Term
| Objectives of Analysis of Drug Action |
|
Definition
A. Identify primary action of drug as distinguished from discussion of resultant effects.
B. Delineate at the molecular level the chemical and/or physical interactions between the drug and site of action
C. Characterize the full sequence and scope of the concentration (dose)-response relationships
D. These will provide for the rational therapeutic use of a drug and the design of new and superior therapeutic agents |
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Term
| Sites of Action (Receptors) |
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Definition
| Membrane proteins, structural proteins, cytoplasmic enzymes, extracellular enzymes or nucleic acids |
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Term
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Definition
| Linear sequence of amino acids connected through amide bonds. All of the covalent bonding within proteins defines the primary structure. |
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Term
|
Definition
| Local ordered structure brought about via hydrogen bonding mainly within the peptide backbone. Most common are alpha helix and strands of beta sheets. |
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Term
|
Definition
| Global folding of a single polypeptide chain. Major driving force in determining the structure is the hydrophobic effect. Stabilized by disulfide bonds between cyteine residues. |
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Term
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Definition
| Made of several protein molecules or polypeptide chains called protein subunits. Stabilized mainly by noncovalent interactions. |
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Term
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Definition
| Generated when a single polypeptide chain turns about itself to make a cylinder; transmembrane regions of receptors are formed by helices because of the constraints imposed by the hydrophobic lipid environment, between 19-24 amino acids |
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Term
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Definition
| Core of most globular proteins, formed by regions of polypeptide chain running in same or opposite direction |
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Term
| Signals can enter cells in several ways: |
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Definition
| Hormones, growth factors, neurotransmitters, steroid hormones |
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Term
| Two axioms of molecular level drug-initiated response |
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Definition
1. The drug molecule and the biological molecule must interact
2. The interaction mus result in selective binding of the drug to the biological molecule before the molecular level drug-initiated response occurs. |
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Term
|
Definition
| Usually an integral membrane protein which is embedded in a cellular or subcellular membrane and facilitates communication between the two sides of the membrane |
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Term
|
Definition
| Drugs which bind reversibly to the receptor and activates receptor-based processes. Mimics the effect of endogenous regulatory compounds |
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Term
|
Definition
| Drugs which bind reversibly and irreversibly to the receptor and have no intrinsic regulatory activity. Binding interferes with the action of the agonist. |
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Term
| Dissociation constant or equilibrium binding constant: Kd |
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Definition
| defines the concentration of drug at which the receptors are half-maximally saturated |
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Term
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Definition
| the degree to which an agonist preferentially binds to a receptor |
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Term
| 3 functions of a receptor-effector system |
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Definition
1. Ligand binding
2. Signal transmission
3. Intracellular messengers |
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Term
| What kind of membrane-pass is a neurotransmitter-gated ionic channel? Voltage-gated ionic channel? G-protein coupled receptors? |
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Definition
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Term
| What does it mean when you have high-affinity and low-affinity binding sites for the ligands on a scatchard plot? |
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Definition
| When it indicates two slopes, it means that there are two receptor subtypes of the same receptor present. If the radioisotope was not specific enough it could have two different types of receptors. |
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Term
| Characteristics of receptor subtypes |
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Definition
| Different anatomical distributions, tissue-specific functions, developmental profiles and/or fundamental differences in their biochemical regulatory activities |
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Term
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Definition
| Sometimes two or more of the same endogenous molecule must bind to the receptor to generate a signal |
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Term
| Neurotransmitter (ligand)-gated ionic channels (and name 5) |
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Definition
Receptors operating via direct receptor control of ion channels.
