Lavi Oud, M.D.

• Department of Critical Care Medicine
• Wayne State University School of Medicine
• Detroit, MI

Bladder control and anal sphincter control are also affected in most cases and may require autonomic drugs for management herbs and pregnancy 30 gm v-gel. In other circumstances quincy herbals cheap v-gel online visa, acute injury or inflammation of muscle leads to spasm and pain jaikaran herbals order v-gel on line amex. The goal of spasmolytic therapy in both chronic and acute conditions is reduction of excessive skeletal muscle tone without reduction of strength 101 herbals buy cheapest v-gel. Drugs for Acute Muscle Spasm Many drugs (eg herbals to relieve anxiety purchase v-gel 30gm online, cyclobenzaprine herbals for prostate buy discount v-gel 30gm online, metaxalone, methocarbamol, orphenadrine) are promoted for the treatment of acute spasm resulting from muscle injury. Cyclobenzaprine, a typical member of this group, is believed to act in the brain stem, possibly by interfering with polysynaptic reflexes that maintain skeletal muscle tone. The drug is active by the oral route and has marked sedative and antimuscarinic actions. None of these drugs used for acute spasm is effective in muscle spasm resulting from cerebral palsy or spinal cord injury. Patients with renal failure often have decreased levels of plasma cholinesterase, thus prolonging the duration of action of succinylcholine. Anesthesia was provided by isoflurane, supplemented by intravenous midazolam and a nondepolarizing muscle relaxant. At the end of the procedure, a low dose of atropine was administered followed by pyridostigmine. A muscarinic receptor antagonist would probably not be needed for reversal of the skeletal muscle relaxant actions of a nondepolarizing drug if the agent used was (A) Cisatracurium (B) Mivacurium (C) Pancuronium (D) Tubocurarine (E) Vecuronium 4. Which of the following drugs is the most effective in the emergency management of malignant hyperthermia The clinical use of succinylcholine, especially in patients with diabetes, is associated with (A) Antagonism by pyridostigmine during the early phase of blockade (B) Aspiration of gastric contents (C) Decreased intragastric pressure (D) Histamine release in a genetically determined population (E) Metabolism at the neuromuscular junction by acetylcholinesterase 6. Regarding the spasmolytic drugs, which of the following statements is not accurate Which drug is most likely to cause hyperkalemia leading to cardiac arrest in patients with spinal cord injuries Which drug has spasmolytic activity and could also be used in the management of seizures caused by overdose of a local anesthetic Myalgias are a common postoperative complaint of patients who receive large doses of succinylcholine, possibly the result of muscle fasciculations caused by depolarization. Which drug administered in the operating room can be used to prevent postoperative pain caused by succinylcholine Phase I depolarizing blockade caused by succinylcholine is not associated with antagonism at muscarinic receptors, nor is it reversible with cholinesterase inhibitors. To offset the resulting side effects, including bradycardia, a muscarinic blocking agent is used concomitantly. One of the distinctive characteristics of pancuronium is that it can block muscarinic receptors, especially those in the heart. It has sometimes caused tachycardia and hypertension and may cause dysrhythmias in predisposed individuals. Prompt treatment is essential in malignant hyperthermia to control body temperature, correct acidosis, and prevent calcium release. Dantrolene interacts with the RyR1 channel to block the release of activator calcium from the sarcoplasmic reticulum, which prevents the tension-generating interaction of actin with myosin. Fasciculations associated with succinylcholine may increase intragastric pressure with possible complications of regurgitation and aspiration of gastric contents. The complication is more likely in patients with delayed gastric emptying such as those with esophageal dysfunction or diabetes. Tizanidine causes hypotension via 2-adrenoceptor activation, like its congener clonidine. Hypotension may occur with tubocurarine (not listed) due partly to histamine release and to ganglionic blockade. Skeletal muscle depolarization by succinylcholine releases potassium from the cells, and the ensuing hyperkalemia can be life-threatening in terms of cardiac arrest. Patients most susceptible include those with extensive burns, spinal cord injuries, neurologic dysfunction, or intra-abdominal infection. The spasmolytic action of diazepam is thought to be exerted partly in the spinal cord because it reduces spasm of skeletal muscle in patients with cord transection. The depolarizing action of succinylcholine at the skeletal muscle end plate can be antagonized by small doses of nondepolarizing blockers. To prevent skeletal muscle fasciculations and the resulting postoperative pain caused by succinylcholine, a small nonparalyzing dose of a nondepolarizing drug (eg, atracurium) is often given immediately before succinylcholine. Activation of 1 