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Principles of Drug 1
| Question | Answer |
|---|---|
| J.N Langley | early 1900s. Physiology. studied effects of procarpine and atropine on smooth muscle. Proposed that there were 'substances' in tissue that react with chemicals to produce contractions. |
| Isolated nerve-skeletal muscle preparation | J.N. Langley. observed that nicotine caused muscle contraction and curare blocked the effect. Demonstrated that effects were not directly on nerve or muscle, but related to binding to a "receptive substance" |
| Paul Erlich | early 1900s. Chemist. Initially studied specificity of dyes used to stain tissue. need 'right sort of affinity'. |
| Synthesized organic chemicals to treat infectious disease | Paul Erlich. Proposed that by altering chemical structure, chemicals could bind and kill organisms without harming host.Chemical receptors in microorganismscan serve as target for chemical 'magic bullet' |
| Salvarsan | Paul Erlich discovered. An organic mercurial (killed spiroketes) intorduced in 1907 to treat syphilis |
| Alfred J. Clark | 1920s. Described drug-receptor relationship in quantitative terms. Assumed that drug-receptor interaction was analogous to adsorption of gasses on metal surface (Langmuir's isotherms) ex. a reversible rxn governed by laws of mass action. Occupancy Theory |
| Occupancy Theory | Action prop to # of receptors occupied. Occupation follows law of mass action. receptors identical and equally accessible (1 drug reacts w/ 1 receptor). drug bound-miniscule compared to drug present in organism. Max drug response-all receptors occupied |
| E.J Ariens | 1950s. If occupancy of receptor were sufficient to produce effect, then all drugs acting on receptors would produce the same max effect (not the case-dif. max effects). coined term intrinsic activity describes effectiveness of drug receptor complex |
| Drug-Receptor Interaction | equation relates drug dose, receptor density and response-hybrid of Clark and Ariens' theories D+R yields DR complex yields effect |
| affinity of a drug for receptor | related to propensity of the DR complex to form divided by the propensity of it to dissociate (K1/K2) |
| intrinsic activity (efficacy) of drug | related to magnitude of K3. @ molecular level, K3 describes intracellular events that occur subsequent to receptor binding, results in observed physiological effect |
| Agonist (full agonist) | ex morphine. possess both affinity and efficacy. binds to receptor and produces effect (K3=1) |
| Partial agonist | possess affinity, but lower efficay than full agonist that binds to same receptor. Have lower maximal effect than full agonist. ex Tramadol and propoxyphene. 0 |
| Antagonist | possess affinity but lack efficacy. Have no agonist activity, block binding of agonist drug or endogenous agonist chemical to receptor. K3=0 ex. Naloxone |
| Drug receptors | macromolecules with complex (unique) structures located on cell membranes or intracellularly. ex proteins and nucleic acids |
| Antibiotics and anticancer drugs | interact with DNA/RNA to kill cells |
| Aspirin | inhibits enzyme cyclooxygenase which inhibits formation of prostaglandins (chemical initiators and perpetuators of inflammation and pain). ecostinoids |
| Morphine | relieves pain by mimicking action of specific peptide neurotransmitters in brain (endorphins) |
| Propranolol | Inderal. Beta blocker. decreases heart rate & blood pressure by blocking norephinephrine receptors in heart (NE normally increases heart rate when released by autonomic nervous system) |
| Diazepam | Valium. binds to 'benzodiazepine' (BDZ) receptors in brain to produce sedation (no endogenous ligand for receptor has been identified). produces antianxiety effect |
| Non-specific acting drugs | antacids(bases)relieve heartburn by neutralizing stomach acid. Produce beneficial therapeutic effect w/o binding to specific receptor molecules |
| Structure Activity Relationships | many drugs chemically resemble endogenous transmitters or hormones so they can 'fit' into protein receptors for endogenous chemicals |
| Binding forces in drug-receptor complexes | typical chemical forces-covalent, ionic, hydrogen, Van derWaals bonds. Slight chemical change in molecule can greatly change these forces and increase or decrease the affinity of drugs for receptors |
| Many drug-receptor interactions | stereoselective. racemic mixtures-1 isomer can be effective while the other is ineffective |
| Drug binding to other macromolecules other than primary receptor | many unwanted or adverse effects may result |
| Individual receptors | proteins. genetically determined. genetic variability in drug response is common |
| Comparing drugs | differences in potency are related to differences in either affinity or efficacy, or both. Differences in max effect (related to K3) are related to efficay differences |
| Individualized Medicine | use genetics of a specific individual to come up with dosage instead of making a best guesstimate |
| Drug-drug antogonism | one drug may antagonize the effects of another by competing for the same receptor |
| Changes in receptors from repeated drug administration | often accounts for the phenomenon of drug tolerance. Could be due to structural changes in the receptor or to a decreased # of receptors(down-regulation)-need to give increased doses to get previous effect |
| Drug binding avidly to a receptor | pharmacological response may still be seen although blood levels of drug are not detectable. *covalent bonds-aspirin to cyclooxygenase |
| Administration of a drug | is an finite time until response is seen(onset of action) and a finite duration of action. Determined by the amount of time it takes to reach critical [drug] @ receptor and how long concentration can be maintained |
| Dose and Response | related. intensity of a response is related to the [drug]at receptor site which is in turn dependent on dose |
| Drug highly lipid soluble | can dissolve in and cross the lipid cell membrane. drug then combines w/an intracellular receptor. ex an enzyme or nuclear DNA sequence |