1. Actylcholine nicotinic
2. Glutamate receptors NMDA type and non-NMDA type (AMPA) (Quisqualate & Kainate)
3. GABA (a and c)
4. Glycine Receptor
5. Opiate receptors |
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Term
| Name 3 examples of voltage-gated ionic channels |
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Definition
1. Sodium channel
2. Calcium channels (L,T,N,P/Q AND R)
3. Potassium channels |
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Term
| Name three functions of receptors coupled to GTP-binding proteins? |
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Definition
1. Activate adenylate cyclase
2. Inhibit adenylate cyclase
3. Activate phosopholipase C or A
which lead to generation of second messengers |
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Term
|
Definition
| Activate adenylate cyclase (B1 and B2 adrenergic receptors, dopamine 1 & 5, glucagon, PGE, serotonin 4 & 7, histamine 2 |
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Term
|
Definition
| Inhibit Adenylate cyclase, a2 adrenergic, AChM2 & 4, dopamine 2,3,4 , opioid, adenosine 1, GABA b, metabotropic glutamate 2,3,4,6,7,8), serotonin 1 |
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Term
|
Definition
| Activate phosopholipase, a1 adrenergic, AchM1,3,5; dopmaine 1, serotonin 2, thyrotropin releasing hormone, mGlur1,5 |
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Term
| What activate phosoplipiase A2? |
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Definition
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Term
| What is an agonist-regulated enzyme and name examples |
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Definition
| They are enzymes with intrinsic enzyme activity such as tyrosine kinase, guanylyl cyclase, serine/threonine kineases, and cytokine and growth hormone receptors |
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Term
| Tyrosine Kinase: Name 5 things about it |
|
Definition
1. Contains a kinase activity capable of phosphorylating proteins on tyrosine residues. Can use ras-raf-MEK-MAP kinease pathway to phosphorylate sustrates and/or translocate to the nucleus
2. Involved with anabolic processes such as growth and differentiation
3. Endocrine hormone receptors
4. Growth factor receptors
5. Receptors for different oncogenes |
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Term
|
Definition
1. Synthesizes cGMP from GTP
2. Atrial natriuretic peptide receptors
3. Nitric oxide receptors |
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Term
|
Definition
| Receptors for activins, inhibins |
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Term
| Cytokine and Growth Hormone Receptors |
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Definition
1. Interleukins (1-12) and Growth Hormone
2. Signal through JAK-STATS |
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Term
| 5 kinds of Drug Receptors |
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Definition
1. Neurotransmitter
2. Voltage-gated ionic channels
3. Receptors coupled to GTP-binding proteins
4. Agonist-regulated enzymes
5. Receptors operating via soluble DNA-binding proteins |
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Term
| soluble DNA binding proteins |
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Definition
1. Steroid hormones
2. Thryoid hormones
3. Vitamin D
4. Retinoids |
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Term
| Neurotransmitter (ligand)-gated ion channels with four alpha helical, hydrophobic, transmembrane regions |
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Definition
1. Nicotinic cholinergic receptor
2. Glutamate and glycine receptors
3. GABAa and GABAc receptors |
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Term
| C protein-coupled receptors: neurotransmitter (ligand)-activated channels with seven alpha helical, hydrophobic transmembrane regions |
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Definition
1. Beta adrenergic receptors
2. Alpha adrenergic receptors
3. AChM receptors
4. Dopamine receptors
5. Serotonin receptors
6. GABAb
7. metabotropic glutamate
8. Rhodopsin |
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Term
| Voltage-gated ion channels with six alpha helical, hydrophobic transmembrane regions |
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Definition
1. Sodium channel
2. Calcium channel |
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Term
| The l-type calcium channels in plasma membrane are responsive to what 3 calcium channel antagonists |
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Definition
1. Hihydropyridines (nifedipine, nimodipine)
2. Phenyalkylamines (verapamil)
3. Benzothiazepines (diltiazem) |
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Term
|
Definition
1. Responsive to calcium channel antagonists
2. IP3 sentivie channels
3. Ryanodine/caffeine-sensitive channels |
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Term
| Cyclic-nucleotide gated channels |
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Definition
1. cGMP-gated channel: rod outer segment
2. cAMP-gated channel: olfactory epithelium |
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Term
|
Definition
1. Control specific gene expression by hormone-dependent regulation of transcription acting on HRE
2. Retinoic acid, Vitamin D, thyroid hormone |
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Term
| 4 ways to regulate receptor signaling and responsiveness |
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Definition
1. The manner in which it respons to a drug depend on its past history and its present state
2. Receptor recognition
3. Signal relay pathways
4. Regulation of ligand or hormone responsiveness |
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Term
|
Definition
| Ligand binding must be reversible, have high affinity, and be specific and initiate catalytic activity |
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Term
|
Definition
1. Second messengers (cAMP, cGMP)
2. Protein phosphorylation-dephosphorylation: serine-treonine kinases such as cAMP-dependent protein kinase
3. Protein-protein interactions |
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Term
| Name a few second messengers |
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Definition
| cAMP, cGMP, Ca2+, IP3, DAG, Arachidonic acid, NO |
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Term
| Protein phosphorylation-dephosphorlylation |
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Definition
| serine-threonine kinases such as cAMP-dependent protein kinase, PKC, CA2_/CaM kinase |
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Term
| Protein-Protein interactions (examples) |
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Definition
| steroid hormones and regulation of gene transcription |
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Term
| Regulation of Ligand or Hormone Responsiveness |
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Definition
1. Receptor desensitization
2. Homologous desensitization
3. Heterologous desensitization |
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Term
|
Definition
Intensity of a biological response decreases over time despite the continued presence of a stimulus of constant intensity.
