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Neurobiol Addict Drugs

by: Mrs. Sierra Bailey

Neurobiol Addict Drugs NPB 168

Mrs. Sierra Bailey
GPA 3.85

Lauren Liets

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Lauren Liets
Class Notes
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Popular in Neurobiology,Physio & Behavior

This 19 page Class Notes was uploaded by Mrs. Sierra Bailey on Tuesday September 8, 2015. The Class Notes belongs to NPB 168 at University of California - Davis taught by Lauren Liets in Fall. Since its upload, it has received 67 views. For similar materials see /class/191812/npb-168-university-of-california-davis in Neurobiology,Physio & Behavior at University of California - Davis.


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Date Created: 09/08/15
LEQIJIRELDALQ pharmokinetics the study ofthe movement of drugs through the body kinetics looking at time course of drug action like the onset and duration com onents of pathway through drugs route of administration absorption distribution targeteffect metabolism elimination routes of administration 1nasal insuf ation 2rectal suppository 3 transdermal ex patch 4 sublingual highly vascularized 5 injections intravenous into veins fast and effective subcutaneous under skin absorption dependent on degree of local tissues muscular into muscles highly vascularized 6oral pillsliquids membrane properties lipid bilayer gt lipophilic can pass thru membrane hydrophilic cannot oilpartition coefficient gt determines how fact a substance will cross a membrane most rec drugs are lipophilic Ncgmivcly charged region degree of ionization at different pH39s for acids and bases 39 more lipophilic at low pH bases more lipophilic at high pH A Wb39r f B PA FW53905 Q 9A FL QLEH IGH L F A CD r1 FoaN I 5 DLSBal Ari ED absorption in GI tract gradient is maintained because of rapid blood ow most of drug will be absorbed in small intestine because of length aspirin is a weak acid not all drugs can tolerate stomach pH eX insulin l Nonionized Nowionizcd 1 66 EL I 4 omng all Nit 0mm Ionized Stomach pH 2 0 G Noanoni zed m1 omen Ill J Ionized lntesli39ne pH 55 i u Nahum drugdist Via heart and circulatory system iV injection will go to pulmonary system before target tissues smoking smoking and iV injections are fastest but iV is the fastest the brain is only about 12 ofbody mass but takes 13 ofblood depot binding tissues take up drug and release it at diff times but the drug will not affect the tissue 1 slow onset 2 prolong effect 3 prevent activity 4 roduce quick termination of effect P blood brain barrier rareapostrema tests the blood s content has typical capillaries A Typical capillary B Brain capillary Cell nucleus Cull nucleus LipidNubia Fndmhelial lmnspnri Veil Endmheiiai m End loot m ash llcytc Fen9rainn A rrelationship between mother and fetus blood rclose appos ion ofblood rpermeability similar to rest ofbody passive diffusion rsimilar drug concentrations halflilc 39 39 J 39 J by half defined by two curves rdistribution elimination rgt exponential I LFE Disuibuuon phm z h 9 N 01 0 6 17 is 24 T urs39l time course of drug clearance drugs leaving body rhalflife can help determine which drug to prescribe for a particular need rrenal excretion than n puma quot 39 cycle Afferent Efferent arteriole arteriole that enters the glomerulus is not filtered and leaves through the efferent arteriole V 39t it 7 33 7 80 A of the plasma y mgum msmrnm Tr Mquf 080m ssazenm communes plasma that enters the glomerulus is filtered L Peritubular i capillary wa pm is i in 3955 W59 tubule STAys HQ Eco To venous system 7 i conserved for the bad Laws V 007 i iine excretibri eliminated 7 lfrag the body mom BrewsColevThumswn Learning LECTURE THREE drug metabolism liver breaks down drugs to be less bio active lipid soluble and smaller so easier to excrete Primary family of enzymes Cytochrome P450 CYP450 12 groups of enzymes Of the 12 groups the most common CYP 13 nfact nearly 50 are broken down by a single enzyme CYP 3A4 Interestingly this lack of speci city is uncommon in enzymatic rxns IMPORTANT nd this family of enzymes in HEPATIC CELLS mostly also in cells lining GI TRACT and IN THE BLOOD PHASE I METABOLISM 1 Oxidation and Reduction recall REDOX oxidation is loss of e reduction is gain of e 2 Hydrolysis PHASE II METABOLISM 1 Conjugation w small ionic molecule taking a chemical group and adding a group often to make it BIOLOGICALLY INACTIVE By modifying with a small ionic molecule metabolic induction is when the drug increases hepatic enzyme