text:
@entilza72: I'm not a MediaTemple customer and don't know details of their platform.
In this post they say:
Vulnerable customer software (blogs, CMS, PHP apps) give attackers access to view and steal database passwords from application configuration files...
I'm not sure what they exactly mean so just trying to isolate the issue and check whether wp-config.php permissions are to blame. That's why I ask to share permissions of these files on hacked sites.
By the way, 500 is not read/write. It is read/execute. Read/write is 600.

subset: commoncrawl


text:
Recipe of the Day
Herman Sourdough Starter
This is a recipe for a sweet sourdough starter known as Herman. There are a number of things that can be made from it. It will take 15 days for the starter to mature and be ready to use the first time you make it.
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From crusty European-style sourdough ryes to sweet Amish friendship breads, you'll love these five-star recipes.
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text:
- Description
Restore Skin Cleanser by Hollister is a skin cleanser that cleanses peristomal and perianal skin of urinary and fecal discharge. It has a gentle and foaming cleanser that lifts away discharge and other irritants.
This skin cleanser is formulated to leave no residue. It rinses away completely and requires no water.
When in use, this cleanser thoroughly cleans and refreshes the skin before use of additional skin care products. It is for use on intact skin.
The skin cleanser is gentle and non-irritating. It can be conveniently used at your bedside.
Restore Skin Cleanser by Hollister is odorless and so won't irritate allergies. It is also soluble in water and so won't stain. This cleanser is recommended for post operative and home use. It comes in 8 oz pump spray bottles and is packaged for convenience individually and in boxes of 12.Restore Skin Cleanser Features and Benefits
- Gentle and Foaming Cleanser
- Cleanses Peristomal and Perianal Skin of Urinary and Fecal Discharge
- Lifts Away Discharge and Other Irritants
- Formulated to Leave No Residue
- Rinses Away Completely
- Requires No Water
- Thoroughly Cleans and Refreshes the Skin
- For Use on Intact Skin
- Gentle and Non-Irritating
- Conveniently Used at Bedside
- Odorless; Won't Irritate Allergies
- Soluble in Water; Won't Stain
- Recommended for Post Operative and Home Use
- Comes in 8 Oz Pump Spray Bottles
- Packaged Individually and in Boxes of 12
- Item Number: 517210
- Additional Information
Additional Information
Manufacturer Hollister Ships Free No Size Chart No
- Reviews
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- Great, fast & efficent service, thanks
Great, fast & efficent service, thanks - will order again when needed
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text:
Are you Saeed Omidi?Claim your profile
Publications (4)0.87 Total impact
- SourceAvailable from: Ali Masoudi-Nejad
Conference Paper: Improved Immune Genetic Algorithm for Clustering Protein-Protein Interaction Network[Show abstract] [Hide abstract]
ABSTRACT: Clustering protein-protein interaction network aims to find functional modules and protein complexes. There are many computational graph clustering methods that are used in this field, but few of them are intelligent computational methods. In this paper, we present a novel improved immune genetic algorithm to find dense subgraphs based on efficient vaccination method, variable-length antibody schema definition and new local and global mutations.BioInformatics and BioEngineering (BIBE), 2010 IEEE International Conference on; 07/2010
- [Show abstract] [Hide abstract]
ABSTRACT: In this chapter, we intend to give a review on some of the important network models that are introduced in recent years. The aim of all of these models is to imitate the real-world network properties. Real-world networks exhibit behaviors such as small-world, scale-free, and high clustering coefficient. One of the significant models known as Barabási–Albert model utilizes preferential attachment mechanism as a main mechanism for power-law networks generation. Ubiquity of preferential attachment in network evolution has been proved for many kinds of networks. Additionally, one can generalize functional form of the preferential attachment mathematically, where it provides three different regimes. Besides, in real-world networks, there exist natural constraints such as age or cost that one can consider; however, all of these models are classified as global models. Another important family of models that rely on local strategies attempt to realize network evolution mechanism. These models generate power-law network through making decisions based on the local properties of the networks.12/2009: pages 191-240;
- [Show abstract] [Hide abstract]
ABSTRACT: In recent years, interest has been growing in the study of complex networks. Since Erdös and Rényi (1960) proposed their random graph model about 50 years ago, many researchers have investigated and shaped this field. Many indicators have been proposed to assess the global features of networks. Recently, an active research area has developed in studying local features named motifs as the building blocks of networks. Unfortunately, network motif discovery is a computationally hard problem and finding rather large motifs (larger than 8 nodes) by means of current algorithms is impractical as it demands too much computational effort. In this paper, we present a new algorithm (MODA) that incorporates techniques such as a pattern growth approach for extracting larger motifs efficiently. We have tested our algorithm and found it able to identify larger motifs with more than 8 nodes more efficiently than most of the current state-of-the-art motif discovery algorithms. While most of the algorithms rely on induced subgraphs as motifs of the networks, MODA is able to extract both induced and non-induced subgraphs simultaneously. The MODA source code is freely available at: http://LBB.ut.ac.ir/Download/LBBsoft/MODA/Genes & Genetic Systems 01/2009; 84(5):385-95. DOI:10.1266/ggs.84.385 · 0.87 Impact Factor
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University of TehranTeheran, Tehrān, Iran


text:
Gazaway Lumber Co Inc
Today:7:00 am - 6:00 pm
Tomorrow:7:00 am - 6:00 pm
2620 W Kingshighway,
Paragould, AR 72450
(870) 236-7666
Business Details
in Business
- Hours:
Regular Hours
- General Info:
- Founded in 1981, Gazaway Ace is a unit of Gazaway Lumber Company and Ace Hardware Family. The company offers bath products from Aquarius Bath Products and Eljer. It also provides a range of patio accessories. The company offers pipe cutting and threading, automotive chip-key cutting and delivery services. It also provides construction services for home owners and builders. Gazaway Ace offers products from Exclusive Pet Food, Red Flannel Dog and Purina Mills. It provides fireplaces, doors and windows. The company offers a range of paints from Pratt and Lambert, Devine Color and Ace Paint. In addition, it provides tools for rent. Gazaway Ace is located in Paragould, Ariz.
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TollFree: (888) 422-3752
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- Payment method:
- master card, visa
- Other Links:
- Categories:
- Lumber, Tools, Paint, Hardware Stores, Building Materials


text:
Internet Software and Services
Company Overview of Enernetics, Inc.
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The Top 10 In Action Sports
01Brick By Brick: Camping Lego Style
02Booze and Bikes: 14 Tours That Let Combine Two of the Best Things in the World
03Who Needs Hollywood? These Incredible Videos Were All Filmed on the Simplest Cameras
04Sam Pilgrim vs. The World: The Champion Aiming To Reclaim His Crown In A New Era Of Biking
05Eccentric Adventures Episode 2: Britain's Most Brutal Illegal Event is All About Cheese
06A Journey Into Darkness: We Went Mountain Biking in the Abandoned Mines of Slovenia
07After the Apocalypse: Inside The World's Most Breathtaking Ghost Towns
08Debate: Let's Stop Hating On Parents Who Want To Raise Adventurous Kids
09Guns, Roses, And Eating Insects: Adventure Cycling in Vietnam
10From Intense Trails to Intensive Care: Dicing with Death In a Mountain Biking Paradise
Salomon Freeski TV: Season 3 Episode 6
A Ski video by salomonfreeskitv - 9,108 views
Mark Abma, Mike Douglas and Dane Tudor are in Girdwood living the good life - skiing Alyeska Resort and heliskiing with Chugach Powder Guides. After a two-week storm, the weather finally clears, and the crew stumbles upon the 'most-stacked' zone of Alaska spine-lines that they've ever seen. Part 1 of 2.
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Amazon.com has purchased CustomFlix, the DVD-on-demand provider that allows television producers, including individual broadcast stations, to cost-effectively make and distribute niche DVD titles over the Internet.
The CustomFlix acquisition follows industry speculation that Amazon would be expanding its DVD operations, though those predictions have centered around the rental side of the business. Amazon would not disclose financial terms of the CustomFlix deal, which closed July 6.
Back to the top
An Inside Look at Four Virtual Reality Start-Ups
What Moves the Social TV Needle?
Mark Kudsi Directs 'Art of Patron Virtual Reality Experience'
BT Renews Intelsat Deal
Top Twitter TV Shows for 2014-15 Season Unveiled
comScore Introduces MobiLens Plus
North Korean Propoganda Art Inspires the Credits of 'The Interview'
Imaginary Forces Creates Kaleidoscopic Titles for 'Bosch'
Filmmaker Embraces Short Documentary Format with Oscar-Nominated 'Crisis Hotline'
North Metro Television Goes Wireless with Comrex LiveShot
Spectra Logic and HauteSpot Networks Introduce Body-Worn Camera Video Surveillance Solution
Huge Ultra HD Display Lights Up Times Square


text:
I'm making a small script to determine if I have an internet connection on OSX. More of just practice, I suppose.
In terminal "ifconfig | grep -cs 'status: active' " will return 1 if there's at least one active connection
The script I have is this
ONLINE=ifconfig | grep -cs 'status: active'
if [[ detect = 1 ]]
echo "Online"
echo "Offline"
However the Variable ONLINE always returns 0. From what I can tell/understand, this has to do with using a pipe inside of the script. A sub-pipe is used when running the command, and ONLINE just gets stuck with 0 as the sub-pipe closes.
I think I see the issue, but I don't know how to get around this. I saw a bunch of work arounds for scripts having this issue with while loops, but nothing where I need the output from ifconfig fed into grep.


text:
Pronunciation: Миңлехуҗа
Added on: 2012-10-20 Listened: 1 timesin: male surnames, ир-ат исемнәре
Pronunciation in Tatar [tt]
- Pronunciation by AqQoyriq (Male from Russia)
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Could you do it better? different accent? Pronounce Миңлехуҗа in Tatar
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Q& property series:
- What are the benefits of buying property as an investment?
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Useful tools:
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Articles and factsheets:
Call the AMP Bank concierge on 133 888or request a call back at a convenient timeBook a call
Important informationShow more
It's important to consider your particular circumstances and read the relevant Product Disclosure Statement or Terms and Conditions before deciding what's right for you. This information hasn't taken your circumstances into account.
Information, apart from AMP Bank product information, is provided by AMP Life Limited. Read our Financial Services Guide for information about our services, including the fees and other benefits that AMP companies and their representatives may receive in relation to products and services provided to you. All information on this website is subject to change without notice.
Concierge services are provided by AMP Bank. Credit provider and product issuer is AMP Bank Limited, Australian credit licence no. 234517. Terms and Conditions are available on request from AMP Bank. Approval is subject to AMP Bank guidelines.


text:
An electro-optical filter made of a support in which an optical guide with a diffused channel waveguide and of a cover, that are created in borosilicate glass, and which includes a gap obtained by the use of suitable spacers, filled with a grating constituted of alternating strips of polymer and liquid crystal called POLICRYPS (Polymer Liquid CRYstal Polymer Slices), and with first electrodes that are coplanar to the support and next to the optical guide with a channel, that electrically control the grating making the filter tunable, and a manufacturing process.
1. Electro-optical tunable filter made of a support in which a diffused channel optical waveguide has been created in a glass support, preferably of the borosilicate type, and by a cover in glass, also preferably of the borosilicate type, characterised by the fact that said support and said cover have a gap between them obtained by using suitable spacers, that said gap is filled with a grating constituted of alternating strips of polymer and liquid crystal (POlymer LIquid CRYstal Polymer Slices) POLICRYPS, and that at least one pair of first electrodes, next to the channel optical waveguide, control the grating electrically.
