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156 Cards in this Set
- Front
- Back
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what nerve carries parasympathetic input to the eye?
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CN III
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what are the effects of parasympathetic stimulation of the eye?
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ciliary muscle contraction -> accomodation
sphincter muscle contraction -> miosis (pupillary constriction) |
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what nerves carries parasympathetic input to the lacrimal and salivary glands?
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CN VII & CN IX
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what nerve carries parasympathetic input to the lungs?
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bronchial muscle contraction
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what nerve carries sympathetic input to the lungs?
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there is no nerve
lungs respond to circulating epinephrine via beta-2 receptors |
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what are the effects of parasympathetic stimulation of the lungs?
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bronchial muscle contraction
increased secretions |
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what are the effects of parasympathetic stimulation of the GI tract?
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increased tone and motility
increased secretions relax sphincters |
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what are the effects of parasympathetic stimulation on the heart?
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SA node -> dec. rate
AV node -> dec. conduction -> AV block |
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what is an orphan receptor?
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acetylcholine binding receptor in vasculature which causes vasodilation on stimulation
called orphan receptors because there is no nerve going to these receptors |
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what is the effect of parasympathetic stimulation on the bladder?
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increase contractility
relax sphincter |
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what parts of the sympathetic nervous system release acetylcholine?
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preganglionic neurons
postganglionic neurons to sweat glands |
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what neurotransmitters are released at the sweat glands?
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cholinergic at all sweat glands except the palm of the hand
norepi at sweat glands in the palm of the hand |
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where are cholinergic receptors located?
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parasympathetic nerve terminals (end of postganglionic fibers)
sympathetic nerve terminals - those that mediate sweating - adrenal medulla somatic motor nerves at neurotransmitter junction preganglionic fibers of ANS release ACh to act upon postganglionic fibers CNS |
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what is the effect of loss of ACh in the CNS?
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confusion
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how is choline transported into a presynaptic nerve terminal?
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Na-choline cotransporter
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what can inhibit the cotransporter of Na and choline?
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hemicholinium
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what happens to choline once it is inside the presynaptic cell?
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combines with acetyl-CoA in a reaction catalyzed by choline acetyltransferase to form acetylcholine, which is then stored in a storage vesicle
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what initiates the formation of storage vesicles?
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deposition of clathrin molecules on the inner surface of the terminal membrane
upon being pinched off from the surface, a "complex vesicle" is formed that eventually gives rise to a mature storage vesicle |
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how is the acetylcholine moved into storage vesicles?
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countertransporter that exchanges protons for acetylcholine
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what is stored in the same vesicles as acetylcholine in presynaptic cholinergic nerves?
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ATP
proteoglycan |
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how are transmitters released from presynaptic nerve cells?
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action potential, carried down the axon by the action of voltage-sensitive sodium channels, invades the nerve terminals
voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium influx of calcium causes fusion of storage vesicals with the surface membrane and release of neurotransmitter |
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what step of nerve signal transmission is blocked by botulism toxin?
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fusion of vesicles with surface membrane
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what is the function of acetylcholinesterase (AChE)?
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AChE is a polymeric enzyme that splits ACh into choline and acetate, thereby terminating signal transmission
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what polypeptide cotransmitter is released with ACh at some cholinergic junctions?
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vasoactive intestinal polypeptide (VIP)
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what enzymes degrade ACh in the plasma?
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esterases, called pseudocholinesterases, that are different in primary structure than AChE in the junctional cleft
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what is the rate-limiting (regulatory) step in the synthesis of ACh?
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uptake of choline into the presynaptic cell by the Na/choline cotransporter
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what action terminates the signal created by cholinergic neurons?
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enzymatic activity of acetylcholinesterase, which splits the acetylcholine into choline and acetate
NOT reuptake into presynaptic nerve cells |
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what drug could be used to block choline uptake into presynaptic cells?
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hemicholinium
although useful in the lab, it is too toxic for human consumption |
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what is the effect of black widow venom on the cholinergic neurons?
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increases ACh release followed by destruction of the cholinergic nerve terminal
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what is the effect of botulinum toxin on the cholinergic neurons?
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blocks fusion of synaptic vesicles with the external membrane
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what is the effect of tetanus toxin?
