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Molecular cloning has also helped in obtaining the receptor protein in larger quantity to study its structure and properties, and in subclassifying receptors. The cell surface receptors with their coupling and effector proteins are considered to be floating in a sea of membrane lipids; the folding, orientation and topography of the system being determined by interactions between the lipophilic and hydrophilic domains of the peptide chains with solvent molecules (water on one side and lipids on the other). In such a delicately balanced system, it is not difficult to visualize that a small molecular ligand binding to one site in the receptor molecule could be capable of tripping the balance (by altering distribution of charges, etc. Each of the four major families of receptors (described later) have a well defined common structural motif, while the individual receptors differ in the details of amino acid sequencing, length of intra/ extracellular loops, etc. Majority of receptor molecules are made up of several non-identical subunits (heteropolymeric), and agonist binding has been shown to bring about changes in their quaternary structure or relative alignment of the subunits, e. Many drugs act upon physiological receptors which mediate responses to transmitters, hormones, autacoids and other endogenous signal molecules; examples are cholinergic, adrenergic, histaminergic, steroid, leukotriene, insulin and other such receptors. In addition, now some truly drug receptors have been described for which there are no known physiological ligands, e. Accordingly, they were said to be mediated by two types of cholinergic receptors, viz. Multiple subtypes of receptors for practically all transmitters, autacoids, hormones, etc. In many cases, receptor classification has provided sound explanation for differences observed in the actions of closely related drugs. Pharmacological criteria Classification is based on relative potencies of selective agonists and antagonists. This is the classical and oldest approach with direct clinical bearing; was used in delineating M and N cholinergic, and adrenergic, H1 and H2 histaminergic receptors, etc. Tissue distribution the relative organ/tissue distribution is the basis for designating the subtype, e. This division was confirmed by selective agonists and antagonists as well as by molecular cloning. Autoradiography has helped in mapping distribution of receptor subtypes in the brain and other organs. Transducer pathway Receptor subtypes may be distinguished by the mechanism through which their activation is linked to the response, e. Molecular cloning the receptor protein is cloned and its detailed amino acid sequence as well as three dimentional structure is worked out. This approach has in the recent years resulted in a flood of receptor subtypes and several isoforms (which do not differ in ligand selectivity) of each subtype. Receptors subserve two essential functions, viz, recognition of the specific ligand molecule and transduction of the signal into a response. Accordingly, the receptor molecule has a ligand binding domain (spatially and energetically suitable for binding the specific ligand) and an effector domain (Fig. The perturbation in the receptor molecule is variously translated into the response. The sequential relationship between drug action, transducer and drug effect can be seen in Fig. Because only a handful of transducer pathways are shared by a large number of receptors, the cell is able to generate an integrated response reflecting the sum total of diverse signal input. Receptors falling in one category also possess considerable structural homology, and belong to one super-family of receptors. Silent receptors these are sites which bind specific drugs but no pharmacological response is elicited. To avoid confusion, the term receptor should be restricted to those regulatory binding sites which are capable of generating a response. Drug action It is the initial combination of the drug with its receptor resulting in a conformational change in the latter (in case of agonists), or prevention of conformational change through exclusion of the agonist (in case of antagonists). In case of nicotinic cholinergic receptor, the molecule (8 nm in diameter) is composed of 5 subunits (2 + + + ) enclosing a transmembrane ion channel within the subunit. When two molecules of acetylcholine bind to the two subunits (B), all subunits move apart opening the central pore to 0. Anions are blocked from passage through the channel by positive charges lining it. The intervening segments connecting the helices form 3 loops on either side of the membrane. The amino terminus of the chain lies on the extracellular face, while the carboxy terminus is on the cytosolic side. The approximate location of the agonist and G-protein binding sites is indicated another recognition site formed by cytosolic segments binds the coupling G-protein. The Gproteins float in the membrane with their exposed domain lying in the cytosol, and are heterotrimeric in composition (, and subunits). So that it can serve signaling functions, the cytosolic concentration of Ca2+ is kept very low (~ 100 nM) by specific pumps located at the plasma membrane and at the endoplasmic reticulum. Moreover, a receptor can utilize different biochemical pathways in different tissues. The diamer of Gi activates membrane K+ channels causing hyperpolarization which depresses impulse generation. The activation of different effectors may depend on the amplitude and pattern of these oscillations. Thus, the same intracellular messenger can trigger different responses depending on the nature and strength of the extracellular signal. Cytosolic Ca2+ is recycled by uptake into the endoplasmic reticulum as well as effluxed by membrane Ca2+ pump. The Gs opens Ca2+ channels in myocardium and skeletal muscles, while Gi and Go open K + channels in heart and smooth muscle as well as inhibit neuronal Ca2+ channels. Direct channel regulation is mostly the function of the diamer of the dissociated G protein. Physiological responses like changes in inotropy, chronotropy, transmitter release, neuronal activity and smooth muscle relaxation follow. Receptors found to regulate ionic channels through G-proteins are listed in Table 4. The receptor is usually a pentameric protein; all subunits, in addition to large intra- and extracellular segments, generally have four membrane spanning helical domains. The subunits are mostly arranged round the channel like a rosette and the subunits usually bear the agonist binding sites. Certain receptor-operated (or ligand-gated) ion channels also have secondary ligands which bind to an allosteric site and modulate the gating of the channel by the primary ligand, e. The enzyme at the cytosolic side is generally a protein kinase, but can also be guanylyl cyclase in few cases. These are then phosphorylated and released to carry forward the cascade of phosphorylations leading to the response. The onset and offset of responses through this class of receptors is the fastest (in milliseconds). Transmembrane enzyme-linked receptors this class of receptors are utilized primarily by peptide hormones, and are made up of a large Fig. The intracellular domain of these receptors lacks intrinsic protein kinase activity. Thus, by controlling phosphorylation of key enzymes, ion channels, transporters, etc. The transmembrane enzyme-linked receptors transduce responses in a matter of few minutes to few hours. Another feature of this class of receptors is that their dimerization also promotes receptor internalization, degradation in lysosomes and down regulation if activation is fast enough. The liganded receptor diamer moves to the nucleus and binds other coactivator/co-repressor proteins which have a modulatory influence on its capacity to alter gene function.
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Oral labetalol therapy is restricted to moderately severe hypertension not responding to a pure blocker, because side effects of both blocker and blocker occur with it. Carvedilol this nonselective + weak selective 1 blocker produces vasodilatation and has additional antioxidant/free radical scavenging properties. However, unlike hydralazine, there is little reflex cardiac stimulation and renin release during long-term therapy. Tachycardia does Adverse effects Prazosin is generally well tolerated at low doses. Apart from postural hypotension related symptoms (particularly in the beginning), other side effects are headache, drowsiness, dry mouth, weakness, palpitation, nasal blockade, blurred vision and rash. Terazosin, Doxazosin these are long-acting congeners of prazosin with similar properties but suitable for once daily dosing (see p. A higher incidence of stroke relative to patients receiving a thiazide diuretic was also noted. Nonselective blockers (Phentolamine, Phenoxybenzamine) the nonselective blockers have been disappointing for routine treatment of hypertension, because fall in t. They are reserved for special situations like pheochromocytoma, clonidine withdrawal, cheese reaction, etc. A combination of blocker with a blocker, or a potent vasodilator (nitroprusside) or clonidine itself can be used to treat the syndrome. Interactions Tricyclic antidepressants and chlorpromazine abolish the antihypertensive action of clonidine, probably by blocking receptors on which clonidine acts. Clonidine is a partial agonist with high affinity and high intrinsic activity at 2 receptors, especially 2A subtype in brainstem. The major haemodynamic effects result from stimulation of 2A receptors present mainly postjunctionally in medulla (vasomotor centre). Clonidine also activates Imidazoline receptors which are distinct from 2 receptors and are present in the brain as well as periphery. Oral Use Clonidine was a popular antihypertensive in the late 1960s and 1970s, but frequent side effects, risk of withdrawal hypertension and development of tolerance have relegated it to a 3rd or 4th choice drug. Adverse effects Sedation, lethargy and reduced mental capacity are common side effects. Dryness of mouth, nasal stuffiness, headache, fluid retention, weight gain, impotence are the other side effects. Interactions Tricyclic antidepressants reverse its action by blocking its active transport into the adrenergic neurones. Opioid withdrawal: Opioid and 2 adrenergic systems converge on the same effectors in many systems; both activate the Gi regulatory protein. Clonidine suppresses sympathetic overactivity of opioid withdrawal syndrome and reduces craving to some extent. It has been used to substitute morphine for intrathecal/epidural surgical and postoperative analgesia. It may be acting by 2 receptor mediated enhancement of salt absorption in gut mucosa. Pharmacokinetics Though methyldopa is transported actively by intestinal amino acid carrier, less than 1/3 of an oral dose is absorbed. However, it is infrequently used now, except to treat hypertension during pregnancy wherein it has a long track record of safety, both for the mother as well as the foetus. Thus, a hyperdynamic circulatory state is induced-angina may be precipitated due to increased cardiac work as