Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
56 Cards in this Set
- Front
- Back
|
which muscarinic receptor is located in the heart?
|
M2
|
|
|
What are the structural features of nicotinic receptors
|
Transmembrane polypeptide whose subunits form cation-selective ion channels
|
|
|
What are the structural features of muscarinic receptors?
|
Seven transmembrane domains whose third cytoplasmic loop is coupled to G proteins
|
|
|
Do the choline esters ( i.e. AcH) get absorbed well into the CNS?
|
NO
choline esters are poorly absorbed and poorly distributed into the CNS |
|
|
Rank in order the choline ester ( AcH, methacholine, carbachol, bethanecol) that is most to least resistant to hydrolysis .
|
Both carbachol and bethanecol are resistant to cholinesterase
Methacholine AcH is least resistant ( effects last only 5 -20 seconds) |
|
|
What intracellular process is stimulated by Muscarinic agonist binding?
|
Muscarinic agonist binding activates the IP3, DAG cascade
|
|
|
What is the effect of DAG on smooth muscle calcium channels?
|
DAG opens it
|
|
|
What is the effect does IP3 have intracellular calcium?
|
IP3 releases calcium from endoplasmic and sarcoplasmic reticulum
|
|
|
Activation of muscarinic receptors _______ potassium flux cardiac cell membranes
|
increases
|
|
|
Activation of muscarinic receptors ______potassium flux in ganglion and smooth muscle cells
|
decreases
|
|
|
What is the result of nicotinic agonist binding?
|
Nicotinic receptor binding to BOTH the receptor sites causes a conformational change in the protein that allows sodium and potassium ions to diffuse down their concentration gradients
|
|
|
Nicotinic receptor activation causes _______ of the nerve cell or neuromuscular end plate membrane
|
depolarization
|
|
|
what happens initially if there is prolonged occupancy of the nicotinic receptor?
|
1. the postganglionic meron stops firing
2. the skeletal muscle cell relaxes 3. it prevents electrical recovery o the postjunctional membrane |
|
|
what do you expect to happen if you instill muscarinic agonists in the conjunctival sac?
|
There is contraction of the smooth muscle of the iris sphincter ( miosis) and of the ciliary muscle (accomodation)--> these actions make it easy for the aqueous humor outflow
|
|
|
Why do smaller doses of AcH cause an INCREASE in heart rate
|
It causes vasodilation, resulting in blood pressure that is then followed by a reflex increase in heart rate
|
|
|
what are the 3 specific effects of M2 that leads to bradycardia
|
1. It causes an increase of potassium current in the cells of the sinoatrial and AV nodes
2.There is a decrease in the slow inward calcium current in heart cells 3. a reduction in the hyperpolarization activated current that underlies diastolic depolarization |
|
|
How does AcH activation trigger M3 vasodilation?
|
In the presence of intact endothelium, muscarinic agonists release NO.
the NO activates guanyl cyclase and increases cGMP --> relaxation |
|
|
What pathologic process reverses the normal AcH relaxing of coronary arteriolar smooth muscle cells?
|
damage to the endothelium--> like atherosclerosis --> AcH is able to contract arterial smooth muscle
|
|
|
What are the cardiovascular effects of pilocarpine IV ?
|
It may produce hypertension because of the sympathetic ganglionic discharge caused by activation of postganglionic cell membrane M1 receptors
|
|
|
Muscarinic stimulants ____ the smooth muscle of the bronchial tree
|
Contracts
It also causes the glands of the tracheobronchial mucosa to secrete |
|
|
what is the most abundant nicotinic receptor in the brain?
|
alpha4beta2 oligomer, is the most abundant nictonic receptor in brain, and has a high affinity for agonist
|
|
|
what is an effect of chronic exposure to nicotine release?
|
chronic exposure to nicotine increases high -affinity agonist binding --> greater release of dopamine in the mesolimbic sys.
|
|
|
What are the signs of nicotine toxicity?
|
At high concentrations, nicotine induces tremor, emesis, and stimulation
At still higher levels, causes convulsions, which may end in fatal coma |
|
|
The effects of nicotine on cardiovascular are _____ but in the GI and urinary tracts in ______
|
sympathetic
parasympathetic |
|
|
What are the three groups of cholineterase inhibitors?
|
1. a simple aclohols with a quaternary ammonium
2. carbamic acid esters of alcohols having quaternary or tertiary ammonium (carbamates) 3. organophosphates |
|
|
What are some examples of quaternary ammonium agents?
|
Edrophonium
|
|
|
What are some examples of carbamates?
|
carbaryl
neostigmine |
|
|
what are some organophosphates?
|
echothiophate
parathion malathion |
|
|
Why is physostigmine so well absorbed from the conunctiva, skin, and lungs?