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inhibits affected CNS neurons from releasing GABA and glycine by degrading the protein synaptobrevin
loss of these inhibitory neurotransmitters causes dangerous muscle spasms |
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what is the order of effects seen in administration of increasing doses of IV acetylcholine?
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first, see cardiovascular effects
second, see gland and smooth muscle effects third, see ganglia effects fourth, see neuromuscular junction effects |
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what are the cardiovascular effects of IV acetylcholine?
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vasodilation (via orphan receptors)
increased heart rate (via baroreceptor reflex) stimulation of orphan receptors -> vasodilation -> dec. TPR -> baroreceptor stimulation -> inc. HR |
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what are the gland and smooth muscle effects of IV acetylcholine?
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increased secretions
bronchiole constriction GI stimulation increased sweating decreased heart rate (direct effect via vagal dominance) |
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what are the ganglia effects of IV acetylcholine?
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all sorts of PSNS and SNS effects
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what is important about the neuromuscular effects of IV acetylcholine?
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astronomical doses affect the neuromuscular junction
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what is the subtype of cholinergic receptors that stimulates cardiovascular effects?
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muscarinic ACh receptor
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what is the subtype of cholinergic receptors that stimulates gland and smooth muscle effects?
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muscarinic ACh receptor
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what is the subtype of cholinergic receptors that stimulates ganglia effects?
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nicotinic ACh receptor
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what is the subtype of cholinergic receptors that stimulates neuromuscular junction effects?
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nicotinic ACh receptor
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what cholinergic effects are mediated by muscarinic receptors?
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cardiovascular effects
glands and smooth muscle effects |
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what cholinergic effects are mediated by nicotinic receptors?
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ganglia effects
neuromuscular junction effects |
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what happens to the effects of IV ACh when muscarine is administered instead?
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separation
cardiovascular, gland, and smooth muscle effects happen way before ganglia and neuromuscular junction effects |
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what happens to the effects of IV ACh when nicotine is administered instead?
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reversal of order
ganglia and neuromuscular junction effects happen before cardiovascular, gland and smooth muscle effects |
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where are nicotinic ACh receptors found?
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postganglionic cells in the ganglia of the autonomic nervous system
cells of the adrenal medulla striated muscle (to receive ACh released by somatic neurons) |
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where are muscarinic ACh receptors found?
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receptors for postganglionic neurons of the parasympathetic nervous system
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where are adrenergic receptors found?
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receptors for postganglionic neurons of the sympathetic nervous system
receptors for circulating epinephrine |
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what is bethanechol?
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synthetic acetylcholine analog with a long half-life and muscarinic specificity (aka urecholine)
C | C-N-C-C-O-C-NH2 | | || C CH3 O |
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what gives bethanechol its long half-life?
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terminal amino group rather than methyl group of acetylcholine
C | C-N-C-C-O-C-NH2 | | || C CH3 O |
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what gives bethanechol its muscarinic receptor specificity?
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beta-carbon substitution of a methyl group
C | C-N-C-C-O-C-NH2 | | || C CH3 O |
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what is the other name for bethanechol?
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urecholine
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what type of drug is urecholine?
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synthetic acetylcholine analog with a long half-life and muscarinic specificity (aka bethanechol)
C | C-N-C-C-O-C-NH2 | | || C CH3 O |
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what are the therapeutic uses of muscarinics?
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RELATIVELY RARE
1) GI stimulation in cases of hypomotility 2) treatment of urinary retention 3) pupillary constriction 4) glaucoma |
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what is the muscarinic drug of choice for GI stimulation in cases of hypomotility?
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bethanachol
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what is the muscarinic drug of choice for treatment of urinary retention?
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bethanachol
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how do muscarinic drugs treat urinary retention?
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increases bladder tone
relaxes sphincter |
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what muscarinic drugs are used to cause pupillary constriction necessary for certain surgical procedures?
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any muscarinic drugs will do
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why are muscarinics useful for the treatment of glaucoma?
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aqueous humor drainage is enhanced by the intraocular muscular contraction subsequent to cholinergic stimulation
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what muscarinic drugs are useful for the treatment of glaucoma?
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carbachol
pilocarpine ACh (for brief effects) |
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what is the effect of the quaternary nitrogens on some cholinergic compounds?