a) rapid: change in receptor affinity or signaling effciency, mediated by protein kinases
b) intermediate: alteration in receptor number due to internalization or degradation
c) slow: alterated rate of receptor synthesis: up or down regulation |
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Term
| Homologous desensitization |
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Definition
| Stimulation by one specific agonist causes decreased sensitivity to stimulation by that same agonist while others types remains normal |
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Term
| Heterologous desensitization |
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Definition
| stimulation by one agonist leads to a decreased responsiveness to a structurally unrelated agonist |
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Term
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Definition
| location of the concentration (dose)-response curve along the concentration axis, can affect dosage |
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Term
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Definition
| maximal effect that can be produced by a drug. determined by the intrinsic properties of the drug and its receptor-effector system. |
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Term
| Slope of concentration-effect curve |
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Definition
| reflects the mechanism of action of the drug, including shape of Scatchard plot. Steepness of the curve dictates range of doses useful for achieving clinical effect. |
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Term
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Definition
| Inhibition produced by an antagonist can be overcome by increasing the concentration of the agonist achieving the same maximal effect |
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Term
| Noncompetitive antagonist |
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Definition
| Reversible or irreversible interaction of the antagonist at an allosteric site so that the effect produced by the agonist is decreased; if the drug dissolves in the membrane or interacts with a 2nd messenger, this is referred to as antagonist III |
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Term
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Definition
| concept wherein a maximal apparent effect is achieved when a relatively small fraction of receptors is occupied. When there are spare receptors present, the concentration of drug required to produce a half-maximal effect is less than the Kd. |
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Term
| When are spare receptors encountered? |
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Definition
1. Whenever a receptor acts catalytically
2. When drugs acts to inhibit a step in a reaction sequence |
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Term
| Individual effective concentration |
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Definition
| concentration of a drug that produces a specified effect in a single patient, effect is either present or absent thus a quantal response |
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Term
| Quantal dose-effect curve |
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Definition
| Cumulative frequency distribution of individuals achieving the defined effect as a function of dose |
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Term
| Median effective dose: ED50 |
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Definition
| dose of a drug required to produce a specified effect in 50% of the population |
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Term
|
Definition
| the dose of drug required to kill 50% of the animals |
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Term
| Therapeutic Index: TI = LD50/ED50 |
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Definition
| Ratio used to determine how selective a drug is in producing a desired effect or the safety of the drug. When the ratio is less than 2.0, the compound can be difficult to use in patients without encountering toxicity. |
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Term
| Hyperreactive or hyporeactive |
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Definition
| Refers to individual in whom a drug produces its usual effect at unexpectedly low or high doses |
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Term
|
Definition
| decreased sensitivity to a drug due to previous exposure at the same concentration to the drug. A phenomenon whereby repeated doses of the same concentration of a drug produces a progressively diminishing effect |
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Term
|
Definition
| rapid development of tolerance |
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Term
|
Definition
| usually refers to allergic reactions to a drug and should not be confused with hyperreactivity |
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Term
|
Definition
| a different or unexpected reaction that occurs in a small percentage of patients, not necessarily dose related |
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Term
|
Definition
| use of several drugs is often essential to obtain a desired therapeutic effect or to treat coexisting diseases, increases with age |
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Term
