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TUGASAN TOKSIKOLOGI

NAMA: KEERTHY VENTHEN

NPM: 260110113045

FAKULTAS:FARMASI

ANGKATAN: 2011/2012

1)Sebutkan dan jelaskan beberapa hal yang perlu diperhatikan jika terjadi keracunan baik disebabkan oleh obat, maupun yang disebabkan oleh zat kimia lainnya. ANS:
heavy metal toxicity involve identifying of the toxic elements that are causing the problem and then begin the removal process of these very metals from the body. Hair analysis, urine collection with the use of chelating drugs are often some of the easiest process of diagnosis.

Once the problem is identified treatment is more individualistic purely based on the type of problem one has. Most treatment process involves use of metal chelating drugs or intravenous EDTA chelation. Some patients are also recommended intravenous Vitamin C and replacement mineral infusions that support the body through the metal removal process. Treatment is often successful in curing most of the symptoms though some may linger, which again indicate residual damage to the system.

Jelaskan bagaimana terjadinya toksisitas obat golongan TCA (Tricyclic Antidepressant), dan bagaimana penanganan keracunan obat-obat TCA

ANS TCAs have long been thought to exert their therapeutic effects by inhibiting the presynaptic reuptake of biogenic amines, primarily serotonin and norepinephrine. TCAs can be structurally divided into secondary and tertiary amines. The secondary amines exert more selective effects on norepinephrine reuptake, whereas tertiary amines are more potent reuptake inhibitors of serotonin.

In addition to their effects on these receptor systems, TCAs affect many other receptor systems, resulting in many of their toxic effects. They are antagonists at muscarinic acetylcholine receptors, peripheral alphaadrenergic receptors, and histamine receptors. The cardiovascular toxicity, which is the most common cause of morbidity and mortality from TCAs, is related to their membrane-stabilizing effect through sodium channel blockade and alpha-adrenergic blockade. The effects of these drugs on vascular tone, myocardial action potential, and the autonomic nervous system can cause severe hypotension, dysrhythmias, and conduction delays.

TCAs bind to and inhibit the movement of sodium ions into the fast sodium channel thereby slowing phase O depolarization in the HisPurkinje system and ventricular myocytes. This results in slowed cardiac conduction by slowing the propagation of ventricular depolarization which is manifested as a prolonged QRS on the ECG. The right bundle branch is affected disproportionately by the conduction delay because it has a longer refractory period thereby resulting in a rightward shift of the terminal QRS axis and the right bundle-branch block (RBBB) pattern that is seen on the ECG of some patients who are exposed to TCAs (a characteristic ECG is shown in the image below). Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity. TCAs also block phase 3 repolarization in His-Purkinje myocytes, resulting in prolonged QTc on the ECG. Specifically, TCAs inhibit outward potassium current by blocking potassium channels in phase 3, which ultimately results in prolongation of the QT interval. Prolongation of the QTc usually predisposes to the development of torsades de pointes but in the setting of TCA exposure, it is uncommon because torsades de pointes is more likely to occur in the setting of bradycardia and the anticholinergic effects of these drugs produce offsetting tachycardia. Refractory hypotension, caused primarily by the inhibition of alpha1adrenergic receptors, is one of the most common causes of mortality seen with TCA overdose. This hypotension can be exacerbated by hypoxia, acidosis, and volume-depletion. Although initial reuptake inhibition of norepinephrine (NE) in the central and peripheral nervous

systems can result in a patient initially presenting with hypertension and tachycardia, prolonged blockade can cause depletion of norepinephrine from the presynaptic nerve terminal, which results in the subsequent development of refractory hypotension and bradycardia in cases of serious overdose. This biphasic result is seen because most norepinephrine is recycled at the nerve terminal for rapid reuse. When this reuptake is blocked, the initial hypertension and tachycardia result. However, with serious overdose, all the available synaptic norepinephrine is depleted, resulting in hypotension. Sinus tachycardia is the most common cardiac disturbance seen following TCA overdose. Competitive blockade at muscarinic acetylcholine receptors, thought to primarily play a role though norepinephrine reuptake inhibition, also contributes to the tachycardia. Wide-complex tachycardia is also observed, and it results primarily from prolonged antegrade conduction and the ensuing nonuniform conduction leads to reentrant ventricular dysrhythmias. Neurologic effects of TCAs, including agitation and delirium, primarily result from CNS blockade of muscarinic receptors. TCA seizures, although rare, usually occur within 1-2 hours of ingestion and are thought to occur secondary to increased concentrations of norepinephrine, interactions with GABA and NMDA-glutamate receptors, antidopaminergic properties, anticholinergic properties, and inhibition of neuronal sodium channels. Uncontrolled seizures can result in severe metabolic acidosis, rhabdomyolysis, hyperthermia, and acute renal failure. Resulting seizure-induced acidosis can also exacerbate cardiovascular toxicity.

Pulmonary complications including acute lung injury, aspiration pneumonitis, and acute respiratory distress syndrome (ARDS) may also be seen. One study showed dose-related vasoconstriction and bronchoconstriction in isolated rat lungs associated with amitriptyline exposure. Acute lung injury can also result from coma, hypotension, pulmonary infection, and excessive fluid administration.