well as steal phenomenon. Tolerance to the hypotensive action develops unless diuretics or blockers or both are given together to block the compensatory mechanisms. The mechanism of vascular smooth muscle relaxant action of hydralazine is not clearly known. The chief metabolic pathway is acetylation which exhibits a bimodal distribution in the population: there are slow and fast acetylators. Bioavailability is higher in slow acetylators, but these patients are more prone to develop the lupus syndrome. However, hypotensive effect lasts longer (12 hours), probably because of its persistence in the vessel wall. Applied topically (2% twice daily) it promotes hair growth in male pattern baldness and alopecia areata. The mechanism of increased hair growth is not known; may involve: (a) Opening of K + channels and enhanced microcirculation around hair follicles. It is one of the preferred antihypertensives during pregnancy, especially preeclampsia, because of decades of safety record. Hydralazine is contraindicated in older patients and in those with ischaemic heart disease. Minoxidil It is a powerful vasodilator, the pattern of action resembling hydralazine, i. Myocardial work is reduced-ischaemia is not accentuated, as occurs with selective arteriolar dilators (hydralazine). In patients with heart failure and ventricular dilatation, nitroprusside improves ventricular function and c. This may be responsible for the different pattern of vasodilator action compared to nitrates, as well as for the fact that no nitrate like tolerance develops to nitroprusside action. Nitroprusside has gained popularity in the management of hypertensive emergencies; 50 mg is added to a 500 ml bottle of saline/glucose solution. It decomposes at alkaline pH and on exposure to light: the infusion bottle should be covered with black paper. Side effects mainly due to vasodilatation are- palpitation, nervousness, vomiting, perspiration, pain in abdomen, weakness, disorientation, and lactic acidosis (caused by the released cyanide). It was a popular antihypertensive of the late 1950s and early 1960s, but is now used only as a pharmacological tool. The results convey that efficacywise there is little to choose among the 4 classes of drugs; choice of initial drug has to be guided by associated features/contraindications and acceptable side effects in individual patients. If the cause of hypertension can be identified (hormonal, vascular abnormality, tumour, renal disease, drugs) all efforts should be made to remove it. Nonpharmacological measures (life style modification-diet, Na+ restriction, aerobic With the recognition of 4 groups of first choice antihypertensive drugs viz. The drug for initial therapy is selected on the basis of compelling indications (if present), suitability criteria taking into consideration the age, life style issues, risk factors, concomitant medical conditions, tolerability in respect of the individual patient and cost of different drugs. For each class of antihypertensive drugs, certain patients can be identified who are best suited to be treated with it, and those in whom it should be avoided (see box). Many experts now opine that blockers should no longer be regarded as first choice drugs, except for patients with compelling indications or suitability features. Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society. While A and (in some cases) B are preferred in younger patients (<55 years), C and D are preferred in the older (> 55 years) for the step I or monotherapy. If only partial response is obtained, add a drug from another complimentary class or change to low dose combination (antihypertensive action of the components adds up, while side effects being different, do not). If no response, change to a drug from another class, or low dose combination from other classes. In case of side effect to the initially chosen drug, either substitute with drug of another class or reduce dose and add a drug from another class.
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Naltrexone: Several studies have demonstrated involvement of opioid system in the pleasurable reinforcing effects of alcohol through dopamine mediated reward function. The post-addict treated with the long-acting opioid antagonist naltrexone (see Ch. It reduced alcohol craving, number of drinking days and chances of resumed heavy drinking. Naltrexone is approved for use as adjuvant in comprehensive treatment programmes for alcohol dependent subjects and is being used in India at most deaddiction centres, after the individual has undergone withdrawal and is motivated. In conjunction with social and motivational therapy, it has been found to reduce relapse of the drinking behaviour. Heavy drinking is often associated with nutritional deficiencies, because food is neglected and malabsorption may occur. Astringent action of alcohol is utilized in antiperspirant and aftershave lotions. Alcohol in the form of whiskey or brandy may benefit by causing vasodilatation of blanched mucosae; but further exposure after taking alcohol may be deleterious because alcohol increases heat loss due to cutaneous vasodilatation. Aldehyde dehydrogenase inhibitor Disulfiram It inhibits the enzyme aldehyde dehydrogenase (Fig. When alcohol is ingested after taking disulfiram, the concentration of acetaldehyde in tissues and blood rises and a number of highly distressing symptoms (aldehyde syndrome) are produced promptly. These are-flushing, burning sensation, throbbing headache, perspiration, uneasiness, tightness in chest, dizziness, vomiting, visual disturbances, mental confusion, postural fainting and circulatory collapse. Because of risk of severe reaction, disulfiram is to be used with great caution, only in well-motivated subjects. Disulfiram aversion therapy is indicated in abstinent subjects who sincerely desire to leave the habit. After making sure that the subject has not taken alcohol in the past 12 hours, disufiram is given at a dose of 500 mg/day for one week followed by 250 mg daily. Disulfiram should not be used in patients who are physically dependent on alcohol. Side effects of disulfiram (as such) are infrequent, include rashes, metallic taste, nervousness, malaise and abdominal upset. It inhibits a number of other enzymes as well including alcohol dehydrogenase, dopamine hydroxylase and several cytochrome P450 isoenzymes. Mixing of methylated spirit with alcoholic beverages by bootlegers or its inadvertent ingestion results in methanol poisoning. This is the most important measure; prevents retinal damage and other symptoms; large quantities may be needed. At a concentration of 100 mg/dl in blood it saturates alcohol dehydrogenase and retards methanol metabolism. Ethanol (10% in water) is administered through a nasogastric tube; loading dose of 0. Moreover, the enzyme saturating concentration of ethanol itself produces intoxication and can cause hypoglycaemia. Treatment has to be continued for several days because the sojourn of methanol in body is long. Fomepizole (4-methylpyrazole) is a specific inhibitor of alcohol dehydrogenase and the drug of choice for methanol poisoning by retarding its metabolism. Folate therapy: Calcium leucovorin 50 mg injected 6 hourly has been shown to reduce blood formate levels by enhancing its oxidation. Toxic effects of methanol are largely due to formic acid, since its further metabolism is slow and folate dependent. Manifestations of methanol poisoning are vomiting, headache, epigastric pain, uneasiness, drunkenness, disorientation, tachypnoea, dyspnoea, bradycardia and hypotension. Blurring of vision, congestion of optic disc followed by blindness always precede death which is due to respiratory failure. Ethylene glycol is oxidized in the body by alcohol dehydrogenase to glycoaldehyde and then to glycolic acid-glyoxylic acid-oxalic acid in steps. Ethylene glycol itself can cause intoxication similar to ethanol, but generation of metabolites results in acidosis, cardiopulmonary complications and renal tubular necrosis. Fomepizole used in the same manner as for methanol poisoning is the drug of choice. He was seizure free for the last one year, but reported back one afternoon with the complaint of recurrence of two seizure episodes since morning. On questioning, he revealed that last evening he attended a party with his friends and consumed 4 drinks of whiskey, and was awake till late night. Sedation refers to decreased responsiveness to any level of stimulation; is associated with some decrease in motor activity and ideation. Hypnotic A drug that induces and/or maintains sleep, similar to normal arousable sleep. Those with quicker onset, shorter duration and steeper dose-response curves are preferred as hypnotics while more slowly acting drugs with flatter dose-response curves are employed as sedatives. However, there is considerable overlap; a hypnotic at lower dose may act as sedative. Alcohol and opium have been the oldest hypnotics and continue to be used for this purpose as self-medication by people. Bromides introduced in 1857 are now obsolete, so are chloral hydrate (1869) and paraldehyde (1882). Barbiturates reigned supreme till 1960s when benzodiazepines started eroding their position and have now totally replaced them. In the mean time, a number of other sedative-hypnotics (glutethimide, methyprilon, methaqualone) were introduced but none was significantly different from barbiturates; all are redundant now. Stage 2 (unequivocal sleep) waves with interspersed spindles, K complexes can be evoked on sensory stimulation; little eye movement; subjects are easily arousable. In addition some antihistaminics (promethazine, diphenhydramine), some neuroleptic/antidepressants (chlorpromazine, amitriptyline), some anticholinergic (hyoscine) and opioids (morphine, pethidine) have significant sedative action, but are not reliable for treatment of insomnia. Barbituric acid as such is not a hypnotic but compounds with alkyl or aryl substitution on C5 are. Replacement of O with S at C2 yields thiobarbiturates which are more lipid-soluble and more potent. Barbiturates have variable lipid solubility, the more soluble ones are more potent and shorter acting. They are insoluble in water but their sodium salts dissolve yielding highly alkaline solution. Barbiturates Long acting Phenobarbitone Short acting Butobarbitone Pentobarbitone Ultra-short acting Thiopentone Methohexitone 2. Newer nonbenzodiazepine hypnotics Zolpidem Zaleplon Chloral hydrate, Triclophos, Paraldehyde, Glutethimide, Methyprylon, Methaqualone and Meprobamate are historical sedative-hypnotics no longer used. The sleep is arousable, but the subject may feel confused and unsteady if waken early. The effects on sleep become progressively less marked if the drug is taken every night consecutively. Hangover (dizziness, distortions of mood, irritability and lethargy) may occur in the morning after a nightly dose. The barbiturate site appears to be located on or subunit, because presence of only these subunits is sufficient for their response. The 5-phenyl substituted compounds (phenobarbitone) have higher anticonvulsant : sedative ratio, i. At very high concentrations, barbiturates depress voltage sensitive Na+ and K+ channels as well.
