Unit 1 Flashcards
Pharmacology
Action of drugs on living organisms
Neuropharmacology
Drug-induced changes in functioning of nerve cells
Psychopharmacology
Drug-induced changes in behavioral responding
Neuropsychopharmacology
Drug-induced changes in function of select neurons that influence specific sets of behaviors produced by injury, disease, or other factors
Drug Action
Local
Molecular changes within cells produced by drug binding to a target site/receptor
Drug Effect
Communal
Molecular changes within or between cells that lead to alterations in physiological/psychological function
Liberation
Rate of drug release into a biological system from administered form
Formulation
Mix of drug and excipient (i.e. time released). Can only control rate of delivery only when liberation
Excipient
Chemicals always added to drugs to facilitate ability of drugs to exist in different forms
Bioequivalence
Idea that if two drugs formulations have equal bioavailability and rate of absorption then plasma levels will be similar. NOT ALWAYS TRUE b/c of differing liberation rates/gut acidity
Absorption
Movement of drug from site of admin to blood circulation. Influenced by route of admin and liberation factors
Oral Administration PO
Most popular for safety and economy. Pills, liquids, etc. Must dissolve in stomach and pass through stomach wall to reach capillaries, so must be resistant to strong acids and enzymes. Majority not absorbed until proximal small intestine. Bioavailability affected by food in gut (slow gut movement = slow absorption), first pass effect
Intravenous Administration IV
Most rapid and accurate method b/c it circumvents stomach wall/first pass. Hazardous because of quickness/inability to stop, sterility, and dissolution in toxic fillers
Intramuscular Administration IM
Slow and even delivery of drug in non-aqueous additives (lipophilic oils). Often painful
Subcutaneous Administration SC
Often slow and steady delivery of aqueous drugs depending on blood flow to site. Similar to IM in use of slow delivery through oils
Gaseous Administration
Rapid absorption due to large surface area of pulmonary capillary system
Topical Administration
Direct application to mucosal membranes with rapid absorption into mucosal capillary system and rapid effects
Transdermal Administration
Slow absoprtion through transdermal patches into skin. Use lipophilic substances often dissolved in alcohol that can penetrate skin (lipid bi-layers).
Transport Across Cell Membranes
Rate of drug passage across various cell layers between site of administration and blood is the single most important factor in determining plasma drug levels
Passive Diffusion
From high concentration to low concentration as drugs move down the concentration gradient. Lipophilic/lipid-soluble, non-ionic drugs
Carrier-Mediated Active Transport
From low concentration to high through movement by a transport protein against the concentration gradient. Requires ATP. Ionic/charged drugs
Lipid-soluble Drug
Move across membranes via passive diffusion depending on concentration gradient / lipid solubility. Diffuse into cell membrane and establish a concentration which is always greater than within the cytoplasm. Must be able to penetrate membrane through lipophility, but overly lipophilic drugs can get stuck within the membrane
Salt Forms of Drugs
Substitute HBr/SO4 for hydrogen which increases aqueous solubility, facilitating solution in stomach and into blood for great stability/shelf-life. Once in aqueous environment, salt dissociates, releases drug, and is replaced by H. Problems encountered with drug weight vs salt weight
Ionization of Drugs
Most drugs are weak acids/bases that ionize in water, but depends on pH level [easier to be absorbed when more neutral] and ionization characteristics (pKa) [pH of solution in which drug is 50/50 ionized]
Distribution
Circulation of drug to target sites within a biological system (most blood goes to the brain).
Apparent Volume (Vd)
Distribution of a drug to the body, defined as relative amount of drug that leaves circulation and enters organs. Heavily influenced by lipid solubility. Vd = 3: drug distributed to 3L of body fluid. If Vd is too high, will distribute to areas not meant to be affected (even lipid myelin)
Distribution Phases
First Phase: Blood concentration drops as drug enters brain. High brain:blood ratio
Second Phase: Drug becomes soluble in other body tissues/organs including target which reduces blood concentration. Flips brain:blood ratio as blood diffuses(redistributes) from high [brain] to low [blood]
Third Phase: Drug leaves blood to enter fat (hair, fat, brain. Reservoir for lipophilic drugs)
Blood Brain Barrier
Vascular endothelial cells connevt by tight junctions and secrete basement membrane which force molecules to diffuse through basement membrane matrix. Astrocytes project astrocytic feet around basement membrane which makes barrier to diffusion of polar molecules, must go through basement. Can be opened by osmotic diuretic stress (manitol). Not on vomiting center to allow quick reaction.
