Usmle review 16

DANIL HAMMOUDI.MD

SINOE MEDICAL ASSOCIATION

 

• Buspirone is an anxiolytic used in the management of anxiety disorder and in the short term treatment of generalized anxiety.
• It is also used for nicotinic withdrawal
• Buspirone HCl is an antianxiety agentthat is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs.
• The mechanismof actionof buspirone is unknown. Buspirone differs from typical benzodiazepineanxiolytics in that it does not exert anticonvulsant or musclerelaxanteffects. It also lacks the prominent sedativeeffectthat is associated with more typicalanxiolytics. In vitropreclinicalstudies have shown that buspirone has a high affinity for serotonin(5-HT1A) receptors. Buspirone has no significant affinity for benzodiazepinereceptors and does not affectGABA binding in vitroor in vivowhen tested in preclinicalmodels.
• Buspirone has moderate affinity for brainD2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmittersystems.
• Buspirone HCl is rapidly absorbed in manand undergoes extensive first pass metabolism. In a radiolabeled study, unchanged buspirone in the plasma accounted for only about 1% of the radioactivity in the plasma. Following oral administration, plasmaconcentrations of unchanged buspirone are very low and variablebetween subjects. Peak plasmalevels of 1 to 6 ng/ml have been observed 40 to 90 minutes after single oraldoses of 20 mg. The single-dose bioavailability of unchanged buspirone when taken as a tabletis on the average about 90% of an equivalentdoseof solution, but there is large variability.
• The effects of foodupon the bioavailability of buspirone HCl have been studied in eight subjects. They were given a 20-mg dosewith and without food; the areaunder the plasmaconcentration-time curve(AUC) and peak plasmaconcentration (Cmax) of unchanged buspirone increased by 84% and 116% respectively, but the total amount of buspirone immunoreactive material did not change. This suggests that foodmay decrease the extent of presystemic clearance of buspirone, but the clinicalsignificance of these findings is unknown.
• A multiple-dose study conducted in 15 subjects suggests that buspirone has nonlinear pharmacokinetics. Thus, doseincreases and repeated dosing may lead to somewhat higher bloodlevels of unchanged buspirone than would be predicted from results of single-dose studies.
• In man, approximately 95% of buspirone is plasmaproteinbound, but other highly bounddrugs, e.g.,phenytoin, propranolol, and warfarin are not displaced by buspirone from plasmaproteinin vitro. However, in vitrobinding studies wshowthat buspirone does displace digoxin.
• Buspirone is metabolized primarily by oxidationproducing several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP).

 

• is recommended that buspirone hydrochloridenotbe used concomitantly with MAOinhibitors (See WARNINGS.) Because the effects of concomitantadministrationof buspirone HCl with most other psychotropic drugs have not been studied, the concomitantuse of buspirone HCl with other CNS-active drugs should be approached with caution.
• Cardiovascular:Frequent was nonspecificchestpain; infrequent were syncope, hypotension, and hypertension; rare were cerebrovascular accident, congestive heartfailure, myocardialinfarction, cardiomyopathy, and bradycardia.
• Central Nervous System:Frequent:were dreamdisturbances; Infrequent:were depersonalization, dysphoria, noiseintolerance, euphoria, akathisia, fearfulness, lossof interest, dissociative reaction, hallucinations, suicidal ideation, and seizures; Rare:were feelings of claustrophobia, coldintolerance, stupor, and slurred speechand psychosis.
• EENT:Frequent:were tinnitus, sorethroat, and nasal congestion; Infrequent:were redness and itching of the eyes, altered taste, altered smell, and conjunctivitis; Rare:were inner ear abnormality, eyepain, photophobia, and pressureon eyes.
• Endocrine:Rare:were galactorrheaand thyroid abnormality.
• Gastrointestinal:Infrequent:were flatulence, anorexia, increased appetite, salivation, irritablecolon, and rectalbleeding; Rare:was burning of the tongue.
• Genitourinary:Infrequent:were urinary frequency, urinary hesitancy, menstrual irregularity and spotting, and dysuria; Rare:were amenorrhea, pelvicinflammatory disease, enuresis, and nocturia.
• Musculoskeletal:Infrequent:were musclecramps, muscle spasms, rigid/stiff muscles, and arthralgias.
• Neurological:Infrequent:were involuntary movements and slowed reactiontime; Rare:was muscleweakness.
• Respiratory:Infrequent:were hyperventilation, shortness of breath, and chestcongestion; Rare:was epistaxis.
• Sexual Function:Infrequent:were decreased or increased libido; Rare:were delayed ejaculationand impotence.
• Skin:Infrequent:were edema, pruritus, flushing, easy bruising, hairloss, dry skin, facialedema, and blisters; Rare:were acneand thinning of nails.
• Clinical Laboratory:Infrequent:were increases in hepaticaminotransferases (SGOT, SGPT); Rare:were eosinophilia, leukopenia, and thrombocytopenia.
• Miscellaneous:Infrequent:were weightgain, fever, roaring sensationin the head, weightloss, and malaise; Rare:were alcohol abuse, bleedingdisturbance, lossof voice, and hiccoughs.

