vault.txt

c++ c++ if( x != 3) // i.e., if x not euual to 3 if(x== 3) // i.e., if x euual to 3 constructor : as soon as u create a object of th-A (Cases et al., 1995). Anxiety & Depression effects of 5-HT–active drugs in anxiety & depressive disorders, like effects of selective 5HT reuptake (-)ors (SSRIs), strongly =>a role for 5-HT in neurochemical mediation of these disorders.Mutant mice lacking 5-HT transporter display anxiety & a "depressive-like" phenotype (Fox et al., 2007).5-HT-related drugs c clinical effects in anxiety & depression have varied effects in classical animal models of these disorders, depending on experimental paradigm, species, & strain.For e.g., anxiolytic buspirone (chap 15), a partial agonist at 5-HT 1A receptors, doesnt reduce anxiety in classical approach-avoidance paradigms that were instrumental in development of anxiolytic benzodiazepines.However, buspirone & other 5-HT 1A receptor agonists are effective in other animal behavioral tests used to predict anxiolytic effects.
Furthermore, studies in 5-HT 1A knockout mice => a role for this receptor in anxiety, & possibly depression. Agonists of certain 5HTRs, including 5-HT 2A & 5-HT 2C (e.g., m -chlorophenylpiperazine), have anxiogenic properties in Lab animals & in human studies.lly, these receptors have been implicated in animal models of depression, e.g.,learned helplessness.An impressive finding in humans c depression is abrupt reversal of antidepressant effects of drugs e.g., SSRIs by manipulations that rapidly \/ 5-HT in brain.e.g., p -chlorophenylalanine or a tryptophan-free drink c /\ /\ neutral AAs (Delgado et al., 1990).Curiously, this kind of 5-HT depletion hasn't been shown to worsen or to induce depression in nondepressed subjects, => that continued presence of 5-HT is required to maintain effects of these drugs.This clinical finding adds credence to somewhat less convincing neurochemical findings that suggest a role for 5-HT in pathogenesis of depression.
Pharmacological Manipulation of Amount of 5-HT in Tissues A highly specific mechanism for altering synaptic availability of 5-HTe neurons & their targets in Deiter's nucleus; b/w small interneurons & major output cells of cerebellar cortex, olfactory bulb, cuneate nucleus, hippocampus, & lateral septal nucleus; & b/w vestibular nucleus & trochlear motoneurons. cin cerebral cortex & b/w caudate nucleus & substantia nigra.GABA-containing neurons & nerve terminals have been localized c immunocytochemical methods that visualize glutamic acid decarboxylase or by in situ hybridization of mRNA for this protein.GABA-containing neurons frequently co-express > 1 neuropeptides.most useful compounds for confirmation of GABA-mediated effects have been bicuculline & picrotoxin (Figre 14–10); however, many convulsants whose actions previously were unexplained (including penicillin & pentylenetetrazol ) are relatively selective antagonists of GABA.
Useful therapeutic effects have not yet been obtained through use of agents that mimic GABA (such as muscimol ), (-) its active reuptake (such as 2,4-diaminobutyrate, nipecotic acid, & guvacine ), or alter its turnover (such as aminooxyacetic acid ). Figre 14–10.Amino acid transmitters & congeners.GABA receptors have been divided into 3 main types: A, B, & C.most prominent-GABA A .a ligand-gated Cl – ion channel, an "ionotropic receptor." GABA B - GPCR.GABA C - transmitter-gated Cl – channel.GABA A receptor subunit proteins have been well characterized `.`their abundance.receptor also has been extensively characterized as site of action of many neuroactive drugs, notably BDZs, barbiturates, ethanol, anesthetic steroids, & volatile anesthetics (Figre 14–11).Figre 14–11.Pharmacologic binding sites on GABA A Based on sequence homology to 1st reported GABA A subunit cDNAs, multiple subunits have been cloned, including 6α, 4β, & 3γ subunits - seperate genes.
They appear to be expressed in multiple multimeric, pharmacologically distinctive combinations. + splice variants for several subunits have been described.GABA A is probably penta / tetrameric c subunits that assemble together around a central pore typical for other ionotropic receptors.major form of GABA A receptor contains at least 3 different subunits α, β, & γ, c likely stoichiometry of 2α, 2β, 1γ.All 3 subunits are required to interact c BDZs c profile expected of a native GABA A receptor.Table 14–2 (Fritschy & Mohler, 1995).Table 14–2 Composition, Distribution, & Major Functions of GABA A Receptors SUBUNIT COMPOSITION LOCATION FUNCTION COMMENTS α1β2γ2 Widespread GABA Neurons Sedation, anticonvulsant activity Adult, BZ-sensitive, \/d in drug tolerance?
α2β3γ2 Forebrain, spinal cord Anxiety, muscle relaxant Axon hillock in some cells, BZ- sensitive α2β1γ1 Glia α3β3γ2 Cortex Anticonvulsant activity Embryonic & adult BZ- sensitive α4β2γ2 Thalamus Insensitive to agonist BZ α4β2/3γ2 Dentate gyrus /\d in drug cdrawal? α4β2δ Thalamus Tonic (-)ion Extrasynaptic, BZ-insensitive in adults α4β2/3δ Dentate gyrus α5β3γ2 Hippocampus CA1 Tonic (-)ion Extrasynaptic, BZ-insensitive Sensory Ganglia α6β2/3γ2 Cerebellar granule cells Insensitive to agonist BZ α6β2/3δ Cerebellar granule cells Tonic (-)ion Extrasynaptic, BZ-insensitive, adult γ3, θ, ε Little information BZ, BDZs.GABA B or metabotropic G i (+) K + channels , \/Ca 2+ conductance.Presynaptic GABA B - autoreceptors, + heteroreceptors.Functional GABA B are heterodimers made up of GABA B R 1 & GABA B R 2 subunits (Bettler et al., 2004) GABA C narrow distributed cf A & B subtypes.GABA is potent by an order of magnitude at GABA C >> GABA A , & a no.
of GABA A agonists (e.g., baclofen) & modulators (e.g., BDZs & barbiturates) seem not to interact c GABA C . GABA C are found in retina, spinal cord, superior colliculus, & pituitary (Olsen & Betz, 2005).Glycine Many of features described for GABA A receptor family also apply to (-)ory glycine receptor, which is prominent in brainstem & spinal cord .Multiple subunits assemble into a variety of glycine receptor subtypes.These pharmacological subtypes are detected in brain tissue c particular neuroanatomical & neurodevelopmental profiles.~GABA A complete functional significance of glycine receptor subtypes is ?.There is evidence for clustering of glycine receptors by anchoring protein gephyrin (Sola et al., 2004).An additional role for glycine is as a must co-agonist at NMDA receptors.Glutamate & Aspartate h/\ /\ in brain, & both powerful excitatory effects on neurons in virtually every region of CNS.