receptors on blood vessels by phenylephrine elicits a reflex bradycardia because mean blood pressure is increased. One of the characteristic effects of tubocurarine is its block of autonomic ganglia; this action can interfere with reflex changes in heart rate. Identify the major nondepolarizing neuromuscular blockers and 1 depolarizing neuromuscular blocker; compare their pharmacokinetics. Describe the differences between depolarizing and nondepolarizing blockers from the Describe the method of reversal of nondepolarizing blockade. List drugs for treatment of skeletal muscle spasticity and identify their sites of action and their adverse effects. Drugs Used in Parkinsonism & Other Movement Disorders Movement disorders constitute a number of heterogeneous neurologic conditions with very different therapies. Pathophysiology Parkinsonism (paralysis agitans) is a common movement disorder that involves dysfunction in the basal ganglia and associated brain structures. Naturally occurring parkinsonism-The naturally occurring disease is of uncertain origin and occurs with increasing frequency during aging from the fifth or sixth decade of life onward. Drug-induced parkinsonism-Many drugs can cause parkinsonian symptoms; these effects are usually reversible. At high doses, reserpine causes similar symptoms, presumably by depleting brain dopamine. Although several dopamine receptor subtypes are present in the substantia nigra, the benefits of most antiparkinson drugs appear to depend on activation of the D2 receptor subtype. Mechanisms-Because dopamine has low bioavailability and does not readily cross the blood-brain barrier, its precursor, l-dopa (levodopa), is used. With this combination, the plasma half-life is prolonged, lower doses of levodopa are effective, and there are fewer peripheral side effects. Pharmacologic effects-Levodopa ameliorates the signs of parkinsonism, particularly bradykinesia; moreover, the mortality rate is decreased. However, the drug does not cure parkinsonism, and responsiveness fluctuates and gradually decreases with time, which may reflect progression of the disease. Clinical response fluctuations may, in some cases, be related to the timing of levodopa dosing. In other cases, unrelated to dosing, off-periods of akinesia may alternate over a few hours with on-periods of improved mobility but often with dyskinesias (on-off phenomena). Although drug holidays sometimes reduce toxic effects, they rarely affect response fluctuations. Common adverse effects include anorexia, nausea and vomiting, dyskinesias, and postural hypotension. Behavioral effects, which occur more commonly with bromocriptine than with newer dopamine agonists, include confusion, hallucinations, and delusions. It is effective as monotherapy in mild parkinsonism and can be used together with levodopa in more advanced disease. Pramipexole is administered orally 3 times daily and is excreted largely unchanged in the urine. Adverse effects include anorexia, nausea and vomiting, postural hypotension, and dyskinesias. Mental disturbances (confusion, delusions, hallucinations, impulsivity) are more common with pramipexole than with levodopa. The drug is contraindicated in patients with active peptic ulcer disease, psychotic illness, or recent myocardial infarction. Pramipexole may be neuroprotective because it is reported to act as a scavenger for hydrogen peroxide. Ropinirole-Another non-ergot, this drug has high affinity for the dopamine D2 receptor. It is effective as monotherapy and can be used with levodopa to smooth out response fluctuations. The standard form is given 3 times daily, but a prolonged release form can be taken once daily. Because of severe nausea, pretreatment for 3 days with antiemetics (eg, trimethobenzamide) is necessary. Other side effects of apomorphine include dyskinesias, hypotension, drowsiness, and sweating. Hepatic metabolism of selegiline results in the formation of desmethylselegiline (possibly neuroprotective) and amphetamine. Clinical use-Selegiline has minimal efficacy in parkinsonism if given alone but can be used adjunctively with levodopa. Rasagiline is more potent and has been used as monotherapy in early symptomatic parkinsonism as well as in combinations with levodopa. Gastrointestinal effects include anorexia, nausea, and emesis and can be reduced by taking the drug in divided doses. Other cardiac effects include tachycardia, asystole, and cardiac arrhythmias (rare). Dyskinesias occur in up to 80% of patients, with choreoathetosis of the face and distal extremities occurring most often. Behavioral effects may include anxiety, agitation, confusion, delusions, hallucinations, and depression. Bromocriptine-An ergot alkaloid, bromocriptine acts as a partial agonist at dopamine D2 receptors in the brain. Toxicity and drug interactions-Adverse effects and interactions of monoamine oxidase inhibitors include insomnia, mood changes, dyskinesias, gastrointestinal distress, and hypotension. Combinations of these drugs with meperidine have resulted in agitation, delirium, and mortality. Clinical uses-The drugs are used as adjuncts to levodopacarbidopa, decreasing