| Important Factors that can affect therapeutic outcome |
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Definition
1. Drug-Drug Interactions
2. Protein binding of drugs
3. Pharmacodynamic interactions
4. Genetic factors |
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Term
|
Definition
| Many drugs are extensively bound to plasma albumin (acidic) or a1-acid glycoprotein (basic drugs) |
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Term
| Pharmacodynamic interactions |
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Definition
| Drug interactions at common receptor site or have additive or inhibitory actions at different sites in an organ |
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Term
|
Definition
| major determinants of the normal variability of drug effects and for the striking qualitative and quantitative differences in pharmacological activity of drugs. Greatest effects occur in metabolic processes that are under monogenic control |
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Term
|
Definition
| study of the time course of absorption, distribution, metabolism, and excretion of drugs and their metabolites in the intact organism |
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Term
| What are several factors in transfer of drugs across membranes? |
|
Definition
A. Physiochemical characteristics of the drug
B. Bulk flow
C. pH of selected body fluid or compartments
D. Henderson-Hasselbach Equation |
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|
Term
| Physiochemical characteristics of the drug |
|
Definition
1. Molecular size <200 pass through cell membranes
2. Shape
3. Ionization constant
4. Solubility at site of absorption
5. Relative lipid solubility of its ionized and nonionized forms |
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Term
|
Definition
| accumulation of drug on side of membrane where drug is most highly ionized. Weak bases are passively concentrated in the stomach |
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Term
| Weak acid & weak bases better absorbed where? |
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Definition
| Weak acids are readily absorbed from the stomach. Weak bases are better absorbed from the intestines. |
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Term
|
Definition
a) pH = pKa + log ( [proton acceptor] / [proton/donor]
b) weak acid: pH = pKa + log ( [A-]/[HA]
c) weak base: pH = pKa + log ( [B]/[BH+] |
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Term
|
Definition
| describes rate at which drug leaves site of administration and extent to which this occurs |
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Term
|
Definition
| indicates the extent to which a drug reaches its site of action or a biological fluid from which the drug has access to its site of action |
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Term
|
Definition
| if a drug passes through the liver before it reaches the systemic circ and is metabolized in the liver/excreted in the bile since this will decrease bioavailability |
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Term
| Factors that modify absorption |
|
Definition
1. Physiochemical characteristics of the drug
2. Drug solubility
3. Concentration of the drug
4. Blood flow to site of absorption
5. Area of absorbing surface
6. GI emptying time and intestinal motility |
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Term
|
Definition
1. Oral
2. Sublingual
3. Intravenous
4. Subcutaneous
5. Intramuscular
6. Inhalation
7. Rectal
8. Topical |
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Term
| Factors that influence distribution |
|
Definition
1. Blood flow
2. Capillary permeability
3. Cell membrane transport
4. Drug reservoirs |
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Term
|
Definition
| Heart, liver, kidney, lung, brain, urogenital, retina |
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Term
|
Definition
| Muscle, viscera, skin, fat, bone, aqueous humor |
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|
Term
| Two kinds of drug reservoirs |
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Definition
1. Plasma proteins
2. Tissue reservoirs |
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Term
| 2 kinds of plasma proteins and what do they bind |
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Definition
1. Plasma albumin: binds acidic drugs
2. Alpha-1-acid glycoprotein: binds basic drugs |
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Term
| 4 Tissue reservoirs and what do they bind |
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Definition
1. Bone & Teeth: tetracycline, lead, and have slow release
2. Fat: binds highly lipid soluble drugs and toxicants
3. Lung: binds amine drug to phospholipids
4. Eye: melanin binds atropine, phenothiazines |
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Term
| Biological functions of metabolism |
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Definition
1. To form compounds which are more polar and less lipid soluble
2. Enhance excretion of endogenous chemicals, drugs, and toxicants |
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Term
|
Definition
1. Liver smooth endoplasmic reticulum: major
2. Kidney: ~3% of liver
3. Gi epithelium, lung, skin: less |
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Term
| What are three examples of Phase-I reactions? |