2. Electro-optical tunable filter according to
3. Electro-optical tunable filter according to
4. Electro-optical tunable filter according to
5. Electro-optical tunable filter according to
6. Electro-optical tunable filter according to
7. Manufacturing process for a electro-optical tunable filter according to any of the previous claims characterised by the fact that the optical waveguide on a support of borosilicate glass is obtained through the technique of double ion-exchange, that a first ion-exchange K+/Na+, with a glass support immersed in a first saline bath of potassium nitrate, is carried out at a temperature of between 380� C. and 450� C. for a time of between 60 and 90 minutes, that a mask of metal, preferably aluminium, is deposited by vacuum evaporation on the glass support and defined photolithographically for the determination of the optical waveguide with a channel, that a second exchange Ag+/Na+with the immersion of the glass support in a second saline bath constituted of a mixture of sodium nitrate and silver nitrate is carried out at a temperature of between 320� C. and 350� C. for a time of between 4.5 and 6 hours, that a second photolithographic process is carried out and then a subsequent etching of the metal that is partially removed in such a way as to leave coplanar electrodes for the application of the voltage, that a covering glass is glued to the support containing the optical waveguide, that suitable spacers are used in such a way as to obtain a gap of a few microns, that the gap is filled with a mixture of liquid crystal and pre-polymer for the creation of the grating, that the mixture of liquid crystal and pre-polymer is exposed to a figure of interference, for a suitable period, between two laser strips of a wavelength suitable to bring about the polymerisation of the pre-polymer.
8. Manufacturing process for a electro-optical tunable filter according to
9. Manufacturing process for a electro-optical tunable filter according to claims either 7 or 8 characterised by the fact that the two laser beams have a wavelength of between 320 and 380 nm, and preferably between 350 and 380 nm.
This application is a continuation of PCT Application No. PCT/IT2007/000878, filed Dec. 17, 2007, which claims benefit of Italian Application No. CS2006A000019, filed Dec. 18, 2006.
The invention regards an electro-optical tunable filter with a polymer and a liquid crystal grating and a manufacturing process for the creation of an optoelectronic component with low power consumption for switching and filtering confined optical signals.
Waveguided tunable optical filters created by means of different technologies exist on the market. The most commercially diffused optical filters are fibre Fabry-Perot cavity filters, acousto-optical filters of lithium niobate, thermo-optical filters based on Mach-Zehnder interferometers which are tunable by means of thermo-optical effect on silicon.
One significant disadvantage consists in the absence of zeros in the function of optical transmission, which causes inter-channel crosstalk since it is not possible to suppress the out-of-band optical channels.
Another limitation consists in the limited speed of the tuning mechanism, based on the piezoelectric effect, which has response times that are longer than several milliseconds. Acoustic-optic filters on lithium-niobate and optical filters based on Mach-Zender interferometers made by silicon oxide on silicon technology have both higher manufacturing costs and far greater power consumption than optical filters which are the object of the present invention.
Other characteristics and advantages of the invention will appear from the following description of a technique of creating the invention given as a non-limiting example in the figures and by the description of the chosen illustrations that follow.
With reference to
The grating is constituted by alternating strips of liquid crystal 4 and polymer 5 and is therefore denominated as POLICRYPS (POlymer LIquid CRYstal Polymer Slices). The grating fills a gap formed by the borosilicate glass support 2 and by a second glass 6 which is also of borosilicate BK7.
The glass BK7 is a borosilicate glass with excellent optical, chemical (resistant to acid attacks) and physical properties. It is known by this trade name commercially throughout the glassmaking industry. The trade name is a registered trademark. It is widely used in the field of optics for lenses, prisms, laser cavities.
The optical guides in BK7 are particularly interesting because they have low loss levels (less than 1 dB/cm) and can be created with a high uniformity over a large area through a simple, low cost technological process.
The structure of the grating is obtained through the writing technique described in the patent application IT-A-TO2003A000530 beginning with a mixture of pre-polymer and liquid crystal. The pre-polymer is a commercially available photo-sensitive glue (NOA 61 by Norland), that polymerizes when exposed to ultraviolet light. The liquid crystal used is a nematic liquid crystal commercially indicated by the name 5CB.
Other mixtures constituted of other combinations of photo-sensitive pre-polymers can, however, be identified by experts skilled in the art and used to improve the performances of the component.
The mixture placed between two glasses, one of which contains the waveguide, is exposed to a figure of interference, with a suitable cycle, between two laser beams with a wavelength of 352 nm.
The polymer and the liquid crystal are chosen in such a way that the index of refraction of the polymer is intermediate between the two indexes (ordinary and extraordinary) of the liquid crystal that is an optically anisotropic material. A beam of light confined within the guide "sees" a modulation of the index of refraction in the layer of POLICRYPS above it.
The modulation of the refraction index of the layer of the POLICRYPS produces an optical filtering action on the light that propagates in the waveguide. In fact, according to Bragg's law said to be A the period of the grating, N the effective index of refraction of the guided method and m an integer that represents the level of diffraction, the light at the wavelength λB=2NΛ/m is reflected backwards and is not transmitted to the output of the waveguide.
The ordinary index of refraction of the liquid crystal holds for a light substantially polarized perpendicular to the liquid crystal molecules, in the form of rods, while the extraordinary index is valid for light substantially polarized along the longitudinal axis (director) of the molecules.
At rest, the liquid crystal molecules 4 are aligned perpendicular to the strips of polymer 5, as shown in
By applying an electric field for the electro-optical effect the liquid crystal molecules undergo a re-orientation, therefore the light that travels in the waveguide "sees" a modified refractive index modulation of the grating. In such a way the back-reflected wavelengths change with the variation of the voltage applied.
The filter is therefore tunable and can also be turned off at the voltage at which the re-orientation of the liquid crystal molecules is such that the index of refraction of the liquid crystal is equals to the refraction index of the polymer.
In the case of re-orientation of the molecules only the light which is almost TE polarized, along the horizontal direction x (see
The electro-optical tunable filter object of the present invention is a compact technological solution to resolve the problem of the selection of channels of light that travel in optical fibers. Furthermore, the configuration of the filter can be efficiently and effectively interfaced with conventional fiber optics, as shown in
The optical channel waveguide is obtained by the double ion-exchange technique, K+/Na+ and Ag+/Na+ in a fused saline bath. To obtain the first ionic exchange, K+/Na+, the support in borosilicate glass BK7 is immersed in a first saline bath of potassium nitrate at a temperature of between 380� C. and 450� C. for 60-90 mins.
A slight increase of the index of refraction on the surface of the glass is thus obtained. Then the definition of a mask, which can be in aluminium, for example, follows deposited by vacuum evaporation and photolithographically defined in such a way as to present openings that expose parts of the surface of the substratum of BK7 that correspond to the optical channels with a width of 6-8 μm.
These channels are obtained by a second exchange Ag+/Na+ immerging the support of borosilicate glass BK7 in a second saline bath constituted by a mixture of sodium nitrate and silver nitrate at a temperature between 320� C. and 350� C. for 4.5-6 hours.
Thanks to the presence of the aluminium mask, the second ion exchange produces an increase of the index of refraction of the surface of the glass only in the area defined by the openings of the aluminium mask.
Through a second photolithographic process and a further etching of the aluminium, it is partially removed so as to leave coplanar electrodes for the application of the voltage. The borosilicate glass BK7 then undergoes another heating for 12-24 hours at a temperature of between 320� C. and 350� C. equals to that of the second exchange to attenuate the optical loss caused by silver colloids present in the channel.
A second borosilicate glass BK7 6, that acts as a cover, is glued to the support of borosilicate glass containing the optical guide in such a way as to obtain a gap of a few microns through the use of suitable spacers.
The mixture of liquid crystal and pre-polymer successively fills the gap to create the grating. After writing the grating, already previously mentioned, the end faces of the sample are lapped and polished to allow for coupling with the input optical fiber 7 and output fiber 8 as shown in
In a second preferred embodiment, a variety of sets of four electrodes 9 are created in order to independently apply different voltages in order to control different areas of the grating, each being characterized by its own suitable extension along the axis of propagation, as shown in
In a third preferred embodiment the polarization independence of the operation of the first construction is obtained by adding a second stage of the filter in which an electrical field that is perpendicular to the substrate is applied, as proposed in US-A-2004/0202398. This is achieved by using a further set of four electrodes constituted by two electrodes 10 placed on the internal face of the second glass 6, acts as a cover, and aligned with the electrodes 11 on the substrate containing the waveguide, as shown in
By applying an electric field between the top electrodes 10 and bottom electrodes 11 of this set of four electrodes, the molecules of liquid crystal will tend to align along the field and the index modulation of the grating will be "perceived" by a quasi-TM polarized light beam along the applied electric field. The combination of the control operated by the electrodes 3, 10 and 11 allows a substantial extinction of the transmission at a wavelength of λB for each polarization.
By suitably combining what has been described for the second and the third embodiment, a fourth preferred embodiment is obtained in which the independence of the polarization for a variety of zeros in the optical transmission is obtained. This is obtained through a greater number of electrodes created both on the support and on the cover.
In a fifth embodiment a better symmetry of the applied electrical field with respect to the first embodiment is obtained by the positioning of the electrodes on suitable spacers 12 as shown in
Furthermore, for a suitable density of the electrodes, field lines that start directly from the vertical edges of the electrodes can be obtained, thus further improving the uniformity of the re-orientation of the liquid crystal molecules.
It is understood that the quasi-TE polarization can also be controlled by a further pair of electrodes placed on the cover and substantially aligned with the electrodes described in the first and third preferred embodiments.
It is understood that in the configuration of multiple pairs of electrodes in the second preferred embodiment (
It is also understood the possibility of constructing grating structures which allow the optimization of the spectral response of the electro-optical tunable filter by techniques of apodisation and chirping of the grating as in fiber Bragg gratings.
It is also understood that experts skilled in the art can identify different choices of materials (pre-polymers, liquid crystals, metals for masks, supports and covers) and of process (wavelength of polymerization, process of depositing the mask by sputtering instead of evaporation). It is also understood that for all the constructions the coupling with the optical fibers in input 7 and in output 8 as shown in
A sample tested in a laboratory was fed by a wide band source. The source (based on a erbium doped fiber) emits signals in the C band of transmission of the optical fibers with wavelengths between 1525 and 1575 nm.