fluctuations, improving response, and prolonging "on-time. A formulation combining levodopa, carbidopa, and entacapone is available, simplifying the drug regimen. Toxicity-Adverse effects related partly to increased levels of levodopa include dyskinesias, gastrointestinal distress, and postural hypotension. Other side effects include sleep disturbances and orange discoloration of the urine. Tolcapone increases liver enzymes and has caused acute hepatic failure, necessitating routine monitoring of liver function tests and signed patient consent for use in the United States. Mechanism of action-Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that may involve increasing synthesis or release of dopamine or inhibition of dopamine reuptake. Pharmacologic effects-Amantadine may improve bradykinesia, rigidity, and tremor but is usually effective for only a few weeks. Toxicity-Behavioral effects include restlessness, agitation, insomnia, confusion, hallucinations, and acute toxic psychosis. Miscellaneous effects may include gastrointestinal disturbances, urinary retention, and postural hypotension. Mechanism of action-The drugs (eg, benztropine, biperiden, orphenadrine) decrease the excitatory actions of cholinergic neurons on cells in the striatum by blocking muscarinic receptors. Pharmacologic effects-These drugs may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. They are used adjunctively in parkinsonism and also alleviate the reversible extrapyramidal symptoms caused by antipsychotic drugs. These agents exacerbate tardive dyskinesias that result from prolonged use of antipsychotic drugs. Physiologic and Essential Tremor Physiologic and essential tremor are clinically similar conditions characterized by postural tremor. The conditions may be accentuated by anxiety, fatigue, and certain drugs, including bronchodilators, tricyclic antidepressants, and lithium. Beta blockers should be used with caution in patients with heart failure, asthma, diabetes, or hypoglycemia. Metoprolol, a 1-selective antagonist, is also effective, and its use is preferred in patients with concomitant pulmonary disease. Antiepileptic drugs including gabapentin, primidone, and topiramate, as well as intramuscular injection of botulinum toxin, have also been used to treat essential tremor. There may also be a cholinergic deficit because choline acetyltransferase is decreased in the basal ganglia of patients with this disease. Drug therapy usually involves the use of amine-depleting drugs (eg, reserpine, tetrabenazine), the latter having less troublesome adverse effects. Dopamine receptor antagonists (eg, haloperidol, perphenazine) are also sometimes effective and olanzapine is also used. Though less effective overall, carbamazepine, clonazepam, and clonidine have also been used. Drug-Induced Dyskinesias Parkinsonism symptoms caused by antipsychotic agents (see Chapter 29) are usually reversible by lowering drug dosage, changing the therapy to a drug that is less toxic to extrapyramidal function, or treating with a muscarinic blocker. In acute dystonias, parenteral administration of benztropine or diphenhydramine is helpful. Levodopa and bromocriptine are not useful because dopamine receptors are blocked by the antipsychotic drugs. Tardive dyskinesias that develop from therapy with older antipsychotic drugs are possibly a form of denervation supersensitivity.

Diseases

• Alport syndrome, dominant type
• Chromosome 6, trisomy 6p
• Microcephaly, primary autosomal recessive
• Hearing impairment
• Sackey Sakati Aur syndrome
• Eosophobia
• Idiopathic acute eosinophilic pneumonia
• Glycogenosis type VIII
• Septo-optic dysplasia
• Holocarboxylase synthetase deficiency

Although oral formulations are most commonly used herbs nursery order v-gel without a prescription, buccal and suppository forms of some drugs are available rupam herbals buy discount v-gel 30 gm line. Prolonged analgesia herbs denver discount v-gel 30gm overnight delivery, with some reduction in adverse effects herbs life 30 gm v-gel free shipping, can be achieved with epidural administration of certain strong agonist drugs (eg herbals on york purchase genuine v-gel, fentanyl and morphine) herbals medicine effective v-gel 30 gm. Fentanyl has also been used by the transdermal route providing analgesia for up to 72 h. Cough Suppression Useful oral antitussive drugs include codeine and dextromethorphan. Large doses of dextromethorphan may cause hallucinations, confusion, excitation, increased or decreased pupil size, nystagmus, seizures, coma, and decreased breathing. Treatment of Diarrhea Selective antidiarrheal opioids include diphenoxylate and loperamide. Management of Acute Pulmonary Edema Morphine (parenteral) may be useful in acute pulmonary edema because of its hemodynamic actions; its calming effects probably also contribute to relief of the pulmonary symptoms. Anesthesia Opioids are used as preoperative medications and as intraoperative adjunctive agents in balanced anesthesia protocols. Tolerance Marked tolerance can develop to the just-mentioned acute pharmacologic effects, with the exception of miosis