Autonomic Pharmacology Flashcards
(162 cards)
1
Q
What is constrictor muscle of the eye under the control of?
A
Under parasympathetic control; has muscarinic receptors
2
Q
When constrictor muscle contracts, what occurs?
A
Pupil constricts (miosis)
3
Q
What is dilator muscle of the eye under the control of?
A
Sympathetic control; has α1 receptors
4
Q
What could you do in order to dilate the pupils?
A
Muscarinic antagonists
α1 agonists
5
Q
What are the 2 parts to the ciliary muscle?
A
Radial ciliary muscle and longitudinal muscle
6
Q
Describe radial ciliary muscle
A
It looks like a donut and suspended in the center is the lens of the eye; lens is connected to the radial ciliary muscle through a series of ligaments
7
Q
What is the ciliary muscle under control of?
A
Mostly the parasympathetic division
8
Q
What occurs when radial ciliary muscle relaxes?
A
The opening in the center becomes larger, putting tension on the ligaments and the lens
Lens is stretched and becomes thinner and is fixes in place; enables us to see things clearly at a distance
9
Q
What occurs when radial ciliary muscle contracts?
A
Hole in center becomes smaller; relieves tension on ligaments and lens becomes fatter and moves forward slightly
Can see things close to use
Process is called accomodation
10
Q
What occurs to the longitudinal muscle when radial ciliary muscle contracts?
A
It also contracts since it is connected
When the longitudinal muscle contracts, it tugs down on tissue around the Canal of Schlemm (opening where aqueous humor drains out of the eye)
When longitudinal contracts, it helps draining by opening up Canal of Schlemm
11
Q
What kind of drug assists in draining aqueous humor in glaucoma patient?
A
Muscarinic agonist
12
Q
What are side of effects of drugs that assist in draining aqueous humor in glaucoma patients? What causes these side effects?
A
Blurred vision at a distance and bad night vision
Have difficulty seeing into distance because radial ciliary muscle is locked into contraction
Would also have bad night vision because muscarinic receptors of the constrictor muscle would also be activated, so pupils would not dilate
13
Q
Parasympathetic and sympathetic physiology of heart
A
Sympathetic
β1: increase in rate and force
Parasympathetic
Muscarinic: decrease in rate and force
14
Q
In normal, healthy individuals, what controls systolic and diastolic pressure?
A
Systolic by heart
Diastolic by blood vessels
15
Q
What is systolic BP really controlled by? What is equation?
A
Cardiac output, which is the volume of blood ejected by heart per unit time (usually roughly 5L/min)
Cardiac output = rate x stroke volume
Stroke volume is volume ejected by left ventricle each time it contracts (roughly 70 mL)
16
Q
Parasympathetic and sympathetic physiology of blood vessels
A
Sympathetic
α1: constriction of vascular smooth muscle (vasoconstriction)
β2: relaxation of vascular smooth muscle (vasodilation)
Parasympathetic
Muscarinic receptors in vaascular endothelial cells (not innervated): dilation
17
Q
How can a sharp drop in diastolic pressure lead to a decrease in systolic pressure?
A
When veins dilate significantly, venous side has more blood than normal.
Volume of blood returning to the heart per unit time goes down because it is staying in the veins
Cardiac output goes down and systolic pressure goes down
18
Q
Parasympathetic and sympathetic physiology of lungs
A
In bronchial smooth muscle:
Sympathetic
β2: relaxation (bronchodilation)
Parasympathetic
Muscarinic: constriction
(bronchoconstriction)
Activating muscarinic receptor also results in mucus production
19
Q
How would you treat asthma in a pt with glaucoma?
A
β2 agonist
Muscarinic antagonist would also cause bronchodilation, but would prevent contraction of the ciliary muscle and thus aqueous humor would not drain
20
Q
Parasympathetic and sympathetic physiology of GI tract
A
Smooth Muscle Sympathetic β2: relaxation Parsympathetic Muscarinic: contraction
Sphincter Sympathetic α1: contraction Parsympathetic Muscarinic: relaxation
21
Q
Parasympathetic and sympathetic physiology of bladder
A
Detrusor Muscle Sympathetic β2: relaxation Parsympathetic Muscarinic: contraction
Internal Sphincter (urethral sphincter) Sympathetic α1: contraction Parsympathetic Muscarinic: relaxation
22
Q
What causes need to pee more when anxious?
A
Increased sympathetic dominance causes greater cardiac output and thus greater glomerular filtration and faster urine production
23
Q
What causes loss of bowel control in life-threatening situation?
