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Regional anatomy • Spinal Cord Anterior radicular arery Segmental spinal arter Posterior radicular artery Posterior spinal arteries Posterior radicular artery Anterior radicular artery Segmental medullar artery Segmental spinal artery Posterior branch of left posterior intercostal artery Left posterior intercostal artery B Fig order arava 10mg online medicine man gallery. The radicular arteries follow 10 mg arava visa medicine hat news, and supply buy 20 mg arava treatment 5 of chemo was tuff but made it, the anterior two branches that bracket the posterolateral sulcus and and posterior roots buy arava 10 mg on-line treatment pink eye. These vessels pass directly to the The anterior and posterior spinal arteries are reinforced longitudinally oriented vessels, reinforcing these. The largest of these is the arteria • One midline channel parallels the anterior median radicularis magna or the artery of Adamkiewicz fssure. This vessel arises in the lower thoracic or upper • One midline channel passes along the posterior median lumbar region, usually on the left side, and reinforces the sulcus. These longitudinal channels drain into an extensive internal vertebral plexus in the extradural (epidural) Veins space of the vertebral canal, which then drains into seg­ Veins that drain the spinal cord form a number of longitu­ mentally arranged vessels that connect with major sys­ dinal channels (Fig. The internal vertebral plexus also communicates with intracra­ • Two pairs ofveins oneach side bracket the connections nial veins. The spinal dura mater is the outermost meningeal mem­ brane and is separated from the bones forming the verte­ Subarachnoid space bral canal by an extradural space {Fig. Large with and become part of the outer covering (epineurium) blood vessels are suspended in the subarachnoid space by of the nerves. Arachnoid mater The subarachnoid space extends further inferiorly than The arachnoid mater is a thin delicate membrane the spinal cord. The spinal cord ends at approximately against, but not adherent to, the deep surface of the dura the disc between vertebrae 11 and 111, whereas the Subarachnoid space Posterior spinal artery Pia mater Recurrent meningeal nerves Denticulate ligament Anterior spinal artery Dura mater Fig. The subarachnoid the vertebral canal space is largest in the region inferior to the terminal end of the spinal cord, where it surrounds the cauda equina. It the median plane the roots of the interspinous liga­ extends into the anterior median fssure and reflects as ments and vertebral spinous processes. As the Between the walls of the vertebral canal and the dural roots exit the space, the sleeve-like coatings reflect onto the sac is an extradural space containing a vertebral plexus of arachnoid mater. On each side of the spinal cord, a longitudinally ori­ The vertebral spinous processes can bepalpatedthrough ented sheet of pia mater (the denticulate ligament) the skin in the midline in thoracic and lumbar regions extends laterally from the cord toward the arachnoid and of the back. In lumbar regions, the adjacent spinous processes and the associated laminae oneither side • Medially, each denticulate ligament is attached to the of the midline do not overlap, resulting in gaps between spinal cord in a plane that lies between the origins of the adjacent vertebral arches. When carrying out a lumbar puncture (spinal tap), the • Laterally, each denticulate ligament forms a series of needle passes between adjacent vertebral spinous pro­ triangular extensions along its free border, with the cesses, through the supraspinous and interspinous liga­ apex of each extension being anchored through the ments, and enters the extradural space. When subarachnoid space because the spinal cord terminates procedures are carried out, the patient must be in the around the level of the disc between vertebrae Ll and Lll erect position and not lying on his or her side or in the in theadult. A needle is placed through in the midline in between the spinous processes into the the skin, supraspinous ligament, interspinous ligament, extradural space. Further advancement punctures the and ligamenta flava into the areolartissue and fat around dura and arachnoid mater to enterthe subarachnoid the dura mater. Most needles push the roots awayfrom the tip difuses around the vertebral canal to anesthetize the without causing the patientany symptoms. Once the exiting nerve roots and difuse into the subarachnoid needle is in the subarachnoid space, fluid can be space. Spinal nerves A spinal segment is the area of the spinal cord that Each spinal nerve is connected to the spinal cord by poste­ gives rise to the posterior and anterior rootlets, which rior and anterior roots {Fig. Laterally, the pos­ terior and anterior roots on each side join to form a spinal • The posterior root contains the processes of sensory