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Definition
| Phase I reactions are non-synthetic reactions such as metabolic transformations, catalase, Cu/Zn superoxide dismutase |
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Term
| What is metabolic transformation and give examples. |
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Definition
| Produce more polar metabolites which may be inactive, less active or more active than parent such as oxidation reactions, reduction, hydrolysis of esters and amides. Only microsomal is oxidation reaction. |
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|
Term
| What are Phase-II reactions? |
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Definition
| They are synthetic reactions which produce more polar metabolites which are less active than parent molecule |
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Term
| Give some examples of conjugations? |
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Definition
1. microsomal: glucuronide
2. non-microsomal: acylation, methylation, sulfation, dehalogenation, glutathione |
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|
Term
| What factors affect drug biotransformation? |
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Definition
1. Genetic polymorphisms
2. Drugs or toxicants can induce or inhibit P450 enzymes
3. Drugs or intoxicants can induce or inhibit P450 enzymes
4. Liver and kidney disease
5. Diet |
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|
Term
| What are some examples of genetic polymorphisms that affect drug biotransformation? |
|
Definition
a. inherited autosomal recessive traits
b. decreased synthesis of enzyme leading to decreased activity
c. point mutations in CYP2C9 leading to decreased enzyme activity
d. increased synthesis of enzyme leading to increased activity |
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Term
| How can drugs or toxicants induce P450 enzymes? Give 2 examples. |
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Definition
1. Clofibrate induces CYP4A1 and CYP4A2
2. Phenobarbital, cigarette smoke, tobacco, polycyclic aromatic hydrocarbons induce CYP1A2 |
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Term
| 2 examples of how diet can influence drug biotransformation? |
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Definition
1. Inducers of CYP1A1 and 1A2: crunchy vegetables and charcoal-broiled foods
2. Inhibitor of CYP3A: grapefruit juice |
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Term
| Name several sites for excretion of drugs and metabolites. |
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Definition
| 1. Kidney (major site) 2. Biliary 3. Fecal 4. Lungs 5. Sweat, saliva, milk, tears, hair |
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Term
| What does alkalinization of urine with NaHCO3 do as compared to acidificiation of urine with NH4CL |
|
Definition
1. Increases polarity of weak organize acids, increases excretion of aspirin, phenobarbital
2. Increases polarity of weak organic bases, increases excretion of amphetamine, imipramine |
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Term
|
Definition
| a measure of the body's ability to eliminate a drug which is expressed in volume per unit time |
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Term
| When is steady state reached assuming complete bioavailability? |
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Definition
| It is reached when rate of drug elimination equals the rate of drug adminstration |
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Term
| Most drugs follow what order kinetics? |
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Definition
| They follow first-order kinetics. A constant fraction of drug is eliminated per unit time |
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Term
| What happens to the kinetics if the mechanism for drug elimination becomes saturated? |
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Definition
| It becomes zero-order and a constant amount of drug is eliminated per unit time. Two examples are salicylic acid and ethanol. |
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Term
| What is the volume of distribution? (HINT: concept used with IV dose) |
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Definition
| Amt of drug in the body to the concentration of drug in the blood or plasma. Refers to a volume that would be required to contain all of the drug in the body at the same conc as the blood or plasma. May vary depending on the pKa, and binding. Can change as a function of age, disease, gender, body comp |
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Term
|
Definition
| Time it takes for plasma conc or amt of drug in body to be reduced to 50% |
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Term
| How many doses to reach steady-state and what percent? |
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Definition
| 4 half lives to reach 94% of a new steady state and 5 half-lives to 97% |
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Term
|
Definition
| One/or/series of doses that may be given at the onset with the aim of achieving the target conc rapidly. Main disadvantage is toxicity. |
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Term
|
Definition
% of total P450: 12.7 +/6.2
Substrates: Phenacetin, Caffeine, Aflatoxin B
Selective Inhibitors: Ellipticine