and constipation. Opioid Dependence Methadone, one of the longer acting opioids, is used in the management of opioid withdrawal states and in maintenance programs for addicts. In withdrawal states, methadone permits a slow tapering of opioid effect that diminishes the intensity of abstinence symptoms. Buprenorphine (see later discussion) has an even longer duration of action and is sometimes used in withdrawal states. In maintenance programs, the prolonged action of methadone blocks the euphoria-inducing effects of doses of shorter acting opioids (eg, heroin, morphine). Buprenorphine is a -receptor partial agonist with weak antagonist effects at and receptors. These characteristics can lead to decreased analgesia, or even precipitate withdrawal symptoms, when such drugs are used in patients taking conventional full -receptor agonists. Although prolonged activity of buprenorphine may be clinically useful (eg, to suppress withdrawal signs in dependency states), this property renders its effects resistant to naloxone reversal, since the antagonist drug has a short half-life. In overdose, respiratory depression caused by nalbuphine may also be resistant to naloxone reversal. Naloxone is included in some formulations of these agonist-antagonist drugs to discourage abuse. Effects the mixed agonist-antagonist drugs often cause sedation at analgesic doses. Dizziness, sweating, and nausea may also occur, and anxiety, hallucinations, and nightmares are possible adverse effects. Respiratory depression may be less intense than with pure agonists but is not predictably reversed by naloxone. Tolerance develops with chronic use but is less than the tolerance that develops to the full agonists, and there is minimal cross-tolerance. Physical dependence occurs, but the abuse liability of mixed agonist-antagonist drugs is less than that of the full agonists. Miscellaneous Tramadol is a weak -receptor agonist only partially antagonized by naloxone. Its analgesic activity is mainly based on blockade of the reuptake of serotonin; it is a weak norepinephrine reuptake blocker. Tramadol is effective in treatment of moderate pain and has been used as an adjunct to opioid analgesics in chronic pain syndromes. No significant effects on cardiovascular functions or respiration have been reported. Tapentadol has strong norepinephrine reuptake-inhibiting activity (blocked by antagonists) and only modest -opioid receptor affinity. It is less effective than oxycodone in the treatment of moderate to severe pain but causes less gastrointestinal distress and nausea. Tapentadol has been implicated in the serotonin syndrome and should be used with caution in seizure disorders. Overdose A triad of pupillary constriction, comatose state, and respiratory depression is characteristic; the latter is responsible for most fatalities. Diagnosis of overdosage is confirmed if intravenous injection of naloxone, an antagonist drug, results in prompt signs of recovery. Treatment of overdose involves the use of antagonists such as naloxone and other therapeutic measures, especially ventilatory support. Concomitant use of certain opioids (eg, meperidine) with monoamine oxidase inhibitors increases the incidence of hyperpyrexic coma. Meperidine has also been implicated in the serotonin syndrome when used with selective serotonin reuptake inhibitors. Analgesic Activity the analgesic activity of mixed agonist-antagonists varies with the individual drug but is somewhat less than that of strong full agonists like morphine. Buprenorphine, butorphanol, and nalbuphine afford greater analgesia than pentazocine, which is similar to codeine in analgesic efficacy. Receptors Butorphanol, nalbuphine, and pentazocine are agonists, with weak -receptor antagonist activity. A major clinical use of the opioid antagonists is in the management of acute opioid overdose. Naltrexone decreases the craving for ethanol and is approved for adjunctive use in alcohol dependency programs. Unlike the older drugs, two new antagonists, methylnaltrexone and alvimopan, do not cross the blood-brain barrier. These agents block adverse effects of strong opioids on peripheral receptors, including those in the gastrointestinal tract responsible for constipation, with minimal effects on analgesic actions and without precipitating an abstinence syndrome. Genetic polymorphisms in certain hepatic enzymes involved in drug metabolism are established to be responsible for variations in analgesic response to (A) Buprenorphine (B) Codeine (C) Fentanyl (D) Methadone (E) Tramadol Questions 6 and 7. A young male patient is brought to the emergency department in an anxious and agitated state. He informs the attending physician that he uses "street drugs" and that he gave himself an intravenous "fix" approximately 12 h ago. Which drug will be most effective in alleviating the symptoms experienced by this patient Which drug does not activate opioid receptors, has been proposed as a maintenance drug in treatment programs for opioid addicts, and with a single oral dose, will block the effects of injected heroin for up to 48 h Which drug is a full agonist at opioid receptors