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167 Cards in this Set
- Front
- Back
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first synthetic drug |
aspirin/acetyl salicylic acid (ASA) |
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first antibiotic |
sulfanilomide |
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sulfanilomide side effect |
kidney failure |
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thalidomide |
- sedative used to alleviate morning sickness - caused children to be born with no limbs, affected heart and congenital eye problems
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phase 1 clinical study |
tested on limited subjects |
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phase 2 clinical study |
tested on small group out of target population |
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phase 3 clinical study |
tested on larger population |
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phase 4 clinical study |
assess risk benefits & confirm efficacy |
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3 types of toxicities |
teratogenity mutagenicity reproductive toxicity |
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drug quality critera (5) |
- purity - stability - sterility - limits of potentially toxic impurities - defined amount released at specific rate |
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orphan drugs |
for a condition that affects less than 200,000 people (in the US) |
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Tubocurarine - What does it do - What is the effect on the body - When is it used |
- nAChR antagonist - causes muscle paralysis - surgery |
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pharmacology |
study of drugs - what they are, how they work and what they do |
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2 branches of pharmacology |
pharmacokinetics & pharmacodynamics |
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pharmacodynamics |
- what the drug does to the body - effects elicited (desirable & undesirable) - study of relationship between drug concentration & effects |
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pharmacokinetics |
how the body absorbs & eliminates drug |
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receptors |
- protein molecule found on cell surface or in the cell that receives chemical signals upon ligand binding |
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4 classes of receptors |
- ligand gated ion channels - enzyme linked receptors - GPCR - ligand activated transcription factors |
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ligand gated ion channels |
reside on cell surface and act as gates to control ion passage into cell |
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enzyme linked receptor |
reside on cell surface & cause intracellular enzymatic activity upon extracellular ligand binding |
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GPCR |
reside on cells surface and couple with G proteins that do have enzyme activity to generate intracellular 2nd messengers |
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ligand activated transcription factors |
receptor resides in the cell & stimulates transcription factors to promote DNA transcription to make mRNA & proteins |
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agonist |
chemical that binds to a receptor and activates the receptor to get a cellular response |
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antagonist |
chemical that binds to a receptor and blocks it |
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inverse agonist |
agent that binds to a receptor and induces a pharmacological response opposite to that of an agonist |
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what are the variables in the equation B= (Bmax x [D])/[D] + Kd |
B - fraction of receptors bound Bmax - maximal fraction of total receptors bound D - drug concentration Kd - equilibrium dissociation constant & drug concentration where 1/2 of Bmax is achieved |
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Emax |
- maximum response achieved by agonist - drug efficacy |
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ED50 |
- drug dose where you get 50% of Emax - drug potency |
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what are the independent and dependent variables for quantal dose response curves? |
x - dosage y - % of individuals responding |
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what is potency and how is it expressed? |
- how much drug you need to get an effect of a given magnitude - expressed as ED50 |
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what does a high ED50 mean? |
drug is less potent |
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what is efficacy & how is it expressed? |
- maximum effect that can be achieved with a drug - expressed as Emax |
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what effect does a partial agonist have on efficacy? |
it reduces efficacy and you need a higher dose to get your response |
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constitutive receptor activation |
spontaneous conversion from inactive to active state |
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what 2 things does agonist binding to the receptor (related to receptor activation) |
- conformational change from inactive to active - stabilizes active state |
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what 2 things will spontaneous agonist dissociation do the receptor? |
- conformational change from active to inactive - stabilize inactive state |
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chemical antagonism |
direct interaction of 2 drugs such that the effect of 1 or both drugs is lost |
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example of chemical antagonism |
- protamine (acidic anti-coagulant) & heparin (basic coagulant) |
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physiological antagonism |
indirect interaction of 2 drugs with opposing physiological effects |
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example of physiological antagonism |
histamine + H1R --> vasodilation epinephrine + beta adrenergic receptor --> vasoconstriction * or any other 2 drugs with opposite effects |
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2 groups of antagonists |
competitive & non-competitive |
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what do competitive antagonists do? how do you overcome the effect? what characteristic of the drug will they affect & how do you overcome it? |
- they bind reversibly to the receptor - increase agonist concentration to displace the antagonist - affect drug potency so you need to increase your dose |
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what do non-competitive antagonists do? what characteristic of the drug will they affect? |
- bind irreversibly to the receptor at a different site than that for the agonist - affect drug efficacy |
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what is drug desensitization |
diminished response because of continuous exposure to the drug |
