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220 Cards in this Set

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1. Where are the muscarinic receptors?
Muscarinic cholinergic transmission occurs mainly at autonomic ganglia, at end organs innervated by the parasympathetic division of the ANS, and in the CNS.

These receptors act thru G proteins and thus there is a latency of 100-250 ms associated with muscarinic responses.
2. Where are the nicotinic receptors?
Nicotinic cholinergic receptors are at autonomic ganglia and in the CNS and in the NMJ for skeletal muscle.

All nicotinic receptors are ligand-gated cation-selective channels and have a rapid response of only 5 ms.
3. What are the inhibitors of ACh synthesis, storage, and release?
Drugs that inhibit the synthesis, storage, or release of ACh include:

Botulinum toxin
4. What are the uses for hemicholinium-3 and vesamicol?
Hemicholinium-3 blocks the high-affinity transporter for choline, and thus prevents the uptake of choline required for ACh synthesis.

Vesamicol blocks the ACh-H+ antiporter that is used to transport ACh into vesicles, thereby preventing the storage of ACh.

*Both of these compounds are utilized only in research settings.
5. Botulinum toxin
MOA: Botulinum toxin, produced by C. botulinum, degrades synaptobrevin and thus prevents synaptic vesicle fusion w/the axon terminal (presynaptic) membrane).

PURPOSE: Focal dystonias, toticollis, achalasia, strabismus, blepharospasm, pain syndromes, wrinkles, hyperhidrosis

ADVERSE: Cardiac arrhythmia, syncope, hepatotoxicity, anaphylaxis, injection site pain, dyspepsia, dysphagia, muscle weakness, neck pain, eyelid ptosis, fever

CONTRA: Hypersensitivity; infection at the injection site.
6. What are the inhibitors of ACh degradation?
1. Edrophonium
2. Neostigmine
3. Pyridostigmine
4. Ambenonium
5. Physostigmine

MOA: Inhibit AChE by binding to the enzyme's active site

PURPOSE: (1) Dx of myasthenia gravis, Lambert Eaton syndrome, and disroders resutling in muscle weakness (edrophonium) (2) Urinary or GI motility agent, glaucoma, NMJ diseases such as myasthenia gravis, (neostigmine, pyridostigmine, ambenonium) (3) Reversal of anticholinergic txoicity or induced paralysis in surgery (physostigmine)

ADVERSE: Seizure, bronchospasm, cardiac arrhythmia, bradycardia, cardiac arrest, hypotension or hypertension, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis

CONTRA: Mechanical interstinal or urinary obstruction, concomitant choline ester or depolarizing NM blocker use, cardiovascular disease
8. Therapeutic notes for the inhibitors of ACh degradation (5)
1. Edrophonium is short acting (2-10 min); rapid onset of action makes edrophonium useful for the Dx of muscle weakness
2. For chronic treatment of myasthenia gravis, longer acting cholinesterase inhibitors such as pyridostigmine, neostigmine, and ambenonium are preferred.
3. Neostigmine also has direct cholinergic agonist effect at Nm receptors
4. Topical application of cholinesterase inhibitors to the cornea of the eye decreases intraocular pressure by facilitating the outflow of aqueous humor
5. Non-polar structure makes physostigmine useful for combating CNS anticholinergic toxicity.
9. What is diisopropyl fluorophosphate?
MOA: An organophosphate compound used as an insecticide,a s a substrate for the production of organophosphate chemical weapons, and formerly as a topical miotic medication in ophthalmology


ADVERSE: Respiratory paralysis, bradycardia, bronchospasm, fasciculations, muscle cramps, weakness, CNS depression, agitation, confusion, delirium, coma, bronchorrhea, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis
10. In organophosphate poisoning, the AChE-organophosphate complex is subject to...?
Aging, in which oxygen-phosphorus bonds w/in the inhibitor are broken spontaneously in favor of stronger bonds between the enzyme and the inhibitor. Once aging occurs, the duration of AChE inhibition is increased even further.

However, if strong nucleophiles, such as pralidoxime, are administered before aging has occur, it is possible to recover enzymatic function from the inhibited AChE.
11. Tacrine, Donepezil, Rivastigmine, Galantamine
MOA: AChE inhibitors

PURPOSE: Mild to moderate Alzheimer's disease, dementia

ADVERSE: Diarrhea, nausea, vomiting, cramps, anorexia, vivid dreams

CONTRA: Treatment associated liver function test abnormalities (tacrine)

NOTES: Tacrine, donepezil, and galantamine produce modest symptomatic benefits in AD; Rivastigmine affects both AChE and butyrylcholinesterase by forming a carbamoylate complex w/the enzymes; Galantamine also acts as a non-potentiating ligand of nicotinic receptors.
12. What are the muscarinic receptor agonists?
1. Methacholine
2. Carbachol
3. Bethanechol
4. Cevimeline
5. Pilocarpine
13. Methacholine
MOA: Methacholine is 3x more resistant to hydrolysis by AChE than is ACh. This agent is relatively selective for cardiovascular muscarinic cholinergic receptors

PURPOSE: Dx of asthma

ADVERSE: Dyspnea, lightheadedness, headache, pruritus, throat irritation

CONTRA: Recent heart attack or stroke; aortic aneurysm; uncontrolled hypertension

NOTES: In the Dx of asthma; the bronchial hyperreactivity that is characteristic of asthma causes an exaggerated bronchoconstriction response to parasympathomimetics.
14. Carbachol, bethanechol, cevimeline, pilocarpine
MOA: Carbachol has enhanced nicotinic action relative to other choline esters; Bethanechol is almost completely selective for muscarinic receptors; Pilocarpine and cevimeline (an M1 and M3 agonist) are used to treat xerostomia

PURPOSE: Glaucoma (carbachol); Urinary tract motility agent (bethanechol); Xerostomia in Sjogren's syndrome (cevimeline and pilocarpine)

ADVERSE: sweating, shivering, nausea, dizziness, increased frequency of urination, rhinitis

CONTRA: Acute iritis or glaucoma after cataract extraction; narrow-angle (angle-closure glaucoma)
15. Therapeutic notes for carbachol
Carbachol has enhanced nicotinic action relative to other choline esters.

Carbachol cannot be used systemically b/c of its unpredictable nicotinic action at autonomic ganglia.

Topical application of carbachol to the cornea of the eye results in both pupillary constriction (miosis) and decreased intraocular pressure.
16. What is the only nicotinic receptor agonist?

Succinylcholine is a choline ester that has a high affinity for nicotinic receptors and is resistant to AChE.

It is used to induce paralysis during surgery by means of depolarizing blockage. This effect can be caused by any direct nAChR agonist b/c such drugs activate cholinergic channels and produce depolarization of the cell membrane. To produce depolarizing blockage, the agent must persist at the neuroeffector junction and activate the nicotinic receptor channels continuously.
17. Succinylcholine
MOA: Stimulate opening of nicotinic ACh receptor channel and produce depolarization of the cell membrane; it persists at the neuroeffector junction and activate the nicotinic receptor channels continuously, which results in inactivation of voltage-gated sodium channels so that they cannot open to support further action potentials.

PURPOSE: Induction of neuromuscular blockade in surgery; intubation

ADVERSE: Bradyarrhythmia, cardiac arrest, cardiac arrhythmia, malignant hyperthermia, rhabdomyolysis, respiratory depression, muscle rigidity, myalgia, raised intraocular pressure

CONTRA: Personal or family history of malignant hyperthermia, skeletal muscle myopathies, UMN injury, extensive denervation of skeletal muscle
18. What are two therapeutic considerations for succinylcholine?
1. Short duration of action makes it the DOC for paralysis during intubation
2. It causes transient fasciculations
19. What are muscarinic receptor antagonists?
Anticholinergic compounds that act on muscarinic receptors are used to produce a parasympatholytic effect in target organs.

By blocking normal cholinergic tone, these compounds allow sympathetic responses to predominate.
20. Atropine
MOA: A naturally occurring alkaloid that is a muscarinic receptor antagonist. It has mainly muscarinic activity, marginal nicotinic effect

PURPOSE: AChE overdose, acute, symptomatic bradycardia, premedication for anesthetic procedure, excessive salivation and mucus secretion during surgery, antidote to mushroom poisoning

ADVERSE: Cardiac arrhythmia, coma, respiratory depression, raised intraocular pressure, tachycardia, constipation, xerostomia, blurred vision

CONTRA: Narrow-angle glaucoma
21. What are two therapeutic considerations for atropine
1. Mainly muscarinic activity, marginal nicotinic effect
2. More effective at reversal of exogenous rather than endogenous cholinergic activity
22. Scopolamine
MOA: Tertiary amine that has significant CNS effects; muscarinic receptor antagonists

PURPOSE: Motion sickness; nausea and vomiting

ADVERSE: Alteration in heart rate, drug-induced psychosis, somnolence, xerostomia, blurred vision

CONTRA: Narrow-angle glaucoma

NOTES: Delivered transdermal patch.
23. Pirenzepine, methscopolamine, glycopyrrolate
MOA: Muscarinic receptor antagonists alternative or additive agents to standard peptic ulcer diseases

PURPOSE: Peptic ulcer disease surgically-induced or vagally-induced bradycardia (glycopyrrolate)

