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The bicarbonate/CO buffer pair is effective in buffering in compensate by increasing the excretion of filtered HCO buy kamagra soft 100 mg lowest price erectile dysfunction pills walgreens, 2 3 the body because its components are present in large thereby cheap kamagra soft 100 mg overnight delivery erectile dysfunction treatment in kuwait, diminishing the alkalemia. The respiratory system influences plasma pH by regulating by a gain of acid (other than H CO ) or a loss of HCO. The Respiratory compensation is hyperventilation, and renal kidneys influence plasma pH by getting rid of acid or base compensation is an increased excretion of H bound to uri- in the urine. Metabolic alkalosis is an abnormal process characterized tion of filtered HCO , excretion of titratable acid, and by a gain of strong base or HCO or a loss of acid (other 3 3 excretion of ammonia. Respiratory compensation is hypoventilation, 3 2 3 plasma and replenishes depleted HCO when titratable and renal compensation is an increased excretion of 3 acid (normally mainly H PO ) and ammonia (as NH ) HCO. The stability of intracellular pH is ensured by membrane [HCO ] and is most useful in narrowing down possible 3 transport of H and HCO , by intracellular buffers causes of metabolic acidosis. For example, the in extracellular fluid because ECF is easier to analyze than [H ] of arterial blood is normally 35 to 45 nmol/L (pH intracellular fluid and is the fluid used in the clinical eval- 7. In practice, systemic arterial ance; inputs and outputs of acids and bases are matched so blood is used as the reference for this purpose. Measure- 426 CHAPTER 25 Acid-Base Balance 427 ments on whole blood with a pH meter give values for strength of the solution. A strong acid has a high K and a the [H ] of plasma and, therefore, provide an ECF pH a measurement. A REVIEW OF ACID-BASE CHEMISTRY pH Is Inversely Related to [H ] In this section, we briefly review some principles of acid- [H ] is often expressed in pH units. We define acid, base, acid dissociation tion defines pH: constant, weak and strong acids, pKa, pH, and the Hender- son-Hasselbalch equation and explain buffering. Students pH log10 (1/[H ]) log10 [H ] who already feel comfortable with these concepts can skip where [H ] is in mol/L. Each whole number on the pH scale represents a 10- fold (logarithmic) change in acidity. A solution with a pH Acids Dissociate to Release Hydrogen Ions of 5 has 10 times the [H ] of a solution with a pH of 6. When pH to the Ratio of the Concentrations of an acid (generically written as HA) is added to water, it dis- Conjugate Base and Acid sociates reversibly according to the reaction, HA H For a solution containing an acid and its conjugate base, we A. The species A is a base because it can combine with a can rearrange the equilibrium expression (equation 1) as H to form HA. In other words, when an acid dissociates, it yields a free H and its conjugate (meaning “joined in a pair”) base. Ka [HA] [H ] (4) [A ] The Acid Dissociation Constant Ka Shows the If we take the negative logarithms of both sides, Strength of an Acid At equilibrium, the rate of dissociation of an acid to form [A ] –log [H ] log K log (5) H A , and the rate of association of H and base A a [HA] to form HA, are equal. The equilibrium constant (Ka), which is also called the ionization constant or acid dissoci- Substituting pH for log [H ] and pKa for log Ka, we ation constant, is given by the expression get [H ] [A ] [A ] Ka (1) pH pKa log (6) [HA] [A] The higher the acid dissociation constant, the more an This equation is known as the Henderson-Hasselbalch acid is ionized and the greater is its strength. It shows that the pH of a solution is determined acid (HCl) is an example of a strong acid. It has a high Ka by the pKa of the acid and the ratio of the concentration of and is almost completely ionized in aqueous solutions. Other strong acids include sulfuric acid (H2SO4), phos- phoric acid (H3PO4), and nitric acid (HNO3). A most (99%) of the acid is nonionized and little (1%) is pres- pH buffer is defined as something that minimizes the change ent as acetate and H. The acidity (concentration of free in pH produced when an acid or base is added. A chemical pH buffer is carbonic acid (H2CO3), ammonium ion (NH4 ), and dihy- a mixture of a weak acid and its conjugate base (or a weak drogen phosphate (H2PO4 ). Following are examples of buffers: pKa Is a Logarithmic Expression of Ka Weak Acid Conjugate Base Acid dissociation constants vary widely and often are small H CO HCO H 2 3 3 numbers. It is convenient to convert Ka to a logarithmic (carbonic acid) (bicarbonate) (7) form, defining pKa as H PO HPO 2– H 2 4 4 pK log (1/K ) log K (2) (dihydrogen phosphate) (monohydrogen phosphate) (8) a 10 a 10 a In aqueous solution, each acid has a characteristic pKa, NH NH H 4 3 which varies slightly with temperature and the ionic (ammonium ion) (ammonia) (9) 428 PART VI RENAL PHYSIOLOGY AND BODY FLUIDS Generally, the equilibrium expression for a buffer pair 2– basic form of phosphate: H HPO4 H2PO4. Go- can be written in terms of the Henderson-Hasselbalch ing from left to right as strong base is added, OH com- equation: bines with H released from the acid form of the phos- 2– phate buffer: OH H2PO4 HPO4 H2O. In most cases, pH buffering is effec- 2– tive when the solution pH is within plus or minus one pH [HPO4 ] pH 6. Beyond that range, the pH shift that [HPO4 ] a a given amount of acid or base produces may be large, so The effectiveness of a buffer—how well it reduces pH the buffer becomes relatively ineffective. A good buffer is present in high concentrations and has a pKa close to the desired pH. As a strong acid or strong base is progres- sively added to the solution (shown on the x-axis), the re- Acids are continuously produced in the body and threaten sulting pH is recorded (shown on the y-axis).