nerve. Consequently, posterior and anterior roots forming dura, ligaments, intervertebral discs, and blood vessels. Because the spinal cord is much shorter than the verte­ Below the end of the spinal cord, the posterior and ante­ bral column, the roots of spinal nerves become longer and rior roots of lumbar, sacral, and coccygeal nerves pass infe­ pass more obliquely from the cervical to coccygeal regions riorly to reach their exit points from the vertebral canal. Under certain • eight cervical nerves-C1 to C8, circumstances, thevirus becomes activated and travels along the neuronal bundles to the areas supplied by • twelve thoracic nerves-T1 toT12, that nerve (the dermatome). Importantly, this • fve sacral nerves-S1 to S5, typical dermatomal distribution is characteristic of • one coccygeal nerve-Co. There­ fore cervical nerves C2 to C7 also emerge from the verte­ bral canal above their respective vertebrae. As a consequence, all remaining spinal nerves, beginning with T1, emerge from the vertebral canal below their respective vertebrae. Nerves C2 to C7 emerge superior to pedicles Transition in nomenclature of nerves Nerves T1 to Co emerge inferior to pedicles of their respective vertebrae Fig. Enlarged lymph nodes in the Back pain is an extremely common condition afecting pre- and para-aortic region may produce central posterior almost all individuals at some stage during their life. An enlarging pain relates to the vertebral column and its attachments abdominal aorta (abdominal aortic aneurysm) may cause or relates to other structures. Therefore it is The failure to consider other potential structures that critical to think of this structure as a potential cause of may produce back pain can lead to signifcant mortality back pain, because treatment will be lifesaving. Pain may refer to the back from a number a ruptured abdominal aortic aneurysm may also cause of organs situated in the retroperitoneum. Renal pain, which may not only of the vertebral column but also of the chest and be produced by stones in the renal collecting system or abdomen in order notto miss other important anatomical renal tumors, also typically refers to the back. More ofen structures that may produce signs and symptoms than not this is usually unilateral; however, it can produce radiating to the back. The vertical skin furrowbetween of the vertebral column, and to estimate the approximate muscle masses on either side of the midline is straight position of the inferior end of the spinal cord. Among these fea­ Primary and secondary curvatures tures are the external occipital protuberance, the scapula, in the sagittal plane and the iliac crest (Fig. When viewed from the side, the normal vertebral column The external occipital protuberance is palpable in the has primary curvatures in the thoracic and sacral/ midline at the back of the head just superior to the coccygeal regions and secondary curvatures in the cervical hairline. The iliac crest is palpable along its entire length, from the anterior superior iliac spine at the lower lateral margin of the anterior abdominal wall to the posterior superior Useful nonvertebral skeletal landmarks iliac spine near the base of the back. The position of the A number of readily palpable bony features provide useful posterior superior iliac spine is ofen visible as a "sacral landmarks for defning muscles and for locating structures dimple" just lateral to the midline. In thoracic regions, the spinous processes readily apparent as a longitudinal ridge when the neck is are long and sharply sloped downward so that their tips lie flexed (Fig. In a woman lying on her side in a fetal position, which accentuates the lumbar vertebral spinous processes and opens the spaces between adjacent vertebral arches. Cerebrospinal fluid can be withdrawn from the subarachnoid space in lower lumbar regions without endangering the spinal cord. Because the subarachnoid space can be accessed in the lower lumbar region without endangering the spinal cord, it is important to be able to identify the position of the lumbar vertebral spinous processes. In the lumbar region, the palpable ends of the vertebral spinous processes lie oppo­ site their corresponding vertebral bodies. Identifying major muscles A number of intrinsic and extrinsic muscles of the back can readily be observed and palpated. The erector spinae muscles are visible as two longitudinal columns separated by a furrow in the midline {Fig. In a woman with scapulae externally rotated and forcibly retracted to accentuate the rhomboid muscles. Sciatica is a Of the many common causes of low back pain some name given to pain in the area of distribution of the need to be identifed early to commence appropriate sciatic nerve (L4 to 53). On examination he had a severe injury to The patient has paralysis of the upper and lower limbs the cervical region of his vertebral column with and is therefore quadriplegic.

