By R. Yussuf. Hawaii Pacific University.
A diffusion potential develops for in- trochemical driving “force” buy generic duloxetine 20mg, will equal zero generic duloxetine 60 mg fast delivery, stance discount 20mg duloxetine fast delivery, when ions (e duloxetine 40mg low price. The rising diffusion potential then tion-dependent variable, is generally used to drives the ions back into the cell (potential- describe the permeability of a cell membrane driven ion transport;! Outward K+ dif- to a given ion instead of the permeability fusion persists until equilibrium is reached. In other words, the sum of area, gx is expressed in siemens (S = 1/Ω) per the two or the electrochemical gradient (and m2(! The equilibrium potential (E )x for any spe- Ix will therefore differ from zero when the pre- cies of ion X distributed inside (i) and outside vailingmembranepotential,Em,doesnotequal (o) a cell can be calculated using the Nernst the equilibrium potential, E. This occurs, forx equation: example, after strong transient activation of Na -K+ +-ATPase (electrogenic;! If the membrane is per- (310"K in the body), F is the Faraday constant meable to different ion species, the total con- orchargepermol(=9. It is some- times helpful to convert ln([X] /[X])o i into The membrane potential, Em, can be deter- –ln([X]/[X] ),i o V into mV and ln into log be- mined if the fractional conductances and equi- fore calculating the equilibrium potential librium potentials of the conducted ions are (! Assuming K, Na, and Cl+ + – Nernst equation then becomes are the ions in question, 1 [X]i Em! Electrochemical potential (Em– EK) and ionic currents [K]o= [K]i= Nernst equation 4. Single-channel recoprding (patch-clamp technique) 3 Data analysis 1 Experimental set-up 2 Electrode 1 Measuring unit 0 Pipette solution: –50 –25 0 –25 150mmol/l NaCl Voltage (mV) + 5mmol/l KCl Oscillograph 200ms Clamp voltage 20mV Pipette pA Burst 2 0 K+channel Clamp voltage 0mV Cytosolic 2 side Membrane patch 0 Clamp voltage –20mV Bath solution: 2 5 mmol/l NaCl +150 mmol/l KCl 0 2µm Clamp voltage –40mV 2 2 Single-channel current recording 0 3333 (After R. In single- Na+influxislowbecausethegNaandfNaofrest- channel recording, the membrane potential is ing cells are relatively small. Thisper- sodium current, INa, can rise tremendously mits the measurement of ionic current in a when large numbers of Na+ channels open single channel. The potential produced by of the I/V curve corresponds to the conduct- the transport of one ion species can also drive ance of the channel for the respective ion spe- other cations or anions through the cell mem- cies (see Eq. The K diffusion potential leads to the ef-+ intercepts the x-axis of the curve (I = 0). The flux of Cl, for example, which continues until– ionspeciesproducingcurrentIcanbededuced ECl = Em. In example B, that the cytosolic Cl– concentration is reduced the zero-current potential equals –90mV. Therefore, Cl– ions must have been ac- can also be determined by adding specific tively taken up by the cell, e. Membrane potential, especially in Na, Ca+ 2+ for different ion species (Na, Ca+ 2+, K, Cl, etc. External ligands that bind with the channel of ion channels that are momentarily open. This includes acetylcholine on the Patch–clamp techniques permit the direct postsynaptic membrane of nicotinic synapses measurement of ionic currents through single (cation channels), glutamate (cation chan- ion channels (! C3) does not depend on the change of the pore such as: diameter of its ion channels, but on their aver- — cAMP (e. The ion permeabil- cells and Cl– channels in epithelial cells); ity of a membrane is therefore related to the — cGMP (plays a role in muscarinergic effects open-probability of the channels in question. The whole cell Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Control of ion channels 1 Membrane potential + 2 K Acetylcholine External ligands (nicotinergic) GABA Cl– Na+ Na+ Cl– Cl– Ca2+ Interstice Cytosol cAMP Ca2+ Cl– Cl– cGMP IP3 Ca2+ Na+ Ca2+ pH Tyrosine kinases ATP – Cl 5 K+ Membrane stretch K+ K+ K+ Cl– 3 Intracellular 4 messenger Intracellular substances metabolites! The frequency, not amplitude, of lower than the extracellular Ca2+ concentra- [Ca2+]i oscillation is the quantitative signal for tion [Ca2+]o (ca. When low-frequency [Ca2+]i Ca2+ is continuously pumped from the cytosol oscillation occurs, CaM-kinase II, for example, into intracellular Ca2+ stores such as the is activated and phosphorylates only its target endoplasmic and sarcoplasmic reticulum proteins, but is quickly and completely deacti- (!