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receptor mediated desensitization - 2 forms |
- loss of receptor function because of a change in receptor conformation - reduction of receptor number usually due to feedback effects of the agonist (ex: phosphorylation & internalization) |
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non-receptor mediated desensitization - 3 forms |
- reduction of receptor coupled signalling components (ex: 2nd messenger depletion) - increased metabolic degradation - physiological adaptation |
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3 types of adverse drug effects |
- dose dependent - toxic reaction - allergic reactions |
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how do dose dependent side effects work? |
get worse side effects with increased dose |
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why do you get toxic reactions? |
because of too much drug activity (also dose dependent) |
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cyclosporine - function, adverse effects & side effects |
- immunosuppressant (ex: organ transplants) - side effects: kidney damage, higher risk for infections - allergic effect: rash, hives, itching, breathing difficulties |
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what determines drug toxicity? |
the dose |
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what is therapeutic index/window? |
a measure of drug safety that considers the range of therapeutic agent amounts associated with adverse effects, therapeutic effects and no effect in a population |
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what is the equation for therapeutic index? |
Toxic ED50/beneficial ED50 |
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what is a drug with a narrow therapeutic window? |
warfarin |
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what does warfarin do |
prevents blood from clotting |
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what is a drug with a large therapeutic window? |
aspirin |
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what are the 4 outcomes of patient response to drugs with respect to benefit & toxicity? |
- benefit + toxicity - no benefit + no toxicity - benefit + no toxicity - no benefit + toxicity |
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what are the 3 components of drug administration? |
absorption, distribution, elimination |
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what is drug absorption? |
movement from the point of administration |
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what is drug distribution? |
movement of the drug from the blood to tissues in the body & other sites |
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what are 2 routes for drug administration? |
- systemic & local |
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what route of administration has a systemic effect via the digestive tract? |
enteral |
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what route of administration would an injection have? what type of effect does it have? |
- parenteral - systemic
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what is first pass effect? why does it happen? |
- a phenomenon of drug metabolism where the concentration of a drug is greatly reduced before it reaches the systemic circulation - happens because the drug is absorbed into the small intestine & liver where some of it gets digested |
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what is bioavailability? |
the amount of drug that is available for activity in the target tissue |
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this route of administration bypasses the first pass effect (100% bioavailability) |
parenteral |
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what route of administration has a local affect? |
topical |
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what route will an inhalational drug take? |
topical |
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what 5 physiochemical factors affect oral drug absorption? |
- concentration difference across cell membrane - size - polarity - ionization state - environmental pH |
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when an oral drug is absorbed it can go to 1 of 2 places, what are the 2 places? |
- it can be eliminated in the feces - it can go to the systemic circulation |
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what 3 physiological factors affect drug absorption? hint: they differ among people |
- GI motility - metabolism - changes in GI pH |
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what is volume of distribution (Vd)? |
theoretical volume that the administered drug amount would have to occupy (if uniformly distributed), to provide the same concentration as it currently is in blood plasma |
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what does a high Vd infer? |
retention in volumes outside of plasma |
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what does a low Vd infer? |
retention in plasma |
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lipophilic drugs are poorly excreted by what 2 areas & why? |
- kidney & liver - they bind to plasma proteins (that inhibit glomerular filtration) & then are reabsorbed to go into lipid rich tissues |
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________________ increases polarity, ionization & water solubility of drugs |
metabolism |
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what are prodrugs? |
a drug that is administered in an inactive form and gets converted to its active form through metabolism |
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what are 2 sites for drug metabolism? |
liver & intestine |
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what is the rate limiting step of metabolism |
phase 1 where reactive groups are either added or unmasked |
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what family of genes contribute to phase 1 metabolism? what is the most common form? |
- CYP gene superfamily - CYP P450 3A4 |
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what does CYP 3A4 do to felodipine? how can you reverse this with food? |
- inhibits it (first pass metabolism) - co-administration with grapefruit juice |
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what is felodipine? what is it used for? |
- Ca channel antagonist - lowering blood pressure (relaxes smooth muscle) |
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what prodrug does CYP 3A4 metabolize to give fexofenadine? |
terfenadine |
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what happens if terfenadine isn't metabolized & accumulates in plasma? |
inhibition of many K channels & potential cardiac toxicity |
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how do cyclosporine & rifampicin work? |
cyclosporine is an immunosuppressant used to prevent organ rejection & rifampicin is an antibiotic that induces expression of CYP 3A4 so that some of the cyclosporine is inactivated |
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5 interindividual differences in drug metabolism: |
- diet - environment - age - disease - genetic factors |