Plasma (Depot) Binding
Depots in blood reduce [drug] available for diffusion by non-selectively binding drug to plasma proteins. Bound drug is not free to be metabolized by liver = longer drug action, protected against degradation. Responsible for terminating drug action b/c of redistribution of highly lipid soluble drugs
Metabolism
Breakdown/inactivation of drugs as it goes from prodrug to active form to inactive form. Mostly occurs in the liver (p450 system)
Biotransformation
Phase 1: oxidation hydrolysis, reduction of parent structure to produce a polar metabolite (can dissolve in aqueous sol.) of the drug that can be excreted in urine. All oral drugs undergo this in the gut.
Phase 2: Conjugation with glucuronide, sulfate, acetate, or an amino acid to produce a highly ionized, biologically inactive molecule that can’t cross membranes.
Drug half-life
Amount of time required for removal of 50% of drug in blood
First Order Transformation (Kinetics)
Drug clearance rate proceeds exponentially as usually [conversion enzymes] > [drug to convert]. Rate depends on [drug].
Zero Order Transformation (Kinetics)
Drug clearance rate is fixed as usually [drug to convert] > [conversion enzymes] with drug saturating metabolizing enzymes. Rate depends on [conversion enzymes] (slow)
Enzyme Induction
Increase in [enzymes] available for biotransformation increases the biotransformation rate of all drugs in system. Chronic exposure leads to upregulation of enzymes, which can bloat the liver, influence blood levels
Enzyme Inhibition
Some drugs directly inhibit metabolizing action of enzymes which decreases the biotrans rate of all drugs/natural molecules in system
Drug Competition
Some drugs share metabolizing enzymes which decreases the biotrans rate of both drugs in system, which can produce potentially dangerous drug interactions (alcohol + barbituates)
Individual Characterisitics
INdividual genetic/environmental differences in drug metabolism which can decrease the biotrans rate of drugs in a system. i.e. Asian lack of alcohol dehydrogenase -> weakened alcohol metabolism
Pharmacodynamics
Study of physiological and biochemical interactions of a drug with a target tissue that is responisble for the drug’s effect
Ionotropic Interaction of Receptors
Ligand binds a receptor/ion channel combo -> change in conformation of channel -> open ion channel -> change conductance of ion -> change Vm of cell
Traditional view of receptor actions, only a fraction of NTRs
Metabotropic Interaction of Receptors
Most receptors have acceptor site for ligands that once occupied sets off a cascade of 3rd degree structural changes inducing conformational changes in proteins assoc. w/ the receptor complex. Results in synthesis/release of 2nd messengers which regulate ion conductance, signalling/metabolism
Agonist
A ligand whose binding produces a cellular response. Has biological efficacy/potency
Antagonist
A ligand whose binding produces no cellular response. Has no biological efficacy/potency. No naturally occurring antagonists in brain
Dose Response Curve
Describe amount of biologic or behvaioral effect for a given drug concentration (receptor occupation). ED50 = 50% effective dose. Shape of curve can tell you drug type as they share a curve, while not necessarily placement.
TD50 = 50% toxic dose
Therapeutic Index TI
TD50/ED50
TR = Therapeutic Range: minimum plasma level needed for desired effect as well as maximal plasma level before toxic effects.
Direct Acting Agonist Drugs
Affinity/efficacy at receptor sites produces a response by binding and mimicing NT action. Either receptor subtype-selective or non-specific(mixed agonist)
Indirect Acting Agonist Drugs
Enhance action of NT indirectly by activating (NOT BINDING) receptors. Can stimulate release, inhibit reuptake, block catabolic enzymes, etc
Direct Acting Antagonist Drugs
Have affinity without efficacy, binding without a biological action. Interfere with NT binding to receptor, reducing NT action.