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Several species of Strychnos (Loganaceae) contain strychnine and brucine (dimethoxystrychnine). Cases of unintentional poisoning from seeds of Strychnos nux vomica have been reported (Wang et al. Seeds of Strychnos ignatii in the Phillipine islands have caused similar toxic effects. Excitatory Amino Acids Widely divergent species of plants produce amino acids that mimic the action of glutamate on the central nervous system. Most fast excitatory transmission in the mammalian brain is mediated by inotropic receptors for the amino acid, glutamate, on specialized neurons. Different types of glutamate receptors respond to different excitatory amino acids from plants, acting on one or more of these glutamate receptor subtypes. The consequence of ingestion of excitatory amino acids is excessive stimulation that may result in death of neurons. One of these acids, kainic acid, is present in the marine red alga Digenia simplex. The alga produces domoic acid, an analog of glutamate, as do several species of the marine diatom Nitzschia (Kotaki et al. Acute symptoms are gastrointestinal distress, headache, hemiparesis, confusion, and seizures. Prolonged effects are severe memory deficits and sensorimotor neuropathy (Teitelbaum et al. The fungus Amanita muscaria (fly agaric) got its name from its poisonous actions on flies. Poisoning from this woodland mushroom and from Amanita pantherian (panther agaric, common in western United States) is due to the content of the excitatory amino acid, ibotenic acid (isoxazole amino acid), and to its derivative, muscimol (Li and Oberlies, 2005). The effects are somewhat variable: central nervous system depression, ataxia, hysteria, and hallucinations. The content of ibotenic acid varies with the time of year; more has been reported in spring than in fall. Several other genera of fungi have hallucinogenic actions, notably Psilocybe, containing the indoles, psilocin, and psilocybin (Tsujikawa et al. The pea family (Leguminosae) contains several species that produce excitatory amino acids in the seeds. Willardiine [1-(2-amino2-carboxyethyl)pyrimidine-2,4-dione] has been isolated from Acacia willardiana, Acacia lemmoni, Acacia millefolia, and Mimosa asperata (Gmelin, 1961). Lathyrus sylvestris (flat pea) is a perennial indigenous to Europe and central Asia and naturalized in Canada and northern United States. An acute neurologic condition in sheep begins with weakness and progresses to tremors and prostration, sometimes with clonic movements and seizures (Rasmussen et al. Seeds of Lathyrus sativus (grass pea) are used as food in several countries, including India and Ethiopia. Affected individuals have corticospinal motor neuron degeneration with severe spastic muscle weakness and atrophy but little sensory involvement (Spencer et al. Motor Neuron Demyelination Paralysis develops from some toxins without primary excitation of neurons. Karwinskia humboldtiana, family Rhamnaceae, is a shrub of southwestern United States, Mexico, and Central America. Anthracenones are found in the seeds, the amount varying with stage of growth; green fruit may be more toxic than ripe fruit (Bermudez et al. The clinical syndrome that develops after a latency of several days is ascending flaccid paralysis, beginning with demyelination of large motor neurons in the legs and, in fatal cases, leading to bulbar paralysis (Martinez et al. In addition to neurotoxicity, the anthracenones in Karwinskia, especially peroxisomicine A2, [3,39-dimethyl-3,39,8,89,9,99-hexahydroxy-3,30,4,49-tetrahydro(7,10-bianthracene)-1,19-2H,29H -dione], causes lung atelectasis and emphysema and massive liver necrosis. Inhibition of catalase in peroxisomes has been proposed as the mechanism of cell toxicity (Martinez et al. The common name comes from the most obvious consequence of ingestion of locoweeds: aberrant behavior with hyperexcitability and locomotor difficulty. In animals dying from locoweed poisoning, there is cytoplasmic foamy vacuolation of cerebellar neurons. Inhibition of the Golgi enzyme results in abnormal brain glycoproteins and accumulation of mannose-rich oligosaccharides (Tulsiani et al. The pathology is not limited to the nervous system and the effects of swainsonine poisoning are found in several tissues. A species of the fungus Embellisia, an endophyte on locoweeds, may also produce swainsonine (McLainRomero et al. Parasympathetic Stimulation Several plant alkaloids affect the autonomic nervous system, mimicking the transmitter acetylcholine at autonomic ganglia (nicotinic receptors) or the peripheral endings of the parasympathetic system (muscarinic receptors). The postsynaptic receptors at terminations of the parasympathetic nerve fibers are called "muscarinic" after the selective stimulation of these receptors by muscarine, a quaternary ammonium furan, that was first extracted from the mushroom A. However, this mushroom contains only trace amounts of muscarine, and poisoning is due to its content of ibotenic acid. Some mushrooms of the genera Inocybe, Clitocybe, and Omphalatus contain significant amounts of muscarine, and consumption of toxic species causes diarrhea, sweating, salivation, and lacrimation, all referable to stimulation of parasympathetic receptors (de Haro et al. Parasympathetic Block the belladonna alkaloids (atropine, lhyoscyamine, and scopolamine), known for their block of muscarinic receptors, are found in several genera of Solanaceae, the nightshade family. Datura stramonium (jimson weed) is native to India and contains primarily scopolamine; Hyoscyamus niger (henbane) is native to Europe and contains primarily l-hyoscyamine; Atropa belladonna (deadly nightshade), also native to Europe, contains atropine; Duboisia myoporoides (pituri) in Australia contains l-hyoscyamine. The effects of modest doses of l-hyoscyamine or atropine are referable to muscarinic receptor block: tachycardia, dry mouth, dilated pupils, and decreased gastrointestinal motility. Large doses of either or of scopolamine affect the central nervous system with confusion, bizarre behavior, hallucinations, and subsequent amnesia. Seeds of Datura ferox contain belladonna alkaloids and are contaminants of animal feed in some parts of Europe. In areas where millet, wheat, rye, corn, and bean seeds are used for human consumption, and where D stramonium and Datura metel are common weeds, the grain sometimes has been contaminated with Datura seeds. Symptoms from eating bread made from contaminated flour are typical of poisoning from belladonna alkaloids (van Meurs et al. An unusual source of belladonna poisoning has been reported from eating wasp honey. Polistes species of wasps store honey, and atropine-like poisoning has been reported from consuming the honey when the wasps have gathered nectar from Datura inoxia (Ramirez et al. The seeds of Solanum dulcamara (bittersweet) are brilliant red-orange and are gathered in the fall for flower arrangements. The seeds contain solanine, a glycoalkaloid, responsible for the acute toxicity from ingested seeds, including tachycardia, dilated pupils, and hot, dry skin, as in atropine poisoning (Ceha et al. This long-term sensory neuron blocking effect has therapeutic use in chronic pain (Szalcsany, 2002). The sensory desensitization produced by capsaicin is not due to acute cell death and long-lasting changes in mitochondria in cultured dorsal root ganglion cells have been demonstrated (Dedov et al. It has recently been suggested that capsaicin may also have an action on another ion channel, the 4-aminopyridine-sensitive K+ channel, and may inhibit contractile mechanisms by release of Ca2+ from intracellular storage sites (Fujimoto et al. Skeletal Muscle and Neuromuscular Junction Neuromuscular Junction Block of the neuromuscular junction of skeletal muscle may result from either block of postsynaptic acetylcholine receptors (nicotinic receptors) by an antagonist or by an agonist causing excessive stimulation of the receptor followed by prolonged depolarization. An isomer of nicotine, anabasine, present in Nicotiana glauca (tree tobacco, Solanaceae), produces prolonged depolarization of the junction. Consumption of the leaves of the plant has caused flexor muscle spasm and gastrointestinal irritation, followed by severe, generalized weakness, and respiratory compromise (Mellick et al. Curare, the South American arrow poison is a potent neuromuscular blocking agent used clinically. In warm weather, blooms of bluegreen algae are not uncommon in farm ponds in temperate regions, particularly ponds enriched with fertilizer. Under these conditions, one species of alga, Anabaena flosaquae, produces a neurotoxin, anatoxin A, that depolarizes and blocks acetylcholine receptors, both nicotinic and muscarinic, sometimes causing death in animals that drink the pond water. Methyllycaconitine is a norditerpenoid present in Delphinium barbeyi (tall larkspur, Ranunculaceae) and in some related species. The plant contaminates western pastures in the United States and causes death of livestock. Poisoned cattle show muscle tremors and ataxia followed by prostration and respiratory arrest in fatal cases. The compound has a high affinity for the acetylcholine receptor at the neuromuscular junction like curare.