 

The pancreas secretes a magnificent battery of enzymes that collectively have the capacity to reduce virtually all digestible macromolecules into forms that are capable of, or nearly capable of being absorbed.Three major groups of enzymes are critical to efficient digestion:

 

Proteases

• Digestion of proteins is initiated by pepsin in the stomach, but the bulk of protein digestion is due to the pancreatic proteases. Several proteases are synthesized in the pancreas and secreted into the lumen of the small intestine. The two major pancreatic proteases are trypsin and chymotrypsin, which are synthesized and packaged into secretory vesicles as an the inactive proenzymes trypsinogen and chymotrypsinogen.
• As you might anticipate, proteases are rather dangerous enzymes to have in cells, and packaging of an inactive precursor is a way for the cells to safely handle these enzymes.The secretory vesicles also contain a trypsin inhibitor which serves as an additional safeguard should some of the trypsinogen be activated to trypsin; following exocytosis this inhibitor is diluted out and becomes ineffective - the pin is out of the grenade.
• Once trypsinogen and chymotrypsinogen are released into the lumen of the small intestine, they must be converted into their active forms in order to digest proteins. Trypsinogen is activated by the enzyme enterokinase, which is embedded in the intestinal mucosa.
• Once trypsin is formed it activates chymotrypsinogen, as well as additional molecules of trypsinogen. The net result is a rather explosive appearance of active protease once the pancreatic secretions reach the small intestine.

 

• Trypsin and chymotrypsin digest proteins into peptides and peptides into smaller peptides, but they cannot digest proteins and peptides to single amino acids. Some of the other proteases from the pancreas, for instance carboxypeptidase, have that ability, but the final digestion of peptides into amino acids is largely the effect of peptidases in small intestinal epithelial cells. More on this later.

 

 

Pancreatic Lipase

• The major form of dietary fat is triglyceride, or neutral lipid. A triglyceride molecule cannot be directly absorbed across the intestinal mucosa.Rather, it must first be digested into a 2-monoglyceride and two free fatty acids. The enzyme that performs this hydrolysis is pancreatic lipase, which is delivered into the lumen of the gut as a constituent of pancreatic juice.
• Sufficient quantities of bile salts must also be present in the lumen of the intestine in order for lipase to efficiently digest dietary triglyceride and for the resulting fatty acids and monoglyceride to be absorbed. This means that normal digestion and absorption of dietary fat is critically dependent on secretions from both the pancreas and liver.
• Pancreatic lipase has recently been in the limelight as a target for management of obesity.The drug orlistat (Xenical) is a pancreatic lipase inhibitor that interferes with digestion of triglyceride and thereby reduces absorption of dietary fat. Clinical trials support the contention that inhibiting lipase can lead to significant reductions in body weight in some patients.

 

 

Amylase

• The major dietary carbohydrate for many species is starch, a storage form of glucose in plants. Amylase is the enzyme that hydrolyses starch to maltose(a glucose-glucose disaccharide), as well as the trisaccharide maltotriose and small branchpoints fragments called limit dextrins.
• The major source of amylase in all species is pancreatic secretions, although amylase is also present in saliva of some animals, including man.

 

 

Other Pancreatic Enzymes

• In addition to the proteases, lipase and amylase, the pancreas produces a host of other digestive enzymes, including ribonuclease, deoxyribonuclease, gelatinase and elastase.

 

Epithelial cells in pancreatic ducts are the source of the bicarbonate and water secreted by the pancreas.The mechanism underlying bicarbonate secretion is essentially the same as for acid secretion parietal cells and is dependent on the enzyme carbonic anhydrase.. In pancreatic duct cells, the bicarbonate is secreted into the lumen of the duct and hence into pancreatic juice.

 

Control of Pancreatic Exocrine Secretion

 

• As you might expect, secretion from the exocrine pancreas is regulated by both neural and endocrine controls.During interdigestive periods, very little secretion takes place, but as food enters the stomach and, a little later, chyme flows into the small intestine, pancreatic secretion is strongly stimulated.
• Like the stomach, the pancreas is innervated by the vagus nerve, which applies a low level stimulus to secretion in response to anticipation of a meal. However, the most important stimuli for pancreatic secretion comes from three hormonessecreted by the enteric endocrine system:
• Cholecystokinin:This hormone is synthesized and secreted by enteric endocrine cells located in the duodenum. Its secretion is strongly stimulated by the presence of partially digested proteins and fats in the small intestine. As chyme floods into the small intestine, cholecystokinin is released into blood and binds to receptors on pancreatic acinar cells, ordering them to secrete large quantities of digestive enzymes.