Therapeutic levels for mephenytoin range from 5 to 16 mcg/mL buy discount arava 10 mg line medications a to z, and levels above 20 mcg/mL are considered toxic purchase arava 10mg with amex medicine garden. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well buy 20mg arava fast delivery medications mobic. Chemistry Although not obvious from a two-dimensional representation of its structure 20mg arava sale 10 medications doctors wont take, carbamazepine has many similarities to phenytoin. Three-dimensional structural studies indicate that its spatial conformation is similar to that of phenytoin. Mechanism of Action The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Carbamazepine, like phenytoin, blocks Na channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24–4). Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known. Clinical Uses Although carbamazepine has long been considered a drug of choice for both partial seizures and generalized tonic-clonic seizures, some of the newer antiseizure drugs are beginning to displace it from this role. The drug is also very effective in some patients with trigeminal neuralgia, although older patients may tolerate higher doses poorly, with ataxia and unsteadiness. Pharmacokinetics The rate of absorption of carbamazepine varies widely among patients, although almost complete absorption apparently occurs in all. Slowing absorption by giving the drug after meals helps the patient tolerate larger total daily doses. The drug is approximately 70% bound to plasma proteins; no displacement of other drugs from protein binding sites has been observed. Typically, the half-life of 36 hours observed in subjects after an initial single dose decreases to as little as 8–12 hours in subjects receiving continuous therapy. In patients in whom the blood is drawn just before the morning dose (trough level), the therapeutic level is usually 4–8 mcg/mL. Although many patients complain of diplopia at drug levels above 7 mcg/mL, others can tolerate levels above 10 mcg/mL, especially with monotherapy. Drug Interactions Drug interactions involving carbamazepine are almost exclusively related to the drug’s enzyme-inducing properties. As noted previously, the increased metabolic capacity of the hepatic enzymes may cause a reduction in steady-state carbamazepine concentrations and an increased rate of metabolism of other drugs, eg, primidone, phenytoin, ethosuximide, valproic acid, and clonazepam. Other drugs such as valproic acid may inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels. Other anticonvulsants, however, such as phenytoin and phenobarbital, may decrease steady-state concentrations of carbamazepine through enzyme induction. Other dose-related complaints include mild gastrointestinal upsets, unsteadiness, and, at much higher doses, drowsiness. Considerable concern exists regarding the occurrence of idiosyncratic blood dyscrasias with carbamazepine, including fatal cases of aplastic anemia and agranulocytosis. Most of these have been in elderly patients with trigeminal neuralgia, and most have occurred within the first 4 months of treatment. The mild and persistent leukopenia seen in some patients is not necessarily an indication to stop treatment but requires careful monitoring. The most common idiosyncratic reaction is an erythematous skin rash; other responses such as hepatic dysfunction are unusual. Its activity, therefore, resides almost exclusively in the 10-hydroxy metabolite (especially the S(+) enantiomer, eslicarbazepine), to which it is rapidly converted and which has a half-life similar to that of carbamazepine, ie, 8–12 hours. Oxcarbazepine is less potent than carbamazepine, both in animal models of epilepsy and in epileptic patients; clinical doses of oxcarbazepine may need to be 50% higher than those of carbamazepine to obtain equivalent seizure control. Some studies report fewer hypersensitivity reactions to oxcarbazepine, and cross-reactivity with carbamazepine does not always occur. Furthermore, the drug appears to induce hepatic enzymes to a lesser extent than carbamazepine, minimizing drug interactions. Although hyponatremia may occur more commonly with oxcarbazepine than with carbamazepine, most adverse effects that occur with oxcarbazepine are similar in character to reactions reported with carbamazepine. Clinically, the drug is similar to carbamazepine and oxcarbazepine in its spectrum of action, but it is less well studied in other possible indications. The drug is administered at a dosage of 400–1200 mg/d; titration is typically required for the higher doses. Minimal drug level effects are observed with co-administration of carbamazepine, levetiracetam, lamotrigine, topiramate, and valproate. Although it has long been considered one of the safest of the antiseizure agents, the use of other medications with lesser sedative effects has been urged. Chemistry The four derivatives of barbituric acid clinically useful as antiseizure drugs are phenobarbital, mephobarbital, metharbital, and primidone. Metharbital is methylated barbital, and mephobarbital is methylated phenobarbital; both are demethylated in vivo. Slight changes in the normal acid-base balance, therefore, can cause significant fluctuation in the ratio of the ionized to the nonionized species. This is particularly important for phenobarbital, the most commonly used barbiturate, whose pK is similar to the plasma pH of 7. Mechanism of Action The exact mechanism of action of phenobarbital is unknown, but enhancement of inhibitory processes and diminution of excitatory transmission probably contribute significantly. Like phenytoin, phenobarbital suppresses high-frequency repetitive firing in neurons in culture through + 2+ an action on Na conductance, but only at high concentrations. Clinical Uses Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures, although the drug is often tried for virtually every seizure type, especially when attacks are difficult to control. There is little evidence for its effectiveness in generalized seizures such as absence, atonic attacks, and infantile spasms; it may worsen certain patients with these seizure types. Some physicians prefer either metharbital (no longer readily available) or mephobarbital (especially the latter) to phenobarbital because of supposed decreased adverse effects. Pharmacokinetics, Therapeutic Levels, & Dosage For pharmacokinetics, drug interactions, and toxicity of phenobarbital, see Chapter 22. Documentation of effectiveness is best in febrile seizures, and levels below 15 mcg/mL appear ineffective for prevention of febrile seizure recurrence. The upper end of the therapeutic range is more difficult to define because many patients appear to tolerate chronic levels above 40 mcg/mL. Mechanism of Action Although primidone is converted to phenobarbital, the mechanism of action of primidone itself may be more like that of phenytoin. Clinical Uses Primidone, like its metabolites, is effective against partial seizures and generalized tonic-clonic seizures and may be more effective than phenobarbital. It was previously considered to be the drug of choice for complex partial seizures, but later studies of partial seizures in adults strongly suggest that carbamazepine and phenytoin are superior to primidone. Attempts to determine the relative potencies of the parent drug and its two metabolites have been conducted in newborn infants, in whom drug-metabolizing enzyme systems are very immature and in whom primidone is only slowly metabolized.