with analgesic activity equivalent to morphine, a longer duration of action, and fewer withdrawal signs on abrupt discontinuance than morphine A 63-year-old man is undergoing radiation treatment as an outpatient for metastatic bone cancer. His pain has been treated with a fixed combination of oxycodone plus acetaminophen taken orally. The most appropriate oral medication for his increasing pain is (A) Buprenorphine (B) Codeine plus aspirin (C) Hydromorphone (D) Pentazocine (E) Tramadol 2. It is possible that this patient will have to increase the dose of the analgesic as his condition progresses as a result of developing tolerance. However, tolerance will not develop to a significant extent with respect to (A) Biliary smooth muscle (B) Emesis (C) Pupillary constriction (D) Sedation (E) Urinary retention 3. You are on your way to take an examination and you suddenly get an attack of diarrhea. If you stop at a nearby drugstore for an over-the-counter opioid with antidiarrheal action, you will be asking for (A) Codeine (B) Dextromethorphan (C) Diphenoxylate (D) Loperamide (E) Nalbuphine 4. An emergency department patient with severe pain thought to be of gastrointestinal origin received 80 mg of meperidine. He subsequently developed a severe reaction characterized by tachycardia, hypertension, hyperpyrexia, and seizures. Questioning revealed that the patient had been taking a drug for a psychiatric condition. Which drug is most likely to be responsible for this untoward interaction with meperidine In most situations, pain associated with metastatic carcinoma ultimately necessitates the use of an opioid analgesic that is equivalent in strength to morphine, so hydromorphone, oxymorphone, or levorphanol would be indicated. Pentazocine or the combination of codeine plus salicylate would not be as effective as the original drug combination. Buprenorphine, a mixed agonist-antagonist, is not usually recommended for cancerassociated pain because it has a limited maximum analgesic effect ("ceiling") and because of possible dysphoric and psychotomimetic effects. Chronic use of strong opioid analgesics leads to the development of tolerance to their analgesic, euphoric, and sedative actions. Tolerance also develops to their emetic effects and to effects on some smooth muscle, including the biliary and the urethral sphincter muscles. However, tolerance does not develop significantly to the constipating effects or the miotic actions of the opioid analgesics. Codeine and nalbuphine could decrease gastrointestinal peristalsis, but not without marked side effects (and a prescription). Diphenoxylate is not available over the counter because it is a constituent of a proprietary combination that includes atropine sulfate (Lomotil). Concomitant administration of meperidine and monoamine oxidase inhibitors such as isocarboxazid or phenelzine has resulted in life-threatening hyperpyrexic reactions that may culminate in seizures or coma. Note that concomitant use of selective serotonin reuptake inhibitors and meperidine has resulted in the serotonin syndrome, another life-threatening drug interaction (see Chapter 16). The signs and symptoms are those of withdrawal in a patient physically dependent on an opioid agonist. Mydriasis is a prominent feature of the abstinence syndrome; other symptoms include rhinorrhea, lacrimation, piloerection, muscle jerks, and yawning. Prevention of signs and symptoms of withdrawal after chronic use of a strong opiate like heroin requires replacement with another strong opioid analgesic drug. Methadone is most commonly used, but other strong -receptor agonists would also be effective. They have analgesic efficacy superior to that of codeine, but it is not equivalent to that of strong opioid receptor agonists. Although these mixed agonist-antagonist drugs are less likely to cause respiratory depression than strong activators, if depression does occur, reversal with opioid antagonists such as naloxone is unpredictable. The opioid antagonist naltrexone has a much longer half-life than naloxone, and its effects may last 2 d. A high degree of client compliance would be required for naltrexone to be of value in opioid dependence treatment programs. Fentanyl, hydromorphone, and methadone are full agonists with analgesic efficacy similar to that of morphine. Methadone has the greatest bioavailability of the drugs used orally, and its effects are more prolonged. Tolerance and physical dependence develop, and dissipate, more slowly with methadone than with morphine. These properties underlie the use of methadone for detoxification and maintenance programs. Precursor molecules that release opioid peptides are found at various peripheral sites, including the adrenal medulla and the pituitary gland and in some secretomotor neurons and interneurons in the enteric nervous system. In other tissues, opioid peptides may stimulate the release of transmitters or act as neurohormones. It is an important sensory neuron transmitter in the enteric nervous system and in primary afferents involved in nociception. Substance P contracts intestinal and bronchiolar smooth muscle but