Their widespread distribution initially obscured their roles as transmitters, but there now is broad acceptance that glu possibly asp are principal fast ("classical") excitatory transmitters throughout CNS (Bleich et al., 2003; Conn, 2003). Multiple subtypes of receptors for excitatory amino acids have been cloned, expressed, & characterized pharmacologically, OBO relative potencies of synthetic agonists & discovery of potent & selective antagonists (Kotecha & MacDonald, 2003).Glu receptors ligand-gated ion channel (" ionotropic ") or as " metabotropic " GPCRs (Table 14–3).
Table 14–3 Classification of Glutamate & Aspartate Receptors a FUNCTIONAL CLASSES GENE FAMILIES AGONISTS ANTAGONISTS Ionotropic AMPA GluR1, 2, 3, 4 AMPA CNQX Kainate NBQX (s) -5-fluorowillardine GYK153655 Kainate GluR5, 6, 7 Kainate CNQX KA1, 2 ATPA LY294486 NMDA NR1, 2A, 2B, 2C, 2D Aspartate D-AP5 NMDA 2R-CPPene MK-801 Ketamine Phencyclidine D-aspartate Metabotropic INTRACELLULAR SIGNALING Group 1 ~ dopamine mGluR1 3,5-DHPG, quisqalate AIDA ↑ G i -PLC-IP 3 -Ca 2+ mGluR5 CBPG Group2 ~ DA - 4 mGluR2 APDC, MGS0028 EGLU -↑ G i -AC (↓ cAMP) mGluR3 DCG-IV, LY354740 PCCG-4 Group3 mGluR4 L-Ap4 MAP4 ↑ G i -AC (↓ cAMP) mGluR6 L-AP4 MPPG mGluR7 L-AP4 LY341495 mGluR8 L-AP4, (S)-3,4-DCPG a Glutamate is principal agonist at both ionotropic & Metabotropic receptors for glutamate & aspartate.
CNQX, 6-Cyano-7-nitroquinoxaline-2,3-dione; NBQX, 1,2,3,4-Tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide; D-AP5, D-2-amino-5-phosphonovaleric acid; AIDA, 1-aminoindan-1,5-dicarboxylic acid; CBPG, (S)-(+)-2-(3'-carboxybicyclo(1.1.1)pentyl)-glycine; EGLU, (2S)-α-ethylglutamic acid; PCCG-4, phenylcarboxycyclopropylglycine; MAP4, (S)-amino-2-methyl-4-phosphonobutanoic acid; MPPG, (RS)-a-methyl-4-phosphonophenylglycine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, 2-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid; 3,5-DHPG, 3,5-dihydroxyphenylglycine; DCG-IV, dicarboxycyclopropyl)glycine; L-Ap4, L-2-amino-4-phosphonobutiric acid; (S)-3,4-DCPG, (S)-3,4-dicarboxyphenylglycine. Neither precise no.of subunits that assembles to generate a functional glutamate ionotropic receptor ion channel in vivo nor intramembranous topography of each subunit has been established unequivocally.
ligand-gated ion channels are further classified according to identity of agonists that selectively (+) each receptor subtype, & are broadly divided into NMDA & non-NMDA receptors. non-NMDA : α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), & kainic acid (KA) receptors (Table 14–3).Selective antagonists for these receptors are now available.In case of NMDA receptors, agonists : open-channel blockers e.g., phencyclidine (PCP or "angel dust"), antagonists e.g., 5,7-dichlorokynurenic acid, which act at an allosteric glycine-binding site, & novel antagonist ifenprodil, which may act as a closed-channel blocker.+ activity of NMDA receptors is sensitive to pH & to modulation by a variety of endogenous agents : Zn 2+ , some neurosteroids, arachidonic acid, redox reagents, & polyamines e.g.,spermine.Additional diversity of glutamate receptors arises by alternative splicing or by single-base editing of mRNAs encoding receptors or receptor subunits.
Alternative splicing has been described for metabotropic receptors & for subunits of NMDA, AMPA, & kainate receptors. For some subunits of AMPA & kainate receptors, RNA sequence differs from genomic sequence in a single codon of receptor subunit that markedly affects Ca 2+ permeability of receptor channel (Conn & Pin, 1997).AMPA & kainate receptors mediate fast depolarization at glutamatergic synapses in brain & spinal cord.NMDA receptors are involved in N synaptic transmission, but activation of NMDA receptors is usually ass.more closely c induction of various forms of synaptic plasticity rather than c fast point-to-point signaling in brain.AMPA or kainate receptors & NMDA receptors may be co-localized at many glutamatergic synapses.Activation of NMDA receptors is obligatory for induction of a type of long-term potentiation (LTP) that occurs in hippocampus.NMDA receptors Nly are blocked by Mg 2+ at RMP.
.`.activation of NMDA receptors requires not only binding of synaptically released glutamate, but simultaneous depolarization of postsynaptic membrane. This is achieved by activation of AMPA/kainate receptors at nearby synapses involving inputs from different neurons.AMPA receptors also are dynamically regulated to affect their sensitivity to synergism c NMDA.Thus, NMDA receptors may function as coincidence detectors, being activated only when there is simultaneous firing of > 2 neurons.A well-characterized phenomenon involving NMDA receptors is induction of LTP.LTP refers to a prolonged (hrs to days) /\ in size of a postsynaptic response to a presynaptic stimulus of given strength.NMDA receptors also can induce long-term depression (LTD; converse of LTP) at CNS synapses.nu & pattern of synaptic stimulation may dictate whether a synapse undergoes LTP or LTD (Nestler et al., 2009).
It is believed that NMDA-dependent LTP & LTD reflect insertion & internalization of AMPA receptors, possibly mediated have no muscarinic affinity & no appreciable anticholinergic effects, while clozapine & low-potency phenothiazines have significant anticholinergic adverse effects (Table 16–2). Quetiapine has modest muscarinic affinity, but its active metabolite norquetiapine is likely responsible for anticholinergic complaints (Jensen et al., 2008).Clozapine is particularly ass.c significant constipation, perhaps `.` severely ill population under Rx.Routine use of stool softeners, & repeated inquiry into bowel habits are necessary to prevent serious intestinal obstruction from undetected constipation.In general, avoidance of anticholinergic medications obviates need to secondarily treat problems related to central or peripheral antagonism.Medications c significant anticholinergic properties should be particularly avoided in elderly pts, especially those c dementia or delirium.