| Activating intracellular enzymatic activity | drug binds to the 'outside' of a transmembrane protein |
| Tyrosine Kinase | drug binds to the 'outside' of transmembrane bound to this protein which it activates |
| Ligand gated transmembrane ion channel | drug binds and opens or closes the channel |
| Transmembrane receptor protein drug binding | stimulates a signal transducer protein [G-protein] which in turn generates an intracellular message |
| Threshold | for most drugs, this is the concentration in the body below which no effect is seen |
| Response | effect increases as dose increases |
| Max effect | point where increasing dose no longer increases response |
| Graded dose response curves | plot dose vs. response as a percent of max response attainable. curve can be made from data recorded in whole animal or person or from an isolated tissue preparation. hyperbolic in nature-response increases as drug does |
| Examples of graded dose response curves | ex.1. dose of morphine vs. %pain relief(no effect to complete reflief) ex.2. contraction of isolated smooth muscle(guinea pig ileum) as increasing concentraions of acetylcholine are added to bath |
| ED50 | dose producing 50% of maximum response. measure of drug potency. Acetylcholine is more potent stimulant of smooth muscle contration than the chemical analog propionylcholine |
| Graded dose response curve uses | compare potencies of drugs. when both curves are plotted on an arithmetic scale comparisions are difficult because of the large differences in dosage range. |
| Convenient way to depict dose-response data | plot response against log of dose. hyperbolic curves now assume sigmoidal shape "S" and comparisons of ED50's easier. curves show difference in potency b/w ACh and PrCh, but efficacy the same (full agonists capable of producing 100% contraction) |
| Pilocarpine | drug that mimics many endogeneous effects of acetylcholine. curves show that pilocarpine is less potent than ACh and has a lower efficacy(lower max effect) |
| Drugs competing for receptors | if drug administered in presence of pharmacological antagonist, dose response curve is changed. if higher doses of agonist displaces antagonist, same max effect reached, but dose response curve shifts to right. looks like curve for dif potencies |
| Antagonist binds strongly to a receptor | ex. covalent binding. large amounts of agonist can not displace it. max response attainable is lowered in the presence of the antagonist. curve looks like that of a full and partial agonist |
| Quantal dose response curve | plots dose(or log dose) of drug against # of aminals/ppl demonstrating predetermined response. ex. mice in groups&give dose to each mouse. Dif doses per group. record # mice /group that experience anticipated response(falling asleep-lose righting reflex) |
| Drugs with more than one effect | dose response curve made for each effect. ex. barbituates produce therapeutic effect(sleep) or toxic effect(death). |
| LD50 | dose that kills 50% of the animals |
| Therapeutic index | rough measure of safety. LD50/ED50; bigger the index, the safer the drug. NTI-drugs with narrow therapeutic index. indication of separation b/w midpoint of therapeutic and toxic dose response curves. Does not take into account slopes (shapes) of curves |
| Certain Safety Factor | CSF. if CSF<1, overlap exists b/w tail of curve. CSF=1, no overlap. LD1/ED99 |
| Statistical view of quantal dose response curve | curve is cumulative form of a normal(bell-shaped) frequency distribution. In large population, some ppl affected by small dose of drug, most by 'normal' dose and some only be larger doses |
| Aspirin | used for over a century in medicine. has several prominent used:analgesic(relief of pain), antiinflammatory(relief of inflammation), antipyretic(reduction of fever), antiplatlet effect(reduction of platlet adhesion) |
| Willow bark extracts | used in aspirin and related compounds. (analgesic) found to contain the glucoside salicin (1829) |
| Chemical modification of salicin | led to production of salicylic acid. Although this has analgesic activity, was too irritating to GI tract for clinical use |
| Salts of salicylic acid | ex. sodium salicylate(1875). synthesized and used as oral analgesics since late 1800s |
| Introduction of aspirin | 1899 and has been the 'prototype' analgesic/antiimflammatory drug since then. FDA approved 1939 |
| Mechanism of action of aspirin | aspirin has been used foa a century, but only during the last 35 years that appreciation of how aspirin works has been forthcoming (salicin) hydrolysis oxidation yields (salicylic acid) yields (sodium salicylate) acetylation yields(aspirin) |
| Kurzrok and Leib | 1930 they observed that strips of human uterus actively relax or contract when exposed to human semen |
| von Euler | late 1930s reported muscle contracting activity in seminal fluid. Named the lipid soluble acid "prostaglandin". chemicals found in prostate gland really from seminal vescicle |
| Bergstrom and Samuelsson | more than 20 yrs after von Euler, they isolated and elucidated structure of several prostaglandins and later showed that they were synthesized from a 20-carbon fatty acid known as arachidonic acid. |
| Sir John Vane | 1971, demonstrated that aspirin and related compounds inhibited prostaglandin biiosynthesis and proposed that this inhibition was important mechanism of action of aspirin |
| Bergstrom, Samuelsson and Vane | 1982. won Nobel prize for their work |
| Organic Acids | contain a carboxyl moiety (COOH). Fatty acids are a straight chain of methylene groups terminating with COOH group. Saturated fatty acids contain no double bonds; unsaturated fatty acids contain one or more double bond |
| Transfatty Acids | partially hydrated |
| Glycerol | "poly-alcohol" that forms the backbone of triglycerides and phospholipids |
| Acetic Acid | CH3COOH |
| Butyric Acid | CH3CH2CH2COOH |
| Stearic Acid | CH3(CH2)16COOH-saturated |
| Oleic Acid | CH3(CH2)7CH=CH(CH2)7COOH-unsaturated |
| Arachadonic Acid | CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3COOH-polyunsaturated |
Created by:
arr61
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