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what are the 4 phenotypic groups for drug metabolism & which is the most common? |
- poor metabolizers - intermediate metabolizers - extensive metabolizers (most common; 50-90%) - ultrarapid metabolizers |
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what 2 organs contribute to drug excretion |
liver & kidney |
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drugs to be excreted must be (3 things): |
- lipophilic - low polarity - low ionization |
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how does first order rate of reaction affect rate of drug elimination? |
the rate of elimination decreases as the amount of drug decreases |
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what is clearance? what is the equation? |
- volume of plasma the drug is removed from per unit time - CL = rate of elimination/drug concentration |
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the point where rate of administration = rate of elimination is known as |
steady state |
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what 2 ways can you achieve steady state? |
- multiple dosing - continuous IV infusion |
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3 types of signalling |
- endocrine - paracrine - autocrine |
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endocrine signalling |
hormone is secreted into blood and travels to distant target cells |
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paracrine signalling |
signalling happens close to site of secretion |
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autocrine signalling |
cell releases a ligand where the receptor is on the same cell |
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the release of NE into the bloodstream by the adrenal medulla is an example of _________ signalling |
endocrine |
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induced fit model |
interaction between receptor and ligand causes a conformational change in the receptor to enhance its affinity for the drug |
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what type of receptor is involved in fast synaptic transmission such as that seen in the CNS |
ligand gated receptors |
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what are the 3 superfamilies of GPCRs? |
- A - rhodopsin-like - B - glucagon/VIP/calcitonin - C - metabotropic glu & chemosensor |
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there are 3 components of GPCR signalling - receptor, g protein & effector. what is the GTPase and why? |
the receptor is the GTPase because it binds and hydrolyzes GTP when activated |
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which g protein inhibits the production of cAMP? |
Gi |
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Gs ______ cAMP levels |
increases |
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the ____ g protein increases DAG & IP3 2nd messenger levels
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Gq |
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the mAChR is coupled to what g protein? what 2nd messenger gets released & why? |
- Gq - Ca gets released because of IP3 going to the endoplasmic reticulum where Ca is stored |
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what is the physiological effect of Ca release? |
muscle contraction (cardiac and/or smooth) |
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what is the effector enzyme for Gs? |
adenyl cyclase |
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what 2 effects can cAMP have? |
- activation of PKA - cAMP response element binding protein (CREB) activation & changes in gene transcription |
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example of homologous desensitization: phosphorylation of ________ causes desensitization of GPCRs by ____________ |
- beta arrestins - binding to the GPCR and promoting internalization (either degradation or recycling) |
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activation of a GPCR causing down-regulation of another GPCR is an example of _______________ _____________ (2 words) |
heterologous desensitization |
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what does bordetella pertussis do to g proteins & cAMP levels? |
inactivates the Gi protein and you get increased cAMP levels |
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these 2 toxins cause the Gs protein to stay activated |
pasteurella multocida & vibrio cholera
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what does ligand binding do to - tyrosine kinase receptors with intrinsic catalytic activity? - tyrosine phosphatase receptors with instrinsic catalytic activity? |
- receptor dimerization, autophosphorylation & signal propagation - dephosphorylation, dimer separates & signal stops |
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this 2nd messenger causes relaxation of smooth muscle by reducing Ca levels: |
cGMP |
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receptor serine/threonine kinases work through associated proteins (ex: cytokinase) and are what kind of receptor? |
tyrosine kinase linked receptor |
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what receptors do steroids work on? how? |
- intracellular receptors - by moving through the bilayer and binding, an associated chaperone is lost from the receptor and the complex goes to the nucleus to initiate transcription |
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angiotensin converting enzyme is used for the treatment of ________ |
hypertension |
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what do ACE inhibitors do? what does this do to blood pressure? |
- prevent ACE from turning angiotensin I to angiotensin II - lowers blood pressure |
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what does renin do? |
converts angiotensinogen from the liver to angiotensin I |
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how does viagra increase cGMP? (2 ways) |
- increases NO that binds to guanylate cyclase which makes cGMP from GTP - inhibits phosphodiesterase in the penis
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where does the afferent NS go? |
to the CNS |
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where does the efferent NS go? |
away from the CNS |
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what are the 2 branches of the efferent NS? |
somatic & autonomic |
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the _______ nervous system is voluntary |
somatic |
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the _________ nervous system deals with skeletal muscle & motor neurons |
somatic |
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which efferent NS pathway synapses onto a ganglion before going to target tissue? |
autonomic |
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3 types of muscle cells |
- cardiac - skeletal - smooth |
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when the sympathetic NS is activated, there is increased blood flow to __________ & decreased blood flow from ______________. |
- increased to skeletal muscles - decreased from gut |