Clinical Uses Albendazole is administered on an empty stomach when used against intraluminal parasites but with a fatty meal when used against tissue parasites generic 10mg arava with amex symptoms 7 weeks pregnant. Ascariasis generic 20mg arava visa treatment jalapeno skin burn, trichuriasis generic arava 20mg fast delivery medications requiring prior authorization, and hookworm and pinworm infections—For adults and children older than 2 years with ascariasis and pinworm infections buy arava 20 mg line treatment example, the treatment for ascariasis is a single dose of 400 mg orally (repeated for 2–3 days for heavy infections and in 2 weeks for pinworm infections). These treatments typically achieve good cure rates and marked reduction in egg counts in those not cured. For hookworm infections and trichuriasis, albendazole at 400 mg orally once daily for 3 days is now recommended, with albendazole showing improved efficacy over mebendazole. In addition, combination of either mebendazole or albendazole with ivermectin to treat trichuriasis markedly improved treatment outcomes. Hydatid disease—Albendazole is the treatment of choice for medical therapy and is a useful adjunct to surgical removal or aspiration of cysts. One reported therapeutic strategy is to treat with albendazole and praziquantel, to assess response after 1 month or more and, depending on the response, to then manage the patient with continued chemotherapy or combined surgical and drug therapy. Neurocysticercosis—Indications for medical therapy for neurocysticercosis are controversial, since antihelminthic therapy is not clearly superior to therapy with corticosteroids alone and may exacerbate neurologic disease. Corticosteroids are usually given with the antihelminthic drug to decrease inflammation caused by dying organisms. Albendazole is now generally considered the drug of choice over praziquantel because of its shorter course, lower cost, improved penetration into the subarachnoid space, and increased drug levels (as opposed to decreased levels of praziquantel) when administered with corticosteroids. Other infections—Albendazole is the drug of choice in the treatment of cutaneous larva migrans (400 mg daily for 3 days), visceral larva migrans (400 mg twice daily for 5 days), intestinal capillariasis (400 mg daily for 10 days), microsporidial infections (400 mg twice daily for 2 weeks or longer), and gnathostomiasis (400 mg twice daily for 3 weeks). It also has activity against taeniasis (400 mg daily for 3 days), trichinosis (400 mg twice daily for 1–2 weeks), and clonorchiasis (400 mg twice daily for 1 week). It appears to be less active than diethylcarbamazine or ivermectin for this purpose, but it is included in combination with either of those drugs in control programs. Albendazole has been recommended as empiric therapy to treat those who return from the tropics with persistent unexplained eosinophilia. Considering protozoal infections, albendazole has shown efficacy similar to that of metronidazole, with less toxicity, against giardiasis. Adverse Reactions, Contraindications, & Cautions When used for 1–3 days, albendazole is nearly free of significant adverse effects. Mild and transient epigastric distress, diarrhea, headache, nausea, dizziness, lassitude, and insomnia can occur. In long-term use for hydatid disease, albendazole is well tolerated, but it can cause abdominal distress, headaches, fever, fatigue, alopecia, increases in liver enzymes, and pancytopenia. The drug should not be given to patients with known hypersensitivity to other benzimidazole drugs or to those with cirrhosis. For treatment of paragonimiasis and fascioliasis, the dosage of bithionol is 30–50 mg/kg in two or three divided doses, given orally after meals on alternate days for 10–15 doses. Adverse Reactions, Contraindications, & Cautions Adverse effects, which occur in up to 40% of patients, are generally mild and transient, but occasionally their severity requires interruption of therapy. These problems include diarrhea, abdominal cramps, anorexia, nausea, vomiting, dizziness, and headache. Skin rashes may occur after a week or more of therapy, suggesting a reaction to antigens released from dying worms. Bithionol should be used with caution in children younger than 8 years because there has been limited experience in this age group. Basic Pharmacology Diethylcarbamazine, a synthetic piperazine derivative, is rapidly absorbed from the gastrointestinal tract; after a 0. The plasma half-life is 2–3 hours in