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A limited number of studies of this phenomenon by other investigators are no more definitive. Investigations of adverse effects of solvents on old animals have been quite limited. Attention has been primarily focused on age-related susceptibility of rodents to liver damage. Rikans and Hornbrook (1997) reviewed studies showing increased susceptibility of geriatric F-344 rats to allyl alcohol, but there was no apparent age dependency with bromobenzene. Dermal absorption could be influenced by loss of integrity of the stratum corneum, reduction in skin surface lipids and atrophy of the dermal capillary network (Roskos et al. Total lung capacity does not change with age, but vital capacity (mobile volume) diminishes progressively due to loss of lung elasticity and strength of the respiratory muscles. Residual capacity (fixed volume) increases with progressive narrowing and closure of small airways (Ritschel, 1988). Other alterations contributing to lower pulmonary absorption include decreases in alveolar surface area, membrane permeability and capillary blood volume, and thicker alveolar cell membranes (Clewell et al. Age influences the distribution of xenobiotics in the body, as well as their metabolism and elimination (Bressler and Bahl, 2003). Relatively lipid-soluble solvents accumulate in adipose tissue and are released slowly to sites of action, metabolism, and elimination. McLean and Le Couteur (2004) presented evidence that aging of the sinusoidal endothelium reduced oxygen delivery and drug transfer from blood to hepatocytes. Schmucker (2005) and Herrlinger and Klotz (2001) did not find significant relationships between aging and P450 activities in human liver. Information is available on certain age-related aspects of xenobiotic clearance other than metabolism. Plasma protein binding of drugs generally remains unaltered or diminishes modestly with age (Grandison and Boudinot, 2000). Renal clearance diminishes with advancing age, due to parallel annual decreases of 0. Blood levels of the parent compounds remained relatively constant during adulthood, but metabolite levels or amounts metabolized frequently varied during the pediatric and geriatric years (Sarangapani et al. Gender Some of the physiological and biochemical differences between men and women have the potential to alter tissue dosimetry and health effects of certain solvents. The investigators located few data on gender-dependent dermal or pulmonary absorption of solvents or other chemicals. Distribution of water- and lipid-soluble solvents can vary substantially between men and women (Schwartz, 2003). Women typically have smaller volumes of distribution for polar solvents, but larger volumes of distribution for lipophilic solvents (Gandhi et al. Nomiyama and Nomiyama (1974) found that women retain less inhaled acetone and ethyl acetate than similarly exposed men. The major sex differences in P450-mediated hepatic metabolism in rats are not seen in humans or most other mammals (Nakajima, 1997). Some of the differentially expressed genes involve drug and steroid metabolism, but the biological significance of these variances is unknown. No marked gender differences in P450-catalyzed oxidation reactions have been identified in humans (Schmucker et al. Women were found to have a higher blood:air partition coefficient, a higher percent of body fat and higher maximum rate of benzene metabolism than men. Relatively little is known about potential influences of contraceptives, hormone replacement therapy, or pregnancy on the metabolism and disposition of xenobiotics (Gleiter and GundertRemy, 1996). The menstrual cycle with its hormone changes may influence the metabolism of some xenobiotics (Fletcher et al. Plasma volume increases 50% in pregnant women, resulting in a decrease in albumin concentration and plasma protein binding of many drugs (Fletcher et al. Cardiac output increases 50%, due to increases in stroke volume and heart rate (Silvaggio and Mattison, 1994). Uterine blood flow, renal plasma flow, and glomerular filtration rise substantially, though no information on hepatic blood flow is apparently available. Simulated vinyl chloride levels, for example, were 4 orders of magnitude lower in the neonates. Fetal/neonatal isopropanol levels were forecast to be orders of magnitude lower than maternal levels. Genetics A variety of genetic polymorphisms for biotransformation have been found to occur at different frequencies in different ethnic groups (Daly et al. Polymorphisms for xenobiotic-metabolizing enzymes may affect the quantity and quality of enzymes and the outcomes of exposures to solvents (Ingelman-Sundberg et al. It is important to note that culturally linked environmental factors also contribute to ethnic differences in metabolism and disposition of solvents and other chemicals. It is often difficult to disentangle the influences of genetic traits from those of different lifestyles, socioeconomic status, and geographic settings. These pathways, however, can lead to production of cytotoxic, mutagenic metabolites in the kidney. Increased susceptibility to different cancers has been reported to be associated with certain genetic polymorphisms, which occur with different frequencies in different ethnic groups (Daly et al. Genetic polymorphisms, variable transporter activities, genetic variants of receptors and regulatory proteins, and environmental factors can play roles in individual variability in P450 induction (Tang et al. Exogenous Factors P450 Inducers Considerable effort has been devoted to investigation of effects of enzyme inducers on solvent metabolism and toxicity. Preexposure to many of these can thus markedly increase the metabolic activation and adverse effects of certain solvents. Although levels/activities are highest in liver, induction in extrahepatic tissues can result in increased metabolic activation in situ that may be toxicologically significant. It is worthy of note that many chemicals that induce P450s also induce detoxifying enzymes (e. A number of naturally occurring organosulfur compounds in allium vegetables have been demonstrated to induce these enzymes in the liver, kidney, intestines, and lungs of Wistar rats (Guyonnet et al. As described previously in the Metabolism subsection, increased metabolic capacity in an individual is of little consequence for environmentally encountered levels of blood-flowlimited (i. Thus, genetically predisposed or induced individuals should be at no greater cancer risk from these solvents than the average person. It should be recalled that mechanisms of P450 inhibition can be categorized as reversible, quasireversible, and irreversible. With quasi-reversible inhibition, the metabolite and enzyme form a complex that is so stable that the intact enzyme may be unavailable for further metabolism. With mechanism based or suicide inhibition, the reactive metabolite irreversibly inhibits the enzyme by binding to its active site. Note the demarcation between vacuolated/necrotic centrilobular and midzonal cells, and normally appearing periportal cells in (C). Identification of isoform-selective, nontoxic inhibitors may eventually lead to modulation of human xenobiotic metabolism for therapeutic purposes (Halpert et al. Physical Activity Exercise can significantly affect the kinetics of xenobiotics (van Baak, 1990), but is often not considered in occupational risk assessments of solvents. In contrast, pulmonary blood flow and metabolism are rate limiting for uptake of the more lipophilic solvents (Johanson and Filser, 1992). Heavy exercise can increase pulmonary uptake of relatively polar solvents as much as five-fold in human subjects (Astrand, 1983). Light exercise doubles uptake of relatively lipid-soluble solvents, but no further increases occur at higher workloads.