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the compounds carry a positive charge, hence systemic entry of these compounds is severely limited
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why should muscarinics never be administered IV or IM?
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acute respiratory distress
- increased glandular secretion - constriction of smooth muscles of airways cardiovascular collapse - cardiac arrest or extreme bradycardia - vascular collapse following profound vasodilation due to stimulation of muscarinic receptors of the vasculature |
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what are the contraindications for muscarinic drugs?
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asthma
peptic ulcer coronary insufficiency |
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why are muscarinic drugs contraindicated for patients with peptic ulcers?
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acid and enzyme secretions are stimulated leading to further irritation or perhaps perforation
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why are muscarinic drugs contraindicated for patients with coronary insufficiency?
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since b.p. drops, coronary perfusion may be so inadequate that an infarct may occur
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what is the classic muscarinic antagonist?
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atropine
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what drug must be kept close at hand when muscarinic drugs are administered?
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atropine (muscarinic antagonist)
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from where does atropine originate?
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"bella donna" alkaloids
- cause pupillary dilation |
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what effects are seen with atropine administration?
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pupillary dilation (mydriasis)
blurring of vision (cycloplegia) dry secretions bronchiolar relaxation HR increases b/c of vagal block decrease GI motility urinary retention confusion |
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why are there no direct effects noticed on BP on atropine secretion?
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vascular muscarinic receptors are not innervated, so there is no tone, and thus nothing to block with atropine
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what is the rhyme that describes the symptoms of anti-muscarinic therapy?
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mad as a hatter (confusion)
dry as a bone (can't sweat) red as a beet (can't sweat) blind as a stone (blurry vision) |
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what are the GI uses for muscarinic antagonists?
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peptic ulcers (principle is to decrease secretions)
GI hypermotility |
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what are the ophthalmic uses for muscarinic antagonists?
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pupillary dilation
contraindicated in glaucoma (antiparasympathetic effects can impair anterior chamber drainage) |
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what are the respiratory uses for antimuscarinic agents?
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preanesthetics
OTC cold medications asthma |
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why are antimuscarinic drugs used as preanesthetics?
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aid in relaxing and drying airways since many gas anesthetics irritate the respiratory tract
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why are antimuscarinic drugs used as over the counter cold medications?
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dry up nasal secretions
antihistamines can block muscarinic receptors (classical H1 blockers also block muscarinic receptors) |
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what are the cardiovascular uses for antimuscarinic drugs?
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treatment of heart block or sinus arrest due to vagal stimulation can be aided by antimuscarinics
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what receptors do antihistamines block?
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muscarinic receptors
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what receptors can classical H1 blockers block?
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muscarinic receptors
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what CNS use should be avoided in the elderly?
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parkinson's disease
this was an old use and there are better drugs available, however antimuscarinics may be used in concord with newer drugs available |
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what is the current, accepted, CNS use for antimuscarinic drugs?
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treatment of motion sickness
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what is the advantage of scopolamine as a motion sickness medication?
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scopolamine has an oxygen bridge, which makes it difficult to add a quaternary proton and therefore allows for more penetration into the CNS
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where does scopolamine show its greatest effects?
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shows far greater CNS than PSNS effects
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describe the toxicity of muscarinic antagonists
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atropine and other muscarinic antagonists are relatively safe compounds
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what are the potential side effects of antimuscarinic drugs?
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rapid pulse rate, due to vagal block
pupillary dilation hot, dry, flushed skin excitement/delirium/confusion structural changes result in decreased lipid solubility |
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what happens to the SNS at toxic doses of antimuscarinic drugs?
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stimulated
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what effects of antimuscarinic drugs cause pupillary dilation?
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peripheral and CNS effects
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why do patients on antimuscarinic drugs experience hot, dry, flushed skin?
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sweating is blocked
this thermoregulatory problem is especially problematic for children induced hyperthermia can be dangerous |
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what can cause decreased CNS effects of antimuscarinic drugs?
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structural changes resulting in decreased lipid solubility
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what is ipratropium bromide?
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an anticholinergic drug used for the treatment of chronic obstructive pulmonary disease and acute asthma
it blocks the muscarinic acetylcholine receptors in the smooth muscles of the bronchi in the lungs, opening the bronchi |
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what is a quaternary amine?