ADVERSE: Cardiac arrhythmia, malignant hyperthermia, anaphylaxis, seizure, constipation, xerostomia, urinary retention, decreased sweating

CONTRA: GI obstruction, narrow-angle glaucoma

NOTES: Methscopolamine and glycopyrrolate have delayed but measurable CNS cognitive anticholinergic effects.
24. Ipratropium, tiotropium
MOA: Muscarinic receptor antagonists


ADVERSE: Paralytic ileus, anaphylaxis, oropharyngea edema, abnormal taste in mouth, xerostomia (nasal spray)

CONTRA: Hypersensitivity

NOTES: Ipratropium is more effective than β-adrenergic agonists in the treatment of COPD, but less effective in treating asthma. Relative to ipratropium, tiotropium has been shown to have similar, and possibly superior, efficacy as a bronchodilator in the treatment of COPD.
25. Oxybutynin, propantheline, terodiline, tolterodine, trospium, darifenacin, solifenacin
MOA: Oxybutynin, propantheline, tolterodine, and trospium are nonspecific muscarinic receptor antagonists, whereas darifenacin and solifenacine are selective M3 receptor antagonists

PURPOSE: Hyperreflexic and overactive bladder, urge incontinence

ADVERSE: Constipation, diarrhea, nausea, dry mouth, application-site erythema, pruritus

CONTRA: Narrow angle glaucoma; use w/caution in pts with BPH

NOTES: Tolterodine may cause less dry mouth than oxybutynin, and the newer M3-selective agents darifenacin and solifenacin may cause less dry mouth and constipation than nonselective agents.
26. What are nicotinic receptor antagonists used for?
Selective nicotinic receptor antagonists are used primarily to produce nondepolarizing (competitive) neuromuscular blockade during surgical procedures.

Non-depolarizing NMJ blocking agents act by antagonizing nicotinic ACh receptors directly, thus preventing endogenous ACh binding and subsequent muscle cell depolarization.

This leads to a flaccid paralysis similar in presentation to that of myasthenia gravis.
27. Pancuronium, tubocurarine, vecuronium, rocuronium, mivacurium
MOA: Selectively antagonize nicotinic receptors, thus preventing endogenous ACh binding and subsequent muscle cell depolarization (nondepolarizing blockade)

PURPOSE: Induction of neuromuscular blockade in surgery, intubation

ADVERSE: Hypertension, tachyarrhythmia, apnea, bronchospasm, respiratory failure, salivation, flushing (mivacurium)

CONTRA: Hypersensitivity
28. Therapeutic considerations for pancuronium, tubocurarine, vecuronium, rocuronium, mivacurium
Pancuronium and tubocurarine are long-acting agents; vecuronium and rocuronium are intermediate-acting agents; mivacurium is a short acting agent.

Nondepolarizing blocking agents have variable adverse effects associated with ganglionic blockade, which can be reversed by administration of AChE inhibitors.
29. Trimethaphan and mecamylamine
MOA: Selectively antagonize nicotinic receptors, thus preventing endogenous ACh binding and subsequent muscle cell depolarization (nondepolarizing blockade)

PURPOSE: Hypertension in pts with acute aortic dissection

ADVERSE: Paralytic ileus, urinary retention, respiratory arrest, syncope, orthostatic hypotension, dyspepsia, diplopia, sedation

CONTRA: Asphyxia, uncorrected respiratory insufficiency, neonates at risk for paralytic or meconium ileus, shock, coronary insufficiency, glaucoma, recent MI, pyloric stenosis, renal insufficiency, pts treated with sulfonamides
30. Therapeutic considerations for trimethaphan and mecamylamine
Mecamylamine and trimethaphan are administered when ganglionic blockade is desired.

These drugs lower BP while simultaneously blunting the sympathetic reflexes that would normally cause a deleterious rise in pressure at the site of the tear in cases of aortic dissection.
31. Where are the three points of narrowing in the ureters?
1. At the ureteropelvic junction
2. Where they enter the bladder
3. Where they cross the iliac vessels

*These all provide loci where renal calculi may become impacted when they pass from the kidney to the bladder.
32. What are the congenital anomalies of the ureters?
1. Double ureters
2. Uteropelvic junction obstruction
3. Diverticula
4. Hydroureter
5. Megaloureter
33. What are double ureters?
Double ureters (derived from a double or split ureteral bud) are almost invariably associated w/either totally distinct double renal pelves or with anomalous development of a large kidney having a partially bifid pelvis terminating in separate ureters.

Double ureters may pursue separate courses to the bladder but commonly are joined w/in the bladder wall and drain thru a single ureteral orifice. The majority of double ureters are unilateral and of no clinical significance.
34. What is the most common cause of hydronephrosis in infants and children?
Ureteropelvic junction obstruction. It usually presents in infants or children, much more commonly in boys, usually in the left ureter. However, it is bilateral in 20% of cases and may be associated with other congenital anomalies.

In adults, ureteropelvic junction obstruction is more common in women and is most often unilateral.

*There is agenesis of the kidney on the opposite side in a significant number of cases, probably resulting from obstructive lesions in utero.
35. What are diverticula of the ureters?
Diverticula, saccular outpouchings of the ureteral wall, are uncommon lesions that are usually asymptomatic and found incidentally.

They appear as congenital or acquired defects and are of importance as pockets of stasis and secondary infections.
36. What is a hydroureter?

What is a megaloureter?
Dilation (hydroureter), elongation, and tortuosity of the ureters may occur as congenital anomalies or as acquired defects. Congenital hydroureter is thought to reflect some neurogenic defect in the innervation of the ureteral musculature.

Massive enlargement of the ureter is known as megaloureter and is probably due to a function defect of ureteral muscle. Hydronephrosis and decreased renal function results if the lesion goes untreated.
37. What is ureteritis?
Ureteritis may develop as one compponeent of UTIs. The morphologic changes are entirely nonspecific. Only infrequently does such ureteritis make a significant contribution to the clinical problem.

Persistence of infection or repeated acute exacerbations may give rise to chronic inflammatory changes w/in the ureters.
38. What is the morphology of ureteritis?

(What is ureteritis follicularis?)
In certain cases of long-standing chronic ureteritis, specialized reaction patterns are sometimes observed.

The accumulation or aggregation of lymphocytes in the subepithelial region may cause slight elevations of the mucosa and produce a fine granular mucosal surface (ureteritis follicularis).
39. What is the morphology of ureteritis?

(What is ureteritis cystica?)
At other times, the mucosa may become sprinkled w/fine cysts varying in diameter from 1-5 mm *ureteritis cystica). The cysts may aggregate to form small, grapelike clusters.

Histologic sections thru such cysts demonstrate a lining of modified transitional epithelium w/some flattening of the superficial layers of cells.
40. What are the two most common neoplasias of the ureters?
Fibroepithelial polyps and leiomyomas.

The fibroepithelial polyp is a tumor-like lesion that grossly presents as a small mass projecting into the lumen. The lesion occurs more commonly in the ureters (left more than the right) but may also appear in the bladder, renal pelves, and urethra. The polyp presents as a loose, vascularized connective tissue mass lying beneath the mucosa.
41. What about primary malignant tumors of the ureter?
Primary malignant tumors of the ureter follow patterns similar to those arising in the renal pelvis, calyces, and bladder, and the majority are transitional cell CAs.

They cause obstruction of the ureteral lumen and are found most frequently during the 6th and 7th decades of life.

They are sometimes multiple and occasionally occur concurrently w/similar neoplasms in the bladder or renal pelvis.
42. What are the 5 important intrinsic causes of ureteral obstruction?
1. Calculi
2. Strictures
3. Tumors
4. Blood clots
5. Neurogenic
43. What are the four extrinsic causes of ureteral obstruction?
1. Pregnancy
2. Periureteral inflammation
3. Endometriosis
4. Tumors
44. What is the main difference between proximal and distal causes of ureteral obstruction?
Unilateral obstruction results from proximal causes, whereas bilateral obstruction arises from distal causes, such as BPH.
45. What is sclerosing retroperitoneal fibrosis?
This refers to an uncommon cause of ureteral narrowing or obstruction characterized by a fibrous proliferative inflammatory process encasing the retroperitoneal structures and causing hydronephrosis.
46. What is the pathogenesis of sclerosing retroperitoneal fibrosis?

What is Ormond disease?
The disorder occurs in middle to late age. In some cases, specific causes can be identified such as drugs, adjacent inflammatory conditions, or malignant disease.

*However, 70% of cases have no obvious cause and are considered primary or idiopathic (Ormond disease)
47. What are the microscopic features of sclerosing retroperitoneal fibrosis?
On microscopic exam, the inflammatory fibrosis is marked by a prominent inflammatory infiltrate of lymphocytes, often with germinal centers, plasma cells, and eosinophils.

Sometimes, foci of fat necrosis and granulomatous inflammation are seen in and about the fibrosis.
48. What are the congenital anomalies of the bladder?
1. Diverticula
2. Exstrophy
3. Miscellaneous anomalies (vesicoureteral reflux, congenital fistulas, persistent urachus, urachal cysts)
49. What are bladder diverticula?
A bladder or vesical diverticulum consists of a pouchlike eversion or evagination of the bladder wall. Diverticula may arise as congenital defects but more commonly are acquired lesions frmo persistent urethral obstruction.