The sample worked correctly. This was demonstrated by the spectrum acquired by an optical spectrum analyzer and shown in
The output spectrum in
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PHTX 515 - PHARMACOLOGY FOR NURSE ANESTHETISTS 2004 AUTONOMIC NERVOUS SYSTEM PHARMACOLOGY Edward JN Ishac, Ph.D. Associate Professor, Dept. Pharmacology and Toxicology Blackwell-Smith Building, Room 742 Office: 828-2127 Lab: 828-2126 E-mail: firstname.lastname@example.com Website url: www.courses.vcu.edu/ptxed/pmc515 Many side effects of drugs can be detected by their autonomic responses. In the clinic or hospital the well being of patients can be monitored by autonomic signs (i.e., heart rate, blood pressure, respiration, etc.) and the drugs that can affect these responses. It is very important to have a good basic understanding of autonomic physiology and the resultant physiological responses which occur when either the sympathetic or parasympathetic branches of the autonomic nervous system (ANS) are stimulated or inhibited. Most drugs discussed in this unit can be considered to either mimic or block components of the sympathetic or parasympathetic branches of the ANS. Knowing this, you can often predict the pharmacological effects, side effects and therapeutic properties of most drugs in this section once you have an understanding of the ANS. RECOMMENDED READING: Pharmacology & Physiology in Anesthetic Practice, 3rd Ed (1999) Ed Stoelting. Chapter 9. Anticholinesterase Drugs & Cholinergic Agonists Chapter 10. Anticholinergic drugs Chapter 12. Sympathomimetics Chapter 14. Alpha- & Beta-Adrenergic Receptor Antagonists ADDITIONAL READING (if required): Basic and Clinical Pharmacology, 9th Ed. (2004); Ed. Katzung. Section II: Autonomic Drugs. Chapter 6. Introduction to Autonomic Pharmacology. Chapter 7. Cholinoceptor-Activating & Cholinesterase Inhibiting Drugs. Chapter 8. Cholinoceptor-Blocking Drugs. Chapter 9. Adrenoceptor-Activating & Other Sympathomimetic Drugs. Chapter 10. Adrenoceptor Antagonist Drug. Dr. Ishac Autonomic Nervous System 2 INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM (ANS) Edward JN Ishac, Ph.D. Associate Professor, Department of Pharmacology and Toxicology Smith 742, 828-2127, e-mail: email@example.com Learning Objectives: 1. Understand the role of the ANS in maintaining homeostasis by regulating cardiovascular, respiratory, gastrointestinal, reproductive, endocrine, metabolic, etc. functions. 2. Understand the functional organization of the ANS and of its two branches, the sympathetic and parasympathetic nervous systems. 3. Understand the principle of chemical neurotransmission and its modulation by drugs. I. DIFFERENT ROLES OF THE SOMATIC NERVOUS SYSTEM AND THE ANS Nervous system: i) Somatic (voluntary control of skeletal muscle) ii) Autonomic (involuntary, visceral, vegetative) The role of ANS is to regulate the activity of structures or organs not normally under voluntary control eg. respiration, circulation, digestion, body temperature, metabolism, sweating and secretions from certain glands. Dr. Ishac Autonomic Nervous System 3 II. ANATOMICAL DIVISIONS OF ANS (Figs. 1A,B) It is important to remember that the division of the ANS into the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) is an anatomic classification and does not depend on the type of transmitter involved or whether the effect elicited is excitatory or inhibitory. An alternate classification can be based on the transmitter molecules released (e.g. acetylcholine or norepinephrine). Most organs receive reciprocal innervation by both divisions, although there are exceptions (e.g. peripheral vasculature only receives sympathetic innervation). Sympathetic and parasympathetic effects usually oppose one another, with one of the two dominating under resting conditions (e.g. dominant parasympathetic "tone" on the heart). This autonomic tone is very important for predicting the effects of autonomic drugs and is influenced by age, physical fitness or underlying disease. The SNS dominates during anger and stress and gives rise to the 'Flight or Fight' response (↑BP,↑HR, ↓GI motility, relax bronchial SM). While the PNS is most important when the individual is resting or trying to conserve energy 'Feeding and Breeding' (↓HR, ↑GI motility, contract bronchial SM) see Table 1. A. Sympathetic (thoracolumbar) Nervous System (SNS) a. T1-12; L1-3 b. Location of ganglia (principally in the paravertebral and prevertebral ganglia) c. Preganglionic fibers (short); myelinated d. Postganglionic fibers (long); non-myelinated e. Type of activation; synchronized f. Types of receptors on effector organs (alpha-, beta-, dopamine-receptors) B. Parasympathetic (craniosacral) Nervous System (PNS) a. Cranial nerves III, VII, IX, X; S2-3 b. Location of ganglia (principally distributed diffusely in the walls of the innervated tissue) c. Preganglionic fibers (long); myelinated d. Postganglionic fibers (short); non-myelinated e. Type of activation; localized f. Types of receptors on effector organs (muscarinic & nicotinic) III. FUNCTIONAL ORGANIZATION OF THE ANS A. The elementary unit of ANS is the autonomic reflex arc, made up of sensory receptors, afferent neurons, central sites of integration, and efferent nerves. B. Transmission of information between neurons or between a neuron and a target cell occurs through the synapse by the release of a specific neurotransmitter, and activation of specific receptors on the target cell by the transmitter. Raynaud's Syndrome: (Example of malfunction of ANS) Excessive sympathetic tone in nerves supplying hands and feet. Minor cold, or thought of cold, causes pronounced vasoconstriction that can be severe enough to cause necrosis of tissue. Three-phase color sequence (white to blue (↓O2) to red (vessels reopen). Dr. Ishac Autonomic Nervous System 4 C. Receptor Subtypes in the Autonomic Nervous System Adrenoceptors Cholinoceptors Alpha α1, α2 Muscarinic M1, M2, M3, M4/M5 Beta β1, β2, β3 Nicotinic Nn, Nm Dopamine D1, D2, D3, D4, D5 Dr. Ishac Autonomic Nervous System 5 Dr. Ishac Autonomic Nervous System 6 Table 1. Direct effects of autonomic nerve activity on some organ systems Effect of Sympathetic Parasympathetic Organ Action1 Receptor Action Receptor2 Eye Iris Radial muscle Contracts α1 … … Circular muscle … … Contracts M2, M3 Ciliary muscle Relaxes β2 Contracts M3 Heart Sinoatrial node Accelerates β1, (β2) Decelerates M2 Contractility Increases β1, (β2) Decreases (atria) M2 Vascular smooth muscle Skin, splanchnic vessels Contracts α1 … … Skeletal muscle vessel Relaxes β2 … … Contracts α1 … … Relaxes M2 … M1 Bronchiolar smooth muscle Relaxes β2 Contracts M3 Gastrointestinal tract Smooth muscle Walls Relaxes β2 Contracts M3 Sphincters Contracts α1 Relaxes M Secretion Increases M3 Myenteric plexus Inhibits α1 … … Genitourinary smooth muscle Bladder wall Relaxes β2 Contracts M3 Sphincter Contracts α1 Relaxes M Uterus, pregnant Relaxes β2 … … Contracts α1 … … Penis, seminar vesicles Ejaculation α1 Erection M Skin Pilomotor smooth muscle Contracts α1 … … Sweat glands Thermoregulatory Increases M … … Apocrine (stress) Increases α1 … … Metabolic functions Liver Gluconeogenesis α/β2 … … Liver Glycogenolysis α/β2 … … Fat cells Lipolysis α2, β33 … … Kidney Renin release β1 … … Specific receptor type: α = alpha, β = beta, M = muscarinic 1 The endothelium of most blood vessels releases :endothelium-derived relaxing factor," which causes marked vasodilation in response to muscarinic stimuli. However, unlike the receptors innervated by sympathetic cholinergic fibers in skeletal muscle blood vessels, these muscarinic receptors are not innervated and respond only to circulating muscarinic agonists. 2 Vascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibers. 3 Alpha2 inhibits; β3 stimulates. Dr. Ishac Autonomic Nervous System 7 SYMPATHETIC NERVOUS SYSTEM Edward JN Ishac, Ph.D. Associate Professor, Department of Pharmacology and Toxicology Smith 742, 828-2127, e-mail: firstname.lastname@example.com Learning Objectives: Understand the mechanism of action of drugs acting at different levels of the sympathetic nervous system: a) at sites in the CNS to affect sympathetic "tone" b) at sympathetic ganglia c) at enzymes involved in the synthesis of epinephrine (EPI) & norepinephrine (NE) d) at sites of catecholamine storage, release, uptake or metabolism at the postganglionic sympathetic nerve terminal e) at pre- and post-synaptic adrenergic receptors Norepinephrine (NE) = Noradrenaline (NA) Epinephrine (EPI) = Adrenaline (AD, ADR) Noradrenergic = Adrenergic Isoproterenol = Isoprenaline (ISO) I. SYNTHESIS OF TRANSMITTER (Figs. 2A,B) The amino acid tyrosine enters the neuron by active transport. In the cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (DOPA), which is converted to dopamine (DA) by the enzyme DOPA decarboxylase. Dopamine is actively transported into storage vesicles where dopamine-β-hydroxylase converts dopamine to norepinephrine (NE). This is the end product in sympathetic nerve terminals. Rate-limiting step: Tyrosine hydroxylase. 50% of the dopamine synthesized is metabolized by MAO before entering the storage vesicle. In the adrenal medulla, norepinephrine is converted to epinephrine (EPI) by the enzyme phenylethanolamine N-methyltransferase. II. STORAGE OF TRANSMITTER The active transport of dopamine into granular storage vesicles is necessary for the formation of NE because of the localization of dopamine-β-hydroxylase inside the vesicles. NE is stored in association with ATP (4:1). Vesicles "leaky" - NE must be pumped back. Dr. Ishac Autonomic Nervous System 8 Schematic diagram of a generalized noradrenergic junction. 1. Tyrosine (Tyr) is transported into nerve terminal (varicosity) by sodium-dependent carrier 2. Tyr converted to dopamine, then transported into storage vesicle (inhibited by reserpine) 3. Dopamine is converted to NE by dopamine-β-hydroxylase. The conversion of NE to epinephrine occurs only in the adrenal medulla and some brain regions 4. Transmitter release occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. . Release inhibited by guanethidine and bretylium. 