α 1 Receptors antagonism is ass. c risk of orthostatic hypotension & can be particularly problematic for elderly pts who have poor vasomotor tone.cf high-potency typical agents, low-potency typical agents have significantly greater affinities for α 1 receptors & greater risk for orthostasis.While risperidone has a K i that => greater α 1 -adrenergic affinity than chlorpromazine, thioridazine, clozapine, & quetiapine, in clinical practice risperidone is used at 0.01-0.005x dosages of these medications, & thus causes a relatively lower incidence of orthostasis in non-elderly pts.`.`clozapine-Rxd pts have few other antipsychotic options, potent mineralocorticoid fludrocortisone is sometimes tried at dose of 0.1 mg/day as a volume expander.
ADRs Not Predicted by Monoamine Receptor Affinities Adverse Metabolic Effects Such effects have become area of greatest concern during long-term antipsychotic Rx, lleling overall concern for high prevalence of pre - diabetic conditions & T2DM, & 2x /\ CVS mortality of schizophrenia pts (Meyer & Nasrallah, 2009). Aside from Wt gain, 2 predominant metabolic adverse seen c antipsychotic drugs are dyslipidemia , 1`ly elevated serum TAGs , & impairments in glycemic control.Low-potency phenothiazines were known to elevate serum TAG values, but this effect was not seen c high-potency agents (Meyer & Koro, 2004).As atypicals became more widely used, significant /\s in fasting TAG levels were noted during clozapine & olanzapine exposure, & to a lesser extent, c quetiapine (Meyer et al., 2008).Mean /\s during chronic Rx of 50-100 mg/dL are common, c serum TAG levels exceeding 7000 mg/dL in some pts.
c++ c++ if( x != 3) // i.e., if x not euual to 3 if(x== 3) // i.e., if x euual to 3 constructor : as soon as u create a object of th-A (Cases et al., 1995). Anxiety & Depression effects of 5-HT–active drugs in anxiety & depressive disorders, like effects of selective 5HT reuptake (-)ors (SSRIs), strongly =>a role for 5-HT in neurochemical mediation of these disorders.Mutant mice lacking 5-HT transporter display anxiety & a "depressive-like" phenotype (Fox et al., 2007).5-HT-related drugs c clinical effects in anxiety & depression have varied effects in classical animal models of these disorders, depending on experimental paradigm, species, & strain.For e.g., anxiolytic buspirone (chap 15), a partial agonist at 5-HT 1A receptors, doesnt reduce anxiety in classical approach-avoidance paradigms that were instrumental in development of anxiolytic benzodiazepines.However, buspirone & other 5-HT 1A receptor agonists are effective in other animal behavioral tests used to predict anxiolytic effects.
Furthermore, studies in 5-HT 1A knockout mice => a role for this receptor in anxiety, & possibly depression. Agonists of certain 5HTRs, including 5-HT 2A & 5-HT 2C (e.g., m -chlorophenylpiperazine), have anxiogenic properties in Lab animals & in human studies.lly, these receptors have been implicated in animal models of depression, e.g.,learned helplessness.An impressive finding in humans c depression is abrupt reversal of antidepressant effects of drugs e.g., SSRIs by manipulations that rapidly \/ 5-HT in brain.e.g., p -chlorophenylalanine or a tryptophan-free drink c /\ /\ neutral AAs (Delgado et al., 1990).Curiously, this kind of 5-HT depletion hasn't been shown to worsen or to induce depression in nondepressed subjects, => that continued presence of 5-HT is required to maintain effects of these drugs.This clinical finding adds credence to somewhat less convincing neurochemical findings that suggest a role for 5-HT in pathogenesis of depression.
Pharmacological Manipulation of Amount of 5-HT in Tissues A highly specific mechanism for altering synaptic availability of 5-HTe neurons & their targets in Deiter's nucleus; b/w small interneurons & major output cells of cerebellar cortex, olfactory bulb, cuneate nucleus, hippocampus, & lateral septal nucleus; & b/w vestibular nucleus & trochlear motoneurons. cin cerebral cortex & b/w caudate nucleus & substantia nigra.GABA-containing neurons & nerve terminals have been localized c immunocytochemical methods that visualize glutamic acid decarboxylase or by in situ hybridization of mRNA for this protein.GABA-containing neurons frequently co-express > 1 neuropeptides.most useful compounds for confirmation of GABA-mediated effects have been bicuculline & picrotoxin (Figre 14–10); however, many convulsants whose actions previously were unexplained (including penicillin & pentylenetetrazol ) are relatively selective antagonists of GABA.
Useful therapeutic effects have not yet been obtained through use of agents that mimic GABA (such as muscimol ), (-) its active reuptake (such as 2,4-diaminobutyrate, nipecotic acid, & guvacine ), or alter its turnover (such as aminooxyacetic acid ). Figre 14–10.Amino acid transmitters & congeners.GABA receptors have been divided into 3 main types: A, B, & C.most prominent-GABA A .a ligand-gated Cl – ion channel, an "ionotropic receptor." GABA B - GPCR.GABA C - transmitter-gated Cl – channel.GABA A receptor subunit proteins have been well characterized `.`their abundance.receptor also has been extensively characterized as site of action of many neuroactive drugs, notably BDZs, barbiturates, ethanol, anesthetic steroids, & volatile anesthetics (Figre 14–11).Figre 14–11.Pharmacologic binding sites on GABA A Based on sequence homology to 1st reported GABA A subunit cDNAs, multiple subunits have been cloned, including 6α, 4β, & 3γ subunits - seperate genes.
They appear to be expressed in multiple multimeric, pharmacologically distinctive combinations. + splice variants for several subunits have been described.GABA A is probably penta / tetrameric c subunits that assemble together around a central pore typical for other ionotropic receptors.major form of GABA A receptor contains at least 3 different subunits α, β, & γ, c likely stoichiometry of 2α, 2β, 1γ.All 3 subunits are required to interact c BDZs c profile expected of a native GABA A receptor.Table 14–2 (Fritschy & Mohler, 1995).Table 14–2 Composition, Distribution, & Major Functions of GABA A Receptors SUBUNIT COMPOSITION LOCATION FUNCTION COMMENTS α1β2γ2 Widespread GABA Neurons Sedation, anticonvulsant activity Adult, BZ-sensitive, \/d in drug tolerance?