Sources of Variability: Smoking, omeprazole, genetic polymorphism, 12% PM |
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Term
|
Definition
% of total P450: 12.7 +/6.2
Substrates: Phenacetin, Caffeine, Aflatoxin B
Selective Inhibitors: Ellipticine
Sources of Variability: Smoking, omeprazole, genetic polymorphism, 12% PM |
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Term
|
Definition
4.0 +/- 3.2
Substrates: coumarin, dimethylinitrosamine
Selective Inhibitors: methoxalen
Sources of variability: pyrazole, genetic polymorphism |
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|
Term
|
Definition
.2 +/ .3
Substrates: Cyclophosfamide
Selective Inhibitors: sulfahaphenazole |
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Term
| Sympathetic Nervous System: Thoracolumbar |
|
Definition
1. Fight or flight
2. SHORT myelinated (B-type fibers) preganglion neurons exit the spinal cord at the THORACIC and LUMBAR levels
3. Postganglion to preganglion is 100:1
4. POST ganglion is LONG (C-type fibers) |
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Term
| Parasympathetic Nervous System: Craniosacral |
|
Definition
1. Housekeeping, recovery and rest
2. LONG, myelinated (B-type fibers) preganglion neurons exit spinal cord at cranial and sacral levels
3. Innervates structures in head, neck, thorax, abdomen; travel in CN3, 7, 9, 10
4. Postganglion are SHORT
5. Pregang: Postgang: 1:1 |
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Term
| 5 Essential Features of Neurotransmission |
|
Definition
1. Synthesis
2. Storage
3. Release
4. Interaction with ligand binding sites
5. Termination of action (reuptake, enzymatic destruction, diffusion) |
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|
Term
| Name the three major neurotransmitter substances of demonstrated importance in the ANS |
|
Definition
1. Cholinergic transmitter:acetylcholine
2. Adrenergic transmitter: norepinephrine and epinephrine |
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|
Term
| Synthesis and catabolism of AcH |
|
Definition
1. Acetyl CoA + coline - (CAT) --> ACh
(CAT is choline acetyltransferase)
2. ACh - (AChEase) --> choline + acetate
(ACHEase = acetylcholinesterase) |
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|
Term
| Name several neurotransmitter substances of importance in the ANS |
|
Definition
| Dopamine, serotonin, ATP, substance P, endorphins, vasoactive intestinal polypeptide |
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|
Term
| What are some sites of cholinergic transmission? (release AcH) |
|
Definition
A) ALL AUTONOMIC GANGLIA
B) PARASYMPATHETIC POSTGANGLION NEURON
C) NEUROMUSCULAR JUNCTION |
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|
Term
| What are some sites of adrenergic transmission? (Releases NE or EPI) |
|
Definition
A) SYMPATHETIC POSTGANGLION NEURON (NE)
B) ADRENAL MEDULLA (80% EPI AND 20% NE) |
|
|
Term
| Give some examples of cholinergic nicotinic postsynaptic receptors in the ANS. |
|
Definition
a. all autonomic ganglia (C6 type)
b. adrenal medulla (C6 type)
c. neuromuscular junction (C10 type) |
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|
Term
| How does cholinergic muscarinic postsynaptic receptors affect the heart, smooth muscles, secretory glands, and CNS |
|
Definition
1. Heart: AChM2 can decrease heart rate, open K+ channels and inhibit adenylate cyclase
2. Smooth muscles: AChM2 and AChM3 (can active PLC-B causing contraction of smooth muscle)
3. Secretory glands: AChM3 (can activate PLC-B causing exocrine secretion)
4. CNS: AChM1,2,3,4,5 (1) stimulatory effects, close K+ channels, activate PLC-B, and activate PLA2 (2) can open K+ channels and inhibit adenylate cyclase (3) can activate PLC-B (4) inhibit adenylate cyclase, inhibit Ca@+ causing inhibition of neurotransmitter release (5) active PLC-B with unknown effects |
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Term
| Give some examples of alpha 1 and 2 adrenergic receptors agonists and antagonists. |
|
Definition
a1 agonist: phenylephrine
a1 antagonist: prazosin
a2 agonists: clonidine
a2 antagonist: yohimbine |
|
|
Term
| What is the a1 rank order of potency to ligands? |
|
Definition
| Epinephrine > norepinephrine > dopamine >isoproterenol |
|
|
Term
| Beta adrenergic receptors, where are they located? |
|
Definition
B1: located in the heart
B2: located everywhere else |
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|
Term
| What does BETA receptor stimulation usually lead to overall? in the GI tract, kidney, and heart. |
|
Definition
| Usually leads to some type of dilatory or relaxation response. In GI tract: both alpha and beta produces relaxation of smooth muscles; kidney: leads to renin secretion; heart: increases heart rate and contractility |
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Term
|
Definition
| Isoproternol > Epinephrine = Norepinephrine > Dopamine |
|
|
Term
|
Definition
| Isoproterenol > Epinephrine > > Norepinephrine > Dopamine |
|
|
Term
| Give some examples of presynaptic autoreceptors/heteroreceptors in the ANS on sympathetic nerve terminals. |
|
Definition
1. a2 receptors inhibit NE release
2. b2 receptors facilitate NE release
3. Muscarinic receptors inhibit NE release - AChM2 |
|
|
Term
| Give some examples of presynaptic autoreceptors/heteroreceptors in the ANS on parasympathetic nerve terminals. |
|
Definition
1. Muscarinic receptors inhibit ACh release - AChM2
2. Nicotinic receptors facilitate ACh release
