Midterm2 Study Guide
Midterm2 Study Guide PHCL2001
U of M
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This 14 page Study Guide was uploaded by Huiyu Li on Tuesday December 15, 2015. The Study Guide belongs to PHCL2001 at University of Minnesota taught by Gregory Connell in Fall 2015. Since its upload, it has received 25 views. For similar materials see Basic Principles of Pharmacology: A Drug's Fantastic Voyage in Pharmaceutics at University of Minnesota.
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Date Created: 12/15/15
Lecture 10 topics bled into other lectures also Signal Transduction The mechanism by which cell surface receptors receive information from extracellular signals such as hormones and neurotransmitters, and amplify this information through the actions of second messengers. Signal transduction is the central communication between cells. Second Messenger molecules produced (or released ie. ions such as Ca2+, Na+, K+) from signal transduction, activate intrinsic pathways to processes such as protein secretion, cell differentiation, and cell division through amplification. It is produced to further signal transduction. They work by relaying signals received at receptors on the cell surface to target molecules in the cytosol and/or nucleus Image: Pathway for blood coagulation/clotting; example of Classical signal transduction in which there are multiple steps to modulate the amplification/signal transduction pathway which propagates a rapid response also known as an enzymatic cascade Coagulation inactive enzymes converted to active enzymes = amplification. Small stimulus results in a large output. (blood clotting) Warfarin (Coumadin) anticoagulant. Mechanism of action: interferes with process of mature protein clotting. Block formation of post translational modification (after protein is produced > modifies) process to stop clotting. (See image and explanation below) Image: Heparin is also known as an anticoagulant, interfering with the blood clotting mechanism and commonly used in the clinical setting due to its rapid response due to inhibiting Thrombin directly.. Right image shows how Warfarin interferes with blood clotting it basically prevents the production of prothrombin by interfering with the action of Vit K epoxide reductase which is Vit Kdependendent.. which in turn prevents production of Thrombin which is needed to convert fibrinogen into fibrin which in turn contributes to the blood clot Image: Heparin enhances the ability of antithrombin (AT) to bind with Thrombin, preventing blood clotting Heparin The acute anticoagulant. This drug inhibits the thrombin induced platelet aggregation. Heparin simultaneously binds to thrombin and antithrombin. Aspirin covalently modify irreversible inhibitor of cyclooxygenase. Also known as Acetyl salicylic Acid. It’s function when it comes to blood clot is that the Acetyl group of the aspirin (see right image below) modifies/inhibits Cyclooxygenase (specifically COX1, a type of protein), via transfer, which is an irreversible reaction. Cyclooxygenase can be found everywhere in the body, which is why aspirin targets a lot of different areas. Ways to modulate aspirin giving LOW DOSE which… results in localized amplification reduces amount of platelets present during blood clot NOTE: There is no toxicity or adverse event caused by aspirin as there is a HIGH PLATELET TURNOVER where platelets are constantly produced and replaced Platelet activation mechanism collagen is exposed to circulating platelets when the endothelium is damaged. They are then bound directly to collagen with collagen specific glycoprotein surface receptors. This starts the signaling cascade which activates platelet integrins and adheres to platelets at the site of injury. Aspirin interferes with platelet activation, increasing the clotting time. Image: Note that P2Y i12an ADPreceptor that plays a major role in the amplification for platelet activation. Aspirin (in red) interferes with collagen (“acetylates” cyclooxygenase present in collagen, I believe?) which increases the time it takes for blood to clot Aspirin can lead to the thinning of blood as well. Phospholipid bilayer function it separates cell contents from extracellular contents; contains semipermeability properties and also serves as a RESERVOIR FOR SECOND MESSENGERS Phospholipase breaks bonds in phospholipid; It is the ENZYME that CLEAVES BOND in phospholipids this allows for the