Although most diverticula are small and asymptomatic, they may be clinically significant, as they constitute sites urinary stasis and predispose to infection and the formation of bladder calculi. They may also predispose to vesicoureteral reflex.
50. What cause congenital vs. acquired diverticula?
Congenital diverticula may be due to a focal failure of development of the normal musculature or to some urinary tract obstruction during fetal development.

Acquired diverticula are most often seen w/prostatic enlargement (BPH or neoplasia), producing obstruction to urine outflow and marked muscle thickening of the bladder wall.

In both the congenital and acquired forms, the diverticulum usually consists of a round to ovoid, saclike pouch the varies from less than 1 cm to 5 to 10 cm in diameter.
51. What is exstrophy of the bladder?
Exstrophy of the bladder implies the presence of a developmental failure in the anterior wall of the abdomen and in the bladder, so that the bladder either communicates directly thru a large defect with the surface of the body or lies as an open sac.

These lesions are amenable to surgical correction, and long term survival is possible. ***There is an increased tendency toward the development of CA later in life, mostly adenocarcinoma of the colon.
52. What is a persistent urachus?
Rarely, the urachus may remain patent in part or in whole (persistent urachus). When it is totally patent, a fistulous urinary tract is created that connects the bladder with the umbilicus. At times, the umbilical end or the bladder end remains patent, while the central region is obliterated.

This may predispose to infections, urachal cysts, or carcinomas (mostly glandular tumors resembling colonic adenocarcinomas).
53. What are the common etiologic agents of cystitis?
1. E. coli
2. Proteus
3. Klebsiella
4. Enterobacter
5. Candida albicans
6. Schistosoma haematobium
7. Chlamydia
8. Mycoplasma
54. What is the morphology of cystitis?

What is the morphology of hemorrhagic cystitis?
Most cases of cystitis take the form of nonspecific acute or chronic inflammation of the bladder. In gross appearance, there is hyperemia of the mucosa, sometimes associated with exudate.

When there is a hemorrhagic component, the cystitis is designated hemorrhagic cystitis. This form of cystitis sometimes follows radiation injury or antitumor chemo and is often accompanied by epithelial atypia. *Adenovirus infection also causes a hemorrhagic cystitis
55. What is the morphology of suppurative cystitis and ulcerative cystitis?
The accumulation of large amts of suppurative exudate may merit the designation of suppurative cystitis.

When there is ulceration of large areas of the mucosa, or sometimes the entire bladder mucosa, this is known as ulcerative cystitis.
56. What is the morphology of chronic cystitis?
Persistence of infection leads to chronic cystitis, which differs from the acute form only in the character of the inflammatory infiltrate. There is more extreme heaping up of the epithelium w/the formation of red, friable, granular, sometimes ulcerated surface.

Chronicity of the infection gives rise to fibrous thickening in the muscularis propria and consequent thickening and inelasticity of the bladder wall.
57. What is the morphology of the follicular and eosinophilic variants of chronic cystitis?
Follicular cystitis is characterized by the aggregation of lymphocytes into lymphoid follicles w/in the bladder mucosa and underlying wall.

Eosinophilic cystitis is manifested by infiltration with submucosal eosinophils together with fibrosis and occasionally giant cells.
58. What is the triad of symptoms in clinical cystitis?
1. Frequency which in acute cases may necessitate urination every 15-20 min
2. Lower abdominal pain localized over the bladder region or in the suprapubic region
3. Dysuria

Associated w/these localized changes, there may be systemic signs of inflammation such as elevation of temp, chills, and general malaise.
59. What is interstitial cystitis ?
This is a persistent, painful form of chronic cystitis occurring most freq in women and associated w/inflammation and fibrosis of all layers of the bladder wall.

It is characterized clinically by intermittent, often sever, suprapubic pain, urinary frequency, urgency, hematuria, and dysuria w/o evidence of bacterial infections, and cytoscopic findings such as fissures and punctate hemorrhages in the bladder mucosa after luminal distention.
60. What are Hunner ulcers?
Some but not all pts exhibit morphologic features of chronic mucosal ulcers (Hunner ulcers), which is termed the late (classic, ulcerative) phase.

Inflammation cells and granulation tissue may involve the mucosa, lamina propria, and muscularis, and mast cells may be particularly prominent.

In the early (nonclassic, nonulcerative) form, recent submucosal hemorrhages are noted.
61. What is malacoplakia?
This designation refers to a peculiar pattern of vesical inflammatory reaction characterized macroscopically by soft, yellow, slightly raised mucosal plaques 3-4 cm in diameter and histologically by infiltration with large, foamy macrophages with occasional multinucleate giant cells and interspersed lymphocytes.

The macrophages have abundant granular cytoplasm. The granularity is PAS positive.

*In addition, laminated mineralized concretions resulting from depositions of calcium in enlarge lysosomes, known as Micaelis-Gutmann bodies are typically present in the macrophages and between cells.
62. What causes malacoplakia?
It is clearly related to chronic bacterial infection, mostly by E.coli or occasionally Proteus species.

It occurs with increased freq in immunosuppressed transplant recipients.

The unusual-appearing macrophages and giant phagosomes point to defects in phagocytic or degradative function of macrophages such that phagosomes become overloaded w/undigested bacterial products.
63. What is polypoid cystitis?
Polypoid cystitis is an inflammatory condition resulting from irritation to the bladder mucosa.

Although indwelling catheters are the most commonly cited culprits, any injurious agent may give rise to this lesion.

*The urothelium is thrown into broad, bulbous, polypoid projections as a result of marked submucosal edema.

This type of cystitis may be confused w/papillary urothelial CA both clinically and histologically.
64. What is cystitis glandularis and cystitis cystica?
These terms refer to common lesions of the urinary bladder in which nests of transitional epithelium grow downward into the lamina propria and undergo transformation of their central epithelial cells into cuboidal or columnar epithelium lining (cystitis glandularis) or cystic spaces lined by urothelium (cystitis cystica).

*In a variant of cystitis glandularis, goblet cells are present, and the epithelium resembles intestinal mucosa (intestinal or colonic metaplasia)
65. What is the morphology of cystitis cystica?
In cystitis cystica, the cysts are usually 0.1 to 1 cm in diameter, filled with clear fluid, and lined by cuboidal or urothelial cells.
66. When does squamous metaplasia occur?
As a response to injury, the urothelium often converts to squamous epithelium, which is a more durable lining.

This contrasts with the normal finding of glycogenated squamous epithelium commonly found in women at the trigone.
67. What is nephrogenic metaplasia (nephrogenic adenoma)?
Nephrogenic metaplasia also represents a reaction of the urothelium to injury. The overlying urothelium may be focally replaced by cuboidal epithelium, which can assume a papilllary growth pattern.

In addition a tubular proliferation in the underlying lamina propria and superficial detrusor muscle may produce lesions that histologically mimic a CA.
68. What are urothelial (transitional cell) tumors?
These tumors represent about 95% of all bladder tumors and run the gamut from small benign lesions that may never recur, to tumors of low or indeterminate malignant potential, to lesions that invade the bladder wall and frequently metastasize. Many are multifocal at presentation.

Although most commonly seen in the bladder, any of the urothelial lesions described here may be seen at any site where there is urothelium, from the renal pelvis to the distal urethra.
69. What are the two distinct precursor lesions to invasive urothelial CA?
1. The more common are noninvasive papillary tumors
2. Flat urothelial CA (CIS)
70. What are noninvasive papillary tumors?

What are CIS lesions?
These lesions demonstrate a range of atypia, and several grading systems exist to reflect their biologic behavior.

The CIS lesion is by definition high grade and hence not assigned a grade. In about 1/2 the pts w/invasive bladder CA, at the time of presentation the tumor has already invaded the bladder wall, and there is no associated precursor lesion.
71. What sign indicates a major decrease in survival in invasive urothelial CA?
Although invasion into the lamina propria worsens the prognosis, the major decrease in survivial is associated w/tumor invading the muscularis propria (detrusor muscle)

Once muscularis propria invasion occurs, there is a 50% 5 year mortality rate.
72. What are the morphological patterns of urothelial cell tumors?
They may vary from purely papillary to nodular or flat. The tumors may be invasive or noninvasive.

Papillary lesions appear as red, elevated excresences varying in size from less than 1 cm in diameter to large masses up to 5 cm in diameter.

Multicentric origins may produce separate tumors. The histologic changes encompass a spectrum from benign papilloma to highly aggressive anaplastic CAs.

Overall, the majority of papillary tumors are low grade. Most arise from the lateral or posterior walls at the bladder base.
73. What is the morphology of (exophytic) papillomas in the bladder?
Papillomas represent 1% or fewer of bladder tumors, commonly seen in young pts.

The tumors usually arise singly as small (0.5 to 2.0 cm), delicate structures, superficially attached to the mucosa by a stalk.