is an arteriolar vasodilator (possibly via nitric oxide release). Name the major opioid agonists, rank them in terms of analgesic efficacy, and identify specific dynamic or kinetic characteristics. Describe the cardinal signs and treatment of opioid drug overdose and of the List acute and chronic adverse effects of opioid analgesics. Drugs of Abuse Drug abuse is usually taken to mean the use of an illicit drug or the excessive or nonmedical use of a licit drug. It also denotes the deliberate use of chemicals that generally are not considered drugs by the lay public but may be harmful to the user. The older term "physical (physiologic) dependence" is now generally denoted as dependence, whereas "psychological dependence" is more simply called addiction. Management of overdose includes maintenance of a patent airway plus ventilatory support. Flunitrazepam (Rohypnol), a potent rapid-onset benzodiazepine with marked amnestic properties, has been used in "date rape. Withdrawal Physiologic dependence occurs with continued use of sedativehypnotics; the signs and symptoms of the withdrawal (abstinence) syndrome are most pronounced with drugs that have a half-life of less than 24 h (eg, ethanol, secobarbital, methaqualone). However, physiologic dependence may occur with any sedativehypnotic, including the longer acting benzodiazepines. Treatment of sedative-hypnotic withdrawal involves administration of a long acting sedative-hypnotic (eg, chlordiazepoxide or diazepam) to suppress the acute withdrawal syndrome, followed by gradual dose reduction. Clonidine or propranolol may also be of value to suppress sympathetic overactivity. Ethanol is not listed in schedules of controlled substances with abuse liability although it is clearly a heavily abused drug. Effects Sedative-hypnotics reduce inhibitions, suppress anxiety, and produce relaxation.

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The therapeutic efficacy of the older antipsychotic drugs correlates with their relative affinity for the D2 receptor herbals export purchase 30gm v-gel visa. Unfortunately goyal herbals private limited v-gel 30gm without prescription, there is also a correlation between blockade of D2 receptors and extrapyramidal dysfunction herbals information order 30gm v-gel. Other receptors-Most of the newer atypical antipsychotic agents have higher affinities for other receptors than for the D2 receptor herbals 2015 v-gel 30gm overnight delivery. The receptor-binding characteristics of the newer antipsychotic drugs have led to a serotonin hypothesis as an alternative to the dopamine hypothesis of the nature of schizophrenia herbals laws discount v-gel online master card. Most of the atypical drugs cause less extrapyramidal dysfunction than standard drugs herbals kidney stones order v-gel 30gm free shipping. With the exception of haloperidol, all antipsychotic drugs block H1 receptors to some degree. Effects Dopamine receptor blockade is the major effect that correlates with therapeutic benefit for older antipsychotic drugs. Dopaminergic tracts in the brain include the mesocortical-mesolimbic pathways (regulating mentation and mood), nigrostriatal tract (extrapyramidal function), tuberoinfundibular pathways (control of prolactin release), and chemoreceptor trigger zone (emesis). Mesocortical-mesolimbic dopamine receptor blockade presumably underlies antipsychotic effects, and a similar action on the chemoreceptor trigger zone leads to the useful antiemetic properties of some antipsychotic drugs. Adverse effects resulting from receptor blockade in the other dopaminergic tracts, a major problem with older antipsychotic drugs, include extrapyramidal dysfunction and hyperprolactinemia (see later discussion). Note that almost all antipsychotic agents block both 1 and histamine H1 receptors to some extent. Treatment of schizophrenia-Antipsychotic drugs reduce some of the positive symptoms of schizophrenia, including hyperactivity, bizarre ideation, hallucinations, and delusions. Consequently, they can facilitate functioning in both inpatient and outpatient environments. Overall efficacy of the antipsychotic drugs is, for the most part, equivalent in terms of the management of the floridly psychotic forms of the illness, although individual patients may respond best to a specific drug. However, clozapine is effective in some schizophrenic patients resistant to treatment with other antipsychotic drugs. Older drugs are still commonly used, partly because of their low cost compared with newer agents. However, none of the traditional drugs has much effect on negative symptoms of schizophrenia. Newer atypical drugs are reported to improve some of the negative symptoms of schizophrenia, including emotional blunting, social withdrawal, and lack of motivation. Other psychiatric and neurologic indications-The newer antipsychotic drugs are often used with lithium in the initial treatment of mania. Several second-generation drugs are approved for treatment of acute mania; two of these (aripiprazole and olanzapine) are approved for maintenance treatment of bipolar disorder. Nonpsychiatric indications-With the