availabilityactivation so the pharmacological effect diminishes the opposite is true for metabolic inhibition first pass metabolism primariy seen in orally administered drugs must tolerate acidic environment of the GI tract must be able to cross epithelium layer in GI tract where the rst metabolic enzymes are sometimes seen must pass through liver which is site of primary metabolism drug goes to systemic circulation basically by the time the drug gets to target tissue it has already degraded to some degree drug tolerance state of decreasing response to a subsequent administration of a drug the duration or level ofdrug decreases 1 metabolic tolerance enzymatic effects metabolic induction cross tolerance due to limited enzymes for multiple drugs drug A can build up a tolerance for drug B because both drugs have same metabolic enzymes 2 pharmacodynamic tolerance mediated at the target level decreased effect on interaction ofdrug at target affects receptors or cells drug dependence aka abstinence syndrome appearance of withdrawal effects the way to get rid ofthese effects is to readminister the drug pharmacodynamics study of the interaction of drugs and receptors in target tissue which lead to physiopharmacological effects mechanism of drug action at molecular level effects initiated by drugreceptor binding this binding leads to some kind of fxnal change in the target cell the binding is usually ionic and reversible ock and key model agonist receptor gt drug actioneffect antagonist receptor gt will be effects but just not at the receptor characteristics of receptors metabotropic one large protein winding through the membrane membrane spanning domains will wind 5 7 12X thru the membrane generally alpha helix extracellular loops contain spec amino acids which comprise of the binding portion ofthe receptor the binding causes a conformational change in receptor the intensity of response depends on the number of receptors that are bound Neuronal Responses to Receptor Binding primary messenger chemical that is binding drug or NT secondary messengers via these metabotropic receptors Gprotein mediated molecules like cAMP cGMP Ca2 DAG IP3 tertiary response txn factors affecting gene expression protein kinase activation phosphorylation Can elicit fast rxns ION CHANNEL OPENING Can elicit slower rxns SYNTHESIS OF RECEPTORS CHANNELS SECONDARY MESSENGERS SYNAPTOGENESIS LEARNING MEMORY DoseResponse Curves threshocl dose min dose to elicit a measurable response drug efficacy yaxis peak maximum amount of response possible the efficacy of a drug within a class is the time for all drugs but potency ED effective dose ED50 dose that yields half maximal response ED100 dose that yields max response OSC CS onsc UWCS P Maximum response b M vir WW 7 HM bus 17AM new M E r W M Threshold Fae SE man 1313100 i Dose Hydromorphine Morphine iLJr Codeine g 100 39g gt Aspirin 390 3 75 l 5 d El 0 H t on AAAAAAAAAAAAAAAAA VS 4 55 g a L 5 E1350 Iquot 100 7 an Dosemg POTENCY X aXis How strong is the drug How much drug does it take to reach the same effect In order to achieve a particular level of response yaxis compare how much of each drug dose on Xaxis Shift to right on graph is LESS POTENT more dose required to acheive same desired level of response ie pain relief Sedation x O O antiAnxiety Percentage responding ReSpiratory 50 39 39 depression iiT Dso iTDSO 5 1ED 50 E a Iquot 1 Marg iniof safety gt D c o w Iquot r COMPETITIVE vs NONCOMPETITIVE ANTAGONISTS Agonists and Antagonists Agonist binding gt mimics of action of Ligand Antagonist Bind gt BlockInhibit activity ofendogenous ligand Competitive antagonist binds to the same site Nancampetitive binds at unique site Still inhibits the binding of another drug IN PRESENCE OF ANTAGONIST competitive DECREASES POTENCY OF DRUG IN PRESENCE OF ANTAGONIST noncompetitive DECREASES POTENCY AND EFFICACY right shifted curve and decreased slope ofthe curve OVERALL Competitive antagonist DECREASES POTENCY while the Non competitive antagonist DECREASES POTENCY AND EFFICACY Maximum O O U Q A Percentage increase in response latency ooj9 quotMame E 1 39 G D g 5 y W E 5 q E W 1 3g E 5 3 Pretreated w1th g amp noncompetitive a g antagonlst K Low High Dose of morphine DRUG INTERACTIONS A Physiological antagonism A B ABgtA AB is less than effect ofA B counteracts A Two drugs not in same class ex one stimulant and one depressant that push body in OPPOSITE DIRECTIONS net result somwhere between the two drugs independently Long term Heroin users feel baseline sedated Often will combine drug use with