The individual finger-like papillae have a central core of loose fibrovascular tissue covered by transitional epithelial cells ***that are histologically identical to normal urothelium.***
74. What is the morphology of inverted papillomas?
In contrast to the above exophytic papilloma, inverted papillomas are benign lesions consisting of interanastomosing cords of cytologically bland urothelium extending down into the lamina propria.
75. What are papillary urothelial neoplasms of low malignant potential (PUNLMP)?
PUNLMP share many histologic features with papillomas, the only differences being either thicker urothelium or diffuse nuclear enlargement in PUNLMP. Mitotic figures are rare.

At cytoscopy, PUNLMP tend to be larger than papillomas and may be indistinguishable from low and high grade papillary CAs.
76. What are low-grade papillary urothelial CAs?
Low-grade papillary urothelial CAs are characterized by an orderly appearance both architecturally and cytologically.

The cells are evenly spaced and cohesive. There is minimal but definite evidence of nuclear atypia consisting of scattered hyperchromatic nuclei, infrequent mitotic figures predominantly towards the base, and mild variation in nuclear size and shape.

Only rarely do these tumors pose a threat to the pt's life.
77. What are high-grade papillary urothelial CAs?
High-grade papillary urothelial CAs contain cells that may be dyscohesive and have large hyperchromatic nuclei. Some of the cells show frank anaplasia.

Mitotic figures, including atypical ones, are frequent.

Architecturally, there is disarray with loss of polarity. These tumors have a much higher incidence of invasion into the muscular layer, a higher risk of progression than low-grade lesions, and significant metastatic potential.
78. Where do aggressive invasive bladder tumors typically invade?
Aggressive tumors may not only extend into the bladder wall, but with progression, invade the adjacent prostate, seminal vesicles, ureters, and retroperitoneum.

Some produce fistulous communications to the vagina or rectum. About 40% of these deeply invasive tumors metastasize to regional lymph nodes.

Hematogeneous dissemination, principally to the liver, lungs, and bone marrow, generally occurs late and only with highly anaplastic tumors.
79. What defines CIS?

How is it similar to a high-grade papillary urothelial CA?
*Carcinoma in situ is defined by the presence of any cytologically malignant cells w/in a flat urothelium.

CIS may range from full-thickness cytologic atypia to scattered malignant cells in an otherwise normal urothelium.

A common feature shared with high-grade papillary urothelial CA is the lack of cohesiveness, which leads to shedding of malignant cells into the urine.
80. What is the morphology of CIS?
Grossly, CIS usually appears as an area of mucosal reddening, granularity, or thickening w/o an intraluminal mass.

It is commonly multifocal and may involve most of the bladder surface and extend into the ureters and urethra.

If untreated, 50-75% of CIS cases progress to muscle-invasive CA.
81. What are the clinical features of invasive urothelial CA?
Invasive urothelial CA, which is detected early, may be superficial in the lamina propria and can be associated w/either papillary urothelial CA, usually high grade, or with CIS.

**The most important factor in determining prognosis is the extent of spread, or staging.
82. What are the unusual variants of urothelial CA?
These include the nested variant w/deceptively bland cytology lymphoepithelioma-like CA and small cell CA.
83. What are squamous cell CAs of the bladder?
These represent about 3-7% of bladder CAs in the US, but in countries endemic for urinary schistosomiasis, they occur much more frequently.

Pure squamous cell CAs are nearly always associated with chronic bladder irritation and infection.
84. What are mixed urothelial cell CAs with areas of squamous CA?
These are more frequent than pure squamous cell CAs.

Most are invasive, fungating tumors or infiltrative and ulcerative. True papillary patterns are almost never seen.

*The differentiation varies widely, from the highly differentiated lesions producing abundant keratohyaline pearls to anaplastic giant cell tumors showing little evidence of squamous differentiation

They often cover large areas of the bladder and are deeply invasive by the time of discovery.
85. What are adenocarcinomas of the bladder?
Adenocarcinomas of the bladder are rare and they are histologically identical to adenocarcinomas seen in the GI tract.

Some arise from urachal remnants or in association with extensive intestinal metaplasia.

Rare variants include the highly malignant signet-ring cell CA, and mixed adenocarcinoma and urothelial cell CAs.
86. Where do urachal adenocarcinomas usually occur in the bladder?
Urachal tumors occur in the dome or anterior wall, arise within the wall rather than from the mucosa, and extend out of the bladder toward the umbilicus.
87. What is the prevalence of bladder CA?
Resembles that of bronchogenic CA, being more common in men than in women, in industrialized nations than in developing nations, and in urban than in rural dweller.

About 80% of pts are between the ages of 50-80. It is not familial.
88. What are the six big risk factors for urothelial CA?
1. Cigarette smoking
2. Industrial exposure to arylamines, particularly 2-naphthylamine
3. Schistosoma haematobium
4. Heavy long term exposure to cyclophosphamide
5. Long term use of analgesics
6. Prior exposure of the bladder to radiation
89. What mutations are linked to superficial papillary tumors and occasionally noninvasive flat tumors?
Chromosome 9 deletions.

Chromosome 9 (9p, 9q) deletions are the only genetic changes that are present frequently in superficial papillary tumors and occasionally noninvasive flat tumors.
90. What is the result of 9p deletion?
The 9p deletions (9p21) involve the tumor-suppressor gene p16INK4a, which encodes an inhibitor of a cyclin-dependent kinase.
91. What mutations are linked to invasive urothelial cell CAs?
Deletions of 17p, including the region of the p53 gene, as well as mutations in the p53 gene.
92. What are the two pathways for bladder carcinogenesis based on these genetic mutations?
1. Initiation by deletions of tumor-suppressor genes on 9p and 9q, leading to superficial papillary tumors, a few of which may then acquire p 53 mutations and progress to invasion

2. Initiation by p53 mutations, leads to CIS, and with loss of chromosome 9, progresses to invasion.
93. What are the clinical features of bladder tumors?
Bladder tumors produce painless hematuria, sometimes w/frequency and urgency. About 60% of neoplasms, when first discovered, are single, and 70% are localized to the bladder.

Patients with urothelial tumors, whatever their grade, have a tendency to develop new tumors after excision, and recurrences may exhibit a higher grade.
94. What are benign mesenchymal tumors?
A great variety of benign mesenchymal tumors may arise in the bladder. Collectively, they are rare. The most common is leiomyoma. They all tend to grow as isolated, intramural, encapsulated, oval to spherical masses, varyign in diameter up to several centimeters. On occasion, they assume submucsal pedenculated positions.

They have the histologic features of their counterparts elsewhere.
95. What are sarcomas in the bladder?

What are the most common ones in children? Adults?
These are are. Inflammatory spseudotumors, postoperative spindle cell nodules, and various carcinomas may assume sarcomatoid growth patterns, and be mistaken histologically for sarcomas.

*The most common sarcoma in infancy or childhood is embryonal rhabdomyosarcoma. The most common sarcoma in the bladder in adults is leiomyosarcoma.
96. What is the morphology of sarcomas?
As a group, sarcomas tend to produce large masses that protrude into the vesicle lumen. Their soft, fleshy, gray-white gross appearance suggests their sarcomatous nature.
97. What is the morphology of bladder obstruction?
In the early stages, there is only some thickening of the bladder wall, presumably due to hypertrophy of the smooth muscle.

The mucosal surface at this time may be entirely normal. W/progressive hypertrophy of the muscle coat, the individual muscle bundles greatly enlarge and produce trabeculation of the bladder wall. In the course of time, crypts form and may then become converted into true acquired diverticula.
98. What is a urethral caruncle?
A urethral caruncle is an inflammatory lesion presenting as a small, red, painful mass about the external urtheral meatus in the female pt.

The lesion consists of a hemispheric, friable, 1-2 cm nodule that occurs singly, either just outside or just inside the external urethral meatus.

***On histologic exam, it is composed of a highly vascularized, young, fribroblastic connective tissue, usually heavy infiltrated with leukocytes.
99. What genetic mutation contributes to erythromelalgia, an inherited condition associated w/severe burning pain in response to mild thermal stimuli?
A gain of function in Na 1.7 contributes to erythromelalgia; it produces hyperexcitability of nociceptors.
100. Morphine
MOA: Natural or semisynthetic agonist of the u-opioid receptor that results in inhibition of neurotransmission. Morphine is metabolized in the liver, and its active metabolite M6G is excreted in kidney. M6G has analgesic activity

PURPOSE: Pain (moderate to severe); analgesia for a mechanically ventilated pt.

ADVERSE: Respiratory depression, hypotension, confusion, and abuse potential, constipation, nausea, vomiting, dizziness, headache, sedation, urinary retention, and pruritus

CONTRA: Severe asthma, paralytic ileus, respiratory depression/hypoventilation, upper airway obstruction.
101. Therapeutic considerations for morphine
1. Morphine is metabolized in the liver, and its active metabolite M6G is excreted in kidney; dose adjustment may be required in pts with renal disease
2. Controlled-release oral preparations reduce the number of daily doses, but these formulations are associated with abuse potential.
3. IV of subcutaneous morphine is commonly used in pt controlled analgesia devices
4. Epidural or intrathecal morphine can produce highly effective analgesia by achieving locally high concentrations in the dorsal horn of the spinal cord.
102. Codeine
MOA: Natural agonist of the u-opioid receptor that result in inhibition of neurotransmission. The analgesic effects result largely from its hepatic demethylation to morphine via P450 2D6 and 3A4.