5. Released NE can activate post- and presynaptic receptors 6. Response terminated by neuronal uptake, extraneuronal uptake and diffusion out of the cleft 7. Enzymatic inactivation by MAO and COMT III. RELEASE OF TRANSMITTER AND AUTOREGULATION Arrival of an action potential at the sympathetic neuron causes depolarization of the membrane of the varicosities. NE is released from the storage vesicles by an exocytotic process: the vesicular and neuronal membranes fuse, an opening forms and the contents of the vesicle are delivered into the synaptic cleft. Release of NE is regulated by feedback mechanisms 'autoreceptors'. Released NE can activate presynaptic alpha2-adrenoceptors to inhibit further transmitter release and/or presynaptic beta2-adrenoceptors to enhance transmitter release (more important for circulating catecholamines eg. EPI). Dr. Ishac Autonomic Nervous System 9 IV. TERMINATION OF TRANSMITTER RESPONSE (Figs. 3,3B) A. Reuptake into the noradrenergic neuron (70-80%, neuronal uptake, uptake 1), followed by re-entry into the storage vesicles and/or enzymatic inactivation. This is the most important mechanism (NE > EPI, ISO not transported). Inhibited by cocaine, imipramine. B. Active transport into the effector cells (10-20%, extraneuronal uptake, uptake 2) followed by enzymatic inactivation (EPI > NE). C. Passage into the circulation and enzymatic destruction in the liver by MAO and COMT. Relative proportion of the different mechanisms depends on: i. Size of synaptic junction ii. Density of innervation iii. Neuronal release of transmitter (NE) iv. Circulating transmitter (EPI, NE) Dr. Ishac Autonomic Nervous System 10 Enzymatic metabolism of catecholamines a. Catechol-O-Methyltranferase (COMT) b. Monoamine Oxidase (MAO, outer mitochondrial membrane) • Major urinary metabolites: 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG) and 3-methoxy-4-hydroxymandelic acid (VMA) • Inhibitors of MAO and COMT have little prompt effects MAO COMT Location in cell Outer mitochondrial membrane Cytosol Location in body Symp. nerve, placenta (MAOA) Most tissues, not in platelets (MAOB) sympathetic. nerves liver, kidney, brain (MAOA + MAOB) Effect of inhibition on Increases NE level in symp. neuron, potentiates no effect NE levels release by tyramine-like drugs O H MAO R CH2 N R R C H O R C OH R CH2OH R R HO COMT CH3O HO HO Dr. Ishac Autonomic Nervous System 11 V. ADRENERGIC RECEPTOR SUBTYPES Alpha1: EPI > or = NE >> ISO Beta1: ISO > EPI = NE Alpha2: NE > EPI >> ISO Beta2: ISO > or = EPI >> NE Beta3: ISO = NE > EPI Receptor Tissue Actions Alpha1 Most vascular smooth muscle Contraction Pupillary dilator muscle Contraction (dilation) Pilomotor smooth muscle Erects hair Vas deferens Contraction Liver Glycogenolysis Intestinal smooth muscle Relaxation Intestinal sphincters Contraction Alpha2 Some vascular smooth muscle Contraction Nerve terminals (NE & ACh) Inhibit transmitter release Platelets Aggregation Fat cells Inhibition of lipolysis Beta1 Heart Increase force, rate, cond. velocity Coronary blood vessels Dilatation Kidney Renin release Beta2 Bronchial smooth muscle Relaxation Intestinal smooth muscle Relaxation Uterine smooth muscle Relaxation Vascular smooth muscle Relaxation NA nerve terminals Facilitation of release Beta3 Fat cells Lipolysis VI. SECOND MESSENGER SYSTEMS FIGS. 4A,B Receptor Location G Protein Second Messenger α1 Effector tissues: smooth muscle, glands Gq ↑Ca2+, ↑IP3, DAG α2 Nerve endings, some smooth muscle Gi ↓cAMP β1 Heart, juxtaglomerular apparatus Gs ↑cAMP β2 Smooth muscle, lung Gs ↑cAMP β3 Adipose cells Gs ↑cAMP D1, D5 Vascular smooth muscle, brain, renal Gs ↑cAMP D2, D3, D4 Brain, cardiovascular system Gi ↓cAMP Dr. Ishac Autonomic Nervous System 12 Schematic representation of adrenergic receptors and their second messenger systems. Dr. Ishac Autonomic Nervous System 13 VII. AGONISTS: SYMPATHOMIMETIC AGENTS Sympathomimetic agents can be divided into three classes: Directly acting: combine with alpha- and/or beta-adrenoceptors and hence activate them directly (eg. epinephrine, norepinephrine). Indirectly acting: act by release (displacement) of NE from sympathetic nerve terminals; the released NE then activates the receptor (eg. tyramine, amphetamine). Mixed acting: have both direct and indirect activity (eg. ephedrine). A. Directly Acting Sympathomimetics 1. Catecholamines (CAs). The catecholamines may be thought of as being derived from the following 'parent compound': phenylethylamine. Most of the agonists, such as epinephrine (EPI), norepinephrine (NE), dopamine (DA), isoproterenol (ISO) and others have hydroxyl groups on the ring in the #3 or #4 positions. OH 3 2 1 OH 4 CH2 CH2 NH2 5 6 Catechol Phenylethylamine Modifications of the parent compound, phenylethylamine can drastically alter the behavior of the molecule as a ligand for the various receptor subtypes (alpha- or beta-receptors). a. Norepinephrine (noradrenaline): • Activates: both alpha, beta1, beta3, beta2 (weakest) receptors • Substrate for MAO & COMT, does not cross BBB b. Epinephrine (adrenaline): • Activates both alpha, beta1, beta2, beta3 (weakest) receptors • Substrate for MAO & COMT, does not cross BBB • Drug of choice: Acute hypersensitivity reactions (anaphylaxis) c. Dopamine: - precursor of NE and EPI • Activates alpha1, beta1, dopamine receptors • Substrate for MAO & COMT, does not cross BBB • Drug of choice: Shock (septic), i.v. infusion, maintains renal blood flow d. Isoproterenol (isoprenaline): • Activates all beta receptors • Substrate for COMT, does not cross BBB Dr. Ishac Autonomic Nervous System 14 2. Non-Catecholamines. Most still retain the phenylethylamine skeleton, benzene ring is sometimes replaced by another chemical moiety. Note these agents are generally not good substrates for COMT which requires both hydroxyl groups. Substitutions on the alpha carbon decrease MAO activity. a. Selective beta2-agonists Albuterol, ritodrine, terbutaline, metaproterenol • major use in the treatment of asthma • may be administered orally or by inhalation Oral: onset 1-2 hrs, 4-6 hrs duration Inhalation: onset 5-10 min 3-4 hrs duration • premature labor, relax uterus, ritodrine • hydroxyl groups at 3 & 5 positions (not substrates for COMT) • bulky groups on the amino terminal (↑β2-selectivity) • relax bronchial smooth muscle, ↓ airway resistance • adverse effects: cardiovascular side effects (HR, BP), less by inhalation compared to oral administration b. Selective beta1-agonists Dobutamine, Prenalternol • cardiac stimulant, congestive heart failure (tolerance/desensitization) • ↑ force without HR or O2 increases c. Selective alpha1-agonists Methoxamine, phenylephrine, metaraminol (direct/indirect) • limited clinical use • used in the treatment of hypotension or shock • phenylephrine also used as a nasal decongestant • adverse effects: cardiovascular side effects d. Selective alpha2-agonists Clonidine (others include guanfacine, α-methyldopa) • used in the treatment of hypertension central action (medulla oblongata) on postjunctional α2-receptors to decrease sympathetic outflow → ↓ BP • adverse effects: impotence, dry mouth, sedation, rebound hypertension upon withdrawal Dr. Ishac Autonomic Nervous System 15 B. Indirectly Acting Sympathomimetics: 1. Displacement of Transmitter: Act by release (displacement) of NE from sympathetic nerve terminals; the released NE then activates the receptor(s). Compete with NE for uptake 1 (Fig. 5A). Commonly cause tachyphylaxis (Fig 5B). a. Amphetamine, methamphetamine (greater CNS activity), Methylphenidate (Ritalin) • powerful CNS stimulant, performance enhancer, physical and mental (abuse) • ↑alertness, mood, self-confidence, concentration • depression of appetite (?), tolerance (tachyphylaxis) • toxicity: cardiovascular, restlessness, tremor, insomnia • tolerance and psychological dependence develops Figure 5A. Indirect-acting sympathomimetics Figure 5B. Tachyphylaxis b. Ephedrine (mixed) • direct action (alpha- and beta-receptors) • indirect action to release norepinephrine c. Tyramine • Not a drug, found in food sources eg. beer, red wine, aged cheeses. • Interaction with MAO inhibitors • Can precipitate a hypertensive crisis (↑BP, ↑HR) Dr. Ishac Autonomic Nervous System 16 2. Inhibition of NE reuptake (Fig. 6) Inhibition of the neuronal uptake mechanism can: • prevent the action of indirectly acting agents (e.g. amphetamine) • inhibit the actions of agents that require neuronal uptake to gain access into the varicosity (e.g. guanethidine) • potentiate the effects of NE (ie. not removed from synaptic junction). a. Cocaine b. Tricyclic antidepressants - imipramine, amitriptylline, clomipramine (tricyclics have significant muscarinic- and α- adrenoceptor blocking activity at high doses (overdose) c. Atomoxetine (used for ADHD) d. Guanethidine (not major action) Figure 6. Blockade of NE re-uptake 3. Inhibition of Metabolic Degradation of CAs (Figs. 3,3B). a. Inhibition of COMT Not clinically used (no major importance) • pyragallol (experimental, toxic) • tropolone Dr. Ishac Autonomic Nervous System 17 b. Inhibition of MAO (Tranylcypromine, Pargyline, Phenelzine, Isocarboxazid) • NE will accumulate in terminal • interaction with tyramine-like drugs (Fig. 7) Two isozymes present: • MAO-A (clorgiline, antidepressant) • MAO-B (selegiline, Deprenyl, Parkinson's Disease.) MAO COMT Location in cell mitochondrial membrane Cytosol Location in body symp. nerve, placenta (MAOA) most tissues, platelets (MAOB) not in symp. liver, kidney, brain (MAOA + MAOB) nerve Effect of inhibition increases NE level in symp. neuron, potentiates release by no effect on ME levels tyramine-like drugs Inhibitors tranylcypromine (non-selective) Pyrogallol clorgyline (MAOA-selective) selegiline (MAOB-selective) Clinical use of mental depression (non-selective or MAOA-selective) None inhibitors Parkinson's disease (MAOB-selective) Interactions MAO inhibitors potentiate effects of tyramine (due mainly None to blocking metabolism of tyramine by MAO in liver) Dr. Ishac Autonomic Nervous System 18 C. Therapeutic uses of Sympathomimetic Drugs 1. Asthma (major use) • bronchodilation with ↓airway resistance • beta2-selective agents eg. albuterol, terbutaline 2. Nasal Decongestant (common use) • vasoconstriction (ephedrine, phenylephrine) 3. Allergic Reactions • acute hypersensitivity reactions (food, bee sting, drug allergy) • bronchospasm (due to histamine release) • epinephrine (im) physiological antagonist: drug of choice 4. Hypotension (acute) • due to antihypertensive agents, spinal anesthesia, hemorrhage • α-receptor agonists: phenylephrine, methoxamine, metaraminol 5. Hypertension (chronic) • decrease sympathetic outflow from CNS • centrally acting α2-receptor agonists: clonidine, α-methyl-dopa 6. Shock (need to treat cause) • blood loss, cardiac failure, septic shock, cardiac obstruction • inadequate perfusion, requires immediate attention to maintain BP • dopamine (drug of choice), epinephrine 7. Congestive Heart Failure • ↑cardiac performance without ↑demand on heart • dobutamine 8. Cardiac Heart Block & Cardiac Arrest • stimulate cardiac β1-receptors • epinephrine or isoproterenol 9. Ophthalmic • dilate the pupil (phenylephrine) • glaucoma α1-receptor agonists eg. epinephrine (↑ outflow) α2-receptor agonists eg. clonidine (↓ secretion) β-receptor blockers eg. timolol (↓ secretion) Dr. Ishac Autonomic Nervous System 19 10. Premature Labor • suppress uterine contractions: ritodrine, terbutaline (not FDA approved, cheaper & longer acting) 11. Attention deficit hyperactivity disorder (ADHD) • Amphetamine-like agents ie methylphenidate (Ritalin) • NE-uptake inhibition: atomoxetine 12. Other: • Obesity (amphetamine-like agents) • Nacrolepsy (amphetamine-like agents) D. Toxic Effects of Sympathomimetic Agents • Generally extensions of their receptor-mediated effects • Adverse cardiovascular effects can include: excessive rise in blood pressure with pressor agents, which can give rise to cerebral hemorrhage excessive myocardial stimulation can accompany the actions of beta-adrenoceptor agonists • CNS stimulation: restlessness, dizziness, insomnia etc with sympathomimetics which can pass into the CNS eg. amphetamine. • - α2-receptor agonists dry mouth, sedation, impotence, Dr. Ishac Autonomic Nervous System 20 E. Cardiovascular Effects Of Sympathomimetics Sympathomimetics have prominent effects on the cardiovascular system. It is extremely important to keep in mind that autonomic function is under the control of the CNS; and that there are reflexes involved which may over ride any direct drug actions. General hemodynamics: BP = CO x TPR BP = blood pressure TPR = total peripheral arterial resistance CO = cardiac output CO = stroke volume x heart rate Integration: in order to maintain homeostasis and the appropriate coordinated autonomic state, the individual afferent and efferent components of the sympathetic and parasympathetic nervous systems are integrated within the CNS (Figs 8A,B). Dr. Ishac Autonomic Nervous System 21 Figure 8C. Cardiovascular effects of infusions of NE, ISO and EPI in humans. Heart rate is given in beats/min, blood pressure in mm Hg, and peripheral resistance in arbitrary units. Dotted line in the BP record is the calculated mean arterial blood pressure. Cardiovascular Effects of Catecholamines in Humans Cardiovascular function Norepinephrine Isoproterenol Epinephrine Systolic blood pressure +++ 0+ ++ Diastolic blood pressure ++ -- - Total peripheral resistance +++ --- -- Heart rate (chronotropic effect) - ++ + Stroke output (inotropic effect) + ++ ++ Cardiac output -0 +++ +++ Mean blood pressure ++ -- +0- 0 = no effect; + = increased; - = decreased. Symbols indicate the approximate magnitude of the response. Dr. Ishac Autonomic Nervous System 22 Direct effects of activation of ANS receptors Alpha1 receptors vasoconstriction ↑ TPR ↑ BP Beta1 receptors ↑ heart rate ↑ CO ↑ BP Beta2 receptors vasodilation ↓ TPR ↓ BP M2 receptors (vagus) ↓ heart rate ↓ CO ↓ BP M receptors (vascular) Vasodilation (NO) ↓ TPR ↓ BP Influence of sympathetic & parasympathetic tone on BP & HR BP (mmHg) HR (bpm) Normal (resting) 120 / 80 70 No tone* 60 / 40 75 * Central and circulation hormone actions removed Note: Athletic individuals have lower HR due to higher vagal tone ie. Lance Armstrong (resting HR 32 bpm) Influence of BP change on ANS tone Resting After ↑ BP After ↓ BP Alpha1 ++++ 0 +++++++ Beta1 + 0 ++ *Beta2 + ++ 0 Vagus (M2) ++ ++++ 0 * Non-innervated, respond to circulation epinephrine (EPI) Note: Vascular M receptors have no major role in BP regulation (Ach is not a circulating hormone. Agonist Actions on BP & HR (high doses) Epinephrine Reversal Dr. Ishac Autonomic Nervous System 23 Figure 8F Cardiovascular Effects of Various Agents α1, β1, (β2) α1 β1, β2, α1 β1, β2 Dr. Ishac Autonomic Nervous System 24 VIII. ANTAGONISTS: SYMPATHOLYTIC AGENTS Adrenergic receptor antagonists: Drugs that have high affinity but no (or low negative or positive) intrinsic activity. Competitive vs. irreversible antagonists. Factors that determine the effect of antagonists in vivo: • Absence or presence of intrinsic activity • Preexisting "tone" at receptor. • Net effect at pre- vs. postsynaptic receptors. • Selectivity for receptor subtype. • Compensatory reflex adjustments. A. Alpha-Adrenoceptor Antagonists Clinical applications: • hypertensive crisis • pheochromocytoma • excess side effects in ADHD • tyramine intake in patients on MAO inhibitors • chronic hypertension • benign prostrate hypertrophy Dr. Ishac Autonomic Nervous System 25 1. Phenoxybenzamine (non-competitive) • irreversible alpha1-blocker, forms covalent bond • also causes some block of ACh, histamine, serotonin receptors • also can inhibit neuronal and extraneuronal uptake • therapy: primary hypertension, pheochromocytoma (acute & chronic) • toxicity: impotence 2. Phentolamine and Tolazoline (competitive) • non selective α1 =α2 antagonist activity • cardiovascular: vasodilation, reflex tachycardia • enhance NA release due to presynaptic alpha2-blockade 3. Prazosin and Terazosin (competitive) • selective α1- > α2-receptors (1000 fold) • cardiovascular effects: reduced peripheral resistance lowered vascular return, no tachycardia • therapy: primary hypertension, benign prostrate hypertrophy • first pass effect 4. Toxicity • postural hypotension (very marked) • tachycardia, arrhythmias, myocardial infarction • ↓ plasma lipids • impotence (significant with phenoxybenzamine) • headache, dizziness, nausea, drowsiness 5. Yohimbine (competitive) • selective α2-antagonist, was used for impotence but removed from the market (available OTC) B. Beta-Adrenoceptor Antagonists. Therapeutically a much more useful class of drugs than alpha-adrenoceptor antagonists. Beta-adrenoceptor antagonists vary in respect to: • relative affinity for beta1- and beta2-adrenoceptors • ability to act as agonists at ß-adrenoceptors (ie. intrinsic ß-activity, partial agonists activity, ISA) • ability to stabilize membranes (local anaesthetic activity) • lipid solubility (least important) General features of beta-blocking agents: • End in –olol (exceptions: Sotalol, Labetalol & Carvedilol) • Agents beginning with A-M are β1-selective (exceptions: Carteolol, Labetalol & Carvedilol) Dr. Ishac Autonomic Nervous System 26 1. Clinical uses: a. Hypertension Together with diuretics, β-blockers are considered 'first-line' treatment for uncomplicated essential hypertension. The usual hemodynamic effect of a β- blocker in a hypertensive patient is shown in the figure below (gradual reduction of total peripheral resistance (TPR) in spite of long-term decrease in cardiac output). Mechanism unclear, but possibilities include action in CNS to reduce sympathetic tone, block of presynaptic β-receptors to reduce NE release, decrease in renin release. Both non-selective and β1-selective drugs are effective. Hemodynamic effects of propranolol in patients with essential hypertension. Dr. Ishac Autonomic Nervous System 27 b. Arrhythmia Mechanism: blockade of catecholamine-induced increases in conductivity and automaticity in heart, and decrease in serum K+ (action in skeletal muscle to enhance uptake). β-blockers with membrane stabilizing properties better eg. metoprolol c. Angina. β-blockers block catecholamine effects on heart. They reduce O2 demand more than O2 supply. Exercise tolerance is increased in patients with angina. β1-selective blocker better eg. atenolol Note: 'rebound' angina upon abrupt cessation of treatment, less rebound with pindolol (non-selective, partial agonist) d. Glaucoma (major use): ↓ aqueous humor formation (timolol) e. Heart failure (Congestive, CHF): (Metoprolol, Labetalol & Carvediolol) Decrease load and O2 demand of heart MERIT-HF: Use of Metoprolol in CHF JAMA 2000, 283, p1295-1302 Mortality ↓34%, Hospitalization ↓29%, Felt better ↑25 Caution: β-blockers can precipitate latent heart failure by removing compensatory increase in sympathetic effects on heart Contraindicated: unstable CHF, significant bronchospasm, bradycardia or depression f. Other. • Tremor of peripheral origin (β2-receptors in skeletal muscle). • Migraine prophylaxis (mechanism unknown). • Hyperthyroidism: block of cardiac manifestations due to β-receptor supersensitivity (propranolol). • Panic attacks, stage fright g. Untoward effects, contraindications: • Supersensitivity, blockade of beta-receptors can lead to rebound hypertension. Gradual withdrawal recommended • Asthma. Asthma precipitated by blockade of pulmonary β2-receptors. β1- selective agents are preferred in patients with asthma. • Diabetes. Compensatory hyperglycemic effect of EPI in insulin-induced hypoglycemia is removed by block of β2-receptors in liver. β1-selective agents preferred. • Elderly: Effectiveness is decreased with age. Despite decreased sensitivity to the chronotropic effects of β blockade, there may be increased myocardial sensitivity to the negative inotropic effect during exercise. The elderly are at increased risk of orthostatic hypotension, reduced peripheral circulation, and mental status changes with β blockers. than in younger adults. Dr. Ishac Autonomic Nervous System 28 h. Labetalol, Carvedilol • Used for chronic hypertension, CHF, hypertensive crisis (better than α- receptor blocker, can decrease both BP & HR effects) • competitive antagonist at both α- and β-adrenoceptors • β1 = β2 activity > α-activity (some intrinsic β-adrenoceptor activity) • can cause postural hypotension due to α-receptor block C. Agents that Decrease the Quantity of NE in Nerve Terminals. 1. Direct inhibition of synthesis (Figs. 2A,10) • Alpha-methyl-p-tyrosine (inhibits tyrosine hydroxylase) treatment of pheochromocytoma (long-term, diffuse tumor) 2. False transmitters (Fig. 10) a. Alpha-methyl-DOPA alpha-methyl-NE • Prodrug (ie. converted to alpha-methyl-NE) • alpha2 action (alpha-methyl-NE) • hypertension: central action → ↓ sympathetic outflow b. Alpha-methyl-m-tyrosine metaraminol • metaraminol also has activity at alpha-receptors (<NE) c. Tyramine + MAO inhibition octopamine Dr. Ishac Autonomic Nervous System 29 3. Inhibition of intraneuronal storage of CAs (FIGS. 11A,B) Reserpine: "leaky" vesicle (also depletes 5-HT stores) and inhibits transport of NE from cytosol to vesicle. Leads to gradual depletion of NE stores Inhibition of Vesicular Storage of NE Consequences of Reserpine Treatment Major side effects include: lethargy, diarrhea, depression (very long lasting). 4. Prevention of normal transmitter release (Fig. 12) • Used in the treatment of hypertension and arrhythmias. • Side effects include: diarrhea, nasal congestion, impotence, postural hypotension. • Competes with TCA's for uptake process. a. Bretylium (local anesthetic action, arrhythmias, premedication) b. Guanethidine (reuptake inhibitor, inhibits release) Dr. Ishac Autonomic Nervous System 30 SUMMARY Dr. Ishac Autonomic Nervous System 31 PARASYMPATHETIC NERVOUS SYSTEM Edward JN Ishac, Ph.D. Associate Professor, Pharmacology and Toxicology Smith 742, 828-2127, e-mail: email@example.com Learning Objectives: Understand the steps involved in cholinergic neurotransmission, and how drugs can interfere with these processes. Figure 1 Functional organization of the cholinergic nerve terminal I. STEPS IN CHOLINERGIC NEUROTRANSMISSION A. Acetylcholine (ACh) synthesis: Choline is transported into the nerve terminal and acetyl CoA produced by mitochondria is transported to the cytosol. The enzyme choline acetyltransferase synthesizes acetylcholine (Ach) from choline and acetyl CoA. Choline co-transports with Na+ and is the rate limiting step in the synthesis of Ach (inhibited by hemicholinium-3). B. ACh storage: ACh is stored in vesicles. Nerve impulses cause a calcium- dependent quantal release of ACh. Botulinum toxin (food poisoning) is potent inhibitor of ACh release. C. ACh release: Arrival of an action potential at the parasympathetic neuron causes depolarization of the membrane leading to an influx of Ca2+. ACh is released from the storage vesicles by an exocytotic process: the vesicular and neuronal membranes fuse, an opening forms and the contents of the vesicle (ACh, ATP, PG) are delivered into the synaptic cleft (1000-50,000 ACh/vesicle; 300,000 vesicles/terminal; need only 1000 ACh mepp action potential). Dr. Ishac Autonomic Nervous System 32 Figure 2. Schematic diagram of a generalized cholinergic junction. 