phospolipid backbone structure to attach to other groups, producing other second messengers (LIPIDDERIVED i.e. phosphatidylinositol, which is the phospholipid backbone attached to a 6C sugar) Right image: Phospholipase C plays a part in the formation of two lipidderived second messengers Diacylglycerol (DAG) and Inositol Trisphosphate (IP ) 3 Diacyglycerol (DAG): lipid derived second messenger that activates protein kinase C; located in inner layer of plasma membrane Inositol Trisphosphate (IP ): l3pid derived second messenger that releases Ca from the 2+ endoplasmic reticulum **Both of these second messengers contribute to AMPLIFICATION** Image: Arachidonic Acid is also a lipidderived second messenger produced by phospholipase A 2hich is then a precursor to Cyclooxygenase production (I believe..?) Know the intrinsic and extrinsic pathways (different ways to get to the same place) *examples he talked about is there are many ways to thin blood. coagulation happens at different steps in the pathways. intrinsic pathway (contact activation pathway) starts by forming complex collagen and then initiates clot formations. Involve in inflammation. extrinsic pathway (tissue factor pathway) converts fibrinogen to fibrin. “thrombin burst” occurs which means thrombin is rapidly released. They both end at the common pathway paths to coagulation. The drugs we talked about (aspirin, heparin, warfarin) are anticoagulants and take different steps to modulate the same effect by hitting different targets down the cascade. Lecture 11 G protein coupled receptor (GPCR) and an associated signaling cascade. (know why it is called that and what it does) Binds the guanine nucleotides GDP and GTP. GDP and GTP are heterotrimers ( 3 subunits) associated with the inner surface of the plasma membrane and the transmembrane receptors of hormones (GPCRs = G protein coupled receptors) . cAMP signal transduction pathway hormone → GPCR → G protein → adenylyl cyclase → cAMP → PKA → gene regulatory protein → gene transcription Cyclic AMP (cAMP) is a second messenger that modulates downstream molecules of the signal transduction pathway which ultimately modifies gene transcription cAMP phosphodiesterase (hydrolyzes/breaks down phosphodiester) terminates the signal transduction pathway (See image below) PIP2 signal transduction pathway signal → GPCR → PLC → PIP2 splitted into DAG (diacylglycerol) and IP3 (inositol 1,4,5triphosphate) . DAG recruits the protein kinase PKC to the membrane and activates the enzyme. IP3 diffuses into cytosol, where it binds to an IP3 receptor and calcium channel in the membrane of the sER to release calcium ions into the cytosol. Glucocorticoid receptor (know the process) when glucocorticoid receptor binds to glucocorticoids, the primary mechanism of action is gene transcription. LigandGated Ion Channel large groups of intrinsic transmembrane proteins allow passage of ions upon activation by a specific chemical. 3 signals derived from lipase ????? Lecture 12 ED50 Dose 50% effective in people. LD50 the lethal dose 50% (kills people). Call this the safety margin. Lecture 13: Pharmacodynamics The actions of the drug on the body (what the drug does); Study of the physiological and biochemical effects of drugs on the body, including the mechanism of action and the quantitative relationships between drug concentration and the observed effect Dose Response curve Quantitative representation of a drug’s effect as a function of that drug’s concentration. Graded doseresponse relationships dose of a drug is described in terms of a percentage of the maximal response o Magnitude or response Quantal doseresponse relationships dose of drug is described in the terms of the cumulative percentage of subjects exhibiting a defined allornone effect. o Frequency of response o Therapeutic index and safety factors Kd of a drug When the yaxis is at 0.5, [D] = Kd; a reflection of the affinity of drug for the receptor Drug’s potency and efficacy: Potency The concentration of the drug needed to reach under same effect. “Most potent drug” the one with highest affinity (most left on xaxis of graph) AND highest efficacy (most upper on yaxis of graph) Efficacy The maximum response achievable from a drug. “Most efficacious drug” the one(s) with highest yaxis value (affinity may differ location on xaxis) “Least efficacious drug” the one(s) with the lowest yaxis value Therapeutic Index TI=LD50/ED50, usually the higher the TI, the better. Safety Factors CSF=LD1/ED99 E maximal response that the system is able to produce under saturating stimulation max K E–Equilibrium dissociation constant of AR* and cellular response element complex Antagonist binds to same receptor of agonist and produces little to no response (no biological effect in absence of agonist) Able to overcome antagonist effect due to INCREASING DRUG CONCENTRATION ***Noncompetitive antagonist would decrease the efficacy of the drug, competitive antagonist would decrease the potency of the drug.