PURPOSE: Pain (mild to moderate)

ADVERSE: Respiratory depression, hypotension, confusion, and abuse potential; seizure with excessive dose; constipation, nausea, vomiting, dizziness, headache, sedation, urinary retention, and pruritus

CONTRA: During delivery of a premature infant; premature infants

NOTES: Much less effective than morphine in pain treatment; Used for its antitussive and antidiarrheal effects; Quinidine reduces analgesic effects of codeine by inhibiting bioactivation of codeine to morphine
103. Oxycodone and hydrocodone
MOA; Semisynthetic agonists of the u-opioid receptor that result in inhibition of neurotransmission.

PURPOSE: Pain (moderate to severe)

ADVERSE: Respiratory depression, hypotension, confusion, and abuse potential; constipation, nausea, vomiting, dizziness, headache, sedation, urinary retention, and pruritus

CONTRA: severe asthma, paralytic ileus, respiratory depression/ hypoventilation, upper airway obstruction

NOTES: More effective analogues of codeine in the treatment of pain
104. Methadone
MOA: Synthetic agonists of the u-opioid receptor that result in inhibition of neurotransmission; methadone has a long duration of action

PURPOSE: Detox of pts with opioid addiction; severe pain

ADVERSE: Respiratory depression, hypotension, confusion, and abuse potential; constipation, nausea, vomiting, dizziness, headache, sedation, urinary retention, and pruritus

CONTRA: Hypersensitivity

NOTES: Due to its long duration of action, methadone is used to achieve long-lasting pain relief in cancer pts
105. Fentanyl, alfentanil, sufentanil
MOA: Synthetic agonists of the u-opioid receptor that result in inhibition of neurotransmission; methadone has a long duration of action

PURPOSE: Pain (moderate to severe)

ADVERSE: Respiratory depression, hypotension, confusion, and abuse potential; constipation, nausea, vomiting, dizziness, headache, sedation, urinary retention, and pruritus

CONTRA: Severe asthma, paralytic ileus, respiratory depression/hypoventilation, upper airway obstruction
106. What is fentanyl?
Fetanyl is 75-100x more potent than morphine and is bioavailable thru several routes.

Transmucosal administration (as lozenge) is useful in pediatric pts.

A transdermal patch releases the drug slowly over time to provide long-acting systemic analgesia.
107. What is alfentanil and sufentanil?

Which is more potent?
Alfentanil and sufentanil are structurally related to fentanyl.

Alfentanil is more potent than fentanyl.

Sufentanil is less potent than fentanyl.
108. Remifentanil
MOA: Synthetic agonists of the u-opioid receptor that result in inhibition of neurotransmission; Remifentanil contains a methyl ester moiety that is essential for activity, but that is also the substrate for the action of numerous nonspecific tissue esterases. Thus, it also has unusually rapid metabolism and elimination.

PURPOSE: Pain (moderate to severe); adjunct to general anesthesia

ADVERSE: Same as morphine. Additionally, muscle rigidity is observed

CONTRA: Do not use for epidural or intrathecal administration b/c the glycine in the formulation may cause neurotoxicity

NOTES: Has unusually rapid metabolism and elimination. *Permits precise matching of the drug dose to the clinical response;

*However, its rapid offset of action during anesthesia requires coadministration of a longer-acting drug to maintain analgesia postoperatively.
109. What is meperidine?
Another phenylpiperidine is meperidine, which is a u-agonist w/analgesic efficacy similar to morphine; 75-100 mg of meperidine is equivalent to 10 mg of morphine. *It causes mydriasis rather than miosis.

Its analgesic activity is reduced by half when taken orally, and it often produces dysphoria.

**The toxic meperidien metabolite normeperidine can cause increased CNS excitability and seizures.

*Normeperidine is excreted by the kindye and its elimination half-life is longer than that of meperidine ; therefore, meperidine toxicity is a particular problem w/repeated dosing of the drug or in pts with chronic kidney disease.
110. Meperidine
MOA: Synthetic agonist of the u-opioid receptor that result in inhibition of neurotransmission w/analgesic efficacy similar to morphine

PURPOSE: Pain (moderate to severe)

ADVERSE: Same as morphine; additionally, euphoria and mydriasis are observed.

CONTRA: Recent or concomitant MAOI

NOTES: *Recent or concomitant MAOI is an absolute contraindication due to the risk of life-threatening serotonin syndrome; coadministration w/selegiline or sibutramine is usually avoided due to the risk of serotonin syndrome.
111. Levorphanol
MOA: Synthetic u-opioid agonist. Exerts analgesic effects thru receptors in periventricular and periaqueductal gray matter in brain and spinal cord, thereby altering pain perception and transmission.

PURPOSE: Pain (moderate to severe)

ADVERSE: Same as morphine

CONTRA: Hypersensitivity

NOTES: Available in IV and oral forms.
112. Propoxyphene
MOA: Structurally related to methadone. Mild centrally-acting analgesia

PURPOSE: Pain (mild to moderate)

ADVERSE: Same as morphine

CONTRA: Hypersensitivity

NTOES: Propoxyphene markedly increases serum level of carbamazepine
113. What are the partial and mixed agonists of u-opioid receptors?
These include the partial u agonists butorphanol and buprenorphine, as well as nalbuphine, a k agonists with u antagonists activity.

Butorphanol and buprenorphine produce morphine like analgesia, but with milder euphoric symptoms.

Nalbuphine and similar compounds are effective analgesics b/c of their action at k receptors, but are also associated w/undesirable psychological dysphoria. The reduced tendency of these agents to produce euphoria may diminish the likelihood of substance abuse behavior in susceptible individuals.
114. Butorphanol and buprenorphine
MOA: Partial u-receptor agonists

PURPOSE: Pain (moderate to severe); adjunct to balanced anesthesia

ADVERSE: Hypotension, palpitations, tinnitus, respiratory depression, upper respiratory infection; dizziness, sedation, insomnia and nasal congestion with long-term intranasal administration

CONTRA: Hypersensitivity

NOTES: Produce morphine-like analgesia, but with milder euphoric symptoms; available in intranasal spray and IV formulations
115. Nalbuphine
MOA: A k agonist with u antagonist activity

PURPOSE: Pain (moderate to severe); adjunct to balanced anesthesia

ADVERSE: Respiratory depression, hypersensitivity (frequent**); sweating, nausea, vomiting, dizziness, sedation

CONTRA: Hypersensitivity

NOTES: Its u-antagonist activity may precipitate withdrawal in pts who have received opioids chronically.
116. What are the 3 opioid receptor antagonists?
1. Naloxone
2. Naltrexone
3. Alvimopan
117. Naloxone and naltrexone
MOA: Antagonists of u-opioid receptor, thereby blocking endogenous or exogenous opioid effects

PURPOSE: Acute opioid toxicity (Naloxone); opioid, alcohol addiction (Naltrexone)

ADVERSE: Cardiac arrhythmia, hypertension, hypotension, hepatotoxicity, pulmonary edema, opioid withdrawal; DVT and pulmonary embolism (naltrexone).

CONTRA: Acute hepatitis or liver failure (naltrexone)

NOTES: Combo of yohimbine and naloxone results in greater anxiety, tremors, palpitations, hot and cold flashes, as well as elevated plasma cortisol levels.
118. Alvimopan
MOA: Alvimopan is a potent antagonist of peripheral u0opioid receptors

PURPOSE: Post-operative ileus and opioid-mediated bowel dysfunction

ADVERSE: Diarrhea, flatulence, abdominal pain, nervousness, polyuria, elevated LFTs

CONTRA: Hypersensitivity to alvimopan

NOTES: Limited human studies show that alvimopan prevents morphine-induced constipation, but has no effect on morphine analgesia
119. How does aspirin act?
Acetylsalicylic acid acts by covalently acetylating the COX active site in both COX-1 and COX-2. Aspirin is rapidly absorbed and distributed throughout the body. Chronic aspirin use can produce gastric irritation and erosion, hemorrhage, vomiting, and renal tubular necrosis.

It is of great value in the treatment of mild to moderate pain.
120. What is celecoxib?
The coxibs are COX-2 selective enzyme inhibitors. Currently, only celecoxib remains in clinical use in the US.

This class of drugs was originally reserved for pts who required NSAIDS but were at high risk for developing GI, renal, or hematologic side effects.
121. What is ibuprofen?
The widely used compound ibuprofen is a derivative of propionic acid.

Used primarily for analgesia and anti-inflammatory action, it also is an antipyretic, and it has a lower incidence of adverse effects than aspirin.
122. What is naproxen?
Another common propionic acid derivative is naproxen. Compared to ibuprofen, naproxen is more potent and has a longer half-life; therefore, it can be administered less freq w/equivalent analgesic efficacy.

Its adverse effect profile is similar to ibuprofen, and it is generally well tolerated.

As with all NSAIDs, ibuprofen and naproxen can cause GI complications ranging from dyspepsia to gastric bleeding.
123. What is diclofenac and ketorolac?
The pyrrole acetic acid derivative diclofenac and ketorolac are used to treat moderate to severe pain.

Ketorolac can be administered orally or parenterally, while diclofenac is available in oral formulations.