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The teratogenicity of phenytoin has been compared in several inbred strains of mice. New genomic approaches have begun to identify genes associated with differential susceptibility of mouse strains to valproic acid (Finnell et al. One study has demonstrated more than a doubling of mean serum folate concentrations across all sex and age groups since then (Dietrich et al. While this survey indicates partial success of the folate fortification program, women capable of becoming pregnant were urged to continue to follow the U. Stress Disease Chronic hypertension is a risk factor for the development of preeclampsia, eclampsia, and toxemia of pregnancy, and hypertension is a leading cause of pregnancy-associated maternal deaths. Uncontrolled maternal diabetes mellitus is a significant cause of prenatal morbidity. Cytomegalovirus infection is associated with fetal death, microcephaly, mental retardation, blindness, and deafness (MacDonald and Tobin, 1978) and maternal infection with Toxoplasma gondii is known to induce hydrocephaly and chorioretinitis in infants (Alford et al. Hyperthermia is a potent experimental animal teratogen (Edwards, 1986), and there is a body of evidence associating maternal febrile illness during the first trimester of pregnancy with birth defects in humans, most notably malformations of the central nervous system (Warkany, 1986; Milunsky, et al. Diverse forms of maternal toxicity may have in common the induction of a physiologic stress response. Understanding potential effects of maternal stress on development may help interpret developmental toxicity observed in experimental animals at maternally toxic dosages. Various forms of physical stress have been applied to pregnant animals in attempts to isolate the developmental effects of stress. Subjecting pregnant rats or mice to noise stress throughout gestation can produce developmental toxicity (Kimmel et al. Restraint stress produces increased fetal death in rats (Euker and Riegle, 1973) and cleft palate (Barlow et al. Nevertheless, studies investigating the relationship of maternal stress and pregnancy outcome have indicated a positive correlation between stress and adverse developmental effects, including low birth weight and congenital malformations (Stott, 1973; Gorsuch and Key, 1974). Placental Toxicity Nutrition A wide spectrum of dietary insufficiencies ranging from proteincalorie malnutrition to deficiencies of vitamins, trace elements, and/or enzyme cofactors is known to adversely affect pregnancy (Keen et al. Centers for Disease Control and Prevention to recommend folate supplementation for women of childbearing age and folate supplementation of some foodstuffs. In 1996, the United States Food and Drug Administration mandated enrichment of cereal grain products with folate the placenta is the interface between the mother and the conceptus, providing attachment, nutrition, gas exchange, and waste removal. The placenta also produces hormones critical to the maintenance of pregnancy, and it can metabolize and/or store xenobiotics. Placental toxicity may compromise these functions and produce or contribute to untoward effects on the conceptus. Slikker and Miller (1994) list 46 toxicants known to be toxic to the yolk sac or chorioallantoic placenta, including metals such as cadmium (Cd), arsenic, or mercury, cigarette smoke, ethanol, cocaine, endotoxin, and sodium salicylate (Daston, 1994; Slikker and Miller, 1994). Cd is among the best studied of these, and it appears that the developmental toxicity of Cd during mid- to late gestation involves both placental toxicity (necrosis, reduced blood flow) and inhibition of nutrient transport across the placenta. Maternal injection of Cd during late gestation results in fetal death in rats, despite little cadmium entering the fetus (Parizek, 1964; Levin and Miller, 1980). Despite fetal Cd burdens almost tenfold higher than those following maternal administration, only a slight increase in fetal death was observed. Cd is a transition metal similar in its physicochemical properties to the essential metal zinc (Zn). Cadmium may also competitively inhibit other Zn-dependent processes in the placenta. Coadministration of Zn ameliorates the developmental toxicity of administered Cd, further indicating that interference of Cd with Zn metabolism is a key to its developmental toxicity (Ferm and Carpenter, 1967; Daston, 1982). Maternal Toxicity A retrospective analysis of relationships between maternal toxicity and specific prenatal effects found species-specific associations between maternal toxicity and adverse developmental effects. Yet, among rat, rabbit, and hamster studies, 22% failed to show any developmental toxicity in the presence of significant maternal toxicity (Khera, 1984, 1985). The approach of tabulating literature data suffers from possible bias in the types of studies published (e. In a study designed to test the potential of maternal toxicity to affect development, Kavlock et al. Developmental effects were agent-specific, ranging from complete resorption to lack of effect. An exception was an increased incidence of supernumerary ribs (ribs on the first lumbar vertebra), which occurred with 7 of the 10 compounds. When these compounds were administered at high dosages producing maternal toxicity (weight loss or lethality), a variety of adverse developmental outcomes was noted, including increased intrauterine death (two compounds), decreased fetal weight (two compounds), supernumerary ribs (two compounds), and enlarged renal pelves (two compounds). In addition, two of the compounds produced no developmental toxicity despite substantial maternal toxicity. These diverse developmental responses led the authors to conclude that maternal toxicity defined by weight loss or mortality is not associated with any consistent syndrome of developmental effects in the rat. However, clear delineation of the relative role(s) of indirect maternal and direct embryo/fetal toxicity is difficult. Acetazolamide inhibits carbonic anhydrase and is teratogenic in mice (Hirsch and Scott, 1983). Although maternal weight loss is not correlated with malformation frequency, maternal hypercapnia potentiates the teratogenicity of acetazolamide. In C57Bl/6J mice, maternal hypercapnia alone results in right forelimb ectrodactyly, the characteristic malformation induced by acetazolamide. Diflunisal, an analgesic and anti-inflammatory drug, causes axial skeletal defects in rabbits. A single dose of diflunisal on day 5 of gestation was teratogenic and produced a maternal anemia that lasted through day 15. Concentration of the drug in the embryo was less than 5% of the peak maternal blood level, and diflunisal was cleared from maternal blood before day 9, the critical day for induction of similar axial skeletal defects by hypoxia. Thus, the teratogenicity of diflunisal in the rabbit was probably due to hypoxia resulting from maternal anemia. Phenytoin, an anticonvulsant, can affect maternal folate metabolism in experimental animals, and these alterations may play a role in the teratogenicity of this drug (Hansen and Billings, 1985). Further, maternal heart rates were monitored on gestation day 10 after administration to susceptible A/J mice and resistant C57Bl/6J mice (Watkinson and Millikovsky, 1983). Heart rates were depressed by phenytoin in a dose-related manner in the A/J mice but not in C57Bl/6J mice. A mechanism of teratogenesis was proposed relating depressed maternal heart rate and embryonic hypoxia. Supporting studies have demonstrated that hyperoxia reduces the teratogenicity of phenytoin in mice (Millicovsky and Johnston, 1981). Reduced uterine blood flow has been proposed as a mechanism of teratogenicity caused by hydroxyurea, which produces elevated systolic blood pressure, altered heart rate, decreased cardiac output, severely decreased uterine blood flow, and increased vascular resistance in pregnant rabbits (Millicovsky et al. Embryos exhibited craniofacial and pericardial hemorrhages immediately after treatment (Millicovsky and DeSesso, 1980a), and identical embryopathies were achieved by clamping the uterine vessels of pregnant rabbits for 10 minutes (Millicovsky and DeSesso, 1980b). Metallothionein synthesis is inducible by a wide variety of chemical and physical agents including metals, alcohols, urethane, endotoxin, alkylating agents, hyper- or hypothermia, and ionizing radiation (Daston, 1994). Estrogens induce pleiotropic effects, acting on many types of cells with estrogen receptors, and can display cell and organ-specific agonist and antagonist actions. Manifestations include malformations and functional alterations of the male and female reproductive tract and brain. In adulthood, male offspring show hypospadias, while females exhibit excessive vaginal keratinization and epidermoid tumors of the vagina. In male offspring, sterility is observed at high doses, the result of retained rete testes and Mullerian duct remnants, abnormal sperm morphology and motility, cryptorchidism, abnormal reproductive tract secretions, and inflammation (Newbold, 1995). Other estrogenic (or anti-estrogenic) developmental toxicants include estradiol (Biegel et al. Female offspring are generally more sensitive than males and altered pubertal development, reduced fertility, and reproductive tract anomalies are common findings.
- Lung problems including pneumonia or pneumonitis
- More lead will leach into hot liquids like coffee, tea, and soups than into cold beverages.
- Twisted loop of the bowel (volvulus)
- You notice chest pain, leg pain, confusion, weakness, numbness, or other new symptoms.
- · IV drug use
- Your head is placed in a special frame using screws to keep it still during the procedure. Numbing medicine is applied where the screws contact the scalp. Sometimes, the procedure is done in the MRI and a frame is not used around your head.
- Valproic acid: 50 to 100 mcg/mL
- Learning disabilities
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Treatment of metal poisoning is sometimes used to prevent, or even attempt to reverse, toxicity. The typical strategy is to give metal chelators that will complex the metal and enhance its excretion (Klaassen, 2001). Most chelators are not specific and will interact with a number of metals, eliminating more than the metal of concern. In addition, the vast array of biological metal ligands is a formidable barrier to chelator efficacy (Klaassen, 2001). Metal chelation therapy should be considered a secondary alternative to reduction or prevention of toxic metal exposures. Such therapy can be used for many different metals including lead, mercury, iron, and arsenic. For detailed discussion on the pharmacology of chelation therapy, see Klaassen (2001). The word arsenic is from the Persian word Zarnikh, as translated to the Greek arsenikon, meaning "yellow orpiment. Arsenicals have been used since ancient times as drugs and even today are very effective against acute promyelocytic leukemia (Soignet et al. Arsenic exists in the trivalent and pentavalent forms and is widely distributed in nature. The most common inorganic trivalent arsenic compounds are arsenic trioxide and sodium arsenite, while common pentavalent inorganic compounds are sodium arsenate, arsenic pentoxide, and arsenic acid. Important organo-arsenicals include arsenilic acid, arsenosugars, and several methylated forms produced as a consequence of inorganic arsenic biotransformation in various organisms, including humans. Occupational exposure to arsenic occurs in the manufacture of pesticides, herbicides, and other agricultural products. Environmental arsenic exposure mainly occurs from arsenic-contaminated drinking water. Environmental exposure to arsenic also occurs from burning of coal containing naturally high levels of arsenic (Liu et al. It is not known, however, to what extent arsenic-treated wood products contribute to human exposure. Skin is a potential route of exposure to arsenic, and systemic toxicity has been reported in persons having dermal contact with solutions of inorganic arsenic Pharmacology of Metals Metal and metal compounds have a long history of pharmacological use. Metallic agents, largely because of their potential toxicity, have been often used in chemotherapeutic settings. For instance, mercury was used in the treatment of syphilis as early as the 16th century. Today, many metallic chemicals remain valuable pharmacological tools in the treatment of human disease, as exemplified by the highly effective use of platinum compounds in cancer chemotherapy. In addition, gallium and titanium complexes are