α2β3γ2 Forebrain, spinal cord Anxiety, muscle relaxant Axon hillock in some cells, BZ- sensitive α2β1γ1 Glia α3β3γ2 Cortex Anticonvulsant activity Embryonic & adult BZ- sensitive α4β2γ2 Thalamus Insensitive to agonist BZ α4β2/3γ2 Dentate gyrus /\d in drug cdrawal? α4β2δ Thalamus Tonic (-)ion Extrasynaptic, BZ-insensitive in adults α4β2/3δ Dentate gyrus α5β3γ2 Hippocampus CA1 Tonic (-)ion Extrasynaptic, BZ-insensitive Sensory Ganglia α6β2/3γ2 Cerebellar granule cells Insensitive to agonist BZ α6β2/3δ Cerebellar granule cells Tonic (-)ion Extrasynaptic, BZ-insensitive, adult γ3, θ, ε Little information BZ, BDZs.GABA B or metabotropic G i (+) K + channels , \/Ca 2+ conductance.Presynaptic GABA B - autoreceptors, + heteroreceptors.Functional GABA B are heterodimers made up of GABA B R 1 & GABA B R 2 subunits (Bettler et al., 2004) GABA C narrow distributed cf A & B subtypes.GABA is potent by an order of magnitude at GABA C >> GABA A , & a no.
of GABA A agonists (e.g., baclofen) & modulators (e.g., BDZs & barbiturates) seem not to interact c GABA C . GABA C are found in retina, spinal cord, superior colliculus, & pituitary (Olsen & Betz, 2005).Glycine Many of features described for GABA A receptor family also apply to (-)ory glycine receptor, which is prominent in brainstem & spinal cord .Multiple subunits assemble into a variety of glycine receptor subtypes.These pharmacological subtypes are detected in brain tissue c particular neuroanatomical & neurodevelopmental profiles.~GABA A complete functional significance of glycine receptor subtypes is ?.There is evidence for clustering of glycine receptors by anchoring protein gephyrin (Sola et al., 2004).An additional role for glycine is as a must co-agonist at NMDA receptors.Glutamate & Aspartate h/\ /\ in brain, & both powerful excitatory effects on neurons in virtually every region of CNS.
Their widespread distribution initially obscured their roles as transmitters, but there now is broad acceptance that glu possibly asp are principal fast ("classical") excitatory transmitters throughout CNS (Bleich et al., 2003; Conn, 2003). Multiple subtypes of receptors for excitatory amino acids have been cloned, expressed, & characterized pharmacologically, OBO relative potencies of synthetic agonists & discovery of potent & selective antagonists (Kotecha & MacDonald, 2003).Glu receptors ligand-gated ion channel (" ionotropic ") or as " metabotropic " GPCRs (Table 14–3).
Table 14–3 Classification of Glutamate & Aspartate Receptors a FUNCTIONAL CLASSES GENE FAMILIES AGONISTS ANTAGONISTS Ionotropic AMPA GluR1, 2, 3, 4 AMPA CNQX Kainate NBQX (s) -5-fluorowillardine GYK153655 Kainate GluR5, 6, 7 Kainate CNQX KA1, 2 ATPA LY294486 NMDA NR1, 2A, 2B, 2C, 2D Aspartate D-AP5 NMDA 2R-CPPene MK-801 Ketamine Phencyclidine D-aspartate Metabotropic INTRACELLULAR SIGNALING Group 1 ~ dopamine mGluR1 3,5-DHPG, quisqalate AIDA ↑ G i -PLC-IP 3 -Ca 2+ mGluR5 CBPG Group2 ~ DA - 4 mGluR2 APDC, MGS0028 EGLU -↑ G i -AC (↓ cAMP) mGluR3 DCG-IV, LY354740 PCCG-4 Group3 mGluR4 L-Ap4 MAP4 ↑ G i -AC (↓ cAMP) mGluR6 L-AP4 MPPG mGluR7 L-AP4 LY341495 mGluR8 L-AP4, (S)-3,4-DCPG a Glutamate is principal agonist at both ionotropic & Metabotropic receptors for glutamate & aspartate.
CNQX, 6-Cyano-7-nitroquinoxaline-2,3-dione; NBQX, 1,2,3,4-Tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide; D-AP5, D-2-amino-5-phosphonovaleric acid; AIDA, 1-aminoindan-1,5-dicarboxylic acid; CBPG, (S)-(+)-2-(3'-carboxybicyclo(1.1.1)pentyl)-glycine; EGLU, (2S)-α-ethylglutamic acid; PCCG-4, phenylcarboxycyclopropylglycine; MAP4, (S)-amino-2-methyl-4-phosphonobutanoic acid; MPPG, (RS)-a-methyl-4-phosphonophenylglycine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, 2-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid; 3,5-DHPG, 3,5-dihydroxyphenylglycine; DCG-IV, dicarboxycyclopropyl)glycine; L-Ap4, L-2-amino-4-phosphonobutiric acid; (S)-3,4-DCPG, (S)-3,4-dicarboxyphenylglycine. Neither precise no.of subunits that assembles to generate a functional glutamate ionotropic receptor ion channel in vivo nor intramembranous topography of each subunit has been established unequivocally.
ligand-gated ion channels are further classified according to identity of agonists that selectively (+) each receptor subtype, & are broadly divided into NMDA & non-NMDA receptors. non-NMDA : α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), & kainic acid (KA) receptors (Table 14–3).Selective antagonists for these receptors are now available.In case of NMDA receptors, agonists : open-channel blockers e.g., phencyclidine (PCP or "angel dust"), antagonists e.g., 5,7-dichlorokynurenic acid, which act at an allosteric glycine-binding site, & novel antagonist ifenprodil, which may act as a closed-channel blocker.+ activity of NMDA receptors is sensitive to pH & to modulation by a variety of endogenous agents : Zn 2+ , some neurosteroids, arachidonic acid, redox reagents, & polyamines e.g.,spermine.Additional diversity of glutamate receptors arises by alternative splicing or by single-base editing of mRNAs encoding receptors or receptor subunits.