the presence of acidic urine but about 10 hours if the urine is alkaline, a Henderson-Hasselbalch trapping effect (see Chapter 1). Diethylcarbamazine immobilizes microfilariae and alters their surface structure, displacing them from tissues and making them more susceptible to destruction by host defense mechanisms. Wuchereria bancrofti, Brugia malayi, Brugia timori, and Loa loa—Diethylcarbamazine is the drug of choice for treatment of infections with these parasites because of its efficacy and lack of serious toxicity. Microfilariae of all species are rapidly killed; adult parasites are killed more slowly, often requiring several courses of treatment. The extent to which W bancrofti and B malayi adults are killed is not known, but after appropriate therapy microfilariae do not reappear in the majority of patients. Lymphatic filariasis is treated with 2 mg/kg three times a day for 12 days, and loiasis is treated with the same regimen for 2–3 weeks. Antihistamines may be given for the first few days of therapy to limit allergic reactions, and corticosteroids should be started and doses of diethylcarbamazine lowered or interrupted if severe reactions occur. For patients with high L loa worm burdens (more than 2500 circulating parasites/mL), strategies to decrease risks of severe toxicity include (a) apheresis, if available, to remove microfilariae before treatment with diethycarbamazine, or (b) therapy with albendazole, which is slower acting and better tolerated, followed by therapy with diethylcarbamazine or ivermectin. Diethylcarbamazine may also be used for chemoprophylaxis against filarial infections (300 mg weekly or 300 mg on 3 successive days each month for loiasis; 50 mg monthly for bancroftian and Malayan filariasis). Other uses—For tropical eosinophilia, diethylcarbamazine is given orally at a dosage of 2 mg/kg three times daily for 2–3 weeks. Diethylcarbamazine is effective in Mansonella streptocerca infections, since it kills both adults and microfilariae. Limited information suggests that the drug is not effective, however, against adult Mansonella ozzardi or Mansonella perstans and that it has limited activity against microfilariae of these parasites. An important application of diethylcarbamazine has been mass treatment to reduce the prevalence of W bancrofti infection, generally in combination with ivermectin or albendazole. Adverse Reactions, Contraindications, & Cautions Reactions to diethylcarbamazine, which are generally mild and transient, include headache, malaise, anorexia, weakness, nausea, vomiting, and dizziness. Adverse effects also occur as a result of the release of proteins from dying microfilariae or adult worms. Reactions are particularly severe with onchocerciasis, but diethylcarbamazine is no longer commonly used for this infection, because ivermectin is equally efficacious and less toxic. Reactions to dying microfilariae are usually mild in W bancrofti, more intense in B malayi, and occasionally severe in L loa infections. Reactions include fever, malaise, papular rash, headache, gastrointestinal symptoms, cough, chest pain, and muscle or joint pain. These include lymphangitis with localized swellings in W bancrofti and B malayi, small wheals in the skin in L loa, and flat papules in M streptocerca infections. Patients with attacks of lymphangitis due to W bancrofti or B malayi should be treated during a quiescent period between attacks. Doxycycline has recently been shown to have significant macrofilaricidal activity against W bancrofti, suggesting better activity than any other available drug against adult worms. Doxycycline acts indirectly, by killing Wolbachia, an intracellular bacterial symbiont of filarial parasites. It may prove to be an important drug for filariasis, both for treatment of active disease and in mass chemotherapy campaigns. Basic Pharmacology Ivermectin, a semisynthetic macrocyclic lactone derived from the soil actinomycete Streptomyces avermitilis, is a mixture of avermectin B1a and B1b. It does not effectively kill adult worms but blocks the release of microfilariae for some months after therapy. After a single standard dose, microfilariae in the skin diminish rapidly within 2–3 days, remain low for months, and then gradually increase; microfilariae in the anterior chamber of the eye decrease slowly over months, eventually clear, and then gradually return. With repeated doses of ivermectin, the drug appears to have a low-level macrofilaricidal action and to permanently reduce microfilarial production.