promising metal compounds in cancer chemotherapy. Deposition in airways and absorption of arsenicals from lungs is dependent on particle size and chemical form. Arsenic has a predilection for skin and is excreted by desquamation of skin and in sweat, particularly during periods of profuse sweating. Arsenic in the fingernails and hair has been used as a biomarker for exposure, including both current and past exposures, while urinary arsenic is a good indicator for current exposure. Methylation of inorganic arsenic species is no longer considered as a detoxication process, as recent work has identified the highly toxic trivalent methylated arsenicals. Some animal species even lack arsenic methylation capacity, perhaps as an adaptation mechanism. Arsenate (As5+ ) is rapidly reduced to arsenite (As3+ ) by arsenate reductase (presumably purine nucleoside phosphorylase). However, large variations in arsenic methylation occur due to factors such as age and sex, and it is suspected that ge- netic polymorphisms may exist. Symptoms of acute intoxication include fever, anorexia, hepatomegaly, melanosis, cardiac arrhythmia and, in fatal cases, eventual cardiac failure. Acute arsenic ingestion can damage mucous membranes of the gastrointestinal tract, causing irritation, vesicle formation, and even sloughing. Anemia and leucopenia, particularly granulocytopenia, occur a few days following high-dose arsenic exposure and are reversible. Intravenous arsenic infusion at clinical doses in the treatment of acute promyelocytic leukemia may be significantly or even fatally toxic in susceptible patients, and at least three sudden deaths have been reported (Westervelt et al. Arsine gas, generated by electrolytic or metallic reduction of arsenic in nonferrous metal production, is a potent hemolytic agent, producing acute symptoms of nausea, vomiting, shortness of breath, and headache accompanying the hemolytic reaction. In humans, chronic exposure to arsenic induces a series of characteristic changes in skin epithelium. Diffuse or spotted hyperpigmentation and, alternatively, hypopigmentation can first appear between 6 months to 3 years with chronic exposure to inorganic arsenic. Liver injury may progress to cirrhosis and ascites, even to hepatocellular carcinoma (Centeno et al. Repeated exposure to low levels of inorganic arsenic can produce peripheral neuropathy. This neuropathy usually begins with sensory changes, such as numbness in the hands and feet but later may develop into a painful "pins and needles" sensation. Both sensory and motor nerves can be affected, and muscle tenderness often develops, followed by weakness, progressing from proximal to distal muscle groups. Peripheral vascular disease has been observed in persons with chronic exposure to inorganic arsenic in the drinking water in Taiwan. Arsenic-induced vascular effects have been reported in Chile, Mexico, India, and China, but these effects do not compare in magnitude or severity to Blackfoot disease in Taiwanese populations, indicating other environmental or dietary factors may be involved (Yu et al. Some studies have shown an association between high arsenic exposure in Taiwan and Bangladesh and an increased risk of diabetes mellitus, but the data for occupational exposure is inconsistent (Navas-Acien et al. Additional research is required to verify a link between inorganic arsenic exposure and diabetes. The hematologic consequences of chronic exposure to arsenic may include interference with heme synthesis, with an increase in urinary porphyrin excretion, which has been proposed as a biomarker for arsenic exposure (Ng et al. Mechanisms of Toxicity the trivalent compounds of arsenic are thiol-reactive, and thereby inhibit enzymes or alter proteins by reacting with proteinaceous thiol groups. Pentavalent arsenate is an uncoupler of mitochondrial oxidative phosphorylation, by a mechanism likely related to competitive substitution (mimicry) of arsenate for inorganic phosphate in the formation of adenosine triphosphate. In addition to these basic modes of action, several mechanisms have been proposed for arsenic toxicity and carcinogenicity. Unlike many carcinogens, arsenic is not a mutagen in bacteria and acts weakly in mammalian cells, but can induce chromosomal abnormalities, aneuploidy, and micronuclei formation. Arsenic can also act as a comutagen and/or co-carcinogen (Rossman, 2003; Chen et al. These mechanisms are not mutually exclusive and multiple mechanisms likely account for arsenic toxicity and carcinogenesis. Carcinogenicity the carcinogenic potential of arsenic was recognized over 110 years ago by Hutchinson, who observed an unusual number of skin cancers occurring in patients treated for various diseases with medicinal arsenicals. Arsenic-induced skin cancers include basal cell carcinomas and squamous cell carcinomas, both arising in areas of arsenicinduced hyperkeratosis. The basal cell cancers are usually only locally invasive, but squamous cell carcinomas may have distant metastases. In humans, the skin cancers often, but not exclusively, occur on areas of the body not exposed to sunlight (e. Animal models have shown that arsenic acts as a rodent skin tumor copromoter with 12-O-teradecanoyl phorbol-13acetate in v-Ha-ras mutant Tg. This includes arsenicinduced tumors of the urinary bladder, and lung, and potentially the liver, kidney, and prostate. In contrast to most other human carcinogens, it has been difficult to confirm the carcinogenicity of inorganic arsenic in experimental animals.
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Immune Responses In addition to the activation of an inflammatory response, immune-mediated reactions may also lead to severe liver injury (Ju, 2005). Drugs and chemicals that have been suggested to cause immune-mediated injury mechanisms in the liver include halothane, tienilic acid, and dihydralazine (Ju, 2005; Uetrecht, 2007). A delay in onset of the injury or the requirement for repeated exposure to the drug and the formation of antibodies against drug-modified hepatic proteins are characteristic features of immune reactions (Ju, 2005). However, the mechanisms of these immune-mediated liver injuries are not well understood. In support of the hapten hypothesis, antibodies against drug-modified proteins were detected in the serum of patients with halothane hepatitis (Vergani et al. This suggests that additional activating factors may be necessary to induce immune-mediated liver injury. Immune-mediated (allergic) idiosyncratic hepatotoxicity Diclofenac (analgesic) Halothane (anesthetic) Nitrofurantoin (antibiotic) Phenytoin (anticonvulsant) Tienilic acid (diuretic) B. Nonimmune-mediated (non-allergic) idiosyncratic hepatotoxicity Amiodarone (antiarrhythmic) Bromfenac (alagesic)-withdrawn from market Diclofenac (analgesic) Disulfiram (alcoholism) Isoniazid (antituberculosis) Ketoconazole (antifungal) Rifampicin (antimicrobial) Troglitazone (antidiabetes)-withdrawn from market Valproate (anticonvulsant) source: Kaplowitz N: Idiosyncratic drug hepatotoxicity. A cytotoxic immune response occurs only when the T-cell receptor stimulation with the antigen is accompanied by an independent co-stimulation of the T cell. In the absence of this co-stimulatory signal, the antigens derived from drug-modified proteins induce immune tolerance (Ju, 2005; Uetrecht, 2007). Hepatotoxic doses of acetaminophen caused a loss of lymphocytes from spleen, thymus, and draining hepatic lymph node and immunesuppression (Masson et al. These mechanisms could be the reason that tolerance appears to be the default reaction to drug-induced protein modifications in most people. However, impairment of these mechanisms in a limited number of patients can make them susceptible to the immune-mediated liver disease (Ju, 2005; Uetrecht, 2007). Idiosyncratic Liver Injury Idiosyncratic drug hepatoxicity is a rare but potentially serious adverse event, which is not clearly dosedependent, is at this point unpredictable and affects only very few of the patients exposed to a drug or other chemicals. However, idiosyncratic toxicity is a leading cause for failure of drugs in clinical testing and it is the most frequent reason for posting warnings, restricting use, or even withdrawal of the drug from the market (Li, 2002; Kaplowitz, 2005) (Table 13-4). In addition, idiosyncratic hepatotoxicity is observed after consumption of herbal remedies and food supplements (Stickel et al. There are no known mechanisms of cell injury specific for idiosyncratic hepatotoxins. A number of drugs including halothane (anesthetic), nitrofurantoin (antibiotic), and phenytoin (anticonvulsant) are thought to cause injury mainly by immune (allergic) mechanisms as described in the previous paragraph (Kaplowitz, 2005; Uetrecht, 2007). Diclofenac (analgesic) can elicit allergic and nonallergic mechanisms of toxicity (Boelsterli, 2003). Because only very few patients (1 in 10,000 or less) treated with these drugs actually experience significant hepatotoxicity, the prevailing opinion at the present time is that an enhanced individual susceptibility with the failure to adapt to a mild adverse drug reaction is a key factor in the pathogenesis (Watkins, 2005). However, only a small subgroup of these patients develops severe hepatotoxicity (Mitchell et al. This raises the possibility that one or several gene defects, which prevent effective adaption to drug-induced cellular stress, may be involved in idiosyncratic reactions (Watkins, 2005). The antidiabetic drug troglitazone (Rezulin r ) was withdrawn from the market due to idiosyncratic hepatotoxicity. In preclinical studies troglitazone did not cause any relevant liver toxicity and despite extensive investigations since withdrawal of the drug, the mechanism of toxicity remains unclear (Chojkier, 2005). Several studies suggest that very high concentrations of troglitazone can induce mitochondrial dysfunction in vitro (Haskins et al. Because the conditions applied in these studies are not relevant for human exposure, the proposed mechanism cannot explain the idiosyncratic toxicity in humans. However, the data suggest that troglitazone can cause a subclinical mitochondrial stress, which could sensitize hepatocytes to troglitazone. Although the animals did not develop severe hepatic injury as observed in humans, the injury in mice occurred also after a lag time, which is consistent with the hypothesis that a certain threshold of mitochondrial stress has to be reached to cause cell injury (Ong et al. Overall, these findings support the concept that a clinically silent genetic deficiency in individuals can trigger the hepatotoxicity of a drug, which by itself may only cause a mild and clinically silent cellular stress. This recent insight indicates the need for a paradigm shift for preclinical toxicity studies (Jaeschke, 2007). The assumption in traditional toxicity studies is that an adverse effect of a drug can be detected by progressively increasing the dose. It may be necessary to include experiments with genetically deficient animals in these studies if there is any evidence for clinically silent adverse effects of these drugs. In addition to the genetic makeup, which may render individuals more susceptible to stress induced by the metabolism of drugs or chemicals, a second "hit" such as a systemic inflammatory response can also contribute to the unmasking of the toxicity at least in experimental models (Ganey and Roth, 2001). Because idiosyncratic hepatotoxicity is a rare event for most drugs, it is likely that a combination of gene defects and adverse events need to be present simultaneously in an individual to trigger the severe liver injury. A detailed genomic analysis of patients with idiosyncratic responses to drug exposure may give additional insight what gene expression profile renders a patient susceptible (Watkins, 2005). Traditional mechanistic investigations in combination with genomic and proteomic approaches have the greatest potential to yield important new insight into pathomechanisms. Braet F, Wisse E: Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Breuhahn K, Longerich T, Schirmacher P: Dysregulation of growth factor signaling in human hepatocellular carcinoma. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Decker K: Biologically active products of stimulated liver macrophages (Kupffer cells). Direct action versus requirement for hepatocyte activation in different mouse strains. Fabregat I, Roncero C, Fernandez M: Survival and apoptosis: a dysregulated balance in liver cancer. Geier A, Fickert P, Trauner M: Mechanisms of disease: Mechanisms and clinical implications of cholestasis in sepsis. Homolya L, Varadi A, Sarkadi B: Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate. Jaeschke H: Cellular adhesion molecules: Regulation and role in the pathogenesis of liver disease. Jaeschke H: Role of inflammation in the mechanism of acetaminopheninduced hepatotoxicity. Mechanisms of neutrophilinduced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. Jaeschke H: Troglitazone Hepatotoxicity: Are we getting closer to understanding idiosyncratic liver injury? Jaeschke H, Kleinwaechter C, Wendel A: the role of acrolein in allyl alcoholinduced lipid peroxidation and liver cell damage in mice. Jungermann K, Katz N: Functional specialization of different hepatocyte populations. Jungermann K, Kietzmann T: Oxygen: Modulator of metabolic zonation and disease of the liver. Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study. Wake K: Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Wiedow O, Meyer-Hoffert U: Neutrophil serine proteases: Potential key regulators of cell signalling during inflammation. Zhang Y, Chong E, Herman B: Age-associated increases in the activity of multiple caspases in Fisher 344 rat organs. Ziegler K, Frimmer M: Cyclosporin A protects liver cells against phalloidin: Potent inhibition of the inward transport by cholate and phallotoxins. In addition, the kidney synthesizes and releases hormones, such as renin and erythropoietin, and metabolizes vitamin D3 to the active 1,25-dihydroxy vitamin D3 form. A toxic insult to the kidney therefore could disrupt any or all of these functions and could have profound effects on total body metabolism. Fortunately, the kidneys are equipped with a variety of detoxification mechanisms and have considerable functional reserve and regenerative capacities.