*** Inverse/Reverse Agonist binding the receptor at the same position as agonist but have opposite effects. Spare Receptors multiple different ligands acting at same receptors with different responses. Maximal responses are achieved at less than maximal receptor occupancy. A certain number of receptors are “spare.” Lecture 14/15: **most potent drug is drug A ** most efficacious drug is drug A and drug B lower affinity = higher potency How do you calculate the Kd of a drug from the above graph? When the yaxis is at 0.5, [D] = Kd Lecture 16: Chemotherapy Selectivity VS specificity Selectivity depicts a molecule with greater affinity for one receptor (or any process for that matter) over another. The key is that implicit in this definition (or rather characterization), is that the selectivity can be "overcome" by overloading the system, and the "other" receptor experiences binding and/or activation. Specificity takes selectivity one step further, where no increase in the ligand or molecule of interest can activate the other receptor(s). Selective Toxicity: The exploitation of the differences between host and infectious agents. Unique cellular structures Unique biochemical pathways Similar biochemical pathways Quantal outcomes lower/adjust issue but NOT cure it (i.e. did drug lower blood glucose? VS did drug cure diabetes?) Resistance Misdiagnosis cannot treat every infection with antivirus/biotic/fungal (different targets) Inherent resistance every member of microbe species is resistant Acquired resistance over time, members of microbe species acquire resistance (evolution) and can be caused by overuse of antibiotics such as penicillin Combination Therapy designed to avoid the emergence of drugresistance Vertical Gene Transfer transfer of genes from the parental generation to the offspring via sexual/asexual reproduction. ** Chromosomal resistance. Horizontal Gene Transfer transfer of genes between organisms other than traditional reproduction such as transformation, transduction, or conjugation. ** sex, plasmid and transposon; mediated resistance. Prophylaxis Preventative medicine; accounts for 3050% of Rx administered antibiotics in U.S. Bactericidal kills microbe Bacteriostatic inhibiting the multiplication of the bacteria by stopping from moving, growing, and dividing Lecture 17: Drugs of Abuse Abuse liability Over medicating/abuse of drug by self medicating a prescribed drug. Route of administration inhalation (smoking) is an efficient route to administer lipophilic drugs Reinforcing properties o Positive euphoria o Negative withdrawal symptoms Dependence due to.. o Abstinence syndromes o Cravings \ ↑ rate of ↑[drug] in brain → ↑ intensity of euphoria ↑ drug lipophilicity → ↑ crossing blood brain barrier ***All addictive drugs activate the mesolimbic dopamine (DA) system** DA Hypothesis of addiction: phasic DA release codes for prediction error of reward and constitutes a strong learning signal Addiction: high motivation to obtain and use drug despite negative consequences – compulsive drug use chronic, relapsing brain disease as the drugs change the brain's structure and how it works Why do people take recreational drugs? o to feel good (high), feel better, do better (enhance performance), or curiosity/peer pressure Intoxication: acute pharmacological effects; poisoning Euphoria: happiness or pleasantness; rush=intense excitement Abstinence syndrome: drug withdrawal; is an indication of physical dependence; results from adaptation to repeated exposure to drug Abuse potential: reinforcing properties of drug Tolerance (acquired): reduction in response to drug after repeated administration; requires an increased dose to produce the same effect. Crosstolerance: tolerance to primary drug results in tolerance to class of drugs Detoxification: treating drug dependence by gradually weaning individual from drug
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