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Myelinated nerves are blocked terized by an overall hyperactive state in the brain in faster than unmyelinated safe arava 20 mg medicine wheel. The diameter is the most which the neurons rapidly depolarize and stimulate important factor because small unmyelinated fbers neighboring neurons to also depolarize resulting in an will be affected before large myelinated fbers generic arava 20 mg without a prescription medications hard on liver. The (A) Small diameter nerve fbers are blocked before depolarization occurs when sodium fows into the larger nerve fbers order arava 20mg without prescription treatment 2nd degree heart block. It short acting benzodiazepines should be avoided be- works in the thalamus and is used for absence sei- cause of their higher addictive potential buy arava 20 mg lowest price treatment 8th february. Potassium channel blockers is intermediate acting and therefore would have a would not help control a seizure. The para- els are thought to be decreased, so inhibiting the ace- sympathetic nervous system stimulates these recep- tylcholine receptor would not be appropriate treatment. Normally, acetylcholine (B) Donepezil is an acetylcholinesterase inhibitor used release onto muscarinic receptors causes bradycardia, to treat Alzheimer’s disease. In (A) Amitriptyline is a tricyclic antidepressant that can Parkinson’s disease, cholinergic activity is increased. Mirtazapine is an atypi- tonin syndrome when used with monoamine oxidase cal antidepressant that increases the release of norepi- inhibitors but not hypertensive crisis after consuming nephrine and serotonin by a2 antagonism. This dilation of the pupil facilitates ophthal- petite and would not be benefcial in a patient with mologic examination. Letter D represents the cholinergic receptors on the bladder to decrease con- binding to the receptor. It is This mechanism of action would not serve this patient extensively metabolized in the liver to numerous me- nor does darifenacin work in this manner. Neuroleptics inhibit dopa- amine oxidase inhibitor used in the treatment of de- mine reuptake at all doses. There are many (C) Lorazepam is a benzodiazepine that blocks sei- drugs used to control or limit seizure activity. Its Carbamazepine is a drug that may cause blurred vi- most common side effect is sedation and does not sion and diplopia with use. Its most common side effect is metabolism, so dosage adjustments early in therapy sedation and does not usually cause visual distur- may be necessary. Which of (A) Impermeability to the blood–brain barrier the following would be expected following steady state (B) Long duration of action intravenous dosing of agent X, a b2-receptor agonist? Which of the follow- 3 A 58-year-old woman who is obese presents to the ing agents prevents the development of preterm labor? What is the effect of have tumors less than 3 cm in size and are confned to the ibuprofen on her anticoagulation regimen? Which of the following patients would be most likely to suffer an adverse event related to this medication? It is anticipated that the procedure (C) A 45-year-old man with hyperparathyroid adenoma will take approximately 16 h. Which of the following agents will have limited cedure, the ophthalmologist dilates his pupils with effcacy in the management of this patient? Which of the fol- (A) Labetalol lowing describes an effect of the sympathetic nervous (B) Methyldopa system? The started on a trial of terazosin, after which his symp- pain stops, so he disregards the episode entirely until toms improve dramatically. Which of the following the next day when he experiences a “funny feeling in describes terazosin’s drug class? The intended effect of sotalol in- 2 (C) Anticholinergic volves modifying which phase of the cardiac myocyte (D) b -Adrenergic agonist action potential? Later, he developed ventricular tachycardia and is treated with 19 A 35-year-old man presents to the emergency depart- an antiarrhythmic. After a week of antiarrhythmic ment complaining of a cough and runny nose of treatment, he began having diffculty breathing. His surgery goes smoothly, but the next day he develops chest palpita- 20 A 54-year-old woman with severe essential hyperten- tions. Metoprolol is started to keep his supraventricu- sion refractory to treatment switched to a new antihy- lar tachycardia from interfering with ventricular pertensive drug 1 month ago. She has passed calcium oxalate stones in determined that she is experiencing Prinzmetal an- the past and likely has another stone. She is given a her for the stone, which of the following diuretics prescription for nifedipine to relax her vascular could be started to prevent future calcium oxalate smooth musculature. Which (B) Dry cough of the following is a calcium channel blocker that (C) Erectile dysfunction works primarily on vascular smooth muscle? Which of the 27 A 57-year-old man with hypertension presents to his following physiologic effects of nitric oxide will be primary care physician for a follow-up checkup. Which of the following param- (E) Spontaneous minute ventilation increases eters is most likely to change because of his metopro- lol therapy? Which of the following patients will (D) Creatinine clearance require the largest doses of inhalational anesthetic (E) White blood cell count agents? She recovers well initially but soon (B) Patient 2: blood pressure of 150/80 mm Hg, pulse 5 develops left heart failure. Her physician prescribes 100 beats/minute multiple medications to treat different aspects of heart (C) Patient 3: blood pressure of 120/80 mm Hg, pulse 5 failure, including isosorbide dinitrate. Which of the following sources of you expect to be