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The living matter that is injured is termed the uneconomic form (or undesirable), and the matter protected is called the economic form (or desirable). They may be related to each other as parasite and host or may be two tissues in one organism. This biological diversity interferes with the ability of ecotoxicologists to predict the toxic effects of a chemical in one species (humans) from experiments performed in another species (laboratory animals). However, by taking advantage of the biological diversity, it is possible to develop chemicals that are lethal for an undesired species and harmless for other species. In agriculture, for example, there are fungi, insects, and even competitive plants that injure the crop, and thus selective pesticides are needed. Similarly, animal husbandry and human medicine require chemicals, such as antibiotics, that are selectively toxic to the undesirable form but do not produce damage to the desirable form. Drugs and other chemicals used for selective toxic purposes are selective for one of two reasons. Either (1) the chemical is equally toxic to both economic and uneconomic cells but is accumulated mainly by uneconomic cells or (2) it reacts fairly specifically with a cytological or a biochemical feature that is absent from or does not play an important role in the economic form (Albert, 1965, 1973). Selectivity resulting from differences in distribution usually is caused by differences in the absorption, biotransformation, or excretion of the toxicant. The selective toxicity of an insecticide spray may be partly due to a larger surface area per unit weight that causes the insect to absorb a proportionally larger dose than does the mammal being sprayed. The effectiveness of radioactive iodine in the treatment of hyperthyroidism (as well as its thyroid carcinogenicity) is due to the selective ability of the thyroid gland to accumulate iodine. A major reason why chemicals are toxic to one, but not to another, type of tissue is that there are differences in accumulation of the ultimate toxic compound in various tissues. This, in turn, may be due to differences in the ability of various tissues to transport or biotransform the chemical into the ultimate toxic product. Selective toxicity caused by differences in comparative cytology is exemplified by a comparison of plant and animal cells. Plants differ from animals in many ways-for example, absence of a nervous system, an efficient circulatory system, and muscles as well as the presence of a photosynthetic mechanism and cell walls. The fact that bacteria contain cell walls and humans do not has been utilized in developing selective toxic chemotherapeutic agents, such as penicillin and cephalosporins, that kill bacteria but are relatively nontoxic to mammalian cells. Selective toxicity can also be a result of a difference in biochemistry in the two types of cells. For example, bacteria do not absorb folic acid but synthesize it from p-aminobenzoic acid, glutamic acid, and pteridine, whereas mammals cannot synthesize folic acid but have to absorb it from the diet. Thus, sulfonamide drugs are selectively toxic to bacteria because the sulfonamides, which resemble p-aminobenzoic acid in both charge and dimensions, antagonize the incorporation of p-aminobenzoic acid into the folic acid molecule-a reaction that humans do not carry out. Species differences in response to carcinogenic chemicals represent an important issue in regulatory risk assessment. The validity of this approach of course depends on the relevance of the experimental animal model to humans. Large differences in carcinogenic response between experimental animal species are not unusual. For example, mice are highly resistant to the hepatocarcinogenic effects of the fungal toxin aflatoxin B1. Dietary doses as high as 10,000 parts per billion (ppb) failed to produce liver cancer in mice, whereas in rats dietary doses as low as 15 ppb produced a significant increase in liver tumors (Wogan et al. Mice express this enzyme constitutively, whereas rats normally express a closely related form with much less detoxifying activity toward aflatoxin epoxide. Thus, dietary treatment can dramatically change the sensitivity of a species to a carcinogen. Other examples in which large species differences in response to carcinogens have been observed include the development of renal tumors from 2,3,5-trimethylpentane and d-limonene in male rats (Lehman-McKeeman and Caudill, 1992), the production of liver tumors from "peroxisomal proliferators" such as the antilipidemic drug clofibrate and the common solvent trichloroethylene (Roberts, 1999), and the induction of nasal carcinomas in rats after inhalation exposure to formaldehyde (Monticello and Morgan, 1997). Identifying the mechanistic basis for species differences in response to chemicals is an important part of toxicology because only through a thorough understanding of these differences can the relevance of animal data to human response be verified. Individual Differences in Response Even within a species, large interindividual differences in response to a chemical can occur because of subtle genetic differences. Hereditary differences in a single gene that occur in more than 1% of the population are referred to as genetic polymorphism and may be responsible for idiosyncratic reactions to chemicals, as discussed earlier in this chapter. However, genetic polymorphism may have other important but less dramatic effects than those described for acute idiosyncratic responses (such as that occurring in pseudocholinesterase-deficient individuals after succinylcholine exposure). For example, it is recognized that approximately 50% of the Caucasian population has a gene deletion for the enzyme glutathione S-transferase M1. This enzyme has no apparent significant physiologic function, and thus homozygotes for the gene deletion (e. However, epidemiologic studies have indicated that smokers who are homozygous for the null allele Species Differences Although a basic tenet of toxicology is that "experimental results in animals, when properly qualified, are applicable to humans," it is important to recognize that both quantitative and qualitative differences in response to toxic substances may occur among different species. Chapter 6 provides additional examples of genetic differences in biotransformation enzymes that may be important determinants of variability in individual susceptibility to chemical exposures. Genetic polymorphism in physiologically important genes may also be responsible for interindividual differences in toxic responses. For example, studies in transgenic mice have shown that mice possessing one copy of a mutated p53 gene (a so-called tumor suppressor gene; see Chap. In humans, there is evidence that possessing one mutated copy of a tumor suppressor gene greatly increases the risk of developing certain cancers. For example, retinoblastoma is a largely inherited form of cancer that arises because of the presence of two copies of a defective tumor suppressor gene (the Rb gene) (Wiman, 1993). Individuals with one mutated copy of the Rb gene and one normal copy are not destined to acquire the disease (as are those with two copies of the mutated gene), although their chance of acquiring it is much greater than that of persons with two normal Rb genes. This is the case because both copies of the gene must be nonfunctional for the disease to develop. With one mutated copy present genetically, the probability of acquiring a mutation of the second gene (potentially from exposure to environmental mutagens) is much greater than the probability of acquiring independent mutations in both copies of the gene as would be necessary in people with two normal Rb alleles. Simple blood tests may ultimately be developed that allow an individual to learn whether he or she may be particularly susceptible to specific drugs or environmental pollutants. Although the public health significance of this type of information could be immense, the disclosure of such information raises many important ethical and legal issues that must be addressed before wide use of such tests. The study of "gene-environment" interactions, or "Ecogenetics" (Costa and Eaton, 2006) is a rapidly developing field of substantial relevance to toxicology. It is likely that the majority of chronic diseases develop as a result of the complex interplay between multiple genes and the myriad of environmental factors, including diet, lifestyle, and occupational and/or environmental exposures to toxic substances. The first is that the effects produced by a compound in laboratory animals, when properly qualified, are applicable to humans. On the basis of dose per unit of body surface, toxic effects in humans are usually in the same range as those in experimental animals. On a body weight basis, humans are generally more vulnerable than are experimental animals. When one has an awareness of these quantitative differences, appropriate safety factors can be applied to calculate relatively safe doses for humans. All known chemical carcinogens in humans, with the possible exception of arsenic, are carcinogenic in some species but not in all laboratory animals. It has become increas- ingly evident that the converse-that all chemicals carcinogenic in animals are also carcinogenic in humans-is not true (Dybing and Sanner, 1999; Grisham, 1997; Hengstler et al. However, for regulatory and risk assessment purposes, positive carcinogenicity tests in animals are usually interpreted as indicative of potential human carcinogenicity. If a clear understanding of the mechanism of action of the carcinogen indicates that a positive response in animals is not relevant to humans, a positive animal bioassay may be considered irrelevant for human risk assessment (see Chap. This species variation in carcinogenic response appears to be due in many instances to differences in biotransformation of the procarcinogen to the ultimate carcinogen (see Chap. The second principle is that exposure of experimental animals to chemicals in high doses is a necessary and valid method of discovering possible hazards in humans. Practical considerations in the design of experimental model systems require that the number of animals used in toxicology experiments always be small compared with the size of human populations at risk. Obtaining statistically valid results from such small groups of animals requires the use of relatively large doses so that the effect will occur frequently enough to be detected. However, the use of high doses can create problems in interpretation if the response(s) obtained at high doses does not occur at low doses. Thus, for example, it has been shown that bladder tumors observed in rats fed very high doses of saccharin will not occur at the much lower doses of saccharin encountered in the human diet.