stimulant combining heroin with cocaine to not feel jittery B Additive effects A B ABAB AB is added effect Subjected to two drugs that push body in SAME DIRECTION two depressants or two stimulants etc This is why don t drink ALCOHOL and DEPRESSANTS Could result in respiratory cessation C Potentiation A B AB AB AB is amplified Two drugs together that by themself have no connection but together This is why often give Antihistamines and pain killers together IN ORDER TO NOT HAVE TO TAKE AS MUCH PAIN KILLER DOSE One drug potentiates the response ofthe other Not additive the response is even greater than the additive response LECTURE 4 neurons have polarity therfore there is a ow of info electrical signal is summated at hillock there is alot of diversity when it comes to neuron shape shape is correlated with fxn drugs can alter structure and fxn difference of voltages inside and outside of a cell cause an electrical gradient there are chemical and electrical aspects to neuronneuron interaction chemical signaling excitatory stimuli will depolarize target cell inhibitory will hyperpolarize target cell drugs can affect synapses c 7 u 0 gt 739 68 any minimum N l t e quot390 ransmlt ET 06ww w c 0 h Ms fig 239 H C Rcccptor Effector a V enzyme Pomympuc cell body or name cAMP oGMP C17 Dinylglyml D I moral PHOSPHORYLATION 39 f i messages 5 Pminkim Substrate 0AM DEPHOSPHOPRm EIN mosmommzm Pmte a 7 Protein kinase Pmein pmme eJ39 Celluiar l l I effects MNHPIOWW a L A U K Il 7 RIO E K L L c c t 017 Dc 1 Linc a mumum mammmodnlnmry 0 o N 1 E L mdlltnry nodalhr M mum of processes prom Magnum Mnng WW Synthecixvf r 33212223 W3 swim a 5 4 1 cm EN 2 quot9 ZN o vwm w u swzmm r1 5 9 5A 94A b E OPIATES narcotic analgesics a drug that will make you sleepy and relieve pain one can dry out goo from poppy bulb to powder morphine 10 and codeine 5 are active ingredients in goo morphine is more potent than codeine naoxome is an antagonist heroin was once in bayer Heroin forms of heroin back tar W coast IV injection can cause venous sclerosis white heroin powder E coast routes of administration 1 snorting mucous membrane 2 injection IV SC 3 orally 4 inhalation drug elimination kidneys are the primary route of excretion of opiates exposure during pregnancy is bad because opiates will pass through placental barrier and newborns enter into withdrawals within a few hours of birth pharmacoogical effects CNS drowsiness decreased sensitivity to stimuli loss of anxiety and inhibitions muscle relaxant pain reliever decreased ability to concentrate OmthA ANS l I 1 c quot ular and r y r 2 constriction of pupils pin point pupils 3 nausea area postrema vagus nerve to gut AS DOSE INCREASES 1 euphoriaelation rush IV or inhalation 2 nausea worsens good sick learningconditioning OVERDOSE 1 drowsiness can cause loss or consciousness 2 respiratory depression because of loss of CO2 trigger response GI TRACT 1 decreases tonus and motility of muscles in stomach and intestines 2 slower passage thru tract 3 increases absorption of water 4 increased solidity of feces 5 constipation bioassay use of bio system to predict potential effect of a drug opiates change force or contraction not frequency 39 39 er 39s correlated with muscle relaxation ll h NOTE mu and delta are in overlapping areas LECTURE FIVE celular mechanisms note blue cell releases endogenous opiates 1 postsynapticinhibiton traditional 2 axoaxonic inhibition two presynaptic cells inhibition of NT release if purple releases GABA blue disinhibits gray 3 presynapticautoreceptors negative feedback loop presynaptic cell releases NT and neuropeptide 0 up vmmm A B 0pm K channels Close C13 channels Reduce transmitter release Opioid I1L U FOI Lay s Hf M 39 it MW endogenous opiates our body s own natural opiates all come from propeptides products broken by peptidases enzymatically When we take exogenous opiates we mess Wi our natural endogenous opiates 1 proopiomelanocortingt made into hormones and NT betaendorphin mu and delta 2 proenkephalin gt to diff types of encephalin metENK and leuENK mu and delta yh dYHOIPhiHA dynorphin B binds to kappa 4 endomorphingt little it known binds to mu tolerance need to increase the dose after several administration typically s to achieve e full magnitude of effect can occur after single administration depends on pattern of use eg how much how often opiates experience highest level of tolerance signi cant tolerance is possible up to about 40X lethal dose diff onset rates and magnitudes for diff effects euphoriaamp analgesia show rapid tolerance constipation