Macrophage popula- rapid mutation rate of HIV and to minimize drug toxic- tions are depleted or cease to function properly in 3 to ity buy generic duloxetine 60 mg. It is during this time that an HIV- combinations of reverse transcriptase inhibitors and infected person becomes immunodeﬁcient and can die protease inhibitors (Table 51 cheap duloxetine 40mg on line. In this system generic 30 mg duloxetine, drugs of infections that under normal conditions are not life working by different mechanisms produce a sequential threatening purchase 60mg duloxetine fast delivery. It is 586 VI CHEMOTHERAPY can produce a potentially fatal syndrome of lactic acido- TABLE 51. Those at highest risk include women, obese individuals, alcoholics, and patients with prolonged ex- Combinations of Choice posure to NRTIs. All patients should be monitored for the development of hepatotoxicity; the drug should be 2 NRTIs and 1 PI 2 NRTIs and 1NNRTI discontinued if this occurs. Resistance generally re- sults from the appearance of mutations in reverse tran- Secondary Alternatives scriptase; cross-resistance to multiple NRTIs also occurs. It is a thymidine analogue that is ef- that provide it with resistance to the multiple drugs that fective against HIV-1, HIV-2, and human T-cell lym- act via different mechanisms. It is available as a tidrug regimens, it has been estimated that viruses in single agent (Retrovir) or in ﬁxed combinations with 85% of infected people develop resistance to one or lamivudine (Combivir) or lamivudine and abacavir more of the antiretroviral agents. Zidovudine, in combination with one or more sary to produce drugs that either inhibit this resistance other antiretroviral agents, is approved for the treat- or ﬁnd compounds that produce no resistance. In addition, a variety of drugs under devel- nation for the prevention of prenatal and perinatal opment act as inhibitors of viral fusion or viral entry transmission to the baby by HIV-infected pregnant into the host cell. The most common adverse reactions to zidovudine Current therapies do not enhance the host defense sys- are headache, nausea, vomiting, and anorexia. Fatigue, tem; this may account for their incomplete effective- confusion, insomnia, malaise, hepatitis, myopathy, and ness. Bone marrow toxicity occurs in increase the efﬁcacy of other drugs that inhibit viral up to 30% of patients taking zidovudine; anemia, neu- replication. The NRTIs are nucleoside analogues that act as com- Caution should be exercised when zidovudine is ad- petitive inhibitors of reverse transcriptase. After conver- ministered to patients with preexisting anemia or neu- sion to the triphosphate form by host cell kinases, these tropenia and to those with advanced cases of AIDS. All NRTIs lack a 3 -hydroxyl cant renal impairment and may also be necessary in group; thus, their incorporation into a growing DNA those with hepatic impairment. These drugs block HIV Zidovudine should be used cautiously with any replication and therefore the infection of new cells, but other agent that causes bone marrow suppression, such they have little effect on cells already infected with as interferon-, trimethoprim–sulfamethoxazole, dap- virus. Combination therapies often include two NRTIs sone, foscarnet, ﬂucytosine, ganciclovir, and valganci- that are analogues of different bases plus a protease in- clovir. The pharmacokinetic properties of the NRTIs tion of zidovudine; therefore, a dosage reduction of are listed in Table 51. Ribavirin inhibits the phosphoryla- polymerases and various cellular kinases, resulting in tion reactions that activate zidovudine, and zidovudine toxicity. Toxicity varies with the state of the immune sys- similarly inhibits the activation of stavudine; thus, the tem; early in the infection there is less toxicity, while late coadministration of zidovudine with ribavirin or stavu- in the infection there is substantially more. ADH, alcohol dehydrogenase; F, food (high-fat meal) increases absorption; F, food interferes with absorption; FPM, extensive ﬁrst pass metabolism; GT, glucuronyl transferase; H? Stavudine Didanosine Stavudine (d4T, Zerit) is a thymidine nucleoside ana- Didanosine (ddI, Videx) is an adenosine analogue with logue that is active against HIV-1 and HIV-2. It is ap- proved for the therapy of HIV infection as part of a proved as part of a multidrug regimen for the therapy of multidrug regimen and is also used for postexposure HIV infection and is also used as postexposure HIV prophylaxis. The adverse effects with which stavudine is most fre- The most common adverse effect produced by di- quently associated are headache, diarrhea, skin rash, danosine is diarrhea. Abdominal pain, nausea, vomiting, nausea, vomiting, insomnia, anorexia, myalgia, and anorexia, and dose-related peripheral neuropathy may weakness. Pancreatitis occurs rarely, as do hyperuricemia, ness, tingling, or pain in the hands or feet is also com- bone marrow suppression, retinal depigmentation, and mon with higher doses of the drug. Resistance to didanosine appears to re- of hepatic enzymes may be seen in approximately 10 to sult from mutations different from those responsible for 15% of patients.