8. Choline is transported into nerve terminal (varicosity) by sodium-dependent carrier. Rate limiting step, inhibited by hemicholinium. 9. Ach is synthesized from choline and acetyl CoA by acetyltransferase 10. Ach transported to storage vesicle (inhibited by vesamicol) 11. Transmitter release occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. . Release inhibited by botulin 12. Released Ach can activate post- and presynaptic receptors 13. Response terminated by enzymatic degradation by acetylcholinesterase (inhibited by physostigmine and other cholinesterase inhibitors)) 14. Choline retaken up by nerve terminal D. ACh interaction with receptors: Released ACh acts at muscarinic (parasympathetic) and nicotinic (ganglia, CNS, motor endplate) receptors. Muscarinic receptors (5 subtypes cloned to date) are G protein coupled, act via inhibition of adenylate cyclase or activation of phospholipase C. Nicotinic receptors are composed of multiple subunits, forming an ion channel. Pharmacologically distinct receptors in neuronal tissue (ganglia, CNS) and in motor endplate. Agonists and antagonists at different types of receptors are clinically used (see below). Certain snake venoms are potent inhibitors of nicotinic receptors in skeletal muscle. Dr. Ishac Autonomic Nervous System 33 Figure 3. 1. Muscarinic (7 transmembrane, glycoprotein) • M1 -(minor importance) autonomic ganglia, CNS • M2 -heart • M3 -smooth muscle, glands • M4 , M5 • similar to adrenoceptors and other G-protein coupled receptors in structure • M1 , M3 , M5 ↑ IP3 • M2, M4 ↓ cAMP ii. Nicotinic (ion channel, pentamer, 5 subunits) • NN or N1 -ganglia, adrenal medulla (α2β3, α3β2) • NM or N2 -skeletal muscle (infant, α2βδε; adult, α2βδγ) • α-subunit contains Ach binding site E. Termination of ACh action: Ach released into the synaptic cleft is rapidly metabolized by acetylcholinesterase (AChE) to choline and acetate. The choline is then taken up by the nerve terminal for subsequent Ach synthesis. Butyrycholinesterase (pseudocholinesterase) found in the circulation, liver, and other tissues can also metabolize Ach. Dr. Ishac Autonomic Nervous System 34 Acetylcholinesterase Butyrycholinesterase (Pseudocholinesterase) Neuroeffector site Yes Little Circulating Little Yes Methacholine Yes Yes Physostigmine Yes Yes Neuromuscular junction Yes Little II. MUSCARINIC EFFECTS ON ORGAN SYSTEMS (see Table 1) A. Cardiovascular • Heart: Decreased heart rate, decreased contractility and decreased conduction velocity in A-V node due to stimulation of M2 receptors. Not clinically exploited, but important in the action of certain drugs (digitalis, quinidine), which potentiate muscarinic effects in heart. • Vasculature: Vessels are not cholinergically innervated, but have muscarinic receptors on endothelial cells that mediate potent vasodilation via synthesis of nitric oxide (NO). B. Other smooth muscle • GI-tract: Increase tone in intestine, bladder, decreased tone in sphincters. e.g. clinical use: bethanecol in postoperative paralytic ileus, bladder dysfunction. • Lung: contraction of bronchial smooth muscle leads to an increase in air resistance. Also increases bronchial secretions. • Eye: contraction of sphincter muscle (myosis), contraction of ciliary muscle for near vision. • Exocrine glands. • Increased sweating (cholinergic sympathetic), increased salivation, increase in gastric acid secretion Terminology Cycloplegia: Paralysis of ciliary muscle (loss of accommodation, ability to focus) Miosis: Contraction of pupil (leads to pinpoint pupil, ie. Ach) Mydriatic: Relaxation of pupil (leads to pupil dilation, ie. atropine belladonna compound) Dr. Ishac Autonomic Nervous System 35 III. CLASSES OF CHOLINOCEPTOR-ACTIVATING DRUGS CHOLINOCEPTOR STIMULANTS Direct-acting Indirect-acting (receptor agonists) (cholinesterase inhibitors) Muscarinic Nicotinic Reversible Irreversible Choline Alkaloids Ganglionic NMJ Edrophonium, Phosphates esters carbamates A. Directly-Acting Parasympathomimetics Directly acting parasympathomimetics: combine with muscarinic and/or nicotinic cholinoceptors and hence activate the receptor directly. 1. Muscarinic receptor agonists. a. Choline esters • acetylcholine (both muscarinic and nicotinic) • methacholine • carbachol (direct/indirect; muscarinic & nicotinic) • bethanechol b. Alkaloids • muscarine (found in certain mushrooms) • pilocarpine (used in glaucoma) • oxotremorine (synthetic) CNS action (basal ganglia) c. Uses • ophthalmic (Ach, brief miosis) • diagnostic for belladonna poisoning (methacholine) • urinary retention (bethanechol) • reverse GI depression ie. post-operative (bethanechol) • glaucoma (pilocarpine, emergency drug of choice) Dr. Ishac Autonomic Nervous System 36 d Adverse reactions: • cardiac slowing (arrest) • nausea, cramps • bronchoconstriction, precipitate asthma • involuntary defecation, urination • tremor, cns induced convulsions • ↑ sweating, diarrhea SLUDE Salivation, Lacrimation, Urination, Diarrhea, Emesis 2. Nicotinic receptor agonists (ganglionic stimulants) • acetylcholine • DMPP • nicotine (alkaloid) • lobeline B. Indirectly-Acting Parasympathomimetics Indirectly-acting parasympathomimetics: interact with acetylcholinesterase (true) and/or pseudocholinesterase (serum) to prevent the metabolism of Ach. Ach is normally metabolized by cholinesterase which has two sites: an anionic site that binds the quaternary amine and positions the Ach molecule, and an esteratic site which attacks the acyl carbon (Fig. 5A). Main target is acetylcholinesterase but also inhibit pseudocholinesterase. Inhibitors of cholinesterase: Reversible inhibitors Irreversible inhibitors 1. Reversible inhibitors (Fig. 5B). a. Quarternary ammonium compounds • edrophonium (competitive, water stable, 5-10 min action) diagnostic for myasthenia gravis • ambenonium (4-8 hr action) b. Carbamates • physostigmine (tertiary amine, well absorbed, cns activity, can give topically or orally, 0.5-2 hrs action) • neostigmine (quaternary amine, no cns activity, synthetic, some direct action, 0.5-2 hrs action) • pyridostigmine (3-6 hrs action) Dr. Ishac Autonomic Nervous System 37 Figure 5A. Interaction of acetylcholine and Figure 5B Reversible acetylcholinesterase acetylcholinesterase inhibitor 2. Irreversible inhibitors (Fig. 6). a. Organophosphates (highly lipid soluble, >50,000 compounds) • Diisopropyl-fluorophosphate (Isoflurophate, DFP) • Echothiophate (Phospholine) • sarin, suman (nerve gases) • malathion, parathion (pesticides, very lipid soluble) inactive, thiophosphates converted to active compounds, then inactive metabolites (birds/vertebrates) but not insects or fish Parathion more dangerous than malathion b. 'Aging' (Fig. 6): • In time phosphorylation of acetylcholinesterase: becomes irreversible • Isoflurophate – 'aging' 30-45 min • If 'aging' has not occurred, AChE can be regenerated • AChE reactivator, pralidoxime (2-PAM). Dr. Ishac Autonomic Nervous System 38 Figure 6. Irreversible acetylcholinesterase inhibition 3. Actions and Clinical uses of Acetylcholinesterase Inhibitors: a. Eye: • Miosis (sphincter contraction), accommodation block (ciliary muscle contraction) • Glaucoma, as maintenance therapy in chronic wide-angle or secondary glaucoma. Short acting (physostigmine) or long acting (echothiophate) • Combination with α-adrenergic agonist (acts by reducing vascular volume and secretion) or β-receptor antagonist (reduces secretion). • Not emergency treatment in acute narrow angle glaucoma (pilocarpine used) b. GI tract. • Increase in GI-tract motility • Neostigmine used to increase motility in paralytic ileus (post-operative) or atony of urinary bladder (bethanechol preferred). Dr. Ishac Autonomic Nervous System 39 c. Neuromuscular junction.: • Neostigmine is used to increase muscle strength in myasthenia gravis. Action due to both AChE inhibition and direct nicotinic receptor stimulation. • Edrophonium (short acting) is used as diagnostic test to distinguish myasthenic weakness (improved) from cholinergic crisis (worsened). Also used to determine maintenance dose d. Reverse toxicity by anticholinergic agents. • Physostigmine is preferred (CNS action) • Toxicity caused by belladonna agents (atropine-like agents) • Drugs that have anticholinergic side effects (e.g. tricyclic antidepressants). Uses and duration of action of cholinesterase inhibitors used in therapeutics. Duration Uses of Action Alcohols Edrophonium (Tensilon) Myasthenia gravis, 5-15 minutes ileus, arrhythmias Carbamates and related agents Neostigmine (Prostigmine, etc.) Myasthenia gravis, ileus 1/2-2 hours Pyridostigmine (Mestinon, etc.) Myasthenia gravis 3-6 hours Physostigmine (Eserine) Glaucoma 1/2-2 hours Ambenonium (Mytelase) Myasthenia gravis 4-8 hours Demecarium (Humorsol) Glaucoma 4-6 hours Organophosphates Glaucoma Isoflurophate (DFP) 100 hours Echothiophate (Phospholine, etc.) Glaucoma 100 hours Dr. Ishac Autonomic Nervous System 40 4. Toxicity and Treatment of Acetylcholinesterase inhibitors: a. Symptoms resemble excessive muscarinic & nicotinic stimulation Response Receptor ↑ Sweating Muscarinic ↑ Lacrimation, salivation Muscarinic Blurred vision Muscarinic ↑ Bronchosecretions, bronchoconstriction Muscarinic Paralysis (depolarizing block), fasciculations Nicotinic Diarrhea Muscarinic Bradycardia Muscarinic Hypotension/Hypertension Nicotinic Tremor Muscarinic SLUDE Salivation, Lacrimation, Urination, Diarrhea, Emesis b. Treatment of poisoning by organophosphate AChE inhibitors • muscarinic antagonist atropine • AChE reactivator (pralidoxime, 2-PAM) • mechanical respiration. Dr. Ishac Autonomic Nervous System 41 IV. ANTAGONISTS: PARASYMPATHOLYTIC AGENTS Cholinoceptor-blocking agents can be divided into three divisions depending on the site of interaction with ACh: Antimuscarinic Block ACh in parasympathetic effector junctions (muscarinic receptors) Antinicotinic block ACh in ganglia (both parasympathetic and sympathetic, NN or N1-receptors) Antinicotinic block ACh in neuromuscular junctions (skeletal muscle relaxants, NM or N2- receptors) A. Anticholinergic Effects on Organ Systems: 1. Heart: • Removal of vagal tone causes tachycardia, increase in A-V nodal conduction due to block of M2 receptors on target cells. • Clinical use: A-V block, sinus bradycardia. 2. Vasculature. • No effect due to lack of cholinergic innervation, although toxic doses cause pronounced vasodilation 3. Smooth muscle. • GI, urinary tract: relaxation, reduced secretion and motility • Lung: cause bronchial relaxation and ↓ bronchial secretions • Eye: mydriatic (sphincter relaxation), cyclopegic (ciliary muscle relaxation for far vision), diagnostic tool to dilate pupil (homatropine) 4. Secretions. • Antisecretory activity. Dry mouth, dry skin, decreased gastric acid secretion. • Atropine shows little selectivity among above effects. • Used as preoperative medication to reduce salivation, respiratory tract secretion. 