A
There is a massive output from brain that is both sympathetic and parasympathetic
The parasympathetic outflow causes loss of control of bowels
24
Q
What does sympathetic input in both GI tract and bladder cause?
A
Suppresses urination, digestion, and defecation
25
What does parasympathetic input in both GI tract and bladder cause?
Promotes urination, digestion, and defecation
26
Parasympathetic and sympathetic physiology of uterus
Sympathetic
α1: increase contractions
β2: decrease contractions
27
Parasympathetic and sympathetic physiology of salivary glands
Sympathetic
α1, β2: increase viscous secretions
only occurs in extremely fearful situations
Parasympathetic
Muscarinic: increase watery saliva
28
Where is norepinephrine stored? How does it get there?
Stored in nor-adrenergic vesicles
Gets there by 2 mechanisms:
1) produced from dopamine: dopamine can be taken up and converted to norepinephrine inside the storage vesicle
2) norepinephrine can be reused and taken back up into storage vesicle, which is by the vesicular monoamine transporter (which pumps catecholamines back into the storage vesicle)
29
What terminates the action of the norepinephrine?
Prejunctional neuronal uptake
There is a transporter that will pump about 95% of all the norepinephrine that was released back into the sympathetic neuronal varicosity where it will either be broken down by MAO or retaken up by the storage vesicle
30
What occurs to remaining 5% of norepinephrine that is not taken up by prejunctional neuronal uptake?
Extraneuronal uptake occurs at the effector cell
| Inside effector cells, there are 2 enzymes that break up norepinephrine: COMT and MAO
31
Epinephrine type
Direct acting adrenergic agonist (non-selective)
32
What receptors does epinephrine act on?
α1, α2, β1 and β2
33
What are the cardiovascular effects of epinephrine?
At very low doses, causes decrease in diastolic blood pressure (because epinephrine has higher binding affinity for β2 receptor in blood vessels than α1 receptors, so vasodilation occurs) and increase in systolic blood pressure (activates β1 receptors)
At slightly higher doses, causes no change in diastolic blood pressure (because binds to both α1 and β2 receptors of blood vessels, which cancel each other out) and increase in diastolic blood pressure
At high levels, causes increase in diastolic pressure (since all α1 receptors are occupied) and systolic pressure
34
Is epinephrine given orally? Why or why not?
No because catecholamines are not effective after oral administration since we have lots of MAO in out GI tract and in our liver
35
What are the pulmonary effects of epinephrine?
Binding to the β2 receptors causes bronchodilation
36
What are the metabolic effects of epinephrine?
Binds to the β2 receptors of hepatocytes, causing hepatocytes to break down glycogen and release glucose into the blood
37
What are the indications for epinephrine?
Stimulate the heart in cardiac emergencies: will activate β1 receptors to increase rate and force; by activating α1 receptors on blood vessels, will cause vasoconstriction and therefore increase in diastolic BP
Treat serious hypersensitivity reactions to other drugs and allergens (including anaphylaxis): in severe allergic reaction, there is massive release of histamine, which causes bronchoconstriction and extreme vasodilation; epinephrine will bind β2 receptors in lungs and vasodilate the bronchi; it will also bind β1 receptors in heart and α1 on blood vessels (to cause vasoconstriction)
Asthma: sometimes used to treat asthma since will cause bronchodilation by activating β2 receptors; however, problem is that some of the epinephrine makes its way to the heart and causes heart rate to go up, making pts uncomfortable
Co-administer with local anesthetics: causes vasoconstriction and thus slows down rate of absorption of local anesthetics
38
What are the direct acting, selective (α, β) adrenergic agonists?
Norepinephrine (α1, α2, β1)
Dopamine (α1, β1)
Dobutamine (α1, β1, β2)
39
Norepinephrine type
A direct acting, selective (α, β) adrenergic agonist
α1, α2, β1
40
What is most common use of norepinephrine?
Most common use is as a vasoconstrictor w/ local anesthetics
41
Why is norepinephrine not normally used in a cardiac emergency?
When exogenous norepinephrine is given, at some point it will slow the heart down
Have no idea why it does this
Doesn't lower systolic pressure because the force of contraction has increased, but still don't want to decrease heart rate in someone who might be in a cardiac emergency
42
Dopamine type
Direct acting, selective (α, β) adrenergic agonist
α1, β1
43
What is dopamine used for?
Cardiac emergency
44
What is added benefit of using dopamine during a cardiac emergency?