 

• Secretin:This hormone is also a product of endocrinocytes located in the epithelium of the proximal small intestine. Secretin is secreted (!) in response to acid in the duodenum, which of course occurs when acid-laden chyme from the stomach flows through the pylorus. The predominant effect of secretin on the pancreas is to stimulate duct cells to secrete water and bicarbonate. As soon as this occurs, the enyzmes secreted by the acinar cells are flushed out of the pancreas, through the pancreatic duct into the duodenum.

 

• Gastrin:This hormone, which is very similar to cholecystokinin, is secreted in large amounts by the stomach in response to gastric distention and irritation. In addition to stimulating acid secretion by the parietal cell, gastrin stimulates pancreatic acinar cells to secrete digestive enzymes.

 

 

• Stop and think about this for a minute - control of pancreatic secretion makes perfect sense.Pancreatic secretions contain enzymes which are needed to digest proteins, starch and triglyceride. When these substances enter stomach, and especially the small intestine, they stimulate release of gastrin and cholecystokinin, which in turn stimulate secretion of the enzymes of destruction.
• Pancreatic secretions are also the major mechanism for neutralizing gastric acid in the small intestine.When acid enters the small gut, it stimulates secretin to be released, and the effect of this hormone is to stimulate secretion of lots of bicarbonate. As proteins and fats are digested and absorbed, and acid is neutralized, the stimuli for cholecystokinin and secretin secretion disappear and pancreatic secretion falls off.

 

1. Inguinal Canal components
   1. Internal inguinal ring
      1. Lateral to inferior epigastrics
      2. Landmark: Middle of inguinal ligament
   2. Canal
      1. Follows spermatic cord course in men
      2. Follows round ligament in women
   3. External inguinal ring
      1. Located at pubic tubercle
      2. Occurs just above inguinal ligament
      3. Medial and inferior to internal inguinal ring

• Inguinal Canal:
    Deep Inguinal Ring - the entrance to the inguinal canal found one inch above the midpoint of the inguinal ligament, lateral to the inferior epigastric artery.
    Superficial Inguinal Ring - the exit of the inguinal canal, a triangular opening in the external oblique aponerosis found just superior lateral to the pubic tubercle.
    Anterior Wall
      External Oblique Aponerosis
      Intercrural Fibers - fibers from the inguinal ligament which arch over the superficial  ring for reinforcement
      Inguinal Ligament - the lower free border of the external oblique running from ASIS to the pubic tubercle
    Posterior Wall
      Transversalis Fascia - fascia on the posterior surface of the transversus abdominus
      Conjoint Tendon - tendon formed by the fusion of the internal oblique aponerosis and transversus abdominus aponerosis
    Floor
      Lacunar Ligament - fibers of the inguinal ligament which do no reach the public tubercle but rather attach to the pecten pubis
      Pectineal Ligament - fusion of fibers from the lacunar ligament and the conjoint tendon
    Roof
      Internal Oblique
      Transverse Abdominus

 

• Spermatic Cord:
  
  

1.  Coverings of the Spermatic Cord:
       1.  Internal Spermatic Fascia – derived from transversalis fascia
       2.  Muscular Layer – cremaster muscle from internal oblique muscle
       Transversalis Abdominus Muscle
       Ilioinguinal Nerve
       Internal Oblique Muscle
       External Spermatic Fascia – derived from external oblique aponeurosis
    

1.  Contents of the Spermatic Cord:
       Vas Deferens
       Testicular Artery
       Cremasteric Artery
       Pampiniform Plexus
       Genital Branch of the Genitofemoral Nerve
2. Findings
   • Inguinal Hernia
     • Small Indirect Hernia may slightly tap end of finger
     • Large Indirect Hernia may be palpable as mass
     • Direct Inguinal Hernia may be felt on pad of finger
   • Spermatic cord tenderness (Funiculitis)
   • Spermatic cord Lipoma
   • Hydrocele

The testis develops primarily inside the abdomen. It comes down to the scrotum by birth. The way down to the scrotum is through the inguinal canal. This canal starts from the abdomen by the so-called internal opening (internal ring) and ends by the so-called external opening (external ring). The testis may stay at any position during its journey of coming down from the neighborhood of the kidney to its final position. This may be due to a short artery of the testicle or due to a short band (gabernaculum), which fixes the testis to the bottom of the scrotum. A short spermatic string (spermatic cord) may be also responsible for the retention of the testis. The testis may be abdominal, inguinal or even a Penndel testis. Penndel testis means that the testis is wandering between the scrotum and any station upwards. It is important for the testis to stay permanently or even mostly inside the scrotum. The testis must enjoy a temperature of 1-1,5 C° lower than the temperature of the body to be able to function and not to develop cancer. Inguinal or Penndel testis is subject also to trauma.

 

 

The position of a typical lower inguinal testis Note that the testis is in position exposing it to injury high temperature of the body

The position of the fixed testis Note that the testits is fixed to the skin and covered with muscles of the scrotum

 

 

	The position of the testis during ist descent 1 inside the abdomen 2 at the interna, inside or external opening of the inguinal canal 3 at the neck of the scrotum 4 normal position in the scrotum H testis