3. A2 receptors inhibit ACh release |
|
|
Term
| What is the mechanism for B1- or B2-adrenergic receptors? |
|
Definition
| Agonists bind to B1- or B2 receptors -> receptor-agonist complex binds to Gs-protein -> GTP for bound GDP exchange -> activation of Gas -> activation of adenylate cyclase -> ATP is converted to cAMP -> activation of cAMP-dependent protein kinase -> phosphorylates intracellular proteins -> pharmacological response |
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|
Term
| What is the mechanism for a2-adrenergic, AChM2, AChM4 receptors? |
|
Definition
1. coupled to the inhibition of adenylate cyclase -> opposite effect of b-receptors
2. agonists bind to a2-receptors -> receptor-agonist complex binds to Gi-protein -> GTP for bound GDP exchange -> activation of Gai -> inhibition of adenylate cyclase -> decrease in conversion of ATP to cAMP -> decrease the activation of cAMP-dependent protein kinase -> inhibition of pharmacological response |
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|
Term
| What is the mechanism for a1-adrenergic, AChM1,3,5? |
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Definition
1. produce effects through increases in intracellular phosphotidylinositol turnover
2. Agonists bind to a1 or AChM receptors -> receptor-agonist complex binds to Gq-protein -> stimulation of membrane bound phospholipase C -> hydrolysis of PIP2 -> produces DAG and IP3
a) DAG activates PKC -> phosophorylation of intracellular proteins
b) IP3 acts to mobilize Ca from ER |
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Term
| Name 2 kind of pharmacological action that can be done in the GANGLIA |
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Definition
1. block transmission
2. activate receptor |
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Term
| Name 11 kinds of pharmacological actions that can take place in the SYNAPSE? |
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Definition
1. inhibit synthesis of neurotransmitter via enzyme inhibition
2. inhibit synthesis of neurotransmitter indirectly via block of high affinity uptake
3. inhibit release of neurotransmitter
4. promote release of NE from postganglion sympathetic nerve terminals
5. Promote release of ACh from postganglionic cholinergic nerve terminals
6. Reduce uptake of NE and/or DA
7. Reduce storage of NE
8. Inhibit metabolism of NE
9. Inhibit metabolism of ACh
10. Block receptors: ANTAGONISTS
11. Activate receptors: AGONISTS |
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Term
| Name 7 major tissues and organs with predominant PARASYMPATHETIC tone |
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Definition
1.Heart: negative ionotropic and chronotropic effect
2.Iris: contraction of sphincter muscle ->miosis
3. Ciliary muscle: contraction -> accommodation
4.GI tract: increased perstaltic movement, sphincter relaxation
5.Urinary bladder: increased contraction of detrussor muscle, sphincter relaxation
6.Bronchial smooth muscle: bronchoconstriction
7.All glands: secretion |
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Term
| Therapeutic Uses of Cholinergic drugs: When could you use muscarinic agonists and cholinesterase inhibitors? |
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Definition
1. Treatment of myasthenia gravis
2. Treatment of urinary retention
3. Treatment of glaucoma |
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Term
| Therapeutic Uses of Cholinergic drugs: When could you use muscarinic antagonists |
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Definition
1. Mydriasis and cycloplegia
2. Antispasmodic: treatment of GI hypermotility and excessive gastric secretion; anti-diarrheal
3. Treatment of urinary incontinence
4. Preoperative medication to reduce salivary secretions and produce sedation
5. Treatment of motion sickness
6. Treatment of carbamate and organophosphate poisoning
7. Treatment of Parkinson's disease |
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Term
| What kind of cholinergic drug would you use to break down adhesions (synechiae) between the iris and lens in iridocyclitis? (Muscarinic agonista, cholinesterase inhibitors, muscarinic antagonists, nicotinic antagonists) |
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Definition
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Term
| Therapeutic Uses of Cholinergic drugs: When could you use nicotinic antagonists (ganglionic blocking drugs)? |
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Definition
1. Hypertensive crisis
2. Controlled hypotension |
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Term
| Name 2 direct acting choline esters (quarternary amines) |
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Definition
| Acetylcholine & Carbachol |
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Term
| Name some characteristics of carbachol including side effects |
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Definition
a. No longer used to manage glaucoma
b. Not destroyed by AChEase: long half-life
c. Non-specific and non-selective
d. Not readily antagonized by atropine
e. Side effects include excessive parasympathetic activity (decrease BP & HR, bronchoconstriction SLUD, transient myopia |
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Term
| Name 2 direct acting cholinomimetic alkaloids (tertiary amines) |
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Definition
a) Muscarine (Amanita muscaria)