3) Jelaskan dengan jelas mekanisme terjadinya toksisitas senyawa golongan organophosfat; simptom keracunan organophosfat, dan cara penanganan keracunan senyawa organophosfat MECHANISME
The primary mechanism of action of organophosphate pesticides is inhibition of carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). AChE is an enzyme that degrades the neurotransmitter acetylcholine (ACh) into choline and acetic acid. ACh is found in the central and peripheral nervous system, neuromuscular junctions, and red blood cells (RBCs). Organophosphates inactivate AChE by phosphorylating the serine hydroxyl group located at the active site of AChE. The phosphorylation occurs by loss of an organophosphate leaving group and establishment of a covalent bond with AChE. Once AChE has been inactivated, ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors. Clinical effects are manifested via activation of the

autonomic and central nervous systems and at nicotinic receptors on skeletal muscle. Once an organophosphate binds to AChE, the enzyme can undergo one of the following: A)Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases B)Reactivation by a strong nucleophile such as pralidoxime (2-PAM) C)Irreversible binding and permanent enzyme inactivation (aging) Organophosphates can be absorbed cutaneously, ingested, inhaled, or injected. Although most patients rapidly become symptomatic, the onset and severity of symptoms depend on the specific compound, amount, route of exposure, and rate of metabolic degradation

SYMPTOMS
The health effects associated with organophosphate poisoning are a result of excess acetylcholine (ACh) present at different nerves and receptors in the body because acetyocholinesterase is blocked. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are tachycardia, hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to

accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. The effects of organophosphate poisoning are recalled using the mnemonic SLUDGEM (Salivation, Lacrimation, Urination, Defecation, Gastrointestinal motility, Emesis, miosis) An additional mnemonic is MUDDLES: miosis, urination, diarrhea, diaphoresis, lacrimation, excitation, and salivation. The onset and severity of symptoms, whether acute or chronic, depends upon the specific chemical, the route of exposure, the dose, and the individuals ability to degrade the compound, which the PON1 enzyme level will affect.

PREVENTION
Current antidotes for OP poisoning consist of a pretreatment with carbamates to protect AChE from inhibition by OP compounds and post-exposure treatments with anti-cholinergic drugs. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime),though the use of "-oximes" has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally. These antidotes are effective at preventing lethality from

OP poisoning, but current treatment lack the ability to prevent postexposure incapacitation, performance deficits, or permanent brain damage. Enzyme bioscavengers are being developed as a pretreatment to sequester highly toxic OPs before they can reach their physiological targets and prevent the toxic effects from occurring. Significant advances with cholinesterases (ChEs), specifically human serum BChE (HuBChE) have been made. HuBChe can offer a broad range of protection for nerve agents including soman, sarin, tabun, and VX. HuBChE also possess a very long retention time in the human circulation system and because it is from a human source it will not produce any antagonistic immunological responses. HuBChE is currently being assessed for inclusion into the protective regimen against OP nerve agent poisoning.Currently there is potential for PON1 to be used to treat sarin exposure, but recombinant PON1 variants would need to first be generated to increase its catalytic efficiency. One other agent that is being researched is the Class III anti-arrhythmic agents. Hyperkalemia of the tissue is one of the symptoms associated with OP poisoning. While the cellular processes leading to cardiac toxicity are not well understood, the potassium current channels are believed to be involved. Class II anti-arrhythmic agents block the potassium membrane currents in cardiac cells, which makes them a candidate for become a therapeutic of OP poisoning. Five days of an organic food diet has been shown to dramatically reduce the organophosphorus pesticides in the urine of children

4)Bagaimanakah mekanisme toksisitas dari golongan obat NSAID terhadap saluran pencernaan kita, dan sebutkan symptom yang terjadi serta bagaimakah cara penanganannya MECHANISME NSAIDs work by inhibiting two enzymes, substances that cause chemical changes in the body, called COX-1 and COX-2. Both enzymes produce prostaglandinschemicals produced in the body's cellsthat promote pain, inflammation, and fever. However, unlike COX-2, COX-1 produces another type of prostaglandin that protects the stomach lining from stomach acid and helps control bleeding. By inhibiting COX-1, NSAIDs increase the risk of a peptic ulcer developing and bleeding Gastroduodenal ulceration and bleeding are the major limitations to the use of non-steroidal anti-inflammatory drugs (NSAIDs). The development of safer NSAIDs or of effective therapies for the prevention of the adverse effects of existing NSAIDs requires a better understanding of the pathogenesis of NSAID-induced ulcer disease. NSAIDs can cause damage to the gastroduodenal mucosa via several mechanisms, including the topical irritant effect of these drugs on the epithelium, impairment of the barrier properties of the mucosa, suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood flow and interference with the repair of superficial injury. The presence of acid in the lumen of the

stomach also contributes to the pathogenesis of NSAID-induced ulcers and bleeding, by impairing the restitution process, interfering with haemostasis and inactivating several growth factors that are important in mucosal defence and repair. In recent years, a fuller understanding of the pathogenesis of NSAID-induced ulcer disease has facilitated some new, very promising approaches to the development of stomach-sparing NSAIDs. SYMPTOMS Abdominal discomfort is the most common symptom of both gastric and duodenal ulcers. Felt anywhere between the navel and the breastbone, this discomfort usually

is a dull or burning pain occurs when the stomach is emptybetween meals or during the night may be briefly relieved by eating food, in the case of duodenal ulcers, or by taking antacids, in both types of peptic ulcers lasts for minutes to hours comes and goes for several days or weeks

Other symptoms of a peptic ulcer may include

weight loss

poor appetite bloating burping nausea vomiting

Some people experience only mild symptoms or none at all. Emergency Symptoms A person who has any of the following symptoms should call a doctor right away:

sharp, sudden, persistent, and severe stomach pain bloody or black stools bloody vomit or vomit that looks like coffee grounds

These alarm symptoms could be signs of a serious problem, such as

bleedingwhen acid or the peptic ulcer breaks a blood vessel perforationwhen the peptic ulcer burrows completely through the stomach or duodenal wall obstructionwhen the peptic ulcer blocks the path of food trying to leave the stomach

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