Alternative splicing has been described for metabotropic receptors & for subunits of NMDA, AMPA, & kainate receptors. For some subunits of AMPA & kainate receptors, RNA sequence differs from genomic sequence in a single codon of receptor subunit that markedly affects Ca 2+ permeability of receptor channel (Conn & Pin, 1997).AMPA & kainate receptors mediate fast depolarization at glutamatergic synapses in brain & spinal cord.NMDA receptors are involved in N synaptic transmission, but activation of NMDA receptors is usually ass.more closely c induction of various forms of synaptic plasticity rather than c fast point-to-point signaling in brain.AMPA or kainate receptors & NMDA receptors may be co-localized at many glutamatergic synapses.Activation of NMDA receptors is obligatory for induction of a type of long-term potentiation (LTP) that occurs in hippocampus.NMDA receptors Nly are blocked by Mg 2+ at RMP.
.`.activation of NMDA receptors requires not only binding of synaptically released glutamate, but simultaneous depolarization of postsynaptic membrane. This is achieved by activation of AMPA/kainate receptors at nearby synapses involving inputs from different neurons.AMPA receptors also are dynamically regulated to affect their sensitivity to synergism c NMDA.Thus, NMDA receptors may function as coincidence detectors, being activated only when there is simultaneous firing of > 2 neurons.A well-characterized phenomenon involving NMDA receptors is induction of LTP.LTP refers to a prolonged (hrs to days) /\ in size of a postsynaptic response to a presynaptic stimulus of given strength.NMDA receptors also can induce long-term depression (LTD; converse of LTP) at CNS synapses.nu & pattern of synaptic stimulation may dictate whether a synapse undergoes LTP or LTD (Nestler et al., 2009).
It is believed that NMDA-dependent LTP & LTD reflect insertion & internalization of AMPA receptors, possibly mediated have no muscarinic affinity & no appreciable anticholinergic effects, while clozapine & low-potency phenothiazines have significant anticholinergic adverse effects (Table 16–2). Quetiapine has modest muscarinic affinity, but its active metabolite norquetiapine is likely responsible for anticholinergic complaints (Jensen et al., 2008).Clozapine is particularly ass.c significant constipation, perhaps `.` severely ill population under Rx.Routine use of stool softeners, & repeated inquiry into bowel habits are necessary to prevent serious intestinal obstruction from undetected constipation.In general, avoidance of anticholinergic medications obviates need to secondarily treat problems related to central or peripheral antagonism.Medications c significant anticholinergic properties should be particularly avoided in elderly pts, especially those c dementia or delirium.
ADRs Not Predicted by Monoamine Receptor Affinities Adverse Metabolic Effects Such effects have become area of greatest concern during long-term antipsychotic Rx, lleling overall concern for high prevalence of pre - diabetic conditions & T2DM, & 2x /\ CVS mortality of schizophrenia pts (Meyer & Nasrallah, 2009). Aside from Wt gain, 2 predominant metabolic adverse seen c antipsychotic drugs are dyslipidemia , 1`ly elevated serum TAGs , & impairments in glycemic control.Low-potency phenothiazines were known to elevate serum TAG values, but this effect was not seen c high-potency agents (Meyer & Koro, 2004).As atypicals became more widely used, significant /\s in fasting TAG levels were noted during clozapine & olanzapine exposure, & to a lesser extent, c quetiapine (Meyer et al., 2008).Mean /\s during chronic Rx of 50-100 mg/dL are common, c serum TAG levels exceeding 7000 mg/dL in some pts.
Their widespread distribution initially obscured their roles as transmitters, but there now is broad acceptance that glu possibly asp are principal fast ("classical") excitatory transmitters throughout CNS (Bleich et al., 2003; Conn, 2003). Multiple subtypes of receptors for excitatory amino acids have been cloned, expressed, & characterized pharmacologically, OBO relative potencies of synthetic agonists & discovery of potent & selective antagonists (Kotecha & MacDonald, 2003).Glu receptors ligand-gated ion channel (" ionotropic ") or as " metabotropic " GPCRs (Table 14–3).
Table 14–3 Classification of Glutamate & Aspartate Receptors a FUNCTIONAL CLASSES GENE FAMILIES AGONISTS ANTAGONISTS Ionotropic AMPA GluR1, 2, 3, 4 AMPA CNQX Kainate NBQX (s) -5-fluorowillardine GYK153655 Kainate GluR5, 6, 7 Kainate CNQX KA1, 2 ATPA LY294486 NMDA NR1, 2A, 2B, 2C, 2D Aspartate D-AP5 NMDA 2R-CPPene MK-801 Ketamine Phencyclidine D-aspartate Metabotropic INTRACELLULAR SIGNALING Group 1 ~ dopamine mGluR1 3,5-DHPG, quisqalate AIDA ↑ G i -PLC-IP 3 -Ca 2+ mGluR5 CBPG Group2 ~ DA - 4 mGluR2 APDC, MGS0028 EGLU -↑ G i -AC (↓ cAMP) mGluR3 DCG-IV, LY354740 PCCG-4 Group3 mGluR4 L-Ap4 MAP4 ↑ G i -AC (↓ cAMP) mGluR6 L-AP4 MPPG mGluR7 L-AP4 LY341495 mGluR8 L-AP4, (S)-3,4-DCPG a Glutamate is principal agonist at both ionotropic & Metabotropic receptors for glutamate & aspartate.
CNQX, 6-Cyano-7-nitroquinoxaline-2,3-dione; NBQX, 1,2,3,4-Tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide; D-AP5, D-2-amino-5-phosphonovaleric acid; AIDA, 1-aminoindan-1,5-dicarboxylic acid; CBPG, (S)-(+)-2-(3'-carboxybicyclo(1.1.1)pentyl)-glycine; EGLU, (2S)-α-ethylglutamic acid; PCCG-4, phenylcarboxycyclopropylglycine; MAP4, (S)-amino-2-methyl-4-phosphonobutanoic acid; MPPG, (RS)-a-methyl-4-phosphonophenylglycine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, 2-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid; 3,5-DHPG, 3,5-dihydroxyphenylglycine; DCG-IV, dicarboxycyclopropyl)glycine; L-Ap4, L-2-amino-4-phosphonobutiric acid; (S)-3,4-DCPG, (S)-3,4-dicarboxyphenylglycine. Neither precise no.of subunits that assembles to generate a functional glutamate ionotropic receptor ion channel in vivo nor intramembranous topography of each subunit has been established unequivocally.
ligand-gated ion channels are further classified according to identity of agonists that selectively (+) each receptor subtype, & are broadly divided into NMDA & non-NMDA receptors. non-NMDA : α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), & kainic acid (KA) receptors (Table 14–3).Selective antagonists for these receptors are now available.In case of NMDA receptors, agonists : open-channel blockers e.g., phencyclidine (PCP or "angel dust"), antagonists e.g., 5,7-dichlorokynurenic acid, which act at an allosteric glycine-binding site, & novel antagonist ifenprodil, which may act as a closed-channel blocker.+ activity of NMDA receptors is sensitive to pH & to modulation by a variety of endogenous agents : Zn 2+ , some neurosteroids, arachidonic acid, redox reagents, & polyamines e.g.,spermine.Additional diversity of glutamate receptors arises by alternative splicing or by single-base editing of mRNAs encoding receptors or receptor subunits.