b) Pilocarpine (Isopto carpine) |
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Term
| Name 4 uses of cholinesterase inhibitors |
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Definition
1. Treatment of open angle glaucoma; acute treatment in narrow-angle glaucoma: MEDICAL EMERGENCY
2. Treatment of myasthnia gravis
3. Overdose of atropine, scopolamine...
4. GI and urinary tract stimulant |
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Term
| Name 4 kinds of side effects from cholinesterase inhibitors. |
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Definition
1. Excessive parasympathetic activity, dec BP & HR, bronchoconstriction, SLUD
2. Conjunctival hypermia, transient myopia
3. NMJ: tremor, fasculation, weakness
4. CNS: restlessness, agitation |
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Term
| Signs, symptoms and treatment of organophosophate poisoning |
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Definition
1. Drugs and chemical commonly producing this poisoning: DFP, parathion, malathion, diazinon, fenthion, "nerve gases"
2. Treatment: Use atropine to block peri. and cen. muscarinic receptors or use pralidoxime to reverse the neuromuscular involvement |
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Term
| Therapeutic uses of sympathetic drugs: agonists |
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Definition
1. Cardiovascular: treat cardiogenic shock, hypertension
2. Bronchial: treat bronchospasm
3. Uterine: delay delivery in premature labor
4. Topical: reduce superficial bleeding, prevent diffusion of local anesthetic, decongest mucous membranes in hay fever, increase aq. humor outflow (glaucoma)
5. Mydriasis w/o cycloplegia |
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Term
| Therapeutic uses of sympathetic antagonists |
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Definition
1. Vascular smooth muscle: treat essential hypertension
2. Decrease sympathetic outflow from the brain: treat essential hypertension
3. Cardiac muscle: treat cardiac dysrhythmias, angina pectoris
4. Treat migraines
5. Reduce formation of aq. humor, (glaucoma) |
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Term
| Name several things that non-selective indirect acting agents can do (Sympathetic) |
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Definition
1. Facilitate release of NE
2. Block the NE re-uptake transporter
3. Inhibit MAO-A (and MAO-B)
4. Inhibit COMT |
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Term
| Name several things that sympathetic neuron blocking drugs can do: |
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Definition
1. Inhibition of synthesis of NE or EPI
2. Disrupts ability of vesicle to transport and store NE
3. Inhibition and release of NE |
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Term
| Name some factors influencing response of effectors to adrenergic drugs |
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Definition
1. Denervation supersensitivity
2. Decentralization supersensitivity
3. Chemically-induced supersensitivity
4. False-neurotransmitters |
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Term
| What is denervation supersensitivity? |
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Definition
5-15 fold enhanced effect to direct acting sympathetic agonists
(1) Postganglionic surgical denervation or lesion
(a) Early: due to loss of re-uptake mechanism
(b) Late (days/weeks): "up-regulation" |
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Term
| What is decentralization supersensitivity? |
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Definition
2-3 fold enhanced effect to direct acting sympathetic agonists
1. Preganglionic denervation or lesion
2. Requires weeks to develop |
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Term
| What is chemically-induced supersensitivity and some examples? |
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Definition
1. Reserpine: sustained depletion of NE
(Decentralization)
2. Cocaine, ouabain (develops rapidly due to blockade of NE re-uptake)
(Denervation) |
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Term
| What are false-neurotransmitters? |
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Definition
| Indirectly acting amines are taken up into adrenergic nerve terminals by nonspecific amine re-uptake pump and can be taken into synpatic vesicles. When the nerve terminal is stimulated, false neurotransmitters are released. Most are less potent than NE,some are equipotent with NE. |
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Term
| Some therapeutic uses of NMJ blocking agents. |
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Definition
1. Muscle relaxation during surgery
2. Relaxation during maximal electroshock
3. Reduce muscle spasms |
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