exception of thioridazine, most phenothiazines have antiemetic actions; prochlorperazine is promoted solely for this indication. H1-receptor blockade, most often present in short side-chain phenothiazines, provides the basis for their use as antipruritics and sedatives and contributes to their antiemetic effects. Reversible neurologic effects-Dose-dependent extrapyramidal effects include a Parkinson-like syndrome with bradykinesia, rigidity, and tremor. This toxicity may be reversed by a decrease in dose and may be antagonized by concomitant use of muscarinic blocking agents. Extrapyramidal toxicity occurs most frequently with haloperidol and the more potent piperazine side-chain phenothiazines (eg, fluphenazine, trifluoperazine). Parkinsonism occurs infrequently with clozapine and is much less common with the newer drugs. Other reversible neurologic dysfunctions that occur more frequently with older agents include akathisia and dystonias; these usually respond to treatment with diphenhydramine or muscarinic blocking agents. Tardive dyskinesias-This important toxicity includes choreoathetoid movements of the muscles of the lips and buccal cavity and may be irreversible. Tardive dyskinesias tend to develop after several years of antipsychotic drug therapy but have appeared as early as 6 mo. Antimuscarinic drugs that usually ameliorate other extrapyramidal effects generally increase the severity of tardive dyskinesia symptoms. Tardive dyskinesia may be attenuated temporarily by increasing neuroleptic dosage; this suggests that tardive dyskinesia may be caused by dopamine receptor sensitization. Autonomic effects-Autonomic effects result from blockade of peripheral muscarinic receptors and adrenoceptors and are more difficult to manage in elderly patients. Of the older antipsychotic agents, thioridazine has the strongest autonomic effects and haloperidol the weakest. Atropine-like effects (dry mouth, constipation, urinary retention, and visual problems) are often pronounced with the use of thioridazine and phenothiazines with aliphatic side chains (eg, chlorpromazine). These effects also occur with clozapine and most of the atypical drugs but not with ziprasidone or aripiprazole. Postural hypotension caused by blockade is a common manifestation of many of the older drugs, especially phenothiazines. In the elderly, measures must be taken to avoid falls resulting from postural fainting. The atypical drugs, especially clozapine and ziprasidone, also block receptors and can cause orthostatic hypotension. Endocrine and metabolic effects-Endocrine and metabolic effects include hyperprolactinemia, gynecomastia, the amenorrhea-galactorrhea syndrome, and infertility. Most of these adverse effects are predictable manifestations of dopamine D2 receptor blockade in the pituitary; dopamine is the normal inhibitory regulator of prolactin secretion. Significant weight gain and hyperglycemia due to a diabetogenic action occur with several of the atypical agents, especially clozapine and olanzapine. Aripiprazole and ziprasidone have little or no tendency to cause hyperglycemia, hyperprolactinemia, or weight gain. Neuroleptic malignant syndrome-Patients who are particularly sensitive to the extrapyramidal effects of antipsychotic drugs may develop a malignant hyperthermic syndrome. The symptoms include muscle rigidity, impairment of sweating, hyperpyrexia, and autonomic instability, which may be life threatening. Drug treatment involves the prompt use of dantrolene, diazepam, and dopamine agonists (see also Table 16-2). Sedation-This is more marked with phenothiazines (especially chlorpromazine) than with other antipsychotics; this effect is usually perceived as unpleasant by nonpsychotic persons. Fluphenazine and haloperidol are the least sedating of the older drugs; aripiprazole appears to be the least sedating of the newer agents. Miscellaneous toxicities-Visual impairment caused by retinal deposits has occurred with thioridazine; at high doses, this drug may also cause severe conduction defects in the heart resulting in fatal ventricular arrhythmias. Most neuroleptics lower the convulsive threshold and may cause seizures, which are usually managed with diazepam or phenytoin. Thioridazine (and possibly ziprasidone) overdose, because of cardiotoxicity, is more difficult to treat. The drug inhibits several enzymes involved in the recycling of neuronal membrane phosphoinositides. The drug is distributed throughout the body water and cleared by the kidneys at a rate one fifth that of creatinine. By interfering with this cycle, lithium may cause a use-dependent reduction of synaptic transmission. Clinical Use Lithium carbonate continues to be used for the treatment of bipolar disorder (manic-depressive disease) although other drugs including valproic acid and carbamazepine are equally effective (see text that follows). Maintenance therapy with lithium decreases manic behavior and reduces both the frequency and the magnitude of mood swings. Antipsychotic agents and/or benzodiazepines are commonly required at the initiation of treatment because both lithium and valproic acid have a