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The inhibitory amino At least five subtypes of GLU receptors have been de- acid transmitters -aminobutyric acid (GABA) and glycine scribed discount kamagra soft 100mg with amex erectile dysfunction over 50, based on the relative potency of synthetic analogs (GLY) bind to their respective receptors discount kamagra soft 100mg visa erectile dysfunction treatment mn, causing hyperpolar- CLINICAL FOCUS BOX 3. When transmission in glu- Intracellular free calcium is an activator of calcium-de- tamatergic neurons functions normally, very low concen- pendent proteases, which destroy microtubules and other trations of EAA appear in the synapse at any time, prima- structural proteins that maintain neuronal integrity. Cal- rily because of the efficient uptake mechanisms of the cium activates phospholipases, which break down mem- presynaptic neuron and neighboring glial cells. This can be seen in severe hypoxia, prostaglandins, some of which constrict blood vessels and such as during respiratory or cardiovascular failure, and in further exacerbate hypoxia/ischemia. Calcium activates ischemia, where the blood supply to a region of the brain cellular endonucleases, leading to DNA fragmentation and is interrupted, as in stroke. In mitochondria, high cal- area is deprived of oxygen and glucose, which are essen- cium induces swelling and impaired formation of ATP via tial for normal neuronal functions, including energy-de- the Krebs cycle. Calcium is the primary toxic agent in EAA- pendent mechanisms for the removal of extracellular EAA induced cytotoxicity. In addition to calcium, nitric oxide (NO) is known to me- The consequences of prolonged exposure of neurons to diate EAA-induced cytotoxicity. One sub- pressing neurons in response to NMDA receptor activation type, a presynaptic kainate receptor, opens voltage-gated kills adjacent neurons. Proposed new treatment strategies promise to enhance Several postsynaptic receptor subtypes depolarize the survival of neurons in brain ischemic/hypoxic disorders. Other strategies include drugs that de- lular GLU, leading to the further release of GLU, and of in- stroy oxygen-free radicals, calcium ion channel blocking creased calcium entry, leading to the further mobilization agents, and NOS antagonists. The GABA enters the Krebs cycle in both neu- ronal and glial mitochondria and is converted to succinic semialdehyde by the enzyme GABA-transaminase. This en- zyme is also coupled to the conversion of -ketoglutarate to glutamate. As in the recycling of glutamate, glutamine is transported into the presynaptic terminal, where it is converted into glutamate. Neurally active peptides are stored in synaptic vesicles and undergo exocytotic release in com- mon with other neurotransmitters. Many times, vesicles containing neuropeptides are colocalized with vesicles containing another transmitter in the same neuron, and both can be shown to be released during nerve stimulation. In these colocalization instances, release of the peptide- containing vesicles generally occurs at higher stimulation frequencies than release of the vesicles containing nonpep- tide neurotransmitters. The list of candidate peptide transmitters continues to grow; it includes well-known gastrointestinal hormones, pi- tuitary hormones, and hypothalamic-releasing factors. As a class, the neuropeptides fall into several families of pep- tides, based on their origins, homologies in amino acid composition, and similarities in the response they elicit at GABAergic neurotransmission. Upon release into the synaptic cleft, GABA can bind to GABA receptors (GABAA, GABAB). The conversion of GABA to succinic semialdehyde is coupled to the conversion of -ketoglutarate to glutamate by Neuropeptide Amino Acid Composition the enzyme GABA-transaminase. In glia, glutamate is converted into glutamine, which is transported back into the presynaptic Opioids terminal for synthesis into GABA. Met-enkephalin Tyr-Gly-Gly-Phe-Met-OH Leu-enkephalin Tyr-Gly-Gly-Phe-Leu-OH Dynorphin Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile -Endorphin Tyr-Gly-Gly-Phe-Met-Thr-Glu-Lys-Ser- ization of the postsynaptic membrane. GABAergic neurons Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe- Lys-Asn-Ala-Ile-Val-Lys-Asn-His-Lys- represent the major inhibitory neurons of the CNS, whereas Gly-Gln-OH glycinergic neurons are found in limited numbers, restricted Gastrointestinal peptides only to the spinal cord and brainstem. Glycinergic transmis- Cholecystokinin Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe- sion has not been as well characterized as transmission using octapeptide (CCK-8) NH2 GABA; therefore, only GABA will be discussed here. Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- The synthesis of GABA in neurons is by decarboxylation Gly-Leu-Met of GLU by the enzyme glutamic acid decarboxylase, a Vasoactive intestinal His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn- marker of GABAergic neurons. GABA is stored in vesicles peptide Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala- and released by exocytosis, leading to the stimulation of Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu- postsynaptic receptors (Fig. Asn-NH2 Hypothalamic and There are two types of GABA receptors: GABAA and pituitary peptides GABAB. The GABAA receptor is a ligand-gated Cl chan- Thyrotropin-releasing Pyro-Glu-His-Pro-NH2 nel, and its activation produces IPSPs by increasing the in- hormone (TRH) flux of Cl ions. The increase in Cl conductance is facili- Somatostatin Ala-Gly-Cys-Asn-Phe-Phe-Trp-Lys- tated by benzodiazepines, drugs that are widely used to Thr-Phe-Thr-Ser-Cys treat anxiety. Activation of the GABAB receptor also pro- Luteinizing hormone- Pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu- releasing hormone Arg-Pro-Gly duces IPSPs, but the IPSP results from an increase in K conductance via the activation of a G protein. Drugs that in- (LHRH) hibit GABA transmission cause seizures, indicating a major Vasopressin Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg- role for inhibitory mechanisms in normal brain function. Gly-NH2 Oxytocin Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu- GABA is removed from the synaptic cleft by transport Gly-NH2 into the presynaptic terminal and glial cells (astrocytes) CHAPTER 3 The Action Potential, Synaptic Transmission, and Maintenance of Nerve Function 57 Peptides are synthesized as large prepropeptides in the Application of somatostatin to target neurons inhibits their endoplasmic reticulum and are packaged into vesicles that electrical activity, but the ionic mechanisms mediating this reach the axon terminal by axoplasmic transport.

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Acutely neuroleptics increase the firing of DA neurons and the release of DA buy kamagra soft 100mg free shipping erectile dysfunction in diabetes type 1. This is because DA antagonists: (1) Block the inhibitory feedback effect of released DA on terminal autoreceptors buy kamagra soft 100mg amex erectile dysfunction genetic. The receptor mediating all three effects appears to be the D2 (or D3) receptor. Thus initially neuroleptics may increase DA turnover and possibly even its action depending on the degree of postsynaptic block. This may also change as the block induces compensating increases in receptor number. LATENCY OF NEUROLEPTIC EFFECT There is no reason why DA receptor block should not occur as soon as the antagonist reaches the brain. We now have a situation in which the drugs that are most useful in schizophrenia are regarded as atypical. While the term was introduced to cover those neuroleptics that do not cause EPSs, it has become synonymous with clozapine which has additional advantages over other neuroleptics (e. Hopefully this distinction between the neuroleptics will become unnecessary as better compounds are developed and the older ones become obsolete. One possibility is that even with a potentially effective drug, the necessary readjust- ments in the neuronal circuitry to reverse or compensate for the disorder-induced malfunction just requires time. These neurons are usually not very active but DA antagonists increase their excitability through the mechanisms outlined above so that their firing rates rise, the pattern of discharge changes from single- to multiple-spike burst discharges and the proportion of neurons firing increases. These changes are also aided by the fact that the excitatory inputs to A9 and A10 neurons normally promote a dendritic release of DA which through inhibitory soma D2 autoreceptors will automatically counteract