Competitive: bind at NT site. Covalent=irreversible. Non-Covalent=reversible (can be compete off by excess of agonist)
Non-Competitive: Bind to regulatory site, inhibiting access
Indirect Acting Antagonist Drug
Reduce action of NT, usually by depleting pre-synaptic stores by releasing NT into the cleft then releasing stores leaving nothing to release
Pharmacodynamic Tolerance
Decrease potency due to reduction in efficacy through which drug acts. Through downregulation in # of receptors or desensitization from reduction of receptors to produce 2nd messengers. Due to chronic drug exposure
Pharmacokinetic Tolerance (Biodispositional Tolerance)
Bio system responds to drug by reducing [drug] delivered to target site by altering metabolism (ie upregulate liver enzymes)
Physiological Tolerance
Tolerance due to secondary effects of drug action as pharmacodynamic tolerance at one synapse alters downstream neurons
Behavioral Tolerance
Reduction in potency of drug based on anticipation of possible adverse effects (ie alcoholics adapting behavior so not to draw attention to self)
Acute Tolerance
Rapid induction of tolerance (w/i 2-24hrs)
Cross Tolerance
Reduction in potency of one drug because of exposure to another in same class (benzos/barbituates/alcohol)
Reverse Tolerance (Sensitization)
Increase in potency of drug following continued exposure to drug (cocaine increasing motor response, likely due to pharmacodynamic/physiological tolerance)
Catecholamine
DA and NE. Share a core catechol group and nitrogen group (amine). Part of monoamine/biogenic amine group. Packaged into vesicles by vesicular monoamine transporters (VMAT) and released primarily by Ca++
Catecholamine Synthesis, Release, and Inactivation
Tryosine –tyrosinehydroxylase-> DOPA –aromatic amino acid decarboxylase-> Dopamine –dopamine b-hydroxylase-> Norepinephrine
Rate Limiting Step
Determines rate of synthesis of a NT.
DA/NE: Tyrosine Hydroxylase
5HT: tryptophan hydroxylase
Ach: choline acetyltransferase
Negative Feedback Mechanism
Maintains rate of production through end-product inhibition
DA/NE: High [DA/NE] inhibits TH
Autoreceptor
Inhibitory receptors on the pre-synaptic terminal that act by closing Ca++ channels
Catecholamine Reuptake
DA and NE Transporters (DATs, NERTs) return NT to terminal for repackaging/elimination to rapidly remove the NT
Catecholamine Metabolism
Enzymatic breakdown of catecholamines by catechol-O-methyltransferase (COMT) which puts a methyl group on the catechol ring or monoamine oxidase (MAO) where oxidation replaces amine. Both reduce binding affinity
Substantia Nigra
DA cells that project to striatum, implicated in motor function. Affected by Parkinson’s Disease
Ventral Tegmental Area
DA cells that project to basal forebrain, cortex, hippocampus implicated in reward and several psychiatric conditions
Slow Acting DA Receptors
Transmitter-receptor interaction causes cascade of structural changes in coupling proteins (g-protein). Influences conductance after a time delay and DNA transcription via 2/3/4 messengers. Induce permanent changes in target neuron physiology.
G-Proteins
Coupling protein on metabotropic receptors on cytoplasmic side of membrane. Activated by intracellular domain of NT receptor.
Alpha: Gi: inhibitory (d2,3,4), Gs: stimulatory (d1,5), Go: other. Based on activation of 2 messenger.