slow onset of action. Although lithium has protective effects against suicide and self-harm, antidepressant drugs are often used concurrently during maintenance. Note that monotherapy with antidepressants can precipitate mania in bipolar patients. Toxicity Adverse neurologic effects of lithium include tremor, sedation, ataxia, and aphasia. Reversible nephrogenic diabetes insipidus occurs commonly at therapeutic drug levels. Edema is a common adverse effect of lithium therapy; acneiform skin eruptions occur; and leukocytosis is always present. Recent analyses suggest that the teratogenic risk is low, but in pregnancy it appears to contribute to low Apgar scores in the neonate. Other Drugs Used in Bipolar Disorder the manic phase in bipolar disorder can be treated with antipsychotic drugs, and both olanzapine and quetiapine are approved as monotherapy for this indication. Valproic acid has antimanic effects equivalent to those of lithium and is now widely used in the Unites States for this indication, often as a first choice in acute illness. Valproic acid may be effective in patients who fail to respond to lithium, and in some instances it has been used in combination with lithium. The antiseizure drugs carbamazepine and lamotrigine are also used both in acute mania and for prophylaxis in the depressive phase. Trifluoperazine was prescribed for a young male patient diagnosed as suffering from schizophrenia. Which statement concerning the adverse effects of antipsychotic drugs is accurate Which statement concerning the use of lithium in the treatment of bipolar affective disorder is accurate He tells you that since he has been on medication he is always thirsty and frequently has to urinate. The drug he is most likely to be taking is (A) Carbamazepine (B) Clozapine (C) Lithium (D) Risperidone (E) Valproic acid 7. A young male patient recently diagnosed as schizophrenic develops severe muscle cramps with torticollis a short time after drug therapy is initiated with haloperidol. Which statement about the pathophysiologic basis of schizophrenia is most accurate Which of the following drugs is established to be both effective and safe to use in a pregnant patient suffering from bipolar disorder In comparing the characteristics of thioridazine with other older antipsychotic drugs, which of the following statements is accurate Although most older antipsychotic drugs block D2 receptors, this action is not a requirement for antipsychotic action. There are no reports of decreased serotonin receptors in the brains of schizophrenics. Phenothiazines such as trifluoperazine cause sedation and are antagonists at muscarinic and adrenoceptors. Postural hypotension, blurring of vision, and dry mouth are common autonomic adverse effects, as is constipation. Effects on the male libido may result from increased prolactin or from increased peripheral conversion of androgens to estrogens. Akathisias (uncontrollable restlessness) resulting from antipsychotic drugs may be relieved by a reduction in dosage. Hyperprolactinemia and the amenorrhea-galactorrhea syndrome may occur as adverse effects during treatment with antipsychotic drugs, especially those like haloperidol that strongly antagonize dopamine receptors in the tuberoinfundibular tract. Clinical effects of lithium are slow in onset and may not be apparent before 1 or 2 weeks of daily treatment. High urinary levels of sodium inhibit renal tubular reabsorption of lithium, thus decreasing its plasma levels. Lithium clearance is decreased by distal tubule diuretics (eg, thiazides) because natriuresis stimulates a reflex increase in the proximal tubule reabsorption of both lithium and sodium. Teratogenic risk is low, but use of lithium during pregnancy may contribute to low Apgar score in the neonate. Confusion, mood changes, decreased sexual interest, and weight gain are symptoms that may be unrelated to drug administration. Tremor and symptoms of nephrogenic diabetes insipidus are characteristic adverse effects of lithium that may occur at blood levels within the therapeutic range. Acute dystonic reactions are usually very painful and should be treated immediately with parenteral administration of a drug that blocks muscarinic receptors such as benztropine. Adding risperidone is not protective, and fluphenazine is as likely as haloperidol to cause acute dystonia. Oral administration of diphenhydramine is a possibility, but the patient may find it difficult to swallow and it would take a longer time to act. What are the second-messenger systems for each of the following receptor subtypes that are blocked by antipsychotic drugs Carbamazepine and valproic acid are effective in bipolar disorder but are contraindicated in the pregnant patient because of possible effects on fetal development.

Cartagena Ipecac (Ipecac). V-gel.

• Thinning mucous to make coughing easier, bronchitis associated with croup, hepatitis, amoebic dysentery, loss of appetite, cancer, and other conditions.
• Dosing considerations for Ipecac.
• What is Ipecac?
• Causing vomiting (emetic).
• How does Ipecac work?

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