and pupil constriction show slow tolerance crosstolerance occurs and appears to be receptor dependent mechanism for opiate tolerance is largely pharmocodynamic W1 aw symptoms opposite the effect of the drug physical dependence characterized by Withdrawal symptoms when drug is removed unpleasant ulike strong motivator for continued use onset within 34 hrs oflast use peaks at 3648 hrs lasts 710 days intensity of symptoms vary with intensity of drug use dose frequency duration of use health of individual crossdependence occurs and appears to be receptor dependent mechanisms of tolerance and J r J largely piicu J 39 PROPOSED MECHANISMS l downregulation of opioid synthesis 2 downregulation of opioid receptors not much evidence for this mechanism eg guinea pigs were given sc morphine and saw a 25 decrease in mu receptors but no change for kappa and delta receptors 3 receptor desensitization by gprotein uncoupling fewer functional receptors lots of evidence for this mechanism Himmelsbach s model of tolerance and withdrawal normal happy state is dependent on drugs after administration of drugs A r Dlsturhed i Dlsturbed Homeostasxs HomeostaSIS Compensatory mechanism I Begin morphine Withdraw treatment morphine 100 300 200 100 Time behaVioral factors involved in dependence reinforcer aspect of drug use that encourages to continue use primaryreinforcers positive and negative positivegt high rush negativegt withdrawal symptoms secondaryreinforcers environmental cues such as smell of someone cooking crack LECTURE SIX treatment protocols eg Opiates no treatment is curative basic goals are to reduce withdrawal symptoms and cravings block effect of drug and increase functional living agonist maintenance approach is to treat with long acting agonist with drugs such as methanodone binds to mu agonist and NMDA antagonist receptors half life is around 20 his and buprenorphine binds to mu agonist and kappa antagonist receptors half life is around 37 hrs catecholamines dopamine norepinephrine and serotonin5HT a Tyrosine M 64 W Tyrosine hydrOXXlase TH H l C CH NH2 l I II C OH Aromatic amino acid decarb oxylase AADC CH3 NH2 0 Dopamine Bhydroxy lase DBH Norepinephrine i H HO 13 C CH2 7 NH2 l HO 011 4 dopamine pathways 1 nigrostriatal substantianigra gt striatum basal ganglia 2 mesolimbic ventral tegmental area gtNAc olfactory tubules a 39l u z 3 mesocortical VTAgt prefrontal cortex cingulate cortex dopamine pathway functions nigrostriatalmotor mesolimbic and mesocortical make up mesocorticolimbic pathwaygt central reward pleasure mood motivation attention and memory sensory processing olfaction and vision hypothalamus gt pituitary hormonal control adrenergic receptorsnorepinephrine alpha and beta are both metabotropic alphal works via phosphoinositide 2quotd messenger which increases intracellular calcium concentration alpha2 l Glgt decrease in cAMP 2 G protein activation of K conductance gt hyperpolarize both beta 7 Gs gt increase in cAMP adrenergic pathways 1 ascending hunger thirst mood hormones 2 descending cerebellum and spinal cord 7 autonomic motor pain synthesis of serotonin 39l39ryptophan hydroxlyaae serotonin receptor pathways llT receptor subtypes 1 5HT1Aworks postsynaptically and is inhibitory decrease in CAMP and activation of Kconduc ance 5HT1B and 5HT1D works with autoreceptors and inhibits presynaptic serotonin release SHTZA workpostsynaptically via phosphoinositide 2nd essenger increasing intracellular calcium concentration activating PKC protein kinase C serotonergic pathways ascending parallel to dopamine ascending pathways modulates dopamine pathways descending medulla cerebellum spinal cord generalens of serotonergic pathways 1 mood depression and other affective states 2 facilitates movement 3 sleep Equot W 4 sexual behavior 5 thermoregulation 6 pain sensation FUNCTIONAL NEUROANATOMY hindbrain 1 myelencephalon medulla 2 metencephalon pons and cerebellum reticular formation 1 motor 2 cardio control 3 pain 4 level of alertness consciousness midbrain 1 mesencephalon PAG pain substantianigra movement VTA reward and reinforcement forebrain 1 diencephalon thalamus and hypothalamus 2 telencephalon neocorteX basal ganglia and limbic system basal ganglia gt motor control caudate and putamen gt dorsal striatum globuspallidus limbic system gt mood motivation memory fear cortical cingulatelimbic corteX subcortical amygdala NAc hippocampus septalnucleas prefrontal cortex because of function decision making risk assessment behavioral inhibition


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