Alternative splicing has been described for metabotropic receptors & for subunits of NMDA, AMPA, & kainate receptors. For some subunits of AMPA & kainate receptors, RNA sequence differs from genomic sequence in a single codon of receptor subunit that markedly affects Ca 2+ permeability of receptor channel (Conn & Pin, 1997).AMPA & kainate receptors mediate fast depolarization at glutamatergic synapses in brain & spinal cord.NMDA receptors are involved in N synaptic transmission, but activation of NMDA receptors is usually ass.more closely c induction of various forms of synaptic plasticity rather than c fast point-to-point signaling in brain.AMPA or kainate receptors & NMDA receptors may be co-localized at many glutamatergic synapses.Activation of NMDA receptors is obligatory for induction of a type of long-term potentiation (LTP) that occurs in hippocampus.NMDA receptors Nly are blocked by Mg 2+ at RMP.
.`.activation of NMDA receptors requires not only binding of synaptically released glutamate, but simultaneous depolarization of postsynaptic membrane. This is achieved by activation of AMPA/kainate receptors at nearby synapses involving inputs from different neurons.AMPA receptors also are dynamically regulated to affect their sensitivity to synergism c NMDA.Thus, NMDA receptors may function as coincidence detectors, being activated only when there is simultaneous firing of > 2 neurons.A well-characterized phenomenon involving NMDA receptors is induction of LTP.LTP refers to a prolonged (hrs to days) /\ in size of a postsynaptic response to a presynaptic stimulus of given strength.NMDA receptors also can induce long-term depression (LTD; converse of LTP) at CNS synapses.nu & pattern of synaptic stimulation may dictate whether a synapse undergoes LTP or LTD (Nestler et al., 2009).
It is believed that NMDA-dependent LTP & LTD reflect insertion & internalization of AMPA receptors, possibly mediated have no muscarinic affinity & no appreciable anticholinergic effects, while clozapine & low-potency phenothiazines have significant anticholinergic adverse effects (Table 16–2). Quetiapine has modest muscarinic affinity, but its active metabolite norquetiapine is likely responsible for anticholinergic complaints (Jensen et al., 2008).Clozapine is particularly ass.c significant constipation, perhaps `.` severely ill population under Rx.Routine use of stool softeners, & repeated inquiry into bowel habits are necessary to prevent serious intestinal obstruction from undetected constipation.In general, avoidance of anticholinergic medications obviates need to secondarily treat problems related to central or peripheral antagonism.Medications c significant anticholinergic properties should be particularly avoided in elderly pts, especially those c dementia or delirium.
α 1 Receptors antagonism is ass. c risk of orthostatic hypotension & can be particularly problematic for elderly pts who have poor vasomotor tone.cf high-potency typical agents, low-potency typical agents have significantly greater affinities for α 1 receptors & greater risk for orthostasis.While risperidone has a K i that => greater α 1 -adrenergic affinity than chlorpromazine, thioridazine, clozapine, & quetiapine, in clinical practice risperidone is used at 0.01-0.005x dosages of these medications, & thus causes a relatively lower incidence of orthostasis in non-elderly pts.`.`clozapine-Rxd pts have few other antipsychotic options, potent mineralocorticoid fludrocortisone is sometimes tried at dose of 0.1 mg/day as a volume expander.
ADRs Not Predicted by Monoamine Receptor Affinities Adverse Metabolic Effects Such effects have become area of greatest concern during long-term antipsychotic Rx, lleling overall concern for high prevalence of pre - diabetic conditions & T2DM, & 2x /\ CVS mortality of schizophrenia pts (Meyer & Nasrallah, 2009). Aside from Wt gain, 2 predominant metabolic adverse seen c antipsychotic drugs are dyslipidemia , 1`ly elevated serum TAGs , & impairments in glycemic control.Low-potency phenothiazines were known to elevate serum TAG values, but this effect was not seen c high-potency agents (Meyer & Koro, 2004).As atypicals became more widely used, significant /\s in fasting TAG levels were noted during clozapine & olanzapine exposure, & to a lesser extent, c quetiapine (Meyer et al., 2008).Mean /\s during chronic Rx of 50-100 mg/dL are common, c serum TAG levels exceeding 7000 mg/dL in some pts.
c++ c++ if( x != 3) // i.e., if x not euual to 3 if(x== 3) // i.e., if x euual to 3 constructor : as soon as u create a object of th-A (Cases et al., 1995). Anxiety & Depression effects of 5-HT–active drugs in anxiety & depressive disorders, like effects of selective 5HT reuptake (-)ors (SSRIs), strongly =>a role for 5-HT in neurochemical mediation of these disorders.Mutant mice lacking 5-HT transporter display anxiety & a "depressive-like" phenotype (Fox et al., 2007).5-HT-related drugs c clinical effects in anxiety & depression have varied effects in classical animal models of these disorders, depending on experimental paradigm, species, & strain.For e.g., anxiolytic buspirone (chap 15), a partial agonist at 5-HT 1A receptors, doesnt reduce anxiety in classical approach-avoidance paradigms that were instrumental in development of anxiolytic benzodiazepines.However, buspirone & other 5-HT 1A receptor agonists are effective in other animal behavioral tests used to predict anxiolytic effects.