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Dexrabeprazole It is the active dextro-isomer of rabeprazole; produces similar acid suppression at half the dose, i. Antacids do not decrease acid production; rather, agents that raise the antral pH to > 4 evoke reflex gastrin release more acid is secreted, especially in patients with hyperacidity and duodenal ulcer; "acid rebound" occurs and gastric motility is increased. Systemic Antacids Sodium bicarbonate It is water soluble, acts instantaneously, but the duration of action is short. However, it has several demerits: (a) Absorbed systemically: large doses will induce alkalosis. Nonsystemic Antacids these are insoluble and poorly absorbed basic compounds; react in stomach to form the corresponding chloride salt. Effective doses (for ulcer healing) of nonselective antimuscarinic drugs (atropine, propantheline, oxyphenonium) invariably produce intolerable side effects. However, reduction in 24 hour acid production is less than H2 blockers because of shorter duration of action (~3 hr. Some patients may even complain of increased pain during the first week of therapy. Major problems in the use of misoprostol are-diarrhoea, abdominal cramps, uterine bleeding, abortion, and need for multiple daily doses. Magnesium trisilicate has low solubility and reactivity; 1 g can react with 10 mEq acid, but in clinical use only about 1 mEq is neutralized. About 5% of administered Mg is absorbed systemically-may cause problem if renal function is inadequate. All Mg salts have a laxative action by generating osmotically active MgCl2 in the stomach and through Mg2+ ion induced cholecystokinin release. On keeping it slowly polymerizes to variable extents into still less reactive forms. This may: (a) cause osteomalacia (b) be used therapeutically in hyperphosphatemia and phosphate stones. This is impaired in renal failure-aluminium toxicity (encephalopathy, osteoporosis) can occur. Magaldrate It is a hydrated complex of hydroxymagnesium aluminate that initially reacts rapidly with acid and releases alum. Such regimen often produced a syndrome characterized by headache, anorexia, weakness, abdominal discomfort, abnormal Ca deposits and renal stones due to concurrent hypercalcaemia and alkalosis. These may be superior to any single agent on the following accounts: (a) Fast (Mag. Healing efficacy has been found similar to cimetidine at 4 weeks, and may be superior in patients who continue to smoke. Antacids should not be taken with sucralfate because its polymerization is dependent on acidic pH. It has potential for inducing hypophosphatemia by binding phosphate ions in the intestine. This practice is considered to contribute to occurrence of pneumonia due to overgrowth of bacteria in the stomach. Intragastric sucralfate provides effective prophylaxis of stress ulcers without acid suppression, and is an alternative to i. Interactions Sucralfate adsorbs many drugs and interferes with the absorption of tetracyclines, fluoroquinolones, cimetidine, phenytoin and digoxin. Drug interactions By raising gastric pH and by forming complexes, the non-absorbable antacids decrease the absorption of many drugs, especially tetracyclines, iron salts, fluoroquinolones, ketoconazole, H2 blockers, diazepam, phenothiazines, indomethacin, phenytoin, isoniazid, ethambutol and nitrofurantoin. Uses Antacids are no longer used for healing peptic ulcer, because they are needed in large and frequent doses, are inconvenient, can cause acid rebound and bowel upset, afford little nocturnal protection and have poor patient acceptability. Antacids are now employed only for intercurrent pain relief and acidity, mostly self-prescribed by the patients as over the counter preparations. Gastroesophageal reflux Antacids afford faster symptom relief than drugs which inhibit acid secretion, but do not provide sustained benefit. Sucralfate polymerizes at pH < 4 by cross linking of molecules, assuming a sticky gel-like consistency. It preferentially and strongly adheres to ulcer base, especially duodenal ulcer; has been seen endoscopically to remain there for ~ 6 hours. Surface proteins at ulcer base are precipitated, together with which it acts as a physical barrier preventing acid, pepsin and bile from coming in contact with the ulcer base. Sucralfate has no acid neutralizing action, but delays gastric emptying-its own stay in stomach is prolonged. It attaches to the surface epithelium beneath the mucus, has high urease activity- produces ammonia which maintains a neutral microenvironment around the bacteria, and promotes back diffusion of H+ ions. Resistance develops rapidly, especially to metronidazole/ tinidazole and clarithromycin, but amoxicillin resistance is infrequent. In tropical countries, metronidazole resistance is more common than clarithromycin resistance. This is a higher degree of round-theclock acid suppression than is needed for duodenal ulcer healing or for reflux esophagitis. One week regimens are adequate for many patients, but 2 week regimens achieve higher (upto 96%) eradication rates, though compliance is often poor due to side effects. For patients who have, in the near past, received a nitroimidazole (for other infections) or a macrolide antibiotic, metronidazole or clarithromycin, as the case may be, should be excluded. All regimens are complex and expensive, side effects are frequent and compliance is poor. Repeated reflux of acid gastric contents into lower 1/3rd of esophagus causes esophagitis, erosions, ulcers, pain on swallowing, dysphagia, strictures, and increases the risk of esophageal carcinoma. Hormonal: gastrin increases, progesterone decreases (reflux is common in pregnancy). Stage 2: > 3 episodes/week of moderately severe symptoms, nocturnal awakening due to regurgitation, esophagitis present or absent. Stage 3: Daily/chronic symptoms, disturbed sleep, esophagitis/erosions/stricture/extraesophageal symptoms like laryngitis, hoarseness, dry cough, asthma. Dietary and other lifestyle measures (light early dinner, raising head end of bed, weight reduction and avoidance of precipitating factors) must be taken. Intragastric pH >4 maintained for ~18 hr/day is considered optimal for healing of esophagitis. Prolonged (often indefinite) therapy is required in chronic cases because symptoms recur a few days after drug stoppage. Antacids are no longer employed for healing of esophagitis, which they are incapable of. Sodium alginate It forms a thick frothy layer which floats on the gastric contents like a raft may prevent contact of acid with esophageal mucosa. Combination of alginate with antacids may be used in place of antacids alone, but real benefit is marginal. Alginate floats on gastric contents and prevents contact of esophageal mucosa with gastric acid 5. Upper gastrointestinal endoscopy reveals an ulcer measuring 12 mm X 18 mm in the 1st part of duodenum. His medical records show that he suffered similar episode of pain about 9 months ago. Subsequently, nearly 3 months back, he suffered from loose motions and abdominal pain which was treated with a 5 day course of metronidazole + norfloxacin. The vestibular apparatus generates impulses when body is rotated or equilibrium is disturbed or when ototoxic drugs act.