Metabotropic Receptor Function
At rest, GDP is bound to alpha g protein subunit. When NT binds, GTP is exchanged for GDP and G protein dissociates from receptor to produce array of GTP-bound G proteins
Cyclic Nucleotide 2nd Messenger Systems
After NT-alpha subunit binding, the unbound alpha activates adenylate cyclase which cleaves ATP to produce cAMP.
cAMP
Can induce structural changes in cells by phorphorylating ion channels with a protein kinase and activate gene expression via CREB (cAMP Response Element Binding Protein). Can be inhibited by D2-4 opening K+ channels to hyperpolarize
Phopholipase A2 and Arachadonic Acid Pathway
Alpha dissociation activates PLA2 which hydrolyzes phophoinositol in membrane which releases arachadonic acid. AA is converted to active metabolites involved in a lot of stuff. Affected by corticosteroids which prevent AA mobilization
Diacylglycerol - Inositol Triphosphate Pathway
Alpha dissociation activates membrane bound phopholipase C (PLC) which cleaves phosphatidylinositol (PIP2) producing IP3 and DAG which releases CA++ from the endoplasmic reticulum. Results in depolarization, activation of intracellular proteins/Ca++ sensitive K+ proteins, binding to calmodulin
Locus Coeruleus
NE cells project to the forebrain, cerebellum, cord, but only 3k nuerons total. Implicated in fight or flight, attention
Norepinephrine Receptors
Post-Synaptic metabotropic
Alpha: a1: active PI 2 messengers to increase Ca++ (excitatory, arousal). a2: inhibit adenylate cyclase, decrease cAMP, act as autoreceptors (inhibitory, sedation, anxiolysis)
Beta: b1 + 2: stimulate adnylate cyclase, increase cAMP (stimulatory). on bronchia: relaxation. on heart: increase constriction
Serotonin 5HT
Involved in a lot of stuff in brain, both good and bad. Similar structure to catecholamines with carboxyl ring and carbon-carbon-nitrogen tail. Packaged into VMATs, released mostly by Ca++ mechanisms. Inhibited by autoreceptors. Reductions lead to depression.
Serotonin Synthesis
Tryptophan –tryptophan hydroxylase-> 5-hydroxytryptophan –aromatic amino acid decarboxylase-> 5-hydroxytryptamine (5HT).
Process blocked by para-chlorophenylalanine (PCPA)
Serotonin Inactivation
Reuptake: 5HT Transporters (SERTs) [NOT 5HT autoreceptors] return NT to terminal for repackaging/elimination. Psychoactives block function by binding (lo dose) or saturating (hi dose) SERTs
Metabolism: Monoamine oxidase (MAO) -> 5-hydroxyindolacetic acid
5HT Organization
B cell groups are a network of 5HT cell groups originating in the brainstem, projecting to forebrain, midbrain, cerebellum, and cord
B7(Dorsal) and B8(median) raphe nucleus innervate a bunch of stuff in a lot of basic functions. All receptors metabotropic (except 5ht3), generally inhibitory
5HT1A Receptor
Inhibitory. Binds to 5HT though Gi coupled receptors which inhibit aden. cyclase and cAMP function, or enhancing K+ channel opening to hyperpolarize. Function implicated in learning, satiety, anxiety, temp reg., and alcohol abuse. Concentrated in hippo, septum, amygdala, raphe. some psych meds are 5ht1a agonists
5HT2A
Binding with 5HT activates PI 2nd messengers which active protein kinase c (PKC) and increase release of Ca++ which can reduce K+ channel opening to excite (can still be inhibitory if on an inhibitory cell)
Acetylcholine
Choline with acetyl coenzyme A, synthesized by choline acetyltransferase (ChAT). ChAT stimulated by high [choline from diet, A CoA] and cell rate of firing (positive feedback). Packaged into vesicular Ach transporter (VACht), released by Ca++ mechs.
Acetylchoine Metabolism
Metabolized by acetylchoinesterase (AchE) which dissociates the choline and acetic acid. Reversible AChE inhibitors: drug dissociates and is metabolized (physostigmine, neostigmine)
Irreversible AChE inhibitors: drug doesn’t dissociate, no metabolism (sarin)
Acetylcholine Reuptake
Choline transporters shuttle choline from synapse back to termine for reuse in Ach synthesis. Rapidly removes precursor from synapse.