the excitation (Fig. Clearly when these autoreceptors are blocked by acute neuro- leptic administration in rats they cannot be activated by released DA, and the neurons fire much more frequently. It was found, however, that if neuroleptic administration was continued for two weeks then neuronal firing stopped. Also while the neurons could not be made to fire by the excitatory NT glutamate, the inhibitory NT GABA activated them by reducing the SCHIZOPHRENIA 361 Figure 17. In (a) the excitatory effect of glutamate released on to the DA neuron from the afferent input is counteracted by the inhibitory effect of DA, presumed to be released from dendrites, acting on D2 autoreceptors. In the absence of such inhibition due to the presence of a typical neuroleptic (b) the neuron will fire more frequently and eventually become depolarised. Atypical neuroleptics, like clozapine, will be less likely to produce the depolarisation of A9 neurons because they are generally weaker D2 antagonists and so will reduce the DA inhibition much less allowing it to counteract the excitatory input. Additionally some of them have antimuscarinic activity and will block the excitatory effect of ACh released from intrinsic neurons (see Fig. Thus it appears that due to their continuous intense activity the neurons eventually become permanently depolarised (confirmed by intra- cellular recording) and inactive (Fig. The induction of depolarisation block in DA neurons needs afferent input to the nuclei, since prior lesion of the striatum and nucleus 362 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 17. Iontophoretic application of GABA the inhibitory NT, at the currents indicated (nA) actually induced firing which is shown as an oscilloscope sweep in (b). The excitatory NT glutamate failed to stimulate the neuron but apomorphine, which normally has an inhibitory effect through D2 receptors, increased firing when given intraventricularly in increasing amounts from 2±5 to 160 mgkg71. These effects are consistent with the neurons being overstimulated and depolarised as a result of chronic neuroleptic dosing and so requiring to be hyperpolarised (inhibited) in order to become active. In a neuron from an untreated rat (c), GABA produces the expected inhibition and glutamate the rapid excitation, shown as an oscilloscope sweep in (d). This again emphasises the importance of feedback loops in DA neuron function and schizophrenia as discussed above. Second, although typical neuroleptics produce depolarisation block of both A9 and A10 neurons, the atypical neuroleptics only induce it in A10 neurons (Chiodi and Bunney 1983). So after an atypical neuroleptic the A9 neurons of the nigrostriatal tract remain functional, which would explain why EPSs are not seen. Another difference is seen with the expression of an immediate-early gene, c-fos, and although its functional significance is not clear, typical neuroleptics induce its protein production in both the striatum and nucleus accumbens while the atypicals only achieve it in the accumbens. The slow time-course of depolarisation block not only offers an explanation for the latency of action of neuroleptic drugs but its occurrence may explain how they actually reduce DA function. Whether it explains their antischizophrenic effect is less certain since it is not possible to determine if such depolarisation occurs in patients on neuro- leptic drugs. Certainly if this is how neuroleptics work it cannot be claimed that they have returned brain function to normal. SCHIZOPHRENIA 363 THE EXTRAPYRAMIDAL SIDE-EFFECTS (EPSs) OF NEUROLEPTIC DRUGS These take three basic forms (1) Acute dyskinesias (2) Parkinsonian-like symptoms, e. It is not surprising that a DA antagonist (especially those acting primarily on D2 receptors) should produce the symptoms of Parkinsonism, a disorder caused by inadequate DA function (see Chapter 15), nor that its intensity or rate of onset over some weeks or months should increase with D2 antagonistic potency. Tolerance to this adverse effect can develop without affecting antipsychotic activity but the speed with which Parkinsonism resolves after stopping therapy may be from 3 to 12months and can persist indefinitely in some cases. The late (tardive) dyskinesias, which mainly involve facial muscles, can take months or years to develop.