Both agents carry a risk of severe adverse effects, including anaphylaxis, acute renal failure, Stevens-Johnson syndrome (a diffuse life threatening rash involving the skin and mucous membranes), and GI bleeding.
124. What is acetaminophen (paracetamol)?
Acetaminophen preferentially reduces central prostaglandin synthesis by an uncertain mechanism; as a result, the drug produces analgesia and antipyresis, but has little anti-inflammatory efficacy.

Acetaminophen is freq combined with weak opioids for the treatment of moderate pain, and preparations featuring acetaminophen combined w/codeine, hydrocodone, oxycodone, pentazocine, or propoxyphene are available.
125. What is the MOA of acetaminophen?
Following deacetylation to its primary amine, acetaminophen is conjugated to arachidonic acid by fatty acid amide hydrolase in the brain and spinal cord. The product of this reaction, N-arachidonoylphenolamine, may inhibit COX-1 and COX2 in the CNS.

N-arachidonoylphenolamine is an endogenous cannabinoid and an agonist at TRPV1 receptors, suggesting that direct or indirect activation of TRPV1 and/or cannabinoid CB1 receptors could also be involved in the mechanism of acetaminophen action.
126. What is tramadol?
Tramadol is a centrally acting analgesic. Analgesia apparently results from a monoaminergic effect w/in the CNS, as well as an opioid effect mediated by a metabolite that is formed by O-demethylation of the parent drug by P450 2D6.

Tramadol has minimal abuse liability but it does cause nausea, dizziness, and constipation. Administration of the drug in combo w/acetaminophen improves its analgesic efficacy.
127. How are antidepressants helpful in analgesia?
It is thought that TCAs produce analgesia both by blocking sodium channels and by increasing the activity of anti-nociceptive noradrenergic and serotonergic projections descending from the brain to teh spinal cord.

In general, the least selective agents (i.e., those w/the broadest neurochemical effects), such as the tricyclics amitriptyline, nortriptyline, and imipramine, have been more effective than the SNRIs desipramine and maprotiline, while SSRIs such as paroxetine, fluoxetine, and citalopram are the least effective.
128. How does venlafaxine and duloxetine work?
Venlafaxine and duloxetine are dual norepinephrine/serotonin reuptake inhibitors w/actions as both antidepressants and analgesics.

These agents are used in the treatment of neuropathic pain and fibromyalgia.

Duloxetine has a balanced action on NE and 5-HT reuptake and a weak action on dopamine reuptake as well.

Although SSRIs have minimal analgesic action by themselves, inhibition of the serotonin reuptake transporter appears to produce some analgesic effects when NE reuptake is also blocked.
129. So how are antidepressants helpful in analgesia (summary)?
Based on results from animal models, the analgesic action appears to be mediated mainly in the spinal cord and to involve the reduction of central sensitization.
130. How are anticonvulsants and antiarrhythmics useful in analgesia?
A number of pharmacologic agents used to control the excessive cellular excitability that leads to seizures or cardiac arrhythmias can also be used to manage the symptoms of some chronic pain conditions.

Of these, the most clinically valuable are the anticonvulsants gabapentin, pregabalin, lamotrigine, and carbamazepine.
131. Gabapentin
MOA: Blocks sodium channels to inhibit action potential initiation or conduction. Structural analogue of GABA, but it does not bind to the GABA receptor. Gabapentin binds to the alpha2delta subunit of voltage-dependent calcium channels, and binding to this site reduces neuronal activity and pain.

PURPOSE: Chronic pain, postoperative pain

ADVERSE: Dizziness, somnolence, confusion, and ataxia

NOTES: Oral bioavialability is not predictable or linear. Some pts required 10x as much drug as others to achieve a similar effect.
132. Pregabalin
MOA: Blocks sodium channels to inhibit action potential initiation or conduction. Newer antiepileptic drug w/a similar structure to gabapentin ; this substituted GABA analogue is more potent and it has a faster onset of action and more predictable bioavailability than gabapentin

PURPOSE: Pregabalin produces an analgesic effect similar to that of gabapentin in pts w/neuropathic pain and fibromyalgia

ADVERSE: Dizziness, somnolence, confusion, and ataxia

NOTES: Also induces a mild euphoric effect in some pts. B/c o fits increased potency, ti is claimed that dose-related adverse effects may be lower w/pregabalin than gabapentin.
133. What is carbamazepine?
Carbamazepine blocks sodium channels to inhibit action potential initiation or conduction.

The drug is used primarily to treat trigeminal neuralgia but it has a relatively high adverse effect profile.

***Can cause aplastic anemia***
134. What is oxycarbazepine?
Oxcarbazepine is a close structural dervivative of carbamazepine w/an additional oxygen atom decorating the benzylcarboxamide group.

This difference alters metabolism of the drug in the liver. More importantly, it reduces the risk of aplastic anemia, which is a serious side effect occasionally associated w/carbamazepine.
135. What is lamotigine?
Lamotrigine, an antiepileptic drug that is also a sodium channel blocker, reduces the painful sensory symptoms that can occur in neuropathy, stroke, multiple sclerosis, and phantom lib; however, it has a high incidence of skin reactions.
136. What about mexiletine?
The use of mexiletine, an antiarrhythmic, is limited by GI effects caused by paralysis of the GI tract.
137. What is lidocaine?
Lidocaine, a use-dependent sodium channel blocker, is typically used as a local anesthetic for regional anesthesia.

This drugs is also used topically in patches for pts w/cutaneous pain, as in pts with post-herpetic neuralgia.

Lidocaine can also be used for regional pain management when administered via IV.
138. Ketamine
MOA: Block NMDA receptor-dependent post-synaptic depolarization

PURPOSE: Analgesia, dissociative anesthesia, sole anesthetic agent for procedures that do not require skeletal muscle relaxation

ADVERSE: Hypertension, tachyarrhythmia, myoclonus, respiratory depression, increased intracranial pressure, hallucinations, vivid dreams, psychiatric symptoms

CONTRA: Hypersensitivity, and severe hypertension

NOTES: Useful in acute severe pain, such as battlefield injury, due to minimal risk of respiratory depression. Wider application of ketamine is limited by its psychomimetic effects

*Increased cardiac output by increasing sympathetic outflow.
139. Dextromethorphan
MOA: Block NMDA receptor-dependent post-synaptic depolarization

PURPOSE: Cough, neuropathic pain

ADVERSE: Dizziness, somnolence, fatigue

CONTRA: Coadministration of MOAI

NOTES: DXM, when used at relatively high doses required for analgesia, also produces dizziness, fatigue, confusion, and psychomimetic effects. Coadministration of MAOI is absolutely contraindicated due to the risk of serotonin syndrome; coadministration w/selegiline or sibutramine is usually avoided.
140. How doe the triptans work for analgesia?
The triptans are selective for the 5-HT1b and 5-HT1d receptor subtypes. These drugs reduce both sensory activation in the periphery and nonciceptive transmission in the brainstem trigeminal nucleus, where they diminish central sensitization.

The triptans also cause vasoconstriction, opposing the vasodilation though tot be involved in the pathophysiology of migraine attacks.
141. What are the names of the 6 triptans?
1. Sumatriptan
2. Rizatriptan
3. Naratriptan
4. Zolmitriptan
5. Almotriptan
6. Electriptan
142. What is the innate immune system?

How is it activated?
The innate immune system, which includes some phagocytes, natural killer cells, and the complement system, is an early part of the immune response and recognizes general features of invading microorganisms.

To activate the innate immune system; anything that are detected in pathogens but are not found in the host - for ex: LPS, Toll-like receptors, etc...
143. What is the adaptive immune system?
B lymphocytes are a component of the adaptive immune system; they produce circulating antibodies in response to infection.

T lymphocytes, another component of the adaptive immune system, interact directly w/infected cells to kill these cells, and they aid in the B cell response.
144. What is the humoral immune response?
In the humoral immune response, foreign particles are displayed in conjunction with MHC II molecules by APCs.

These displayed molecules are recognized by helper T cells, which then stimulates proliferation of B cells who receptors (Ig's) can bind to the foreign pathogen.
145. How are the humoral immune responses strengthened?
During the B-cell response to a foreign peptide, the binding affinity of Igs for the invading pathogen increases.

When mature, the B cell becomes an antibody-secreting plasma cell.
146. What is the cellular immune system?
The cellular immune system is capable of destroying the body's cells once they are infected. Peptides from the pathogen are displayed on cell surfaces by MHC I molecules.

These are recognized by CTLs which destroy the infected cell. Each CTL can destroy one infected cell every 1-5 minutes.
147. What is the key member of the cellular immune system?
class I MHC molecules.
148. What is the composition of an antibody molecule?
An antibody moelcule consists of 2 identical light chains and two identical heavy chains.

There are five types of heavy chains (termed γ, μ, α, δ, ε) and these determine the isotype or class to which an Ig molecule belongs.

The variable regions (C, V, D, J) of the light and heavy chains recognize and bind antigens.
149. How is somatic recombination accomplished (VDJ recombination)?
This is accomplished by deletion of the DNA sequences separating the single V, J, and D segments before they are transcribed into mRNA.