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constricted pupils, relaxed muscles & a low heart rate are characteristic of the ________________ nervous system being activated |
parasympathetic |
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this autonomic nervous system innervates cardiac, exocrine and smooth muscle & has long preganglionic axons near the target tissue |
parasympathetic |
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sympathetic NS axons are shorter and terminate on ganglia in the spinal cord. the postganglionic neurons go to what 4 places & what NT is released? what type of receptors get activated? |
- sweat glands - ACh (nicotinic receptor) - exocrine glands - NE (alpha & beta) - kidney - NE (alpha 1 & beta) - adrenal medulla - NE & adrenaline to the blood (alpha & beta) |
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the somatic NS releases ACh where? what kind of receptor gets activated? |
- neuromuscular junction - nicotinic AChR |
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what is the NT released at preganglionic sympathetic nerves? what receptor is activated? |
- ACh - nicotinic |
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what does the SNS do to the pupils? |
causes dilation |
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what is the enzyme that catalyzes ACh synthesis? ACh breakdown? |
- cholineacetyltransferase - acetylcholinesterase |
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if the M3 AChR couples to Gq, what happens to Ca levels? |
increase |
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what are 3 mAChR agonists? |
- ACh - muscarine - pilocarpine
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what are the side effects of stimulating a mAChR? |
- GI disturbances (nausea/vomiting) - CNS effects - bradycardia - salivation - bronchoconstriction |
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what are side effects of nAChR overstimulation? all of these side effects apply only to the _____ nervous system |
- tremor - convulsions - coma - central |
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what type of drug gives increased ACh similar to exogenous cholinergic agonists? what are the 2 types? |
- cholinesterase inhibitors - reversible and irreversible |
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irreversible cholinesterase inhibitors are indirect acting agents on nicotinic ACh receptors. how do they work? |
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- malathion & sarin - muscarinic side effects - muscle twitches, paralysis, then death |
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what are 2 ways to inhibit irreversible AChE inhibitors? |
- use muscarinic antagonist like atropine to block the receptor. It acts as a competitive antagonist - use pralidoxime to break the covalent bond |
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what would atropine do in the PNS? in the SNS? |
- PNS - block input & cause increase in heart rate, pupil constriction - SNS - pupil dilation |
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what are 2 other uses of muscarinic antagonists? |
- alleviate morning sickness (scopolamine) - reduce bladder activity
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side effects of muscarinic antagonists affect only the ________________ nervous system. what are some of those side effects? |
- parasympathetic - blurred vision, sedation, dilated pupils, dry mouth (decreased salivation), less GI motility (constipation) |
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at what 2 places do nicotinic antagonists work? |
- receptors at autonomic ganglia - receptors at NMJ |
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what are the 2 types of NMJ antagonists? how do they work? |
- depolarizing non-competitive antagonists - form tight bond with receptor & activate it continuously until there is desensitization & muscle paralysis. these cannot be overcome with more ACh - non-depolarizing competitive antagonists - can be overcome with more ACh or by inhibiting its breakdown |
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what type of antagonist is succinylcholine? tubocurare? |
- succinylcholine is a non-competitive depolarizing nAChR antagonist - tubocurare is a competitive non-depolarizing nAChR antagonist |
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sympathetic nerves release catecholamines - what 3 NTs are in that group? |
NE, epinephrine & DA |
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NT feedbacks and acts at the presynaptic receptor to either inhibit or facilitate more release. what happens at alpha 2 adrenergic receptors? beta 2 adrenergic receptors? |
- alpha 2 - inhibition of NT release - beta 2 - more NT release |
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in what 3 ways do adrenergic agonists cause signalling? |
- direct binding to postsynaptic receptor - NE release & signalling - indirectly by preventing reuptake - indirectly by promoting release of NE |
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what is an example of an alpha 1 agonist? what is it used for? what is a side effect? |
- phenylephrine - nasal congestion - constricts blood vessels, pupil dilation - can cause blood pressure increase |
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what is an example of an alpha 2 agonist? what is it used for? how do these drugs work? |
- clonidine, used for hypertension - bind to alpha 2 autoreceptor on presynaptic nerves to prevent NE release (negative feedback) |
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what g protein is associated with alpha 2 agonists? |
Gi |
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what is an example of a beta 1 agonist? what is it used for? |
- dobutamine - heart failure |
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how do beta 1 agonists work? what is a side effect? |
- increase Ca influx & increase muscle contraction - arrhythmias |
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how/where do beta 2 agonists work? what is an example? |
- increase cAMP in the bronchial tissue which inhibits myosin light chain kinase from phosphorylating myosin for muscle contraction - salbutamol |
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how does salbutamol work? what is it used for & what are the side effects? |
- the decreased muscle contraction relaxes smooth muscle - prevent bronchospasm in asthma & relax uterine muscles in premature labor - high levels can cause non-specific activation of beta 1 cardiac receptors & increase heart rate |
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what is an example of a direct adrenergic agonist? what is it used for and what are side effects of its action? |
- adrenaline - anaphylaxis including bronchospasm, mucous membrane constriction & hypotension - arrhythmias |
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what are 2 mechanisms for indirect adrenergic agonists? what is an example? |
- inhibition of reuptake - NE release - cocaine |
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how does cocaine work? what are side effects? |
- prevents reuptake of NE & DA in the synapse - CNS stimulant, increases HR, BP & force of heart contractions, arrhythmias |
