street Journal.