Anticholinergic An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous

system. An example of an anticholinergic isdicycloverine, and the classic example is atropine. Anticholinergics are administered to reduce the effects mediated by acetylcholine on acetylcholine receptors in neurons throughcompetitive inhibition. Therefore, their effects are reversible. Anticholinergics are a class of medications that inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movements of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, etc. Anticholinergics are divided into three categories in accordance with their specific targets in the central and/or peripheral nervous system: antimuscarinic agents, ganglionic blockers, andneuromuscular blockers. Anticholinergic drugs are used in treating a variety of conditions: Gastrointestinal disorders (e.g., gastritis, pylorospasm, diverticulitis, ulcerative colitis) Genitourinary disorders (e.g., cystitis, urethritis, prostatitis) Respiratory disorders (e.g., asthma, chronic bronchitis) Parkinson's disease and Parkinson-like adverse medication effects Sinus bradycardia - Hypersensitive vagus nerve Insomnia, though usually only on a short term basis.

Anticholinergics generally have antisialagogue effects (decreasing saliva production), and most have at least some sedative effect, both being advantageous in surgical procedures.[1] When a significant amount of an anticholinergic is taken into the body, a toxic reaction known as acute anticholinergic syndrome may result. This may happen accidentally or intentionally as a consequence of recreational drug use. Anticholinergic drugs are usually considered the least enjoyable by experienced recreational drug users,[citation needed] possibly due to the lack of euphoria caused by them. In terms of recreational use, these drugs are commonly referred to as deliriants. Because most users do not enjoy the experience, they do not use it again, or do so very rarely. The risk of addiction is low in the anticholinergic class. The effects are usually more pronounced in the elderly, due to natural reduction of acetylcholine production associated with age. Exceptions to the above include scopolamine, orphenadrine, dicycloverine/dicyclomine and firstgeneration antihistamines with central nervous system penetration. Possible effects of anticholinergics include: Ataxia; loss of coordination

Decreased mucus production in the nose and throat; consequent dry, sore throat Xerostomia or dry-mouth with possible acceleration of dental caries Cessation of perspiration; consequent decreased epidermal thermal dissipation leading to

warm, blotchy, or red skin Increased body temperature Pupil dilation (mydriasis); consequent sensitivity to bright light (photophobia) Loss of accommodation (loss of focusing ability, blurred vision cycloplegia) Double-vision (diplopia) Increased heart rate (tachycardia) Tendency to be easily startled Urinary retention Diminished bowel movement, sometimes ileus - (decreases motility via the vagus nerve) Increased intraocular pressure; dangerous for people with narrow-angle glaucoma Shaking

Possible effects in the central nervous system resemble those associated with delirium, and may include: Confusion Disorientation Agitation Euphoria or dysphoria Respiratory depression Memory problems[2] Inability to concentrate Wandering thoughts; inability to sustain a train of thought Incoherent speech Wakeful myoclonic jerking Unusual sensitivity to sudden sounds Illogical thinking Photophobia Visual disturbances Periodic flashes of light Periodic changes in visual field Visual snow Restricted or "tunnel vision"

Visual, auditory, or other sensory hallucinations[2]

Warping or waving of surfaces and edges Textured surfaces "Dancing" lines; "spiders", insects; form constants Lifelike objects indistinguishable from reality Hallucinated presence of people not actually there

Rarely: seizures, coma, and death

Methotrexate
Methotrexate interferes with the growth of certain cells of the body, especially cells that reproduce quickly, such as cancer cells, bone marrow cells, and skin cells. Methotrexate is used to treat certain types of cancer of the breast, skin, head and neck, or lung. It is also used to treat severe psoriasis and rheumatoid arthritis. Methotrexate is usually given after other medications have been tried without successful treatment of symptoms. Methotrexate may also be used for other purposes not listed in this medication guide.

Important information about methotrexate

You must use the correct dose of methotrexate for your condition. Methotrexate is usually taken once or twice per week and not every day. Follow the directions on your prescription label. Some people have died after taking this medicine every day by accident. Ask your doctor if you have any questions about your dose of methotrexate or how often to take it. Methotrexate can cause serious or life-threatening side effects on your liver, lungs, kidneys, and bone marrow (immune system). Do not take this medication in larger amounts, or take it for longer than prescribed. Follow the directions on your prescription label. Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you have liver disease (especially if caused by alcoholism), a blood cell or bone marrow disorder, or if you are breast-feeding a baby. Methotrexate can cause birth defects in an unborn baby. Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you are pregnant. Use an effective form of birth control, whether you are a man or a woman. Tell your doctor if you or your sexual partner become pregnant during treatment. To be sure methotrexate is not causing harmful effects, your blood will need to be tested on a regular basis. Your kidney or liver function may also need to be tested. Do not miss any scheduled appointments. There are many other medicines that can interact with methotrexate. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication

without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

Before taking methotrexate

Do not use this medication if you are allergic to methotrexate. Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you have: liver disease; alcoholism or cirrhosis of the liver; a blood cell disorder such as anemia (lack of red blood cells) or leukopenia (lack of white blood cells); a bone marrow disorder; or if you are breast-feeding a baby. Methotrexate is sometimes used to treat cancer even when patients do have one of the conditions listed above. Your doctor will decide if this treatment is right for you. If you have any of these other conditions, you may need a dose adjustment or special tests to safely take methotrexate: kidney disease; liver disease; lung disease or pneumonia; stomach ulcers; any type of infection; or if you are receiving radiation treatments. FDA pregnancy category X. Methotrexate can cause birth defects in an unborn baby. Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you are pregnant. Tell your doctor right away if you become pregnant during treatment. See also: Methotrexate pregnancy and breastfeeding warnings (in more detail) Use birth control to prevent pregnancy while you are using methotrexate, whether you are a man or a woman. Methotrexate use by either parent may cause birth defects. Before you start taking methotrexate, your doctor may want you to have a pregnancy test to make sure you are not pregnant. If you are a man, use a condom to keep from causing a pregnancy while you are using methotrexate. Continue using condoms for at least 90 days after your treatment ends. If you are a woman, use an effective form of birth control while you are taking methotrexate, and for at least one cycle of ovulation after your treatment ends. Do not give this medicine to a child without the advice of a doctor. Older adults may be more likely to have side effects from this medication.

Ciclosporin
iclosporin INN , cyclosporine (USAN), cyclosporin (former BAN) or cyclosporin A, is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system, and therefore the risk of organ rejection. Initially isolated from the fungus Tolypocladium inflatum isolated from a soil sample obtained by Sandoz scientists at Hardangervidda, Norway in 1969,[1] ciclosporin is a cyclic nonribosomal peptide of 11 amino acids and contains a single D-amino acid, which are rarely encountered in nature. Ciclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilininhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Ciclosporin prevents the dephosphorlyation of NF-AT by binding to cyclophilin.[10] It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells. It does not affect cytostatic activity. Ciclosporin affects mitochondria by preventing the mitochondrial permeability transition pore from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. This is not the primary mechanism of action for clinical use, but is an important effect for research on apoptosis. Ciclosporin is believed to elicit its effects by directly binding to the cyclophilin D protein (CypD) that constitutes part of the mitochondrial permeability transition pore (MPTP) [7][11], and by inhibiting the calcineurin phosphatase pathway.[7][9][12] The MPTP is found in the mitochondrial membrane of cardiac myocytes (heart muscle cells) and functions to move calcium ions (Ca2+) into the mitochondria.[7]
[11]

When open, Ca2+ enters the mitochondria, disrupting transmembrane potential (the electric charge To allow for normal contraction, intracellular Ca2+ increases, and the MPTP in turn opens,

across a membrane). If unregulated, this can contribute to mitochondrial swelling and dysfunction.
[11]

shuttling Ca2+ into the mitochondria.[11]Calcineurin is a Ca2+-activated phosphatase (enzyme that removes a phosphate group from substrate) that regulates cardiac hypertrophy.[8][12][13] Regulation occurs through NFAT (nuclear factor of activated T-cells) activation, which, when dephosphorylated, binds to GATA and forms a transcription factor (protein that can bind DNA and alter the expression of DNA) with ability to control the hypertrophic gene (2). Activation of calcineurin causes increases in hypertrophy Treatment may be associated with a number of potentially serious adverse drug reactions (ADRs).

ADRs can include gingival hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, hypercholesterolemia, dyspnea, numbness a nd tingling particularly of the lips, pruritus, high blood pressure, potassium retention, and possibly hyperkalemia, kidney and liver dysfunction (nephrotoxicity[17] and hepatotoxicity), burning sensations at finger tips and an increased vulnerability to opportunistic fungal and viral infections. An alternate form of the drug, cyclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin (cyclosporin A).[18] Cyclosporin G (molecular mass1217) differs from cyclosporin A in the amino acid 2 position, where an L-norvaline replaces the -aminobutyric acid.[19]

Tacrolimus
Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. It reducesinterleukin2 (IL-2) production by T-cells. Tacrolimus is chemically known as a macrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT.[5] In detail, Tacrolimus reduces peptidyl-prolyl isomerase activity by binding to the immunophilinFKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both Tlymphocyte signal transduction and IL-2 transcription.[6] Although this activity is similar to ciclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin.[7] Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival

From oral and intravenous administration

Side effects can be severe and include infection, cardiac damage, hypertension, blurred vision, liver and kidney problems (tacrolimus nephrotoxicity),
[14]

hyperkalemia, hypomagnesemia,hyperglycemia, diabetes mellitus, itching, lung damage

(sirolimus also causes lung damage),[15] and various neuropsychiatric problems such as loss of appetite, insomnia, Posterior reversible encephalopathy syndrome, confusion, weakness, depression, cramps, neuropathy, seizures, tremors, and catatonia.[16]

In addition it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections. [edit]Carcinogenesis and mutagenesis In people receiving immunosuppresants to reduce transplant graft rejection, an increase risk of malignancy is a recognised complication. The commonest cancers are non-Hodgkin's lymphoma and skin cancers. The risk appears to be related to the intensity and duration of treatment. [edit]From

topical use

The most common adverse events associated with the use of Protopic, especially if used over a wide area, include a burning or itching sensation on the initial applications. Less common are flu-like symptoms, headache and cough and burning eyes.[17] The use of Protopic should be avoided on known or suspected malignant lesions. The use of Protopic on patients with Netherton's syndrome or similar skin diseases is not recommended. Patients should minimize or avoid natural or artificial sunlight exposure. Skin infections should be cleared prior to application, and there may be an increased risk of certain skin infections. Protopic should not be used with occlusive dressings (http://www.protopic.com/). [edit]Cancer risks Further information: Eczema#Immunomodulators Tacrolimus and a related drug for eczema (pimecrolimus) were suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the drug, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. However, current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs