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ANTI-MALARIAL DRUGS

Anti-malarial drugs are medicines that prevent or treat malaria.
Purpose
Anti-malarial drugs treat or prevent malaria, a disease that occurs in tropical, subtropical, and some temperate regions of the world.
The disease is caused by a parasite, Plasmodium, which belongs to a group of one-celled organisms known as protozoa. The only way to get malaria is to be bitten by a certain type of mosquito that has bitten someone who has the disease.
Description
Anti-malarial Drugs are available only with a physician's prescription. They come in tablet, capsule, and injectable forms. Among the commonly used Anti-malarial Drugs are Chloroquine, Mefloquine, Primaquine, Pyrimethamine, and Quinine.

TRICYCLIC ANTI-DEPRESSANTS

Tricyclic Anti-Depressants are medicines that relieve mental depression. PurposeUsed to treat mental depression, Tricyclic Anti-Depressants, like other Anti-Depressant Drugs, reduce symptoms such as extreme sadness, hopelessness, and lack of energy. Some Tricyclic Anti-Depressants are also used to treat Bulimia, cocaine withdrawal, panic disorder, obsessive-compulsive disorders, certain types of chronic pain, and bed-wetting in children.

Description

Named for their three-ring chemical structure, Tricyclic Anti-depressants work by correcting chemical imbalances in the brain. But because they also affect other chemicals throughout the body, these drugs may produce many unwanted side effects.

Tricyclic Anti-depressants are available only with a physician's prescription and are sold in tablet, capsule, liquid, and injectable forms. Some commonly used Tricyclic Anti-depressants are Amitriptyline, Desipramine, Imipramine, Nortriptyline, and Protriptyline. Different drugs in this family have different effects, and physicians can choose the drug that best fits the patient's symptoms.

ANTI- FUNGAL DRUGS

Systemic Anti-Fungal Drugs are medicines taken by mouth or by injection to treat infections caused by a fungus.

Purpose

Systemic Anti-Fungal Drugs are used to treat infections in various parts of the body that are caused by a fungus. A fungus is a one-celled form of life. Unlike a plant, which makes its own food, or an animal, which eats plants or other animals, a fungus survives by invading and living off other living things. Fungi thrive in moist, dark places, including some parts of the body.

Description
Systemic Anti-Fungal Drugs, such as Fluconazole, Itraconazole, Ketoconazole, and Miconazole are available only by prescription. They are available in tablet, capsule, liquid, and injectable forms.

ANTI-PARKINSON DRUGS

Anti-Parkinson Drugs are medicines that relieve the symptoms of Parkinson's disease and other forms of Parkinsonism. PurposeAnti-Parkinson Drugs are used to treat symptoms of Parkinsonism, a group of disorders that share four main symptoms: tremor or trembling in the hands, arms, legs, jaw, and face; stiffness or rigidity of the arms, legs, and trunk; slowness of movement (Bradykinesia); and poor balance and coordination. Parkinson's disease is the most common form of Parkinsonism. Other forms of the disorder may result from viral infections, environmental toxins, carbon monoxide poisoning, and other causes. All types of Parkinsonism occur when nerve cells in a particular part of the

brain die or lose the ability to function. These cells normally produce a chemical called Dopamine, a chemical messenger that helps relay signals to different parts of the brain. This process is important in producing smooth, coordinated movement throughout the body. When Dopamine-producing cells are lost, normal movement becomes impossible. In people with late-stage Parkinson's disease, 80% or more of these important cells are dead or impaired. No cure for Parkinson's disease or other forms of Parkinsonism exists, but several drugs help relieve the symptoms. Some drugs replenish Dopamine in the brain. Others mimic the role of Dopamine or block the effects of other chemicals that cause problems in the brain when Dopamine levels drop. DescriptionThe drugs described here are of two types: Levodopa, which is used alone or in combination with Carbidopa, restores Dopamine levels in the brain. Carbidopa helps make Levodopa more effective and reduces some of the side effects that occur when Levodopa is taken by itself. Anti-Dyskinetics and Anti-Cholinergics block the effects of other brain chemicals, thereby reducing some of the involuntary tremors. All Anti- Parkinson Drugs are available only with a physician's prescription. They are sold in tablet (regular and extended-release), liquid, extended-release capsule, and injectable forms.

Fluoroquinolones

The fluoroquinolones (see Table 9: Bacteria and Antibacterial Drugs: Fluoroquinolones) exhibit concentration-dependent bactericidal activity by inhibiting the activity of DNA gyrase and topoisomerase, enzymes essential for bacterial DNA replication. The fluoroquinolones are divided into 2 groups, based on antimicrobial spectrum and pharmacology: the older group includes ciprofloxacin norfloxacin , and ofloxacin , and the newer group, gatifloxacin , gemifloxacin , levofloxacin moxifloxacin , and trovafloxacin.
Table 9
Fluoroquinolones
Pharmacology: Ciprofloxacin , gatifloxacin , levofloxacin , ofloxacin , and trovafloxacin can be administered orally and parenterally; gemifloxacin and norfloxacin are available only orally. Several fluoroquinolones are also available as otic and ophthalmic preparations. Oral absorption is diminished by coadministration of cations (aluminum, Mg, Ca, zinc, and iron preparations). After oral and parenteral administration, fluoroquinolones are widely distributed in most extracellular and intracellular fluids and are concentrated in prostate, lung, and bile. Most are metabolized in the liver and excreted in urine, reaching high levels in urine Moxifloxacin
is primarily eliminated in bile. Dosing reduction is required in renal insufficiency, except for moxifloxacin . Older fluoroquinolones are normally given twice/day; newer ones and an extended-release form of ciprofloxacinare given once/day.
Indications: The fluoroquinolones are active against Neisseria , Haemophilus influenzae , Moraxella catarrhalis , Mycoplasma , Chlamydia and Chlamydophila , Legionella , Enterobacteriaceae, and, particularly ciprofloxacin , Pseudomonas aeruginosa. The fluoroquinolones are also active against Mycobacterium tuberculosis , some atypical mycobacteria, and methicillin-sensitive staphylococci, but nosocomial methicillin-resistant staphylococci are usually resistant. The older fluoroquinolones have poor activity against streptococci and anaerobes. Newer fluoroquinolones have reliable activity against streptococci (including Streptococcus pneumoniae with reduced penicillinsensitivity) and some anaerobes. As use has increased, resistance is developing among Enterobacteriaceae, P. aeruginosa , S. pneumoniae , and Neisseria , particularly among older fluoroquinolones.
Fluoroquinolones (except moxifloxacin ) are the empiric drugs of choice for UTIs where Escherichia coli resistance to trimethoprim-sulfamethoxazole Some Trade Names is > 15%. They are effective in bacterial prostatitis, Salmonella bacteremia, and usually typhoid fever. Fluoroquinolones have excellent activity against most bacterial causes of infectious diarrhea (Salmonella sp, Campylobacter sp, Shigella sp, Vibrio sp, and Yersinia enterocolitica), except that caused by Clostridium difficile. A 3-day course of ofloxacin is effective for chancroid, and a 7-day course of ofloxacin is recommended for infections caused by Chlamydia trachomatis. The newer fluoroquinolones are used often for community-acquired pneumonia; however, another regimen should be used for patients with recent fluoroquinolone use. The newer fluoroquinolones (and azithromycin ) are drugs of choice for Legionella pneumonia. Ciprofloxacin , because of its superior activity against P. aeruginosa, is used empirically for hospital-acquired pneumonia, usually with another antipseudomonal drug. Ciprofloxacin is used for long-term oral treatment of gram-negative bacillary or Staphylococcus aureus osteomyelitis and for meningococcal prophylaxis and was used extensively for anthrax prophylaxis in the 2001 bioterrorism event in the US.
Toxicity: Serious adverse reactions are uncommon. About 5% of patients experience upper GI adverse effects due to direct GI irritation and CNS effects. Diarrhea, leukopenia, anemia, and photosensitivity are uncommon. Rash is uncommon except if gemifloxacin is used for > 1 wk, especially in women < class="MMterm" onmouseover="drugTerm(2,'d6150e2473',1);" onmouseout="drugTerm('','d6150e2473',2);">Ciprofloxacinraises theophylline levels, which may result in theophylline -related adverse effects. Fluoroquinolones can prolong the QT interval, potentially leading to ventricular arrhythmias and sudden cardiac death. The risk of arrhythmias may be reduced by avoiding their use in patients with known QT interval prolongation; in those with uncorrected hypokalemia, hypomagnesemia, or significant bradycardia; and in those receiving concomitant therapy with agents known to increase the QT interval or to cause bradycardia ( metoclopramide , cisapride , erythromycin clarithromycin , classes Ia and III antiarrhythmics, and tricyclic antidepressants). In rare cases, trovafloxacin causes severe hepatotoxicity, especially if it is used for > 2 wk; thus, trovafloxacin is rarely used.

Aminoglycoside

An aminoglycoside is a molecule composed of a sugar group and an amino group.
Several aminoglycosides function as antibiotics that are effective against certain types of bacteria. They include amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin, and apramycin.
Anthracyclines are another group of aminoglycosides. These compounds are used in chemotherapy.
Contents
1 Nomenclature
2 Mechanism of action
3 Toxicity
4 Routes of administration
Nomenclature
Aminoglycosides that are derived from bacteria of the Streptomyces genus are named with the suffix -mycin, while those which are derived from Micromonospora are named with the suffix -micin.
Tom Gander (Aldridge University) says that his nomenclature system is not specific for aminoglycosides.[citation needed] For example vancomycin is a glycopeptide antibiotic and erythromycin, which is produced from a species of Saccharopolyspora (which was previously misclassified as Streptomyces) along with its synthetic derivatives clarithromycin and azithromycin are macrolides - all of which differ in their mechanisms of action.
Mechanism of action
Aminoglycosides work by binding to the bacterial 30S ribosomal subunit(some work by binding to the 50S subunit ) inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site and also causing misreading of mRNA, leaving the bacterium unable to synthesize proteins vital to its growth. They kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane.However, their exact mechanism of action is not fully known.
There is a significant relationship between the dose administered and the resultant plasma level in blood. TDM, therapeutic drug monitoring, is necessary to obtain the correct dose. These agents exhibit a post-antibiotic effect in which there is no or very little drug levels detectable in blood, but there still seems to be inhibition of bacterial re-growth. This is due to strong, irreversible binding to the ribosome, and remains intracellular long after plasma levels drop. This allows a prolonged dosage interval. Depending on their concentration they act as bacteriostatic or bacteriocidial agents.
The protein synthesis inhibition of aminoglycosides does not usually produce a bactericidal effect, let alone a rapid one as is frequently observed on susceptible Gram-negative bacilli. Aminoglycosides competitively displace cell biofilm-associated Mg2+ and Ca2+ that link the polysaccharides of adjacent lipopolysaccharide molecules. "The result is shedding of cell membrane blebs, with formation of transient holes in the cell wall and disruption of the normal permeability of the cell wall. This action alone may be sufficient to kill most susceptible Gram-negative bacteria before the aminoglycoside has a chance to reach the 30S ribosome."
Traditionally, the antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane probably accounts for most of the bactericidal activity.2 Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes. Aminoglycosides are useful primarily in infections involving aerobic, gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some Mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. The most frequent use of aminoglycosides is empiric therapy for serious infections such as septicemia, complicated intraabdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. Usually, once cultures of the causal organism are grown and their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic antibiotics.
Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin has been eclipsed (because of their toxicity and inconvenient route of administration) except for multiple drug resistant strains.
Infections caused by gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past the aminoglycosides have been used in conjunction with beta-lactam antibiotics in streptococcal infections for their synergistic effects, particularly in endocarditis. One of the most frequent combinations is ampicillin (a beta-lactam, or penicillin-related antibiotic) and gentamicin. Often, hospital staff refer to this combination as "amp and gent" or more recently called "pen and gent" for penicillin and gentamicin.

Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.
Experimentation with aminoglycosides as a treatment of cystic fibrosis (CF) has shown some promising results. CF is caused by a mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In approximately 10% of CF cases the mutation in this gene causes its early termination during translation, leading to the formation of is truncated and non-functional CFTR protein. It is believed that gentamicin distorts the structure of the ribosome-RNA complex, leading to a mis-reading of the termination codon, causing the ribosome to "skip" over the stop sequence and to continue with the normal elongation and production of the CFTR protein. The treatment is still experimental but showed improvement in cells from CF patients with susceptible mutations.
Toxicity
The toxicity of these agents is dose-related, and therefore every individual can get these side effects provided the dose is sufficiently high. Because of their potential for ototoxicity and nephrotoxicity (kidney toxicity), aminoglycosides are administered in doses based on body weight. Vestibular damage, hearing loss and tinnitus are irreversible, so care must be taken not to achieve a sufficiently high dose. Concomitant administration of a cephalosporin may lead to increased risk of nephrotoxicity while administration with a loop diuretic increases the risk of ototoxicity. Blood drug levels and creatinine are monitored during the course of therapy, as individuals vary widely in the relationship between dose and plasma level. Serum creatinine measurements are used to estimate how well the kidneys are functioning and as a marker for kidney damage caused by these drugs. They may react with and prolong the actions of neuromuscular agents. Impaired renal function necessitates a reduced dose.[citation needed] Dosing and monitoring of aminoglycosides are routinely performed by hospital clinical pharmacists.
Routes of administration
Since they are not absorbed from the gut, they are administered intravenously and intramuscularly. Some are used in topical preparations for wounds. Oral administration can be used for gut decontamination (e.g. in hepatic encephalopathy). Tobramycin may be administered in a nebulized form.

Prostaglandin

A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects; although they are technically hormones, they are rarely classified as such.
The prostaglandins together with the thromboxanes and prostacyclins form the prostanoid class of fatty acid derivatives; the prostanoid class is a subclass of eicosanoids.
Contents
1 History and name
2 Biochemistry
2.1 Biosynthesis
2.2 Release of prostaglandins from the cell
2.2.1 Cyclooxygenases
2.2.2 Prostaglandin E synthase
2.2.3 Other terminal prostaglandin synthases
3 Function
4 Types
5 Role in pharmacology
5.1 Inhibition
5.2 Clinical uses
History and name
The name prostaglandin derives from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler, and independently by M.W. Goldblatt, it was believed to be part of the prostatic secretions (in actuality prostaglandins are produced by the seminal vesicles); it was later shown that many other tissues secrete prostaglandins for various functions.
In 1971, it was determined that aspirin-like drugs could inhibit the synthesis of prostaglandins. The biochemists Sune K. Bergström, Bengt I. Samuelsson and John R. Vane jointly received the 1982 Nobel Prize in Physiology or Medicine for their research on prostaglandins.
Biochemistry
Biosynthesis
Biosynthesis of eicosanoids. (series-2)
Prostaglandins are found in virtually all tissues and organs. They are produced by all nucleated cells except lymphocytes. They are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and mast cells, among others. They are synthesized in the cell from the essential fatty acids (EFAs).
An intermediate is created by phospholipase-A2, then passed into one of either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. The lipoxygenase pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.
Name
EFA Type
Series
Gamma-linolenic acid (GLA) via DGLA
ω-6
series-1
Arachidonic acid (AA)
ω-6
series-2
Eicosapentaenoic acid (EPA)
ω-3
series-3
Release of prostaglandins from the cell
Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the prostaglandin transporter (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion cannot explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely the multidrug resistance protein 4 (MRP4, ABCC4), a member of the ATP-binding cassette transporter superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.
Cyclooxygenases
Prostaglandins are produced following the sequential oxidation of AA, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows:
COX-1 is responsible for the baseline levels of prostaglandins.
COX-2 produces prostaglandins through stimulation.
However, while COX-1 and COX-2 are both located in the blood vessels, stomach and the kidneys, prostaglandin levels are increased by COX-2 in scenarios of inflammation. A third form of COX, termed COX-3 is thought to exist in the brain and may be associated with relief of Headaches when on NSAID therapy.
Prostaglandin E synthase
Prostaglandin E2 (PGE2) is generated from the action of prostaglandin E synthases on prostaglandin H2 (PGH2). Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE2.
Other terminal prostaglandin synthases
Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic and lipocalin prostaglandin D synthases (hPGDS and lPGDS) are responsible for the formation of PGD2 from PGH2. Similarly, prostacyclin (PGI2) synthase (PGIS) converts PGH2 into PGI2. A thromboxane synthase (TxAS) has also been identified. Prostaglandin F synthase (PGFS) catalyzes the formation of 9α,11β-PGF2α,β from PGD2 and PGF2α from PGH2 in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD2 and bimatoprost(a synthetic analogue of PGF2α).
Function
There are currently nine known prostaglandin receptors on various cell types. Prostaglandins ligate a subfamily of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).
These varied receptors mean that Prostaglandins thus act on a variety of cells, and have a wide variety of actions:
cause constriction or dilation in vascular smooth muscle cells
cause aggregation or disaggregation of platelets
sensitize spinal neurons to pain
decrease intraocular pressure
regulate inflammatory mediation
regulate calcium movement
control hormone regulation
control cell growth
Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they exert only a paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) function.
Types
Following is a comparison of the prostaglandin types Prostaglandin I2 (PGI2), Prostaglandin E2 (PGE2) and Prostaglandin F2α (PGF2α).
Type
Receptor
Function
PGI2
IP
vasodilation
inhibit platelet aggregation
bronchodilatation
PGE2
EP1
bronchoconstriction
GI tract smooth muscle contraction
EP2
bronchodilatation
GI tract smooth muscle relaxation
vasodilatation
EP3
↓ gastric acid secretion
↑ gastric mucus secretion
uterus contraction (when pregnant)
GI tract smooth muscle contraction
lipolysis inhibition
↑ autonomic neurotransmitters Unspecified
hyperalgesia
pyrogenic
PGF2α
FP
uterus contraction
bronchoconstriction
Role in pharmacology
Inhibition
See also: Prostaglandin antagonist and Mechanism of action of aspirin
Examples of prostaglandin antagonists are:
NSAIDs (inhibit cyclooxygenase)
Corticosteroids (inhibit phospholipase A2 production)
COX-2 selective inhibitors or coxibs
However, both NSAIDs and Coxibs can raise the risk of myocardial infarction.
Clinical uses
Synthetic prostaglandins are used:
To induce childbirth (parturition) or abortion (PGE2 or PGF2, with or without mifepristone, a progesterone antagonist);
To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE1)
To prevent and treat peptic ulcers (PGE)
As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb
In pulmonary hypertension
In treatment of glaucoma (as in bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity)
To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil To treat egg binding in small birds

Beta-lactamase

Beta-lactamases are enzymes (EC 3.5.2.6) produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillins, cephalosporins (are relatively resistant to beta lactmase), cephamycins, and carbapenems (ertapenem). These antibiotics have a common element in their molecular structure: a four-atom ring known as a beta-lactam. The lactamase enzyme breaks that ring open, deactivating the molecule's antibacterial properties.
Beta-lactam antibiotics are typically used to treat a broad spectrum of gram-positive and gram-negative bacteria. Beta-lactamases produced by gram-positive organisms are usually secreted.
Beta-lactamase may be clinically beneficial when orally administered to preserve the natural intestinal flora during the parenteral administration of antibiotics. "This could provide protection against a broad range of nosocomial pathogens," per Dr. Usha Stiefel at the 47th annual Interscience Conference of Antimicrobial Agents and Chemotherapy.
The structure of a Streptomyces β lactamase is given by 1BSG.
Contents
1 Penicillinase
2 Classification of Beta Lactamase
2.1 Functional Classification
2.1.1 Group 1
2.1.2 Group 2
2.1.3 Group 3
2.1.4 Group 4
2.2 Molecular Classification
3 Resistance in gram-negative bacteria
3.1 Extended-spectrum beta-lactamase (ESBL)
3.1.1 Types
3.1.2 TEM beta-lactamases (class A)
3.1.3 SHV beta-lactamases (class A)
3.1.4 CTX-M beta-lactamases (class A)
3.1.5 OXA beta-lactamases (class D)
3.1.6 Others
3.1.7 Treatment
3.2 Inhibitor-resistant β-lactamases
3.3 AmpC-type β-lactamases(Class C)
3.4 Carbapenemases
3.4.1 IMP-type carbapenemases (one of the metallo-b-lactamases)
3.4.2 VIM (Verona integron-encoded metallo-b-lactamase)
3.4.3 OXA (oxacillinase) group of β-lactamases (Class D)
3.4.4 KPC (K. pneumoniae carbapenemase) (Class A)
3.4.5 CMY (Class C)
3.4.6 SME, IMI, NMC and CcrA
4 Treatment of ESBL/AmpC/carbapenemases
4.1 General Overview
4.2 According to genes
4.2.1 ESBLs
4.2.2 Inhibitor-Resistant β-Lactamases
4.2.3 AmpC
4.2.4 Carbapenemases
4.3 According to Species
Penicillinase
Penicillinase is a specific type of β-lactamase, showing specificity for penicillins, again by hydrolysing the beta-lactam ring. Molecular weights of the various penicillinases tend to cluster near 50kD.
Penicillinase was the first β-lactamase to be identified: it was first isolated by Abraham and Chain in 1940 from gram-negative E. coli even before penicillin entered clinical use but penicillinase production quickly spread to bacteria that previously did not produce it or only produced it rarely. Penicillinase-resistant beta-lactams such as methicillin were developed, but there is now widespread resistance to even these.
Classification of Beta Lactamase
Functional Classification
Group 1
CEPHALOSPORINASE, Molecular Class C (not inhibited by clavulanic acid)
Group 1 are cephalosporinases not inhibited by clavulanic acid, belonging to the molecular class C Group 2
Group 2 are penicillinases, cephalosporinases, or both inhibited by clavulanic acid, corresponding to the molecular classes A and D reflecting the original TEM and SHV genes. However, because of the increasing number of TEM- and SHV-derived {beta}-lactamases, they were divided into two subclasses, 2a and 2b.
GROUP 2a
PENICILLINASE, Molecular Class A
The 2a subgroup contains just penicillinases.
GROUP 2b
BROAD SPECTRUM, Molecular Class A
2b Opposite to 2a , 2b are broad-spectrum {beta}-lactamases, meaning that they are capable of inactivating penicillins and cephalosporins at the same rate. Furthermore, new subgroups were segregated from subgroup 2b:
GROUP 2be
EXTENDED SPECTRUM, Molecular Class A
Subgroup 2be, with the letter "e" for extended spectrum of activity, represents the ESBLs, which are capable of inactivating third-generation cephalosporins (ceftazidime, cefotaxime, and cefpodoxime) as well as monobactams (aztreonam)
GROUP 2br
INHIBITOR RESISTANT, Molecular Class A (diminished inhibition by clavulanic acid)
The 2br enzymes, with the letter "r" denoting reduced binding to clavulanic acid and sulbactam, are also called inhibitor-resistant TEM-derivative enzymes; nevertheless, they are commonly still susceptible to tazobactam, except where an amino acid replacement exists at position met69.
GROUP 2c
CARBENICILLINASE, Molecular Class A
Latersubgroup 2c was segregated from group 2 because these enzymes inactivate carbenicillin more than benzylpenicillin, with some effect on cloxacillin.yht
GROUP 2d
CLOXACILANASE, Molecular Class D or A
Subgroup 2d enzymes inactivate cloxacillin more than benzylpenicillin, with some activity against carbenicillin; these enzymes are poorly inhibited by clavulanic acid, and some of them are ESBLs
the correct term is "OXACILLINASE". These enzymes are able to inactivate the oxazolylpenicillins like oxacilli, cloxacilli, dicloxacillin. The enzymes belong to the molecular class D not molecular class A.
GROUP 2e
CEPHALOSPORINASE, Molecular Class A
Subgroup 2e enzymes are cephalosporinases that can also hydrolyse monobactams, and they are inhibited by clavulanic acid
GROUP 2f
CARBAPENAMASE, Molecular Class A
Subgroup 2f was added because these are serine-based carbapenemases, in contrast to the zinc-based carbapenemases included in group 3

Group 3
METALLOENZYME, Molecular Class B (not inhibited by clavulanic acid)
Group 3 are the zinc based or metallo {beta}-lactamases, corresponding to the molecular class B, which are the only enzymes acting by the metal ion zinc, as discussed above. Metallo B-lactamases are able to hydrolyse penicillins, cephalosporins, and carbapenems. Thus, carbapenems are inhibited by both group 2f (serine-based mechanism) and group 3 (zinc-based mechanism)
Group 4
PENICILLINASE, No Molecular Class (not inhibited by clavulanic acid)
Group 4 are penicillinases that are not inhibited by clavulanic acid, and they do not yet have a corresponding molecular class.
Molecular Classification
The molecular classification of β-lactamases is based on the nucleotide and amino acid sequences in these enzymes. To date, four classes are recognised (A-D), correlating with the functional classification. Classes A, C, and D act by a serine-based mechanism, whereas class B or metallo-β-lactamases need zinc for their action"Penicillinase" was discovered in 1940 and re-named Beta-lactamase when the structure of the Beta-lactam ring was finally elucidated.
Resistance in gram-negative bacteria
Among gram-negative bacteria, the emergence of resistance to expanded-spectrum cephalosporins has been a major concern. It appeared initially in a limited number of bacterial species (E. cloacae , C. freundii, S. marcescens, and P. aeruginosa ) that could mutate to hyperproduce their chromosomal class C β-lactamase. A few years later, resistance appeared in bacterial species not naturally-producing AmpC enzymes (K. pneumoniae, Salmonella spp., P. mirabilis) due to the production of TEM- or SHV-type ESBLs. Characteristically, such resistance has included oxyimino- (for example ceftizoxime, cefotaxime , ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam aztreonam), but not 7-alpha-methoxy-cephalosporins (cephamycins); in other words, (cefoxitin and cefotetan) have been blocked by inhibitors such as clavulanate, sulbactam, or tazobactam, and did not involve carbapenems. Plasmid-mediated AmpC β-lactamases represent a new threat, since they confer resistance to 7-alpha-methoxy-cephalosporins (cephamycins) such as cefoxitin or cefotetan are not affected by commercially-available β-lactamase inhibitors, and can, in strains with loss of outer membrane porins, provide resistance to carbapenems.
Extended-spectrum beta-lactamase (ESBL)
Members of the family Enterobacteriaceae commonly express plasmid-encoded β-lactamases (e.g., TEM-1, TEM-2, and SHV-1). which confer resistance to penicillins but not to expanded-spectrum cephalosporins . In the mid-1980s a new group of enzymes, the extended-spectrum b-lactamases (ESBLs), was detected. (first detected in Germany in 1983). ESBLs are beta-lactamases that hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam aztreonam. Thus ESBLs confer resistance to these antibiotics and related oxyimino-beta lactams. Typically, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described.The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates.
Types
TEM beta-lactamases (class A)
TEM-1 is the most commonly-encountered beta-lactamase in gram-negative bacteria. Up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1. Also responsible for the ampicillin and penicillin resistance that is seen in H. influenzae and N. gonorrhoeae in increasing numbers. Although TEM-type beta-lactamases are most often found in E. coli and K. pneumoniae, they are also found in other species of gram-negative bacteria with increasing frequency. The amino acid substitutions responsible for the ESBL phenotype cluster around the active site of the enzyme and change its configuration, allowing access to oxyimino-beta-lactam substrates. Opening the active site to beta-lactam substrates also typically enhances the susceptibility of the enzyme to b-lactamase inhibitors, such as clavulanic acid. Single amino acid substitutions at positions 104, 164, 238, and 240 produce the ESBL phenotype, but ESBLs with the broadest spectrum usually have more than a single amino acid substitution. Based upon different combinations of changes, currently 140 TEM-type enzymes have been described. TEM-10, TEM-12, and TEM-26 are among the most common in the United States.

SHV beta-lactamases (class A)
SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall structure. The SHV-1 beta-lactamase is most commonly found in K. pneumoniae and is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this species. ESBLs in this family also have amino acid changes around the active site, most commonly at positions 238 or 238 and 240. More than 60 SHV varieties are known. They are the predominant ESBL type in Europe and the United States and are found worldwide. SHV-5 and SHV-12 are among the most common.

CTX-M beta-lactamases (class A)
These enzymes were named for their greater activity against cefotaxime than other oxyimino-beta-lactam substrates (eg, ceftazidime, ceftriaxone, or cefepime). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. More than 40 CTX-M enzymes are currently known. Despite their name, a few are more active on ceftazidime than cefotaxime. They have mainly been found in strains of Salmonella enterica serovar Typhimurium and E. coli, but have also been described in other species of Enterobacteriaceae and are the predominant ESBL type in parts of South America. (They are also seen in eastern Europe) CTX-M-14, CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is currently (2006) the most widespread type in E. coli the UK and is widely prevalent in the community.
OXA beta-lactamases (class D)
OXA beta-lactamases were long recognized as a less common but also plasmid-mediated beta-lactamase variety that could hydrolyze oxacillin and related anti-staphylococcal penicillins. These beta-lactamases differ from the TEM and SHV enzymes in that they belong to molecular class D and functional group 2d . The OXA-type beta-lactamases confer resistance to ampicillin and cephalothin and are characterized by their high hydrolytic activity against oxacillin and cloxacillin and the fact that they are poorly inhibited by clavulanic acid. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. While most ESBLs have been found in E. coli, K. pneumoniae, and other Enterobacteriaceae, the OXA-type ESBLs have been found mainly in P. aeruginosa. OXA-type ESBLs have been found mainly in Pseudomonas aeruginosa isolates from Turkey and France. The OXA beta-lactamase family was originally created as a phenotypic rather than a genotypic group for a few beta-lactamases that had a specific hydrolysis profile. Therefore, there is as little as 20% sequence homology among some of the members of this family. However, recent additions to this family show some degree of homology to one or more of the existing members of the OXA beta-lactamase family. Some confer resistance predominantly to ceftazidime, but OXA-17 confers greater resistance to cefotaxime and cefepime than it does resistance to ceftazidime.
Others
Other plasmid-mediated ESBLs, such as PER, VEB, GES, and IBC beta-lactamases, have been described but are uncommon and have been found mainly in P. aeruginosa and at a limited number of geographic sites. PER-1 in isolates in Turkey, France, and Italy; VEB-1 and VEB-2 in strains from Southeast Asia; and GES-1, GES-2, and IBC-2 in isolates from South Africa, France, and Greece. PER-1 is also common in multiresistant acinetobacter species in Korea and Turkey. Some of these enzymes are found in Enterobacteriaceae as well, whereas other uncommon ESBLs (such as BES-1, IBC-1, SFO-1, and TLA-1) have been found only in Enterobacteriaceae.
Treatment
While ESBL-producing organisms were previously associated with hospitals and institutional care, these organisms are now increasingly found in the community. CTX-M-15-positive E. coli are a cause of community-acquired urinary infections in the UK, and tend to be resistant to all oral β-lactam antibiotics, as well as quinolones and sulfonamides. Treatment options may include nitrofurantoin, fosfomycin, mecillinam and chloramphenicol. In desperation, once-daily ertapenem or gentamicin injections may also be used.
Inhibitor-resistant β-lactamases
Although the inhibitor-resistant β-lactamases are not ESBLs, they are often discussed with ESBLs because they are also derivatives of the classical TEM- or SHV-type enzymes. These enzymes were at first given the designation IRT for inhibitor-resistant TEM β-lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct inhibitor-resistant TEM β-lactamases. Inhibitor-resistant TEM β-lactamases have been found mainly in clinical isolates of E. coli, but also some strains of K. pneumoniae, Klebsiella oxytoca, P. mirabilis, and Citrobacter freundii .Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid and sulbactam, thereby showing clinical resistance to the beta-lactam--lactamase inhibitor combinations of amoxicillin-clavulanate (Co-amoxiclav), ticarcillin-clavulanate, and ampicillin/sulbactam, they normally remain susceptible to inhibition by tazobactam and subsequently the combination of piperacillin/tazobactam, although resistance has been described. To date, these beta-lactamases have primarily been detected in France and a few other locations within Europe.
AmpC-type β-lactamases(Class C)
AmpC type β-lactamases are commonly isolated from extended-spectrum cephalosporin-resistant Gram-negative bacteria. AmpC β-lactamases (also termed class C or group 1) are typically encoded on the chromosome of many Gram-negative bacteria including Citrobacter, Serratia and Enterobacter species where its expression is usually inducible; it may also occur on Escherichia coli but is not usually inducible, although it can be hyperexpressed. AmpC type β-lactamases may also be carried on plasmids.AmpC β-lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-β-lactams) but are not inhibited by β-lactamase inhibitors such as clavulanic acid.
Carbapenemases
Carbapenems are famously stable to AmpC β-lactamases and extended-spectrum-β-lactamases. Carbapenemases are a diverse group of b-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems. Aztreonam is stable to the metallo-β-lactamases but many IMP and VIM producers are resistant, owing to other mechanisms. Carbapenemases were formerly believed to derive only from classes A, B, and D, but a class C carbapenemase has been described.
IMP-type carbapenemases (one of the metallo-b-lactamases)
Plasmidmediated IMP-type carbapenemases, 17 varieties of which are currently known, became established in Japan in the 1990s in both enteric gram-negative organisms and in Pseudomonas and Acinetobacter species. IMP enzymes spread slowly to other countries in the Far East, were reported from Europe in 1997, and have been found in Canada and Brazil.
VIM (Verona integron-encoded metallo-b-lactamase)
A second growing family of carbapenemases, the VIM family, was reported from Italy in 1999 and now includes 10 members, which have a wide geographic distribution in Europe, South America, and the Far East and have been found in the United States. VIM-1 was discovered in P. aeruginosa in Italy in 1996; subsequently, VIM-2 -now the predominant variant- was found repeatedly in Europe and the Far East; VIM-3 and -4 are minor variants of VIM-2 and -1, respectively. VIM enzymes mostly occur in P. aeruginosa, also P. putidaand, very rarely, Enterobacteriaceae
Amino acid sequence diversity is up to 10% in the VIM family, 15% in the IMP family, and 70% between VIM and IMP. Enzymes of both the families nevertheless are similar.1 Both are integron-associated, sometimes within plasmids. Both hydrolyse all β-lactams except monobactams, and evade all β-lactam inhibitors.