elevated in this patient’s blood as a intracellular calcium plays the most minor role in direct result of alteplase? Cardiovascular Pharmacology 85 (A) Exchange with sodium (A) Bicarbonate (B) Intracellular transport via voltage-sensitivechannels (B) Chloride (C) Intracellular vacuolar release of calcium (C) Glucose (D) Mitochondria release of calcium (D) Potassium (E) Sarcoplasmic reticulum release of calcium (E) Sodium 30 A 72-year-old man is having an electrocardiogram 34 A 62-year-old man with congestive heart failure and performed by his primary care physician to further hypertension on digoxin takes an extra few pills evaluate intermittent chest pain. Regarding the phase 0 because he is angry about his daughter being pregnant of the cardiac action potential, which of the following out of wedlock. If elec- (A) Calcium channels open resulting in outward trocardiogram is performed, which of the following current would be most likely? She complains of a 4-week history of diarrhea, prove to have additional beneft in the treatment of sweats, and muscle weakness. Which of the following is the most likely explanation (A) Exercise program involving alternating running for these fndings? She is currently the following agents would be best for this patient to taking captopril and hydrochlorothiazide. Which of prevent recurrence of arrhythmia and decrease his the following changes would be expected as a result of risk of mortality? The procedure is going along sion managed with nifedipine presents to his primary uneventfully, and there is no indication of acute blood care physician for follow-up. The and within 15 s, the electrocardiogram shows normal most likely effects of this medication to cause blood sinus rhythm. What is the most likely explanation for pressure reduction likely involve this normalization of the electrocardiogram? The anginal ment complaining of chest pain that has increased in attacks are becoming more frequent, and therapy is frequency, duration, and intensity. She takes a sublingual nitroglycerin sion treated with a b-blocker presents to his primary tablet and within a few minutes has improvement in care physician for follow-up. Which of the following is the most usually runs 130/76 mm Hg and today (at 6-month likely explanation of action of this agent?

In addition order arava 10mg fast delivery medications after stroke, the practical efficacy of a drug for achieving a therapeutic end point (eg arava 20 mg symptoms appendicitis, increased cardiac contractility) may be limited by the drug’s propensity to cause a toxic effect (eg discount 10 mg arava with mastercard medicine quizlet, fatal cardiac arrhythmia) even if the drug could otherwise produce a greater therapeutic effect purchase arava 10 mg without a prescription treatment xanthelasma eyelid. Shape of Dose-Response Curves Although the responses depicted in curves A, B, and C of Figure 2–15 approximate the shape of a simple Michaelis-Menten relation (transformed to a logarithmic plot), some clinical responses do not. Extremely steep dose-response curves (eg, curve D) may have important clinical consequences if the upper portion of the curve represents an undesirable extent of response (eg, coma caused by a sedative-hypnotic). Steep dose-response curves in patients can result from cooperative interactions of several different actions of a drug (eg, effects on brain, heart, and peripheral vessels, all contributing to lowering of blood pressure). Quantal Dose-Effect Curves Graded dose-response curves of the sort described above have certain limitations in their application to clinical decision making. For example, such curves may be impossible to construct if the pharmacologic response is an either-or (quantal) event, such as prevention of convulsions, arrhythmia, or death. Furthermore, the clinical relevance of a quantitative dose- response relation in a single patient, no matter how precisely defined, may be limited in application to other patients, owing to the great potential variability among patients in severity of disease and responsiveness to drugs. Some of these difficulties may be avoided by determining the dose of drug required to produce a specified magnitude of effect in a large number of individual patients or experimental animals and plotting the cumulative frequency distribution of responders versus the log dose (Figure 2–16). The specified quantal effect may be chosen on the basis of clinical relevance (eg, relief of headache) or for preservation of safety of experimental subjects (eg, using low doses of a cardiac stimulant and specifying an increase in heart rate of 20 bpm as the quantal effect), or it may be an inherently quantal event (eg, death of an experimental animal). For most drugs, the doses required to produce a specified quantal effect in individuals are lognormally distributed; that is, a frequency distribution of such responses plotted against the log of the dose produces a gaussian normal curve of variation (colored areas, Figure 2–16). When these responses are summated, the resulting cumulative frequency distribution constitutes a quantal dose-effect curve (or dose-percent curve) of the proportion or percentage of individuals who exhibit the effect plotted as a function of log dose. Shaded boxes (and the accompanying bell-shaped curves) indicate the frequency distribution of doses of drug required to produce a specified effect; that is, the percentage of animals that required a particular dose to exhibit the effect. The open boxes (and the corresponding colored curves) indicate the cumulative frequency distribution of responses, which are lognormally distributed. Quantal dose-effect curves may also be used to generate information regarding the