|
Physotigimine is a naturally occurring tertiary amine . REMEMBER --> the permanent charge makes them polar so they are insoluble
|
|
|
Why are organophosphates especially dangerous to humans?
|
The organophosphate cholinesterase inhibitors are well absorbed from the skin, lung, gut and conjunctiva
|
|
|
How do the quaternary alcohols inhibit acetylcholinesterase?
|
These agents reversibly bind electrostatically and by hydrogen bonds to active site --> preventing AcH from having access
|
|
|
How do the carbamate esters inhibit acetylcholinesterase?
|
These agents have a similar two-step hydrolysis process but the covalent bond of the carbamoylated enzyme is much more resistant to the hydration of the acetyl-enzyme bond
|
|
|
What are the two steps in the acetylcholinesterase process?
|
1. acetylcholine binds to the enzyme's active site --> free choline and the acetylated enzyme
2. the covalent acetyl-enzyme bond is split with the addition of water |
|
|
How long does the quaternary alcohols remain bound to AcHesterase?
|
2- 10 minutes
|
|
|
How long does it take carbamoylated enzyme take to be be released from acetyl
|
30 minutes to 6 hours
|
|
|
How do organophosphates inhibit AcHesterase?
|
These agents bind and hydrolyze AcH esterase --> the active site is phosphrylated
|
|
|
Why does the organophosphates last for a long time?
|
The covalent phosphorus-enzyme bond is extremely stable and hydrolyzes in water at a very slow rate (hundreds of hours)
|
|
|
What is aging of the phosphorylated AcHesterase complex?
|
The process involves the breaking of one of the oxygen-phosphorus bonds of the inhibitor --> strengthens the phosphorus-enzyme bond
|
|
|
Give an example of irreversible cholinesterase inhibitor
|
organophosphate inhibitor
|
|
|
Give an example of reversible cholinesterase inhibitor
|
carbamate
quaternary alcohols (edrophonium) |
|
|
what is the effect of cholinesterase inhibitor on vascular smooth muscle
|
it has minimal effects by direct action on vascular smooth muscle because most vascular beds lack cholinergic innervation
|
|
|
Sooo... if cholinesterase inhibitors have no effects on vascular smooth muscle, then how does it cause an increase in systemic vascular resistance and blood pressure?
|
This effect is initiated at sympathetic ganglia and also at central sympathetic centers,
|
|
|
What is the net cardiovascular effects of moderate doses of cholinesterase inhibitors
|
modest bradycardia
fall in cardiac output increased vascular resistance --> a rise in Blood pressure |
|
|
what are the cardiac effects of the cholinesterase inhibitors?
|
Negative chronotropic, dromotropic, and inotropic effects are made and cardiac output falls
|
|
|
what effects does the cholinesterase inhibitors have at the neuromuscular junction?
|
At therapeutic concentrations moderately prolong and intensify the actions of physiologically released AcH --> increased strength of contraction
|
|
|
what type of glaucoma is treated with cholinesterase inhibitors
|
Acute angle closure glaucoma
|
|
|
what cholinomimetics is used for urinary retention?
|
Bethanechol
|
|
|
what cholinomimetic is used for paralytic ileus or bladder atony?
|
Neostigmine
|
|
|
What muscarinic agonist is used for the treatment of dry mouth
|
Cevimeline
|
|
|
How do myasthenia gravis reduce nicotinic receptor function?
|
1. cross-linking receptors --> leads to internalization and degradation
2. lysis of the postsynaptic membrane 3. binding to the nicotinic receptor and inhibiting function |
|
|
what are the symptoms of excessive stimulation of muscarinic receptors?
|
Abdominal cramps
diarrhea increased salivation excessive bronchial secretions miosis bradycardia |
|
|
What toxicities are Cholinesterase inhibitors are used to reverse?
|
Atropine
Tricyclic antidepressant overdose |
|
|
what effects of the acute nicotinic poisoning cannot be reversed with drugs?
|
Neuromuscular blockade is not responsive and may require mechanical respiration
|
|
|
what are the toxic effects of nicotine toxicity?
|
1. CNS --> convulsions that may lead to coma and respiratory arrest
2. Skeletal muscle end plate depolarization --> depolarization blockade and respiratory paralysis 3. HTN and cardiac arrythmias |
|
|
How do you treat nicotine poisoning?
|
Atropine for the muscarine excess from the parasympathetic ganglion stimulation
Diazepam for the central stimulation |
|
|
Does varenicline have agonist or antagonist properties?
|
Both
Partial agonist- action at alpha4beta2 nicotinic receptors Anatagonist- prevents the stimulant effect of nicotine at presynaptic alpha4beta2 receptors that cause release of dopamine |