OXA (oxacillinase) group of β-lactamases (Class D)
The OXA group of β-lactamases mainly occur in Acinetobacter species and are divided into two clusters. OXA carbapenemases hydrolyse carbapenems very slowly in vitro, and the high MICs seen for some Acinetobacter hosts (>64 mg/L) may reflect secondary mechanisms. They are sometimes augmented in clinical isolates by additional resistance mechanisms, such as impermeability or efflux.
KPC (K. pneumoniae carbapenemase) (Class A)
A few class A enzymes, notably the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Three variants are known, distinguished by one or two amino-acid substitutions. KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids.
The first class C carbapenemase was described in 2006 and was isolated from a virulent strain of Enterobacter aerogenes. It is carried on a plasmid, pYMG-1, and is therefore transmissible to other bacterial strains.
SME, IMI, NMC and CcrA
generally of little clinical significance.
CcrA (CfiA). Its gene occurs in c. 1-3% of B. fragilis isolates, but fewer produce the enzyme since expression demands appropriate migration of an insertion sequence. CcrA was known before imipenem was introduced, and producers have shown little subsequent increase.
According to genes
ESBLs
Strains producing only ESBLs are susceptible to cephamycins and carbapenems in vitro and show little if any inoculum effect with these agents.
For organisms producing TEM and SHV type ESBLs, apparent in vitro sensitivity to cefepime and to piperacillin/tazobactam is common, but both drugs show an inoculum effect, with diminished susceptibility as the size of the inoculum is increased from 105to 107organisms.
Strains with some CTX-M–type and OXA-type ESBLs are resistant to cefepime on testing, despite the use of a standard inoculum.

Chloramphenicol

Chloramphenicol is primarily bacteriostatic. It binds to the 50S subunit of the ribosome, thereby inhibiting bacterial protein synthesis.
Pharmacology: Chloramphenicol is well absorbed orally. Parenteral therapy should be IV. It is distributed widely in body fluids, including CSF, and is excreted in urine. Because of hepatic metabolism, active chloramphenicol does not accumulate with renal insufficiency.
Indications: Chloramphenicol has a wide spectrum of activity against gram-positive and gram-negative cocci and bacilli (including anaerobes), Rickettsia , Mycoplasma, and Chlamydia and Chlamydophila. Because of bone marrow toxicity, the availability of alternative antibiotics, and the emergence of resistance, chloramphenicol is no longer a drug of choice for any infection, except serious infections due to a few multidrug-resistant pathogens that retain susceptibility to this antibiotic. However, outcomes of chloramphenicol treatment of meningitis caused by relatively penicillin-resistant pneumococci have been discouraging.
Toxicity: Chloramphenicol can cause 2 types of bone marrow depression: a reversible dose-related interference with iron metabolism and an irreversible idiosyncratic form of aplastic anemia. The reversible form is most likely with high doses or prolonged treatment and in patients with severe liver disease. Serum iron and saturation of serum iron-binding capacity increase; reticulocytes decrease; and vacuolization of RBC precursors, anemia, leukopenia, and thrombocytopenia develop. Irreversible idiosyncratic aplastic anemia occurs in < class="MMterm" onmouseover="drugTerm(1,'d200994e2120',1);" onmouseout="drugTerm('','d200994e2120',2);">Chloramphenicol should not be used topically because small amounts may be absorbed and, rarely, can cause aplastic anemia.
Hypersensitivity reactions are uncommon. Optic and peripheral neuritis may occur with prolonged use. Nausea, vomiting, and diarrhea may occur.
The neonatal gray baby syndrome, which involves circulatory collapse, is often fatal. The cause is high blood levels resulting from inability of the immature liver to metabolize chloramphenicol . To avoid the syndrome, infants ≤1 mo are not given > 25 mg/kg/day initially and doses are adjusted to serum levels.