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nitrogen with four attached groups, which causes the nitrogen to have a fixed positive charge
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what is glycopyrrolate?
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antimuscarinic drug used heavily in the U.S. as a preanesthetic
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why is glycopyrrolate more desirable than atropine as a preanesthetic?
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it has a quaternary amine which results in reduced CNS effects
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what is xerostomia?
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dry mouth due to a lack of saliva
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what is a common complaint of systemic antimuscarinic therapy?
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xerostomia (dry mouth)
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what does the acronym "SLUDGE" stand for?
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S - salivation
L - lacrimation U - urinary D - diarrhea G - gastric E - emptying |
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what is the "depolarizing blockade"?
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nicotine stimulates receptors at low doses and then blocks at higher doses
**does not occur at muscarinic receptors** |
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what causes the depolarizing block phenomenon of the nicotinic receptors?
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nicotine is not degraded by cholinesterases, so the synaptic longevity may be responsible for the depolarizing block
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where is stimulation followed by blockade most commonly seen?
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both SNS and PSNS ganglia
at the neuromuscular junction, nicotine exerts mostly a blocking phenomenon |
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what is the result of nicotine stimulation on the adrenal medulla?
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since the adrenal medulla is a "big ganglion", nicotine stimulation results in a large release of catecholamines
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what are the CNS effects of nicotinic stimulation?
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stimulation
vomiting ACh release |
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what are the cardiovascular effects of nicotinic stimulation?
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mostly stimulation: increased HR and BP and then decreased HR and BP at higher doses
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what are the GI effects of nicotinic stimulation?
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PSNS stimulation then block at higher doses
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what are the salivary gland effects of nicotine stimulation?
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PSNS stimulation, then blockade
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are all nicotinic receptors identical?
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nicotinic receptors at the neuromuscular junction are slightly different from the receptors at the ganglia
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what two ganglionic blockers should you know?
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trimethaphan
mecamylamine |
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what type of drug is trimethaphan?
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ganglionic blocker nicotinic antagonist
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what type of drug is mecamylamine?
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ganglionic blocker nicotinic antagonist
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what effects are mediated by ganglionic blockers?
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since both SNS and PSNS ganglia are blocked, all innervated organs will lose their tone
even though a single organ may receive both SNS and PSNS tone, most organ systems will have a clear-cut, predominant tone the effect seen when a ganglion is blocked will serve as an indicator of which tone was dominant |
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what is the predominant tone of arterioles?
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SNS
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what is the effect of a ganglionic block to the arterioles?
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decreased BP
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what is the predominant tone of sweat glands?
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SNS
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what is the effect of a ganglionic block to the sweat glands?
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decreased perspiration
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what two organ systems are mediated only by sympathetic tone?
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arterioles
sweat glands |
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what is the predominant tone in heart rate?
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PSNS
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what is the effect of ganglionic block on the heart rate?
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tachycardia
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what is the predominant tone in the eye?
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PSNS
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what is the effect of ganglionic block on the eyes?
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mydriasis (pupillary dilation)
cycloplegia (blurry vision) |
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what is the predominant tone in the gastrointestinal tract?
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PSNS
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what is the effect of ganglionic block of the gastrointestinal tract?
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decreased tone and motility
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what is the predominant tone in the bladder?
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PSNS
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what is the effect of ganglionic block of the bladder?
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urinary retention
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what is the predominant tone in the salivary glands?
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PSNS
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what is the effect of ganglionic block of the salivary glands?
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dry mouth
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what are the therapeutic uses of ganglionic blockers?
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have been used to treat hypertension, but there are too many side effects
still used infrequently in cases of malignant hypertension |
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how is acetylcholine normally degraded?
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acetylcholinesterase
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describe the process by which acetylcholine is degraded by acetylcholinesterase?
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1) negative charge on AChE attracts quaternary nitrogen so that the free OH can make a nucleophilic attack on the acyl carbon of AChE
2) ACh collapses releasing choline plus the acetylated enzyme 3) hydrolysis of enzyme leads to regeneration of AChE |
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what is the frequency of the acetylcholinesterase reaction?