5. CNS. • CNS effects prominent in belladonna toxicity ("mad as a hatter, red as a beet, blind as a bat, hot as hell, dry as a bone"). • Scopolamine skinpatch used in motion sickness. • Elderly are more susceptible to the CNS adverse effects, including confusion and mental status alterations Dr. Ishac Autonomic Nervous System 42 B. Antimuscarinic Agents: Inhibition of the action of Ach on muscarinic receptors can unmask nicotinic effects or unmask sympathetic tone ie. injected antimuscarinic can lead to increase in heart rate. 1. Belladonna alkaloids (well absorbed, CNS effects) • atropine (deadly nightshade, 7-10d) • homatropine (1-3 d) • scopolamine (3-7 d) 2. Synthetic antimuscarinics • ipratropium (quaternary amine) • pirenzepine (tri-cyclic, M1-selective) • benztropine (Parkinson's Disease) • gycopyrolate (quaternary amine) • cyclopentolate (tertiary amine) • propantheline (Probanthine, quaternary amine) C. Clinical Uses of Antimuscarinic Agents: 1. respiratory (decrease bronchial secretion) 2. asthma (ipratropium) 3. ophthalmologic (mydriasis, cycloplegia) 4. Parkinson's disease (benztropine) 5. cardiovascular (prevent HR changes with AchE inhibition) 6. motion sickness (scopolamine) 7. GI disorders: • peptic ulcers (pirenzepine) • diarrhea 8. cholinergic poisoning eg. pesticides, mushrooms D. Toxicity and Treatment of Antimuscarinic Agents Toxicity is an extension of their antimuscarinic effects: ie. dry mouth, mydriasis, tachycardia, hot flushed skin, agitation and delirium. Also side-effect of 'therapeutic' action: ie. mydriasis when used for motion sickness. High concentrations may cause ganglionic-blockade leading to hypotension. Treatment of antimuscarinic poisoning: cholinesterase inhibitor eg. neostigmine or physostigmine. For reversal of hypotension may use sympathomimetics such as phenylephrine or methoxamine. Dr. Ishac Autonomic Nervous System 43 E. Other Parasympatholytics 1. Hemicholinium: inhibit the uptake of choline (↓ synthesis of Ach) 2. Botulinus toxin: prevent release of Ach Used to treat facial muscle spasms, strabismus, facial wrinkles V. PHARMACOLOGY OF THE EYE "The eye is a good example of an organ with multiple ANS functions, controlled by several different autonomic receptors." (Katzung, 1998, Pg 87) A. Mechanism of action of drugs used in the treatment of glaucoma. Increased intraocular pressure: Untreated → blindness a. Open-angle (chronic) – usually treated with beta-blockers b. Closed-angle (narrow-angle) – dilated iris can occlude outflow, (Pilocarpine or surgical removal of part of iris (iridectomy)) Terminology: Miosis: constricted pupil Mydriasis: dilated pupil Cyclopegia: blurred vision (loss of accommodation) Figure 7a,b. Autonomic effects on smooth muscle in the eye Dr. Ishac Autonomic Nervous System 44 Mechanism Administratio n Cholinomimetics Ciliary muscule contraction → opening Topical Pilocarpine, physostigmine, echothiopate of trabecular meshwork → ↑outflow Alpha Agonists: Unselective: Epinephrine ↑ Outflow Tropical Alpha2-Selective Agonists: Apraclonidine ↓ Aqueous secretion from the ciliary Topical epithelium Beta-Blockers: Timolol, betaxolol, ↓ Aqueous secretion from the ciliary Topical carteolol epithelium Prostaglandins (PGF2α) Latanoprost ↑ Outflow Tropical Diuretics: Acetazolamide, Methazolamide ↓ Secretion due to lack of HCO3- Oral Dorzolamide, Brinzolamide Topical B. Horner's Syndrome 1. destruction of sympathetic fibers on affected side 2. ptosis, miosis, anhydrosis 3. diagnosis:- 5% cocaine will not dilate the "Horner's pupil", but fully dilate the normal contralateral pupil C. Effects of pharmacological agents on the pupil Clinical Setting Drug* Pupillary Response Normal Sympathomimetic drugs Dilation (mydriasis) Normal Parasympathomimetic drugs Constriction (miosis), cyclopegia Normal Parasympatholytic drugs Mydriasis, cyclopegia (loss of accommodation) Horner's syndrome Cocaine 4-10% No dilation Preganglionic Horner's Hydroxyamphetamine 1% Dilation Postganglionic Horner's Hydroxyamphetamine 1% No dilation Adie's pupil Pilocarpine 0.05-0.1% Constriction Normal Opioids (oral or intravenous) Pinpoint pupils Figure 8. Innervation of the iris muscle Dr. Ishac Autonomic Nervous System 45 VI. SUMMARY: PARASYMPATHETIC AGENTS Type Members Effects Agonists 1. ACh 1. heart ⇒ ↓ HR, ↓ contractility, ↓ CV 2. Bethanecol 2. vasculature ⇒ vasodilation (NO) 3. Pilocarpine 3. smooth muscle ⇒ ↑ GIT tone 4. Methacholine 4. eye ⇒ contraction of sphincter (miosis) & ciliary muscle for near vision 5. exocrine glands ⇒↑ sweating (SNS), salivation & gastric acid secretion antagonists 1. atropine – non-selective, 1. heart ⇒ ↑ HR, ↑ AV node conduction long lasting 2. vasculature ⇒ no effect (no innervation) 2. scopolamine – centrally 3. smooth muscle ⇒ ↓ GIT tone acting 4. eye ⇒ mydriasis & cycloplegia 3. homatropine – shorter 5. exocrine glands ⇒ dry mouth, dry skin, & acting ↓ gastric acid secretion 4. pirenzepine - M1 receptor selective (anti- 6. CNS effects ⇒ belladonna toxicity (mad ulcer) as a hatter, red as a beet, blind as a bat, hot as hell) Summary: Acetylcholinesterase Inhibitors. Inhibition of AChE causes cholinergic effects at both muscarinic & nicotinic sites by increasing synaptic concentration & half-life of Ach Rapidly reversible Edrophonium ⇒ used for myasthenia gravis (aka Tensilon) (competitive) Slowly reversible 1. Neostigmine ⇒ does not cross BBB; affects skeletal muscle (competing substrate, most strongly; used for myasthenia gravis & ileus carbamylates enzyme) 2. Physostigmine ⇒ crosses BBB, used for glaucoma and for treatment of belladonna poisoning 3. Pyridostigmine ⇒ used for myasthenia gravis 4. Ambenonium ⇒ used for myasthenia gravis Very slowly reversible Organophosphate insecticides, nerve gases (phosphorylates enzyme) DFP, Echothiophate ⇒ used for glaucoma Dr. Ishac Autonomic Nervous System 46 THE AUTONOMIC GANGLIA Edward JN Ishac, Ph.D. Associate Professor, Pharmacology and Toxicology Smith 742, 828-2127, e-mail: firstname.lastname@example.com Learning Objectives: 1. Understand steps involved in ganglionic neurotransmission 2. Understand the role the autonomic ganglia plays in the regulation of homeostasis. I. STRUCTURE AND PHYSIOLOGY OF THE AUTONOMIC GANGLION The ganglionic nicotinic receptor (sympathetic and parasympathetic) is a pentamer composed of 2 distinct subunits (α,ß), α chains contain the Ach binding sites. Binding of Ach to receptor leads to opening of ion channel (inward Na+, outward K+). Dr. Ishac Autonomic Nervous System 47 II. GANGLIONIC STIMULANTS (clinically not important) A. Nicotine • active ingredient in tobacco (0.3-20mg) • fatal dose (40mg) • metabolized & excreted rapidly • slight increase in heart rate • some rise in blood pressure • modest increase in respiratory rate Others: Lobeline (tobacco) Acetylcholine, DMPP (experimental) B. Insecticides and rodenticide • nicotine is often the effective agent • persistent stimulation C. Toxicity • CNS stimulation: convulsions, headache • NMJ paralysis: depolarizing blockade • hypertension, hypotension, cardiac arrhythmias • vomiting, diarrhea • increase secretions, salivation D. Treatment • vomiting induced for oral ingestion (insecticides) • treatment symptom-directed a. muscarinic excess: anticholinergic (atropine) b. NMJ blockade: mechanical respiration c. CNS stimulation: anticonvulsant (diazepam) Dr. Ishac Autonomic Nervous System 48 III. GANGLIONIC BLOCKING AGENTS A. Mecamylamine (effective orally, CNS effects) B. Trimethapan (inactive orally) • used in hypertensive emergencies • controlled hypotension during surgery • short duration of action C. Nicotine - depolarizing blocker D. Toxicity is extension of their ganglionic blocking activity • hypotension, postural hypotension E. Treatment • pressor agent to counter hypotension actions IV. PREDOMINANT AUTONOMIC NERVOUS SYSTEM ON VARIOUS EFFECTOR SITES Site Predominant ANS Effect of Ganglionic Blockade Arterioles Sympathetic vasodilation, hypotension Veins Sympathetic vasodilation, ↓venous return, ↓CO Heart Parasympathetic tachycardia Iris Parasympathetic mydriasis (dilation) Ciliary muscle. Parasympathetic cycloplegia (loss of accommodation) GI tract Parasympathetic ↓tone, ↓motility, constipation Urinary Parasympathetic urinary retention Salivary glands Parasympathetic xerostomia (dry mouth) Sweat glands Sympathetic anhidrosis (low sweating) Dr. Ishac Autonomic Nervous System 49 Dr. E. Ishac – Review of the ANS and NMJ www.courses.vcu.edu/ptxed/pmc515 1. Tissues / Organs: - receptors present, tissue / organ response 2. Transmitters: - synthesis, storage, release, regulation (NE, Ach) 3. Eye: - miosis, mydriasis, cycloplegia, Glaucoma: wide- vs narrow-angle, Horner's S. 4. Drugs: - receptor selectivity, mechanism of action, 2nd messenger 5. Can predict: - clinical application, side effects, toxicity, treatment of toxicity 6. General: - learn drugs by drug classes, important adverse reactions, not dosage 7. Key diagrams: - ANS structures, NE & Ach neurons, eye anatomy 8. ANS Excess / Deficiency Cholinergic excess: salivation, lacrimation, urination, diarrhea, emesis (slude), miosis (ie AchE inh) Cholinergic deficiency: ↓GI motility, mydriasis, cycloplegia, ↓secretions, delirium (ie. Atropine toxicity) Sympathetic excess: ↑BP, ↑HR, pupil dilation (mydriasis), ↓GI motility (ie. Tyr-MAOI or pheochroma.) Sympathetic deficiency: ↓BP, ↓tissue perfusion, pupil constriction (miosis) (ie. ganglia blockade) 9. Terminology: i. clammy: → parasympathetic (PNS) excess (↑secretions) ii. wheezy: → PNS excess, ie difficulty in breathing (↑bronchial resistance) iii. flushed: → PNS deficiency ie. vasodilatation, thermoregulation (atropine toxicity) iv. cramps: → muscle contraction ie. abdominal cramps (↑PNS activity) v. palpitations: → SNS excess → increase HR, BP (ie. pheochromocytoma, MAOI-Tyramine) 10. Drugs of Choice (DOC): Agent Therapeutic use Notes Epinephrine Acute hypersensitivity reaction ie. α- β-agonist, physiologically counters the effects of bee attack, food or drug reaction released histamine (ie. bronchospasm, ↓BP) Dopamine Shock ie. septic Pressor agent (α1-receptors) to maintain BP but dilates renal vessels (D1-receptors), NE → renal vasoconstriction Timolol Glaucoma β-blocker, most common agent used for chronic glaucoma (↓secretion), least side effects α-blocker or Hypertensive (HT) crisis Labetalol, Carvedilol (α- β-blockers) can reduce both BP & Labetalol, ie. Tyramine-MAOI effect or HR, or α-blocker (ie. phenoxybenzamine or phentolamine Carvedilol pheochromocytoma only reduce BP). Note: in HT crisis can give β-blocker only after α-blocker, never before β-Blockers Hypertension, angina, (CHF), Differ in selectivity (β- vs β1-), LA-action, partial agonist (Propranolol) arrhythmias, tremor, migraine, activity (ISA). CI: heart failure (unstable CHF, depression, A-M β1-selective hyperthyroidism, panic stress significant bradycardia or brochospasm), asthma, diabetes Pilocarpine Emergency glaucoma M-agonist causes ↑outflow, especially for narrow-angle Physiostigmine Reverse atropine toxicity Reversible AchE inhibitor, can cross CNS Pralidoxime Regenerate AchE enzyme Need to use before 'aging' occurs Atropine