Furthermore, studies in 5-HT 1A knockout mice => a role for this receptor in anxiety, & possibly depression. Agonists of certain 5HTRs, including 5-HT 2A & 5-HT 2C (e.g., m -chlorophenylpiperazine), have anxiogenic properties in Lab animals & in human studies.lly, these receptors have been implicated in animal models of depression, e.g.,learned helplessness.An impressive finding in humans c depression is abrupt reversal of antidepressant effects of drugs e.g., SSRIs by manipulations that rapidly \/ 5-HT in brain.e.g., p -chlorophenylalanine or a tryptophan-free drink c /\ /\ neutral AAs (Delgado et al., 1990).Curiously, this kind of 5-HT depletion hasn't been shown to worsen or to induce depression in nondepressed subjects, => that continued presence of 5-HT is required to maintain effects of these drugs.This clinical finding adds credence to somewhat less convincing neurochemical findings that suggest a role for 5-HT in pathogenesis of depression.
Pharmacological Manipulation of Amount of 5-HT in Tissues A highly specific mechanism for altering synaptic availability of 5-HTe neurons & their targets in Deiter's nucleus; b/w small interneurons & major output cells of cerebellar cortex, olfactory bulb, cuneate nucleus, hippocampus, & lateral septal nucleus; & b/w vestibular nucleus & trochlear motoneurons. cin cerebral cortex & b/w caudate nucleus & substantia nigra.GABA-containing neurons & nerve terminals have been localized c immunocytochemical methods that visualize glutamic acid decarboxylase or by in situ hybridization of mRNA for this protein.GABA-containing neurons frequently co-express > 1 neuropeptides.most useful compounds for confirmation of GABA-mediated effects have been bicuculline & picrotoxin (Figre 14–10); however, many convulsants whose actions previously were unexplained (including penicillin & pentylenetetrazol ) are relatively selective antagonists of GABA.
Useful therapeutic effects have not yet been obtained through use of agents that mimic GABA (such as muscimol ), (-) its active reuptake (such as 2,4-diaminobutyrate, nipecotic acid, & guvacine ), or alter its turnover (such as aminooxyacetic acid ). Figre 14–10.Amino acid transmitters & congeners.GABA receptors have been divided into 3 main types: A, B, & C.most prominent-GABA A .a ligand-gated Cl – ion channel, an "ionotropic receptor." GABA B - GPCR.GABA C - transmitter-gated Cl – channel.GABA A receptor subunit proteins have been well characterized `.`their abundance.receptor also has been extensively characterized as site of action of many neuroactive drugs, notably BDZs, barbiturates, ethanol, anesthetic steroids, & volatile anesthetics (Figre 14–11).Figre 14–11.Pharmacologic binding sites on GABA A Based on sequence homology to 1st reported GABA A subunit cDNAs, multiple subunits have been cloned, including 6α, 4β, & 3γ subunits - seperate genes.
They appear to be expressed in multiple multimeric, pharmacologically distinctive combinations. + splice variants for several subunits have been described.GABA A is probably penta / tetrameric c subunits that assemble together around a central pore typical for other ionotropic receptors.major form of GABA A receptor contains at least 3 different subunits α, β, & γ, c likely stoichiometry of 2α, 2β, 1γ.All 3 subunits are required to interact c BDZs c profile expected of a native GABA A receptor.Table 14–2 (Fritschy & Mohler, 1995).Table 14–2 Composition, Distribution, & Major Functions of GABA A Receptors SUBUNIT COMPOSITION LOCATION FUNCTION COMMENTS α1β2γ2 Widespread GABA Neurons Sedation, anticonvulsant activity Adult, BZ-sensitive, \/d in drug tolerance?
α2β3γ2 Forebrain, spinal cord Anxiety, muscle relaxant Axon hillock in some cells, BZ- sensitive α2β1γ1 Glia α3β3γ2 Cortex Anticonvulsant activity Embryonic & adult BZ- sensitive α4β2γ2 Thalamus Insensitive to agonist BZ α4β2/3γ2 Dentate gyrus /\d in drug cdrawal? α4β2δ Thalamus Tonic (-)ion Extrasynaptic, BZ-insensitive in adults α4β2/3δ Dentate gyrus α5β3γ2 Hippocampus CA1 Tonic (-)ion Extrasynaptic, BZ-insensitive Sensory Ganglia α6β2/3γ2 Cerebellar granule cells Insensitive to agonist BZ α6β2/3δ Cerebellar granule cells Tonic (-)ion Extrasynaptic, BZ-insensitive, adult γ3, θ, ε Little information BZ, BDZs.GABA B or metabotropic G i (+) K + channels , \/Ca 2+ conductance.Presynaptic GABA B - autoreceptors, + heteroreceptors.Functional GABA B are heterodimers made up of GABA B R 1 & GABA B R 2 subunits (Bettler et al., 2004) GABA C narrow distributed cf A & B subtypes.GABA is potent by an order of magnitude at GABA C >> GABA A , & a no.
of GABA A agonists (e.g., baclofen) & modulators (e.g., BDZs & barbiturates) seem not to interact c GABA C . GABA C are found in retina, spinal cord, superior colliculus, & pituitary (Olsen & Betz, 2005).Glycine Many of features described for GABA A receptor family also apply to (-)ory glycine receptor, which is prominent in brainstem & spinal cord .Multiple subunits assemble into a variety of glycine receptor subtypes.These pharmacological subtypes are detected in brain tissue c particular neuroanatomical & neurodevelopmental profiles.~GABA A complete functional significance of glycine receptor subtypes is ?.There is evidence for clustering of glycine receptors by anchoring protein gephyrin (Sola et al., 2004).An additional role for glycine is as a must co-agonist at NMDA receptors.Glutamate & Aspartate h/\ /\ in brain, & both powerful excitatory effects on neurons in virtually every region of CNS.
Their widespread distribution initially obscured their roles as transmitters, but there now is broad acceptance that glu possibly asp are principal fast ("classical") excitatory transmitters throughout CNS (Bleich et al., 2003; Conn, 2003). Multiple subtypes of receptors for excitatory amino acids have been cloned, expressed, & characterized pharmacologically, OBO relative potencies of synthetic agonists & discovery of potent & selective antagonists (Kotecha & MacDonald, 2003).Glu receptors ligand-gated ion channel (" ionotropic ") or as " metabotropic " GPCRs (Table 14–3).