Serotonin

Serotonin (pronounced / (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables.
Contents
1 Function
1.1 Serotonin and SIDS
2 Anatomy
2.1 Gross anatomy
2.2 Microanatomy
2.2.1 Receptors
2.2.2 Termination
2.3 Endothelial cell function and Serotonin
3 Biosynthesis
4 Drugs targeting the 5-HT system
4.1 Psychedelic drugs
4.2 Antidepressants
4.3 Antiemetics
5 Pathology
5.1 Serotonin syndrome
5.2 Chronic diseases resulting from serotonin 5-HT2B overstimulation
6 In unicellular organisms
7 In plants
8 In animals
Function
A hydroxy-group at carbon 5 of the carbon skeleton of L-tryptophan without a carboxyl group gives serotonin its descriptive chemical name, 5-hydroxytryptamine.
In the central nervous system, serotonin plays an important role as a neurotransmitter in the modulation of anger, aggression, body temperature, mood, sleep, human sexuality, appetite, and metabolism, as well as stimulating vomiting.Serotonin has broad activities in the brain, and genetic variation in serotonin receptors and the serotonin transporter, which facilitates reuptake of serotonin into presynapses, have been implicated in neurological diseases. Drugs targeting serotonin-induced pathways are being used in the treatment of many psychiatric disorders, and one focus of clinical research is the influence of genetics on serotonin action and metabolism in psychiatric settings. Such studies have revealed that the variation in the promoter region of the serotonin transporter protein accounts for nearly 10% of total variance in anxiety-related personality,and the effect of this gene on depression was found to interact with the environment.Levels of serotonin in the brain show association with aggression , and a mutation in the gene which codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.Using the ultimatum game as model, it was shown that people whose serotonin levels have been artificially lowered will reject unfair offers more often than players with normal serotonin levels
In addition, serotonin is also a peripheral signal mediator. It is found extensively in the human gastrointestinal tract as about 80-90% of the body's total serotonin is found in the enterochromaffin cells in the gut.In the blood, the major storage site is platelets, which collect serotonin for use in mediating post-injury vasoconstriction.
Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body. Recent research also suggests that intestinal serotonin may inhibit bone formation.Serotonin and SIDS
Defective signalling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS), Italian researchers have found. Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy,genetically modified lab mice to produce low levels of the brain signaling protein serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age.
Researchers now believe that low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, researchers said in the July 4, 2008 issue of Science.
Anatomy
Serotonin system, contrasted with dopamine system.
Gross anatomy
The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the caudal raphe nuclei terminate in the following locations:
Deep cerebellar nuclei
Cerebellar cortex
Spinal cord
On the other hand, axons of neurons in the rostral raphe nuclei terminate in e.g.:
Thalamus
Striatum
Hypothalamus
Nucleus accumbens
Neocortex
Cingulate gyrus
Cingulum
Hippocampus
Amygdala
Thus, activation of this serotonin system has effects on large areas of the brain.
Microanatomy
Serotonin is released from serotonergic varicosities (swellings) into the extra neuronal space, but not from synaptic terminal boutons as other neurotransmitters.[citation needed] Serotonin diffuses over a relatively wide gap (>20µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
Receptors
Main article: 5-HT receptor
5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.citation needed
Termination
Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).
Interestingly, a 2006 study conducted by the University of Washington suggested that a newly discovered monoamine transporter, known as PMAT, may account for 'a significant percentage of 5-HT clearance.Contrasting with the high-affinity SERT, the PMAT has been identified as a low affinity transporter with an apparent Km of 114 micromoles/L for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport capacity than SERT,
"..resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems."
The study also suggests that some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass therapeutic plasma concentrations by up to four magnitudes of ten; ergo, SSRI monotherapy is ineffective in PMAT inhibition. At present, there are no known pharmaceuticals which would appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine albeit at Km values even higher than that of 5-HT (330–15,000 micromoles/L).
Endothelial cell function and Serotonin
5-hydroxytryptamine evokes endothelial nitric oxide synthase activation and stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.
Biosynthesis
The pathway for the synthesis of serotonin from tryptophan
In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform. There is evidence that genetic polymorphisms in both these subtypes influence susceptibility to anxiety and depression in humans. There is also evidence that ovarian hormones can affect the expression of TPH in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome.citation needed Serotonin biosynthesis in plants likewise begins with L-tryptophan, which is however first decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by the cytochrome P450 monooxygenase, tryptamine 5-hydroxylase, yielding serotonin.Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents.
One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.
Drugs targeting the 5-HT system
Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens.
Psychedelic drugs
The psychedelic drugs psilocin psilocybin, DMT, mescaline, and LSD mimic the action of serotonin primarily at 5-HT2A receptor. The empathogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons.
Antidepressants
The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs.
Some drugs inhibit the re-uptake of serotonin, making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs.
SSRI medications have been shown to lower serotonin levels below initial level over time, despite initial increases in serotonin.This decrease in level did not rectify after the medicine was discontinued. However, the novel antidepressant Tianeptine, selective serotonin reuptake enhancer, has mood elevating effects. This has given evidence to the theory that serotonin is most likely used to regulate the extent or intensity of moods, and that low levels are what's associated with SSRI sexual dysfunction and/or "mood blunting" experienced by people on these medications.
Antiemetics
5-HT3 antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results.
Pathology
If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).Low levels of serotonin may also be associated with intense spiritual experiences.
Recent research conducted at Rockefeller University shows that both in patients who suffer from depression and in mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.Obsessive-compulsive disorder (OCD) can be a debilitating disorder with the following two anxiety-related essential features: obsessions (undesirable, recurrent, disturbing thoughts) and compulsions (repetitive or ritualized behaviors). SSRIs, and other medicines which alter serotonin levels, have been approved to be used to treat symptoms of OCD.
Serotonin syndrome
Main article: serotonin syndrome
Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels citation needed
Chronic diseases resulting from serotonin 5-HT2B overstimulation
Main article: Cardiac fibrosis
In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of retroperitoneal fibrosis or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes. citation needed
Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut carcinoid tumors. citation neededThe valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation.citation needed
Serotonergic agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal) pulmonary hypertension, but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans.[citation needed] Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.
In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide),the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis.Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide along with cabergoline in causing valvular heart disease.As a result of this, the FDA removed pergolide from the U.S. market in March, 2007.(Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease)
Because neither the amino acid L-tryptophan nor the SSRI-class antidepressants raise blood serotonin levels citation needed, they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs.citation needed
In unicellular organisms
Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.
In plants
Serotonin is found in mushrooms and plants, including fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genuses. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica). It should be noted that serotonin, unlike its precursors 5-HTP and tryptophan, does not cross the blood–brain barrier, which means that ingesting serotonin in the diet has no effect on brain serotonin levels. Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and hydroxy (OH) groups, are N-oxides, or miss the OH group. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff.
In animals
Serotonin as a neurotransmitter is found in many animals, including insects. Several toad venoms, as well as that of the Brazilian wandering spider and stingray, contain serotonin and related tryptamines. It has also been identified as the trigger for swarm behaviour in locusts.