Concavities representing endosteal scalloping are If the entire carpus moves too far ulnarly order kamagra soft 100 mg online erectile dysfunction age 80, as recognized characteristic of cartilage tissue discount kamagra soft 100 mg mastercard erectile dysfunction doctor in kuwait. This would be typical for by more than one-half of the lunate positioned ulnar to an enchondroma, which is the most common intraosseous the radius when the wrist and hand are in neutral position, bone lesion of the hands. The matrix of the lesion should this would be an ulnar carpal translation type I. If the also be evaluated to see whether there are dots of calcium scaphoid is in the normal position relative to the radial that can be seen in cartilage, or whether there is a more styloid, but there is scapholunate dissociation and the re- diffuse type of bone formation as occurs in an osseous mainder of the carpus moves too far ulnarly, as men- type of tumor as from osteosarcoma. As elsewhere in the tioned for ulnar carpal translation type I, this is called ul- body, if a lesion is very well-defined and if there is bone nar carpal translation type II. The fourth and fifth types enlargement, these are indicative of an indolent or a less of carpal instabilities relate to the carpus displacing dor- aggressive type of lesion. If the carpus, as identi- struction supports the finding of an aggressive lesion, fied by the lunate, has lost its normal articulation with the such as malignancy or infection. To determine the extent radius in the lateral view and is displaced dorsally off the of a lesion, magnetic resonance (MR) is the preferred radius, this is called dorsal radiocarpal instability, or dor- method of imaging. It occurs most commonly follow- able to survey for osseous lesions throughout the body, as ing a severe dorsally impacted distal radius fracture. If many neoplastic conditions spread to other bones or even the carpus is displaced palmarly off the carpus, as iden- to the lung. There are other types of carpal instability patterns that Ganglion is another cause for a focal swelling in the hand, are better detected more by physical examination; these but usually that occurs without underlying bone deformi- will not be covered here. Glomus tumor is a less common, painful soft-tissue le- sion that may be detected with ultrasound or MR imag- ing. Occasionally, a glomus tumor will cause a pressure Infection effect on bone, especially on the distal phalanx under the nail bed. Infection should be suspected when there is an area of cortical destruction with pronounced osteopenia. It is not uncommon to have patients present with pain and Arthritis swelling, and clinically infection may not be suspected when it is chronic, as with an indolent type of infection Using the above scheme of analyzing the hand, wrist, and such as tuberculosis. Soft-tissue swelling is a key point musculoskeletal system, swelling can indicate cap- for this diagnosis as for other abnormalities of the wrist, sular involvement as well as synovitis. Therefore, the diagnosis of infection ation of alignment shows deviation of the fingers at the is most likely when there is swelling and associated os- interphalangeal and metacarpophalangeal joints in addi- teopenia as well as cortical destruction ,or even early fo- tion to subluxation or dislocation at the interphalangeal, cal joint-space loss without cortical destruction. Joint-space loss, the sites of erosions, and the sites of bone production are important to recognize. When iden- Neoplasia tifying the abnormalities, the metacarpophalangeal joint capsules, especially of the index, long and small fingers, When there is an area of abnormality, it helps to determine should be examined carefully to determine whether they the gross area of involvement, then look at the center of are convex, as occurs in for capsular swelling. If the center of the abnormality is in help in establishing whether this is primarily a synovial 20 L. Gilula arthritis, which in some cases exists in combination with Conclusions osteoarthritis. Synovial arthritis is supported by findings of bony destruction from erosive disease. The most com- Application of the the “A, B, C, D’S” system, together mon entities to consider for synovial-based arthritis are with an analysis of parallelism, abnormal overlapping ar- rheumatoid arthritis, and then psoriasis. If there is osteo- ticular surfaces and carpal arcs, can help analyze abnor- phyte production, osteoarthritis is the most common con- malities encountered in the hand and wrist, which can sideration, whereas osteoarthritis associated with erosive help in making a most reasonable diagnosis for further disease, especially in the distal interphalangeal joints, is evaluation of the patient. Punched-out or well- defined lucent lesions of bone, especially about the car- pometacarpal joints in well-mineralized bones, must also References be considered for the robust type of rheumatoid arthritis. Forrester DM, Nesson JW (1973) The ABC’S of Arthritis For deposition types of disease, gout is a classic example. Philadelphia WB Saunders, Philadelphia, tion and “punched-out” lesions of bone. Gouty destruc- Pennsylvania, pp 3 tion depends somewhat on where the gouty tophi are de- 2. Curtis DJ, Downey EF Jr (1992) Soft tissue evaluation in trau- posited, whether they are intraosseous, subperiosteal, ad- ma. Yin Y, Mann FA, Gilula LA, Hodge JC (1996) Roentgeno- graphic approach to complex bone abnormalities. WB Saunders, A classic condition of metabolic bone disease in the Philadelphia, Pennsylvania, pp 293-318 hands is that seen with renal osteodystrophy. Gilula LA, Totty WG (1992) Wrist trauma: roentgenographic bone disease is considered when there are multiple sites analysis. WB Saunders, Philadelphia, Pennsylvania, pp 221-239 out diffuse osteopenia. There is a strong likelihood of renal osteodystro- Traumatic axial dislocations of the carpus. J Hand Surg 14A:446-457 phy when there is subperiosteal resorption, typically 8.

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