margin of safety to be expected from a particular drug used to produce a specified effect. One measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect, is the therapeutic index. The precision possible in animal experiments may make it useful to use such a therapeutic index to estimate the potential benefit of a drug in humans. Of course, the therapeutic index of a drug in humans is almost never known with real precision; instead, drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses. The range between the minimum toxic dose and the minimum therapeutic dose is called the therapeutic window and is of greater practical value in choosing the dose for a patient. The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated. For example, the dose range that provides relief from an ordinary headache in the majority of patients should be very much lower than the dose range that produces serious toxicity, even if the toxicity occurs in a small minority of patients. However, for treatment of a lethal disease such as Hodgkin’s lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller. Finally, note that the quantal dose-effect curve and the graded dose-response curve summarize somewhat different sets of information, although both appear sigmoid in shape on a semilogarithmic plot (compare Figures 2–15 and 2–16). Critical information required for making rational therapeutic decisions can be obtained from each type of curve. Both curves provide information regarding the potency and selectivity of drugs; the graded dose-response curve indicates the maximal efficacy of a drug, and the quantal dose-effect curve indicates the potential variability of responsiveness among individuals. Variation in Drug Responsiveness Individuals may vary considerably in their response to a drug; indeed, a single individual may respond differently to the same drug at different times during the course of treatment. Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that is infrequently observed in most patients. The idiosyncratic responses are usually caused by genetic differences in metabolism of the drug or by immunologic mechanisms, including allergic reactions. An individual patient is hyporeactive or hyperreactive to a drug in that the intensity of effect of a given dose of drug is diminished or increased compared with the effect seen in most individuals. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis. Even before administering the first dose of a drug, the prescriber should consider factors that may help in predicting the direction and extent of possible variations in responsiveness. These include the propensity of a particular drug to produce tolerance or tachyphylaxis as well as the effects of age, sex, body size, disease state, genetic factors, and simultaneous administration of other drugs. Four general mechanisms may contribute to variation in drug responsiveness among patients or within an individual patient at different times. Alteration in Concentration of Drug That Reaches the Receptor As described in Chapter 3, patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood. By altering the concentration of drug that reaches relevant receptors, such pharmacokinetic differences may alter the clinical response. Some differences can be predicted on the basis of age, weight, sex, disease state, and liver and kidney function, and by testing specifically for genetic differences that may result from inheritance of a functionally distinctive complement of drug-metabolizing enzymes (see Chapters 4 and 5). Variation in Concentration of an Endogenous Receptor Ligand This mechanism contributes greatly to variability in responses to pharmacologic antagonists. Thus, propranolol, a β- adrenoceptor antagonist, markedly slows the heart rate of a patient whose endogenous catecholamines are elevated (as in pheochromocytoma) but does not affect the resting heart rate of a well-trained marathon runner. Alterations in Number or Function of Receptors Experimental studies have documented changes in drug response caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. In some cases, the change in receptor number is caused by other hormones; for example, thyroid hormones increase both the number of β receptors in rat heart muscle and cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a β-adrenoceptor antagonist, in ameliorating symptoms of this disease. In other cases, the agonist ligand itself induces a decrease in the number (eg, down-regulation) or coupling efficiency (eg, desensitization) of its receptors. These mechanisms (discussed previously under Signaling Mechanisms & Drug Actions) may contribute to two clinically important phenomena: first, tachyphylaxis or tolerance to the effects of some drugs (eg, biogenic amines and their congeners), and second, the “overshoot” phenomena that follow withdrawal of certain drugs. An antagonist may increase the number of receptors in a critical cell or tissue by preventing down-regulation caused by an endogenous agonist. When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiologic concentrations of agonist. Potentially disastrous withdrawal symptoms can result for the opposite reason when administration of an agonist drug is discontinued. In this situation, the number of receptors, which has been decreased by drug-induced down-regulation, is too low for endogenous agonist to produce effective stimulation. For example, the withdrawal of clonidine (a drug whose α -2 adrenoceptor agonist activity reduces blood pressure) can produce hypertensive crisis, probably because the drug down- regulates α adrenoceptors (see2 Chapter 11). Genetic factors also can play an important role in altering the number or function of specific receptors.