Table 14–3 Classification of Glutamate & Aspartate Receptors a FUNCTIONAL CLASSES GENE FAMILIES AGONISTS ANTAGONISTS Ionotropic AMPA GluR1, 2, 3, 4 AMPA CNQX Kainate NBQX (s) -5-fluorowillardine GYK153655 Kainate GluR5, 6, 7 Kainate CNQX KA1, 2 ATPA LY294486 NMDA NR1, 2A, 2B, 2C, 2D Aspartate D-AP5 NMDA 2R-CPPene MK-801 Ketamine Phencyclidine D-aspartate Metabotropic INTRACELLULAR SIGNALING Group 1 ~ dopamine mGluR1 3,5-DHPG, quisqalate AIDA ↑ G i -PLC-IP 3 -Ca 2+ mGluR5 CBPG Group2 ~ DA - 4 mGluR2 APDC, MGS0028 EGLU -↑ G i -AC (↓ cAMP) mGluR3 DCG-IV, LY354740 PCCG-4 Group3 mGluR4 L-Ap4 MAP4 ↑ G i -AC (↓ cAMP) mGluR6 L-AP4 MPPG mGluR7 L-AP4 LY341495 mGluR8 L-AP4, (S)-3,4-DCPG a Glutamate is principal agonist at both ionotropic & Metabotropic receptors for glutamate & aspartate.
CNQX, 6-Cyano-7-nitroquinoxaline-2,3-dione; NBQX, 1,2,3,4-Tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide; D-AP5, D-2-amino-5-phosphonovaleric acid; AIDA, 1-aminoindan-1,5-dicarboxylic acid; CBPG, (S)-(+)-2-(3'-carboxybicyclo(1.1.1)pentyl)-glycine; EGLU, (2S)-α-ethylglutamic acid; PCCG-4, phenylcarboxycyclopropylglycine; MAP4, (S)-amino-2-methyl-4-phosphonobutanoic acid; MPPG, (RS)-a-methyl-4-phosphonophenylglycine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, 2-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid; 3,5-DHPG, 3,5-dihydroxyphenylglycine; DCG-IV, dicarboxycyclopropyl)glycine; L-Ap4, L-2-amino-4-phosphonobutiric acid; (S)-3,4-DCPG, (S)-3,4-dicarboxyphenylglycine. Neither precise no.of subunits that assembles to generate a functional glutamate ionotropic receptor ion channel in vivo nor intramembranous topography of each subunit has been established unequivocally.
ligand-gated ion channels are further classified according to identity of agonists that selectively (+) each receptor subtype, & are broadly divided into NMDA & non-NMDA receptors. non-NMDA : α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), & kainic acid (KA) receptors (Table 14–3).Selective antagonists for these receptors are now available.In case of NMDA receptors, agonists : open-channel blockers e.g., phencyclidine (PCP or "angel dust"), antagonists e.g., 5,7-dichlorokynurenic acid, which act at an allosteric glycine-binding site, & novel antagonist ifenprodil, which may act as a closed-channel blocker.+ activity of NMDA receptors is sensitive to pH & to modulation by a variety of endogenous agents : Zn 2+ , some neurosteroids, arachidonic acid, redox reagents, & polyamines e.g.,spermine.Additional diversity of glutamate receptors arises by alternative splicing or by single-base editing of mRNAs encoding receptors or receptor subunits.
Alternative splicing has been described for metabotropic receptors & for subunits of NMDA, AMPA, & kainate receptors. For some subunits of AMPA & kainate receptors, RNA sequence differs from genomic sequence in a single codon of receptor subunit that markedly affects Ca 2+ permeability of receptor channel (Conn & Pin, 1997).AMPA & kainate receptors mediate fast depolarization at glutamatergic synapses in brain & spinal cord.NMDA receptors are involved in N synaptic transmission, but activation of NMDA receptors is usually ass.more closely c induction of various forms of synaptic plasticity rather than c fast point-to-point signaling in brain.AMPA or kainate receptors & NMDA receptors may be co-localized at many glutamatergic synapses.Activation of NMDA receptors is obligatory for induction of a type of long-term potentiation (LTP) that occurs in hippocampus.NMDA receptors Nly are blocked by Mg 2+ at RMP.
.`.activation of NMDA receptors requires not only binding of synaptically released glutamate, but simultaneous depolarization of postsynaptic membrane. This is achieved by activation of AMPA/kainate receptors at nearby synapses involving inputs from different neurons.AMPA receptors also are dynamically regulated to affect their sensitivity to synergism c NMDA.Thus, NMDA receptors may function as coincidence detectors, being activated only when there is simultaneous firing of > 2 neurons.A well-characterized phenomenon involving NMDA receptors is induction of LTP.LTP refers to a prolonged (hrs to days) /\ in size of a postsynaptic response to a presynaptic stimulus of given strength.NMDA receptors also can induce long-term depression (LTD; converse of LTP) at CNS synapses.nu & pattern of synaptic stimulation may dictate whether a synapse undergoes LTP or LTD (Nestler et al., 2009).
It is believed that NMDA-dependent LTP & LTD reflect insertion & internalization of AMPA receptors, possibly mediated have no muscarinic affinity & no appreciable anticholinergic effects, while clozapine & low-potency phenothiazines have significant anticholinergic adverse effects (Table 16–2). Quetiapine has modest muscarinic affinity, but its active metabolite norquetiapine is likely responsible for anticholinergic complaints (Jensen et al., 2008).Clozapine is particularly ass.c significant constipation, perhaps `.` severely ill population under Rx.Routine use of stool softeners, & repeated inquiry into bowel habits are necessary to prevent serious intestinal obstruction from undetected constipation.In general, avoidance of anticholinergic medications obviates need to secondarily treat problems related to central or peripheral antagonism. Medications c significant anticholinergic properties should be particularly avoided in elderly pts, especially those c dementia or delirium.
ADRs Not Predicted by Monoamine Receptor Affinities Adverse Metabolic Effects Such effects have become area of greatest concern during long-term antipsychotic Rx, lleling overall concern for high prevalence of pre - diabetic conditions & T2DM, & 2x /\ CVS mortality of schizophrenia pts (Meyer & Nasrallah, 2009). Aside from Wt gain, 2 predominant metabolic adverse seen c antipsychotic drugs are dyslipidemia , 1`ly elevated serum TAGs , & impairments in glycemic control.Low-potency phenothiazines were known to elevate serum TAG values, but this effect was not seen c high-potency agents (Meyer & Koro, 2004).As atypicals became more widely used, significant /\s in fasting TAG levels were noted during clozapine & olanzapine exposure, & to a lesser extent, c quetiapine (Meyer et al., 2008).Mean /\s during chronic Rx of 50-100 mg/dL are common, c serum TAG levels exceeding 7000 mg/dL in some pts.