Pharm -3- Pharmacodynamics

Question Answer What is Pharmacology the study of the interaction of chemicals with biological systems What is Pharmacodynamics the study of the biochemical and physiological effects of drugs and their mechanism of action. What is Pharmacokinetics ADME, absorption, distribution, metabolism, exrection Objectives of pharmacodynamics 1. to show the chemical or physical interactions between a drug and a target cell
2. the sequence and scope of actions of each drug
3. to provide the basis for both the therapeutic use of a drug and the design of new and superior drugs What is a Drug chemical substance that alters physiologic function of cells and tissues through a chemical reaction Chemical substances used to prevent, treat or provide symptomatic relief of disease What are the 5 Basic Principles of Drug Theory 1 binds specifically
2 alter pathways
3 inhibit/activate
4 compare to basal levels
5 proportional response Drugs chemically bind to specific cellular macromolecules known as receptors ultimately triggering some biochemical response. The response can be measured at the level of the cell, tissue, organ or whole organism refers to what part of the drug theory 1 binds specifically II. Drugs do not create new cellular responses but alter preexisting ones refers to what part of drug theory 2 alter pathways III. Drugs inhibit or activate biochemical or physiological processes or replace elements needed to initiate or enhance cellular processes refers to what part of drug theory 3 inhibit/activate IV. The response to and effectiveness of a specific drug must be measured by comparing it to the physiologic activity of the system it affects prior to administration refers to what part of drug theory 4 compare to basal levels V. The response of a system to any given drug is proportional to the dose of the drug, the extent of the physical interaction with its receptors and the number of receptors containing bound drug refers to what part of drug theory 5 proportional response Most drugs are what size MW between 100 and 1000 g/mole a sufficient size gives a compound a unique structure which facilitates what selective receptor binding smaller compounds and ions do not _____ ____ to receptors Bind selectively Why do large drug molecules need to be administered parentally may not readily be absorbed in the GI tract (protein drugs) The hypothesis that drugs must have a complementary shape to the receptor for binding to occur is called Lock and Key Hypothesis Stereo isomerism is important because Normally only one optical isomer of a drug is pharmacologically active Drug Polarity refers to it being either __________ or __________ Hydrophobic or Hydrophilic Site of Drug Action are known as what and give 3 sites of drug action receptor
1 Membrane protein (adrenergic receptor)
2 Cytoplasmic/extracellular enzyme (gastric proton pump, cyclooxygenase (COX)
3 Nucleic acid (alkylating agents) What are the 2 Main categories for receptors Molecules essential to normal cellular function (enzymes, nucleic acid, etc.) and **Molecules specifically involved in intercellular communication (specialized receptors) **Molecules specifically involved in intercellular communication (specialized receptors) are more commonly known as what Generally are G protein linked receptors What are the Common Features of Receptors Molecular Weight 45 to 200 kilodaltons, may be composed of a single or multiple protein subunits, Receptor activities are localized to a discrete portion of the receptor How are receptors Grouped Super families, Families and finally subtypes IE GPCR, Alph or Beta, Alpha1 Alpha 2, Alpha 1a I. What are the characterisitcs of the 7 Trans membrane spanning (TMS) G Protein Coupled Receptors (Metabotropic Receptors) i. 7, nonpolar, transmembrane regions
ii. three extracellular loops
iii. three intracellular loops
iv. extracellular amino terminal tail
v. intracellular carboxy terminal tail
vi. coupled to G proteins Where does the G protein bind to within the GPCR Heterotrimeric G proteins bind to third intracellular loop and carboxy terminal tail What is the time frame for action with GPCR's Minutes What ere the 5 Common features of membrane-bound receptor 1 Hydrophobic and hydrophilic segments
2 Act as signal transducers
3 Initiate a signal transduction pathway
4 May have enzymatic properties
5 Often contain lipid or carbohydrate modifications what type of receptor do 30-50% of drugs affect GPCRs What two subunits of the G protein never separate gamma and Beta what subunit separates away from the betas and gamma subunits of the G protein Alpha subunit alpha stimulatory subtypes cause ____ adenlyle cyclase activity and ______ cAMP Increase adenylyl cyclase activity and Increase cAMP What are common alpha stimulatory receptors B1 adrenergic, B2 adrenergic, glucagon receptor Alpha i subunit subtypes cause ____ adenylyl cyclase activity and ______ cAMP Decrease adenylyl cyclase activity and decrease cAMP What are common alpha i receptors alpha 2 adrenergic receptor, mu opiod receptor Alpha q/11 subtype _________ phospholipase C which then ________ protein kinase C and IP3 increase phospholipase C and then activates protein kinase C and IP3 In desensitization and internalization of receptors what is the key in determining if it gets sent to lysosome or back to the membrane length of stimulation In desensitization and internalization what is the molecule that phosphorylates activated receptors that don't have their G-proteins attached anymore GRK (G protein coupled receptor kinase) What molecule attaches to phosphorylated receptors to signal internalization Beta-arr decreased effect to a drug when used at a similar dose is know as _______ or _______ desensitization or