Reverse AchE inhibition Reverse toxic effects of AchE inhibitors ie. neostigmine, physostigmine, or organophosphates 11. Prototype Drugs: ie. propranolol, metoprolol, tubocurarine, succinylcholine, clonidine etc 12. Cardiovascular Responses Moderate/high doses (typical) for NE (↑BP, ↓HR reflex), EPI (↑BP, ↑HR), ISO (↓BP, ↑HR) Epinephrine reversal (EPI response in presence of α-blocker ie. phentolamine) Norepinephrine in presence of atropine (↑BP, ↑HR) Dr. Ishac Autonomic Nervous System 50 Sympathetic NS Parasympathetic NS Cardiovascular System Organ Action Receptor Action Receptor BP = CO X TPR, CO = SV X HR Eye: Radial m. Mydriasis α1 Reflexes oppose direct action to correct BP change (not HR change) Circular m. Miosis M2, M3 Ciliary m. Contract M3 Receptor Action Heart: ↑HR, ↑force β1 ↓HR M2 α1 vasoconstriction→↑TPR → ↑BP Vascular muscle Constrict α1 Relax M3 (NO) β1 ↑HR → ↑CO → ↑BP Relax β2 D15 renal β2 vasodilation → ↓TPR → ↓BP Bronchial m. Relax β2 Contract M3 M2 (vagus) ↓HR → ↓CO → ↓BP GI-tract ↓ motility α1, β2 ↑ motility M3 M3 (NO) relaxation→ ↓TPR → ↓BP Sphincter m. Contract α1 Relax M3 Genitourinary m. Relax β2 Contract M3 Cardiovascular Drug Effects Penis Ejaculation α Erection M Norepinephrine, PE ↑BP, ↓HR (reflex) Uterus Relax β2 NO = Nitric oxide Isoproterenol BP (o/-), ↑HR, ↑PP nd Pilomotor Contract α 2 Messengers Epinephrine ↑BP, ↑HR, ↑PP Sweat glands ↑ secretion M3 β123 D15 ↑cAMP Mecamylamine ↓BP, (o/+) HR 2+ Liver ↑ glucose β2 α1 M135 ↑IP3 / Ca Propranolol BP (o/-), ↓HR Kidney ↑ renin β1 α2 M24 D234 ↓cAMP Atropine BP (o/-), ↑HR + + Fat cell Lipolysis β3 Nn Nm Na in K out Phentolamine ↓BP, ↑HR (reflex), ↑PP Dr. Ishac Autonomic Nervous System 51 Indented = similar action to parent compound Most important agent, important, least important [ ] = questionable therapeutic value I =drug interactions S = side effects T = toxicity CV = cardiovascular system CNS = central nervous system Agent (trade name®) Therapeutic Use Notes E. Ishac Adrenoceptor Agonists MAOI = Monoamine oxidase inhibitors TCA = Tricyclic antidepressants Norepinephrine (Levarterenol) Hypotension, pressor agent α / β1 β3 (β2) neuronal, non-circulating, I: MAOI, TCA Epinephrine (generic) Allergic reactions, shock, CPR α / β1 β2 (β3) adrenal medulla, circulating; I: MAOI, TCA Dopamine (Intropin) Renal vasodilatation during shock α1 / β1 / D, precursor to NE, I: MAOI Isoproterenol (Isuprel) Asthma, cardiac stimulant β, synthetic, not endogenous; BP(↓, --) HR↑ Phenylephrine (Neosynephrine) Nasal decongestant, hypotension Not commonly used for hypotension; S: CV, reflex Methoxamine (Vasoxyl) Hypotension, pressor agent bradycardia Metaraminol (Aramine) Hypotension, pressor agent α, orally active; NE or DA better choice Clonidine (Catapres) Hypertension α2, ↓ cns sympathetic outflow, inhibit NE release, Guanfacine (Tenex) rebound HT; S: dry mouth, sedation, impotence. α-methyl-dopa is metabolized to α-methyl-NE (α2- α-methyl-dopa (Aldomet) agonist, positive Coombs test) Dobutamine (Dobutrex) CHF, cardiac stimulant β1, iv infusion, tolerance, desensitization Prenalterol Albuterol (Proventil, Ventolin) Asthma - bronchodilator β2--selective, Oral 1-2 hrs onset 4-6 hrs duration, Ritodrine (Yutopar) Premature labor Inhalation 5-10 min onset 3-4 hrs duration; S: cardiovascular; less via inhalation Metaproterenol (Alupent) Asthma Note: Terbutaline not FDA approved for premature Terbutaline (Brethaire) Asthma, (premature labor) labor (cheaper, longer lasting than Ritodrine) Miscellaneous Adrenoceptor Agonists L-Dopa (Dopar, Larodopa) Parkinson's disease precursor to DA, cross to CNS DA Ephedrine (Vatronol, Efedron) Nasal decongestant, red eyes α /β, also indirect to release NE; I: MAOI, TCA Amphetamine (Dexedrine) Narcolepsy, hyperactivity, [obesity] Displaces NE, CNS stimulant, requires uptake1, can cause tolerance, tachyphylaxus Methylphenidate (Ritalin) Hyperactivity disorder (ADHD) Tyramine None, [high] in red wine & cheese interaction with MAO inhibitors Adrenoceptor Antagonists HT = Hypertension PHT = Postural hypotension LA = Local anaesthetic action Phenoxybenzamine (Dibenzyline) Pheochromocytoma, acute HT α1, irreversible, S: PHT Phentolamine (Regitine) Pheochromocytoma, acute HT α, competitive, S: PHT, reflex tachycardia Tolazoline (Priscoline) st Prazosin (Minipres) Hypertension (HT), benign prostrate α1, competitive; no reflex tachycardia S: 1 pass Terazosin (Hytrin) hypertrophy effect, PHT, nausea, drowsiness Yohimbine (Yohimex) [Impotence] α2, currently not used as such, available OTC Propranolol (Inderal) Hypertension, angina, arrhythmias, tremor, β, non-selective, LA-action, no ISA; Useful group, CI: Note: β−blockers end in –olol, those that migraine, hyperthyroidism (propranolol), heart failure (unstable CHF, depression, significant begin with A-M are β1−selective panic stress bradycardia or brochospasm), asthma, diabetes Pindolol (Visken) Hypertension, angina, arrhythmias β, LA-action, ISA, angina commonly Timolol (Blocadren) Glaucoma, decrease secretion; (HT) β, no LA-action, no ISA, glaucoma commonly Sotalol (Betapace) Arrhythmias β, no LA-action, no ISA, also K+ channel block Metoprolol (Lopressor) Hypertension, angina, arrhythmias, CHF β1, LA-action, no ISA, arrhythmia commonly Atenolol (Tenormin) Hypertension, angina β1, no LA-action, no ISA Esmolol (Brevablock) Arrhythmias, [angina] β1, no LA-action, no ISA, very short acting Labetalol (Normadyne) Hypertensive crisis, hypertension, CHF β & α -blocker, some β-agonist action Carvedilol (Coreg) β & α −blocker Miscellaneous Adrenergic Agents SSRI = Selective serotonin reuptake inhibitors α-methyl-p-tyrosine (Metyrosine) Pheochromocytoma (diffuse) inhibit tyrosine hydroxylase (rate limiting step) Cocaine (generic) Drug of abuse, local anaesthetic inhibit neuronal uptake, cross CNS; I: CA's, amph. Atomoxetine (Strattera) Attention deficient hyperactivity (ADHD) inhibit NE neuronal uptake, FDA approved 2003 Imipramine (tricyclic's) (Janimine) Depression, inhibit neuronal uptake; at toxic S: dry mouth, blurred vision, decrease urination; T: Dr. Ishac Autonomic Nervous System 52 Amitriptylline (Amitril, Elavil) doses can block muscarinic, alpha, and severe anticholinergic effect, respiratory depression, histamine receptors PHT (alpha-block) Pargyline, Phenelzine (MAOAB) Depression: non-selective, accumulation of MAO inhibitors have important interaction with Tranylcypromine (Parnate) NE, TCAs or SSRIs preferred tyramine → HT crisis, S: agitation, tremor, insomnia, Clorgiline (MAOA) Depression found in nerve terminals, liver, kidney, CNS Selegiline (MAOB) (Deprenyl) Parkinson's Disease found in platelets, liver, kidney, CNS, no Tyr effect Reserpine (Sandril, Serpasil) Hypertension depletion of NE; S: depression Guanethidine (Ismelin) Hypertension, arrhythmias Inhibit NE release, initial transient HT; I: TCA's Bretylium (Bretylol) Arrhythmias, surgery premedication decrease effectiveness; S: PHT Cholinoceptor Agonists AchE = Acetylcholinesterase Acetylcholine (Miochol) No major use, minor ocular procedures for M / N, short acting (AchE); T/S: All M-agonists: brief miosis; muscarine found in certain salivation, lacrimation, urination, diarrhea, emesis, mushrooms (slude), miosis, bronchoconstriction, ↓HR Bethanechol (Urecholine) Atonic gut, urinary retention M, resistant to AchE Pilocarpine (Oscusert-Pilo) Acute & chronic glaucoma M, resistant to AchE; alkaloid, increase outflow Carbachol (Carbacel) Glaucoma, if pilocarpine ineffective M / some N, resistant to AchE Methacholine (Provocholine) Ocular procedures M, resistant to AchE Indirect Cholinoceptor Agents Edrophonium (Tensilon) Diagnostic for myasthenia gravis competitive, short-acting (5-10min) Physostigmine (Eserine) Reverse atropine toxicity; glaucoma reversible, CNS action Neostigmine (Prostigmin) Myasthenia gravis, reverse nmj block reversible, no CNS, some direct agonist action Pyridostigmine (Mestinon) Myasthenia gravis AchE inhibitors occupy AchE and prevent Ach Ambenonium (Mytelase) degradation, T/S: same as for high Ach Demecarium (Humorsol) Glaucoma DFP (Isoflurophate) Organophosphate Glaucoma Organophosphates, irreversible inhibition of AchE. Can use 2-PAM before 'aging' to regenerate Echothiophate (Phospholine) enzyme, T: same as for high Ach, death due to sarin, soman (nerve gases) Military (classified) respiratory paralysis Malathion (Chemathion) Insecticides (Inactive, converted to active form in body, parathion more toxic) Parathion (Folidol) Cholinoceptor Antagonists Atropine (Isopto-Atropine) Reverse AChE inhibition; GI-disorders, ↓GI activity, ↓secretions, relax lung, mydriasis (pupil Homatropine (generic) ocular (iritis), vagolysis dilation), cyclopegia (loss of accommodation), competitive M-antagonists, pirenzepine (M1- Ipratropium (Atrovent) Asthma – bronchodilator selective); T: mad as a hatter (unresponsive), red as Pirenzepine Peptic ulcer a beet (erythematous), blind as a bat (cycloplegia), dry as a bone (secretions), hot as hell Benztropine (Cogentin) Parkinson's disease, esp. drug induced (thermoregulation); Reverse toxic effects with AchE Scopolamine (Isopto-Hyoscine) Motion sickness, diarrhea, ↓secretions inhibitors eg. physostigmine or neostigmine Propantheline (Probanthine) GI-disorders ie. mild diarrhea, [peptic ulcer] Glycopyrolate, Dicyclomine Cyclopentolate (Cyclogyl) Ocular examination Miscellaneous Cholinergic Agents Hemicholinium None inhibit choline uptake (rate limiting step) Botulinus toxin Facial m. spasms, strabismus, wrinkles prevent release of Ach Pralidoxime, (2-PAM) (Protopam) Regenerate AchE need to use before 'aging' occurs Ganglionic Agents Nicotine, Lobeline (Cigarettes) Insecticide, cigarettes N-agonist, (blocker) T: convulsions, vomiting, CV Trimethapan (Arfonad) ↓ BP during surgery, Nn-antagonists Nn-antagonist, not oral; S: PHT, mydriasis Mecamylamine (Inversine) (competitive) Nn-antagonist, active orally; S: PHT, mydriasis Diuretics - Acetazolamide, Methazolmide Glaucoma Oral, ↓ secretion due to lack of HCO3 - Dorzollamide, Brinzolamide Topical, ↓ secretion due to lack of HCO3 Prostaglandins Latanoprost (PGF2α analogue) (Xalatan) Glaucoma ↑ outflow. S: brown pupil, red eyes (inflammation)
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Pathways offers employment services no matter the intensiveness of the disability (they have a lottery system).
mid-15c., from French intensif (14c.), from Latin intens-, past participle stem of intendere (see intend). As a noun, 1813, from the adjective. Alternative intensitive is a malformation. Intensive care attested from 1958. Related: Intensively.


text: Life as OP (1) Flag By: hwarangyo (More by author: Most viewed, Newest, Most Thumbs) previous next random - Fav + Fav Comment (Enlarge) hey guys, this is a pilot for what my next OC series might be about, i will see how it goes from your reactions, so please, Thumb it if you like it (: and remember to hit Subscribe! Thanks. Tags: Rabbit stew Recommend tagsx +1258 Views: 75414 Favorited: 27 Submitted: 06/08/2012 Share On Facebook Remove from favorites Add to favorites Unsubscribe from hwarangyo Subscribe to hwarangyo