The deletion process is carried out in part by recombinases (encoded by the RAG1 and RAG2 genes), which initiate double-strand DNA breaks at specific DNA sequences that flank the V and D gene segments. After the deletion of all but one V, D, and J segment, the nondeleted segments are joined by ligases.
150. What is this "cutting and pasting" process known as?
Somatic recombination; it produces a rather unique result: unlike most other cells of the body, whose DNA composition is identical, mature B lymphs vary in terms of their rearranged Ig DNA sequences.
151. What are the 5 mechanisms that produce antibody diversity?
1. Multiple germline Ig gene segments
2. Somatic recombination
3. Junctional diversity
4. Somatic hypermutation
5. Multiple combinations of heavy and light chains
152. Where does somatic hypermutation not occur?
Somatic hypermutation does not occur in the genes that encode the T-cell receptors.

This is probably a consequence of the requirement that T-cell receptors must be able to tolerate normal self peptides and also recognize MHC molecules.
153. What are T-cell receptors?
T-cell receptors are similar in function to B-cell receptors (Ig's). Unlike Ig's, however, they can bind to foreign peptide only when it is presented by an MHC molecule.

Their diversity is created by the same mechanisms that produce Ig diversity, w/the exception of somatic hypermutation.
154. What are MHC I molecules?
The class I MHC molecules are encoded by the highly polymorphic HLA-A, -B, and -C loci on chromosome 6.

In addition to presenting foreign peptides on the surfaces of infected cells, they can also bring about transplant rejection when foreign MHC molecules stimulate cytotoxic T cells.
155. What are MHC II molecules?
Class II MHC molecules are heterodimers encoded by genes on chromosome 6.

They present peptides on the surfaces of APCs's. These peptides, in conjunction with class II MHC molecules, are bound by receptors on helper T cells.
156. An individual who expresses a greater variety of MHC molecules has...?
A better chance of dealing effectively with a variety of infectious organisms.

Similarly, A higher degree of polymorphism in the general population increases the chance that any individual will be heterozygous; the decreases the chance that an infectious pathogen can spread easily thru the population.
157. Importance of HLA-B53 allele?

HLA-DRB*1302 allele?
The HLA-B53 allele was shown to have a strong protective effect against severe malaria in the population of Gambia, Africa, and the HLA-DRB*1302 allele protects against HBV in the same population.
158. What are class III MHC molecules?
The class III MHC region spans 680kb and contains at least 36 genes. Among the most important are the genes encoding the complement proteins.
159. What are the differences in the variation between MHC molecules and T-cell receptors/Ig's in individuals and in the population?
Class I and II MHC molecules differ greatly among individuals, but each cell within an individual has the same class I and II molecules.

In contrast, after VDJ recombination the T-cell receptors and Ig's differ from cell to cell within individuals, allowing the body to respond to a large variety of different infectious agents.
160. Allele associated with Type I DM
161. Allele associated with ankylosing spondylitis
162. Allele associated with narcolepsy
HLA-DR2 and DQA1, DQB1

*high relative risk!
163. Allele associated with celiac disease
164. Allele associated with RA
165. Allele associated with myasthenia gravis
166. Allele associated with MS
167. Allele associated with SLE
168. Allele associated with hemachromatosis
169. Allele associated with squamous cell cervical carcinoma
170. A and B antigens
Two antigens, type A and type B occur on the surfaces of the RBCs in a large proportion of humans.

It is these antigens that cause most blood transfusion reactions.

Because of the way these agglutinogens are inherited, people may have neither of them on their cells, they may have one, or they may have both simultaneously.
171. Type O blood
Genotype OO

Neither A nor B agglutinogen is present

Anti-A and Anti-B agglutinins

*Universal donors
172. Type A blood
Genotype OA or AA

A agglutinogens

Anti-B agglutinins
173. Type B blood
Genotype OB or BB

B agglutinogens

Anti-A agglutinins
174. Type AB blood
Genotype AB

A and B agglutinogens

No agglutinins are present

*Universal recipients
175. What is the locus of primary interest in the Rh system?

Type D Rh antigen; it is responsible or RH maternal-fetal incompatibility and for hemolytic disease of the newborn.

Type D antigen is widely prevalent in the population and considerably more antigenic than the other Rh antigens. Anyone who has this antigen is said to be Rh positive, whereas a person who does not have type D antigen is said to be Rh negative.

About 85% of all white people are Rh positive, and about 15% Rh negative.
176. How is the Rh system different from the ABO system?
Unlike the ABO type system, in the Rh type system, spontaneous agglutinins almost never occur.

Instead, the person must first be massively exposed to an Rh antigen, such as by transfusion of blood containing the Rh antigen, before enough agglutinins cause a significant transfusion reaction to occur
177. What is erythroblastosis fetalis?
A disease of the fetus and newborn child characterized by agglutination and phagocytosis of the fetus's red blood cells.

In most instances of this, the mother is Rh negative and the father Rh positive.

The baby has inherited the Rh+ antigen from the father, and the mother develops anti-Rh agglutinins from exposure to the fetus's Rh antigen.

In turn, the mother's agglutinins diffuse through the placenta into the fetus and cause RBC agglutination.
178. Clinical characteristics of newborns w/erythroblastosis fetalis
The jaundiced, erythroblastotic newborn baby is usually anemic at birth, and the anti-Rh agglutinins from the mother usually circulate in the infant's blood for another 1 to 2 months after birth, destroying more and more RBCs.

The hematopoietic tissues of the infant attempt to replace the hemolyzed RBCs. The liver and spleen become greatly enlarged and produce RBCs in the same manner that they normally do during the middle of gestation.

B/c of the rapid production of red cells, many early forms of RBCs, including many nucleated blastic forms, are passed from the baby's bone marrow into the circulatory system, ant it is b/c of the presence of these cells that the disease is called erythroblastosis fetalis.

Mental impairment is not uncommon b/c of kernicterus
179. Treatment of newborn w/erythroblastosis fetalis
Replace the neonate's blood w/Rh- blood.

This procedure may be repeated several times during the first few weeks of life, mainly to keep the bilirubin level low and thereby prevent kernicterus.
180. How is maternal-fetal Rh incompatibility prevented?
The mother is given injections of Rh immune globulin, which consists of anti-Rh antibodies. These antibodies destroy the fetal erythrocytes int he mother's bloodstream before they stimulate production of maternal anti-Rh antibodies.
181. What are the consequences of B cell deficiencies?
Renders the pt especially susceptible to recurrent bacterial infections (pyogenic) such as Streptococcus pneumoniae.

There are reduced serum Ig levels.
182. What are the consequences of T cell deficiencies?
Renders the pt susceptible to viral and other intracellular microbial infections (e.g., pneumocystis jiroveci, atypica mycobacteria, fungi).

Also, the pt is susceptible to virus-associated malignancies such as EBV-associated lymphomas.
183. What are the three types of SCID?
1. X-linked SCID
2. Autosomal recessive SCID due to ADA, PNP deficiency
3. Autosomal recessive SCID due to other causes (RAG)
184. What causes X-linked SCID?

What are the consequences?
These cases affect only male children.

Most of X-linked SCID are caused by mutations in a signaling subunit of a γ receptor for cytokines (codes for IL-2, 4, 7, 9, 15, 21); this causes defective T cell maturation due to lack of IL-7 signals.

The consequence of this block is a profound decrease in the numbers of mature T cells, deficient CMI, and defective humoral immunity. NK cells are also deficient, b/c the receptor for IL-15, the major cytokine involved in NK cell proliferation and mutation, also uses the γ chain.
185. What causes autosomal SCID due to deficient ADA?
About half of autosomal SCID are caused by mutations in an enzyme called adenosine deaminase, which is involved in the breakdown of purines.

Deficiency of ADA leads to the accumulation of toxic purine metabolites in cells that are actively synthesizing DNA, namely, proliferating cells.

Lymphocytes, which actively proliferate during their maturation, are injured by these accumulating toxic metabolites. ADA deficiency results in a block in T cell maturation more than B cell maturation.

*Defective humoral immunity is largely a consequence of the lack of T cell helper function.
186. Mutations in what other gene can also cause autosomal recessive SCID?
SCID can also arise from mutations in RAG1 or RAG2, two of the genes involved in VDJ recombination and the proper formation of T-cell and B-cell receptors (i.e. Ig and T cell receptor gene recombinations and lymphocyte maturation).
187. What is the treatment for SCID?
Without bone marrow transplants, these pts usually die within the first several years.
188. What is X-linked agammaglobulinemia?
In this disorder, B cells in the bone marrow fail to mature beyond the pre-B cell stage, resulting in a marked decrease or absence of mature B lymphocytes and serum immunoglobulins.

Patients with this disorder lack B cells completely and have no IgA, IgE, IgM, or IgD in their serum.
189. What causes X-linked agammaglobulinemia?
The disease is caused by mutations in the gene encoding a kinase called the B cell tyrosine kinase or Bruton tyrosine kinase (Btk), resulting in defective production or function of the enzyme.

The enzyme is activated by the pre-B cell receptor expressed in pre-B cells, and it delivers biochemical signals that promote maturation of these cells.
190. What other conditions commonly occur in individuals with X-linked agammaglobulinemia?
Paradoxically, in about 25% of pts with X-linked agammaglobulinemia, autoimmune disease, notably arthritis, develop as well.

191. What is the treatment for X-linked agammaglobulinemia?
Pts are treated with large amts of gamma globulin.
192. What is DiGeorge syndrome?
Selective defects in T cell maturation are frequently caused by the DiGeorge syndrome, which results from incomplete development of the thymus and parathyroid glands, and a failure of T cell maturation.
193. What is the mechanism of defect in DiGeorge syndrome?
Anomalous development of 3rd and 4ths brachial pouches, leading to thymic hypoplasia.

Pts with this disease tend to improve with age, probably b/c the small amt of thymic tissue that does develop is able to support some T cell maturation.
194. What causes Ig heavy chain deletions?

What are the consequences?
Chromosomal deletion at 14q32 (Ig heavy chain locus)

IgG1, IgG2, or IgG4 are absent; sometimes it's associated with absent IgA or IgE.
195. What is X-linked hyper-IgM syndrome?
The X-linked hyper-IgM syndrome is characterized by defective B cell heavy chain isotype class switching, so that IgM is the major serum antibody and by severe deficiency of CMI against intracellular microbes.
196. What are the causes of X-linked hyper-IgM syndrome?
The disease is caused by mutations in CD40 ligand (CD40L), the helper T cell protein that binds to CD40 on B cells and macrophages and thus mediates T cell-dependent activation of B cells and macrophages.
197. What are the consequences of X-linked hyper-IgM syndrome?
Failure to express functional CD40L leads to defective T cell-dependent B cell responses, such as isotype switching in humoral immunity, and to defective T cell-dependent macrophage activation in CMI.
198. What is common variable immunodeficiency?
Common variable immunodeficiency is a heterogeneous group of disorders that represent a common form of primary immunodeficiency.

These disorders are characterized by poor antibody responses to infections and reduced serum levels of IgG, IgA, and often IgM.

Pts suffer from recurrent infections, autoimmune disease, and lymphomas.
199. What causes common variable immunodeficiency?
The underlying causes include defects in B cell maturation and activation.

Some pts have mutations in genes encoding receptors for B cell growth factors or costimulators involved in T cell-B cell interactions.
200. What is bare lymphocyte syndrome (type 2)?
The bare lymphocyte syndrome (type 2) is a disease caused by a failure to express class II MHC molecules, as a result of mutations in the transcription factors that normally induce class II MHC expression.

The disease is manifested by a profound decrease in CD4+ T cells, b/c of defective maturation of these cells in the thymus and defective activation in peripheral lymphoid organs.
201. What is bare lymphocyte syndrome (type 1)?
This form of bare lymphocyte syndrome is caused by mutations in the TAP2 gene.

The TAP2 protein helps to transport peptides to the ER where they are bound by class I MHC molecules.

A defect in the TAP2 protein destabilizes the class I MHC molecules so that they are not expressed on the cell surface. The result is a severe reduction in the number of functional T and B cells.
202. What causes chronic granulomatous disease?
Chronic granulomatous disease is caused by mutations in the enzyme phagocyte oxidase (specifically, cytochrome b), which catalyzes the production of microbicidal ROS in lysosomes.

As a result, neutrophils and macrophages that phagocytose microbes are unable to kill the microbes.
203. What are the consequences of chronic granulomatous disease?
The immune system tries to compensate by calling in more and more macrophages, and by activating T cells, which stimulate recruitment and activation of even more macrophages.

Therefore, collections of phagocytes accumulate around foci of infections by intracellular microbes, but the microbes cannot be destroyed effectively. These collections resemble granulomas, giving rise to the name of the disease.

Pts develop pneumonia, lymph node infections, and abscesses of the skin, liver, and other sites
204. What causes leukocyte adhesion deficiency?

What are the consequences?
Leukocytes adhesion deficiency is caused by mutations in genes encoding integrins or in enzymes required for the expression of ligands for selectins.

Integrins and selectin ligands are involved in the adhesion of leukocytes to other cells.

As a result of these mutations, blood leukocytes do not bind firmly to vascular endothelium and are not recruited normally to sites of infection.
205. Deficiency in C3 results in?

Deficiency in C2 and C4?
C3 deficiency resutls in severe infections and usually is fatal.

Deficiencies of C2 and C4, two components of the classical pathway, result not in immunodeficiency but in immune complex-mediate diseases resembling lupus.

These lupus like disease result b/c the classical complement pathway is involved in eliminating complexes that are constantly being formed during humoral immune responses. Failure to clear these immune complexes results in their deposition in the tissues.
206. The observation that C2 and C4 deficiencies do not make individuals susceptible to infection suggests what...?
Suggests that the alternative pathway may be adequate for host defense.
207. What is Chédiak-Higashi syndrome?
Chédiak-Higashi syndrome is an immunodeficiency disease in which the lysosomal granules of leukocytes do not function normally. It is caused by a mutation in a gene encoding a lysosomal trafficking regulatory protein.

The immune defect is thought to affect phagocytes and NK cells and is manifested by increased susceptibility to bacterial infections.
208. What is Wiskott-Aldrich syndrome?
The Wiskott-Aldrich syndrome is characterized by eczema, reduced blood platelets, and immunodeficiency.

It is an X-linked disease, caused by a mutation in the WAS gene that encodes a protein that binds to various adapter molecules and cytoskeletal components in hematopoietic cells.

It is believed that b/c of the absence of this protein, platelets and leukocytes are small, do not develop normally, and fail to migrate normally.
209. What is ataxia-telangiectasia?
Ataxia-telangiectasia is a disease chracterized by gait abnormalities (ataxia), vascular malformations (telangiectasia), and immunodeficiency.

The disease is caused by mutations in a gene whose product is involved in DNA repair.

Defects in this protein lead to abnormal DNA repair (e.g., during recombination of antigen receptor gene segments), resulting in defective lymphocyte maturation.
210. What are the five most common causes of acquired immunodeficiencies?
1. HIV infection
2. Irradiation and chemo treatments for cancer
3. Involvement of bone marrow by cancers (metastases, leukemias)
4. Protein-calorie malnutrition due to metabolic derangements
5. Removal of spleen.
211. What is the HIV virus?
HIV is a retrovirus that infects cells of the immune system, mainly CD4+ T lymphocytes, and causes progressive destruction of these cells.

An infectious HIV particle consists of 2 RNA strands within a protein core, surrounded by a lipid envelope derived from infected host cells but containing viral proteins.

The viral RNA encodes structural proteins, various enzymes, and proteins that regulate transcription of viral genes and the viral life cycle.
212. What are the three sequential steps in the life cycle of HIV?
1. Infection of cells
2. Production of viral DNA and its integration into the host genome
3. Production of viral particles
213. How does HIV infect cells?

What types of cells can it infect?
By virtue of its major envelope glycoprotein, called gp120, binding to CD4 and particular chemokine receptors (CXCR4 on T cells and CCR5 on macrophages) on human cells.

Therefore, the virus can efficiently infect only cells expressing CD4 and these chemokine receptors. This includes CD4+ T lymphocytes, macrophages, and dendritic cells.
214. Once the HIV virus integrates itself into the host's cells, how is it activated?
If the infected T cell, macrophage, or dendritic cell is activated by some extrinsic stimulus, such as another infectious microbe, the cell responds by turning on the transcription of many of its own genes and often by producing cytokines.

*An unfortunate consequence of this normal protective response is that the cytokines, and the process of cellular activation itself, also may activate the provirus, leading to production of viral RNAs and then proteins.
215. HIV+ individuals with CCR5 mutations are more or less susceptible towards developing AIDS?
Rare individuals with CCR5 mutations that not not permit HIV entry into macrophages can remain disease free for years after HIV infection, indicating the importance of macrophage infection int eh progression towards AIDS.
216. What causes the depletion of CD4+ T cells after HIV infection?
It is due to a cytopathic effect of the virus, resulting from production of viral particles, as well as death of uninfected cells.

Active viral gene expression and protein production may interfere with the synthetic machinery of the T cells.

Therefore, infected T cells in which the virus is replicating are killed during this process.
217. What is the most reliable indicator of HIV/AIDS progression?
The CD4+ T cell count
218. What is the clinical course of HIV disease?
Blood born virus is detected early after infection and may be accompanied by systemic symptoms typical of acute HIV syndrome

The virus spreads to lymphoid organs, but plasma viremia falls to very low levels and stays this way for many years.

CD4+ T cell counts steadily decline during this clinical latency period, b/c of active viral replication and T cell destruction in lymphoid tissues.

As the level of CD4+T cells falls, there is increasing risk of infection and other clinical components of AIDS.
219. What are the consequences of AIDS?
Pts w/AIDS show defective CTL responses to viruses, even though HIV does not infect CD8+ T cells. It is believed that the CTL responses are defective b/c CD4+ helper T cells are required for full CD8+ CTL responses against many viral antigens.

Pts are at increased risk for infections by extracellular bacteria, probably b/c of impaired helper T cell-dependent antibody responses to bacterial antigens.
220. What causes AIDS dementia?
The dementia that develops in some pts with AIDS is believed to be caused by infection of macrophages (microglial cells) in the brain.