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extremely rapid (about 7000 molecules/second)
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what type of drug is edrophonium?
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competitive acetylcholinesterase inhibitor
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what is the effect of edrophonium on acetylcholine?
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ACh cannot line up for the enzymatic breakup, because the edrophonium ionically binds to the active site where the quaternary amine should line up
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what is the duration of action of edrophonium?
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10 minutes
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what is edrophonium used for?
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test for myasthenia gravis
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what is another name for edrophonium?
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tensilon
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what type of drug is neostigmine?
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carbamate
reversible acetylcholinesterase inhibitor |
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what type of drug is physostigmine?
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carbamate
reversible acetylcholinesterase inhibitor |
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what type of drug is pyridostigmine?
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carbamate
reversible acetylcholinesterase inhibitor |
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how do carbamates work as acetylcholinesterase inhibitors?
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mimic ACh and ties up enzyme (covalently bind to hydroxyl group of second active site on AChE)
the regeneration via hydrolysis is slow but still occurs eventually in two to eight hours |
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what type of drug is isoflurophate?
|
organophosphate
irreversible acetylcholinesterase inhibitor |
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how do organophosphates work as acetylcholinesterase inhibitors?
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phosphorylate AChE enzyme forever, so more AChE must be made for recovery
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what are the effects of organophosphates?
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inhibition of AChE at the muscarinic receptors leads to an enhancement of the organ's cholinergic tone
inhibition of AChE at nicotinic receptors will result in an initial stimulation followed by "depolarizing blockade" generally, one sees massive muscarinic effects plus paralysis of the respiratory (and other skeletal) muscles |
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how can AChE inhibitors help a hypotonic GI tract?
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IV neostigmine will enhance GI motility, but you want atropine available
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what is the MAJOR use for AChE inhibitors?
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treatment of myasthenia gravis
administration of physostigmine will result in increased amounts of ACh in the synaptic cleft to stimulate the fewer receptors present in this disease, causing better skeletal muscle action |
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how are AChE inhibitors used to treat myasthenia gravis?
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administration of physostigmine will result in increased amounts of ACh in the synaptic cleft to stimulate the fewer receptors present in this disease, causing better skeletal muscle action
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what is the effect of the lipophilicity of organophosphates?
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so highly lipid soluble that they are absorbed through the skin and can easily cross the blood brain barrier
they are quite toxic and are used as nerve gases |
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how do organophosphates cause acute respiratory failure?
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enhanced muscarinic activity at the lungs leads to bronchoconstriction and increased secretions
at the same time you're blocking the NMJ (nicotinic) by depolarizing blockade leading to the failure of respiratory muscles in CNS, central respiratory drive is depressed |
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how do organophosphates cause profound bradycardia?
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stimulation of muscarinic receptors at the heart will cause sinus arrest leading to profound bradycardia
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what is the relationship between parathion and paraoxon?
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parathion is the prodrug of paraoxon (active form)
parathion is oxidized in mammalian liver, and in insects |
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what is the relationship between malathion and malaoxon?
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malathion is the prodrug of malaoxon (active form)
malathion is oxidized in insects only |
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what type of drug/chemical is malaoxon?
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insecticide
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what type of drug/chemical is paraoxon?
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insecticide
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what is the advantage of malaoxon over paraoxon?
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malaoxon shows selectivity, whereas paraoxon does not
malathion is only metabolized by insects, whereas parathion is metabolized by mammalian liver as well |
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what is the antidote for organophosphate poisoning?
|
oxime reactivation of AChE
2-PAM has a high affinity for the phosphate and removes it from AChE, reactivating the enzyme |
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what molecule is used for the oxime reactivation of AChE?
|
2-PAM
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what kind of drug is sarin?
|
organophosphate
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why is the oxime reactivation a good example of drug synergy (potentiation)?
|
2-PAM can increase the LD50 of sarin
atropine can increase the LD50 of sarin when added together as a treatment, increases LD50 more than additive effect |
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rank the AChE inhibitors in order from shortest inhibition times to longest
|
1) reversible inhibition - few minutes
2) carbamate inhibition - few hours 3) organophosphate inhibition - permanent inactivation |
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what is the other name for 2-PAM?
|
pralidoxime
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