ACh Organization
Mix between interneurons (striatum) and projection neurons (pons, septum)
Interneurons: Important for muscle control, interact with DA terminals
Nicotinic ACh Receptors nAchR
In muscles, PNS, and some CNS. Stimulatory ionotropic receptors (Na+, Ca++) both pre and post synapse. 5 subunits form an ion channel: two alphas as binding sites, and various beta/gamma/delta combinations for speed regulation. Long-term agonist exposure = desensitization or depolarization blockade (non-stop ion flow -> not enough gradient to re-polarize)
Muscarinic ACh Receptors mAchR
5 different subtypes of metabotropic receptors (use 2nd messengers, inhibitory or stimulatory). Widely distributed throughout CNS (cognition, motor, drug reward) and PNS (heart, smooth gut muscles, bronchioles, and secretions)
Glutamate Synthesis
Glutamine –Glutaminase-> glutamate. Ionized glutamic acid is A.A. used for protein synthesis
Glutamate GLU
Excitatory Ionized glutamic acid is A.A. used for protein synthesis. Packaged into vesicular glutamate transporter (VGLUT 1-3). Found only in neurons that use glutamate, only vglut 1 or 2. Released by Ca++ mechanisms
Glutamate Inactivation
Reuptake: Glutamate transporters (excitatory amino acid transporters EAAT1-5)
Metabolism: Glutamine synthetase. EEAT1/2 takes transmitter into astrocytes and coverts back to glutamine while glutamine synthetase adds backt eh amine group, back into neurons by glutamine transporters. EEAT3 returns transmitter to neuron for repackaging by VGLUT
GLU Organization
Primary fast acting excitatory NT, in pyramidal cortex neurons and cerebellum and hippocampus
GLU Receptors
Metabotropic: 8 subtypes coupled to G proteins to either inhibit cAMP production or activate PI 2nd messenger systems
Ionotropic: 3 subtypes:
AMPA: most active. Depolarization due to increased Na+ influx
Kainate: depolarization due to increased Na+ influx
NMDA: depolarization due to increased Na+/Ca++
NMDA Receptors
Bind to n-methyl-D-aspartate amino acid analog. Allows Ca++ influx to active 2nd messengers, but requires glutamate and glycine/D-serine (co-agonist) to open channel. Co-agonist site usually occupied = rate limiting.
Additional sites: Mg binding within channel blocks at rest, dissociates with depolarization and presence of GLU to open channel. Phencyclidine (PCP)/Ketamine site is non-competitive antagonist at distinct site.
Long-Term Potentiation
Persistent increase in synaptic strength produced by burst of activity in PSN. NMDA important. Single stimulus not enough to open NMDA, but rapid succession (tetanus) opens AMPA and NMDA which allows Ca++ to enter and activate 2nd messengers (phosphorylate AMPAR, insert more AMPAR, all increase GLU sensitivity).
Induction Phase: during tetanus
Expression Phase: enhanced synaptic strength at later time
GLU Toxicity
Excitotoxicity due to overstimulation of NMDAR. Prolonged GLuR stim by high [GLU] leads to necrosis from cell lysis or apoptosis
GABA Synthesis
Glutamate –glutamic acid decarboxylase (GAD)-> GABA. GAD removes carboxyl group from glutamate from metabolic partnership btw glutaminergic neurons and astrocytic glia.
Gamma-aminobutyric acid GABA
Primary fast acting inhibitory NT in brain, as much as half the neurons in cortex, hippo, striatum use GABA. Packaged by vesicular GABA transporter (VGAT) only in neurons with GABA. Released by Ca++ mech PSP.
GABA Reuptake/Metabolism
Reuptake: GAT Transporters, 1/2 on astrocytes, neurons, 3 on astrocytes
Metabolism: Neurons: GABA aminotranferase (GABA-T) produces glutamate and succinate. Astrocytes: GABA-T followed by astrocytic glutamine synthetase which adds back amine glutamine
GABA Receptors
GABA B: Metabotropic. Coupled to G protein to inhibit cAMP production and open K+ channels to hyperpolarize
GABA A: Ionotropic. Cl- channel to blunt depolarization (Cl shunt). 5 subunits within receptor. Most 2alpha, 2beta, one gamma or two alpha one beta two gamma.
Benzos/barb/neurosteroids: allosteric agonists