tachyphylaxis This typically deals more with the rapid effects of phosphorylation or internalization of receptor and no receptor degredation desensitization or tachyphylaxis Like desensitization manifests a decreased response but has long lasting effect due to degradation of the receptor. Down-regulation and tolerance increased response to a drug following increased synthesis of receptors sensitization adaptive response that is a result of receptor blockade (long term treatment with antagonist) Sensitization Results with loss of endogenous ligand sensitization long term treatment with antagonist receptor blockade what are the common alpha q/11 receptor types Alpha 1 adrenergic receptor, angiotensin these receptors are multiprotein subunits usually tatramer or pentamer and make a pore through wich positively or negatively charged molecules flow ligan gated ion-channels what is the timeframe of action of ion channel receptors miliseconds receptors that produce an effect by altering cell's membrane potential ion channel receptors polypeptide receptor that has extracellular hormone binding domain, cytoplasmic enzyme domain, hydrophobic segment that connects the binding domains. tyrosine kinase receptors what is the time frame of action for tyrosine kinase minutes/hours/days receptors effects are on cellular function as well as the regulation of the transcription of gene involved in cell growth and differentiation tyrosin-kinase receptor what are 4 endogenous activators of tyrosin kinase receptors insulin, epidermal growth factor, platelet-derived growth factor, and atrial natriuretic factor. polypetide receptor with extracellular hormone binding domain hydrophobic segment that connects domains, separate mobile tyrosine kinase JANUS KINASE (JAK) Cytokine receptor Receptor that regulates genes involved in synthesis and release of many inflammatory mediators and hematopoeitic factors Cytokine receptor What is the time frame of action of a cytokine receptor hours to days Endogenous activators of cytokine receptors cytokines, growth hormones, erythropoietin, interferon hormone binding receptor with DNA binding domain transcription activating domain which primarily acts to regulate gene transcription intracellular receptors What is the time frame of action of an intracellular receptor hours/days What are the endogenous activators of intracellular receptors corticosteroids
mineralcorticoids
sex steroids
vitamin D
thryoid hormone Drugs that act at nuclear receptors are hydrophobic What are the 4 types of bond in decreasing bond strengths covalent bond
ionic bond
hydrogen bond
Van der Waals measurement of how readily a molecule will bind to a receptor binding affinity Kd concentration of drug required to bind 1/2 of the receptors in a fixed population Kd binding affinity The Higher Kd of the drug the _______ its affinity for the receptor the lower its affinity for the receptor high Kd equals low affinity binding of a drug to a receptor can be reversible or irreversible true or false true true or false binding of a drug to the receptor is a stereoselective reaction true lock and key theory True or false specificity of drug to receptor is not absolute and therefore you can get side effects true L+R <—> LR* —–> biological response law of mass action
L=ligand
R=receptor
R* activated receptor end result of ligand receptor interactions
can be biochemical, physiological or both biologic response- only specific drug-receptor complexes will produce biological response what is the equation for Kd Kd= [L][R]/[LR] ability of a ligand to induce the receptor to adopt an active conformation to get a biological response efficacy Efficacy is measured bewteen what 0-1 substance which bind a receptor and produces a biological response agonist substance which has a maximum biological response can reach that response be either activating 100% or less of the receptors have an efficacy of 1 full agonist A substance that produces even at highest concentrations and 100% receptor binding less than maximum response of system efficacy less than 1 partial agonist substance that produces a decrease in basal activity of a system inverse agonist compounds that increase the affinity or efficacy of agonists for the receptor and act at a site other than the active site allosteric agonist or enhancers What is a chemical antagonist and name an example direct chemical interaction between agonist and antagoinist in such a way that renders the agonist pharmacologically inactive such as chelating agents what is physiological antagonism interaction of two agonists that act independantly but happen to cause opposite effects and cancel each other out. actylcholine and epinepherine's actions on the heart substance that inhibits a biological response by acting at a site beyond the receptor and can block agonist acting through more than one receptor. indirect antagonism Most frequently encountered type of agonist encountered in clinical practice agonist and antagonist compete for the binding site on the receptor competitive antagonist has affinity but no efficacy Types of competitive antagonists reversible antagonist- (equilibrium competitive antagonist)
irreversible antagonist- (nonequilibrium competitive antagonist)
Allosteric Antagonism type of competitive antagonist that binds reversibly to receptor antagonist can be overcome by agonist at receptor reverible antagonism type of competitive antagonist that binds irreversibly via covalent bond to the receptor cannot be overcome by agonist at receptor Irreversible antagonist Chemical compound that reduces the affinity and or efficacy of agonist for receptors by binding and altering receptors conformation binds to distinct location than agonist binding region allosteric antagonist