There are dopamine receptors in the renal arteries, so when you use dopamine, you can increase systolic and diastolic pressure
Can cause dilation of renal arteries so kidney gets a really healthy supply of blood
Epinephrine causes vasoconstriction everywhere and can sometimes decrease supply of blood to kidneys
45
Dobutamine type
Direct acting, selective (α, β) adrenergic agonist
α1, β1, β2
(+) isomer: β1 agonist, weak β2 agonist, α1 antagonist
(-) isomer: α1 agonist, weak β1 and β2 agonist
One of the isomers is α1 agonist and the other is α1 antagonist, so cancel eachother out
46
What is dobutamine used for?
Used as a β1 to get heart going
47
Phenylephrine type
Direct acting, selective (α) agonist
α1
48
What is phenylephrine used for?
Can be used to increase diastolic BP
However, most common use is in various over-the-counter drugs such as in nasal decongestants
It occupies the α1 receptors on the nasal mucosa, causing vasoconstriction so it is easier to breathe
Can also be used in eye drops to treat bloodshot eyes (again vasoconstriction)
To treat hemorrhoids, which are swollen blood vessels in the rectum (again cause vasoconstriction)
Shouldn't be used if hypertensive since can increase diastolic blood pressure
49
Clonidine type
Direct acting, selective (α), adrenergic agonist
α2
50
What is clonidine used for?
Exerts its therapeutic effect in the CNS
Will lower sympathetic tone everywhere in the body, lowering both systolic and diastolic BP
Used to treat chronic hypertension by dampening down sympathetic tone coming from brain
Also used to help treat withdrawal symptoms in opiate and alcohol addiction
Can also be used to treat glaucoma (thought to decrease production of aqueous humor)
Taken orally
Are part of second line drugs for treatment of hypertension
51
What are the side effects of clonidine?
Dry mouth and sedation
52
Brimonidine type
Direct acting, selective (α) adrenergic agonist
α2
53
What is brimonidine used for?
Can be applied topically to eye to decrease interocular pressure in glaucoma patients
Thought to decrease synthesis of aqueous humor
Brimonidine is used over clonidine in eye drops bc it doesn't irritate the eye
54
Isoproterenol type
Direct acting, selective (β) adrenergic agonist
β1, β2
55
What is isoproterenol used for?
Sometimes used to treat asthma but has same problem as epinephrine in that it can bind to β1 receptor in heart also, causing uncomfortable increase in heart rate
56
Albuterol type
Direct acting, selective (β), adrenergic agonist
β2
Are selective, but not specific, for the β2 receptor
If albuterol levels get high enough, will start to bind the β1 receptor
57
What is albuterol used for?
Used in treatment of asthma
| Can be inhaled to get bronchodilation
58
What is a potential problem in using β2 agonists in treatment of asthma?
Will cause receptor down-regulation if the β2 agonists are used too frequently
Could get desensitization and internalization of the β2 receptor on the bronchiolar smooth muscle
Leads to development of pharmacodynamic tolerance
Don't want to keep increasing dose of this because it will eventually start binding to β1 receptors
59
Terbutaline type
Direct acting, selective (β) adrenergic agonist
β2
60
What is terbutaline used for?
Treatment of asthma
| Suppress uterine contractions in premature labor
61
How do indirect acting adrenergic agonists work?
Act by elevating levels of endogenous norepinephrine in the effector junction by a number of mechanisms
62
How do indirect acting adrenergic agonists that are releasers work?
Reverse prejunctional reuptake of norepinephrine; so, norepinephrine is pumped out into the cell junction
Transporter in storage vesicle is reversed as well
63
Amphetamine type
Indirect acting adrenergic agonist
Releaser
64
What is amphetamine used for?
ADHD
Nacrolepsy
Chronic fatigue syndrome
These therapeutic actions occur in CNS and are unrelated to ANS (so details were not discussed)
65
What are risks associated w/ amphetamine?
With elevated norepinephrine levels, will activate β1 receptor in heart and activate α1 receptors in blood vessels
When catecholamine levels get high around heart, there is increased risk of arrhythmias
Cause ventricular arrhythmias
66
Methylpenidate
Indirect acting adrenergic agonist
Releaser
Has similar actions to amphetamine in periphery
Increases norepinephrine levels, but not to same degree as with amphetamine
Risk of an arrhythmia is lower
67
Tyramine
Indirect acting adrenergic agonist
Releaser
Not actually a drug, but a natural breakdown product from tyrosine that is found in certain foods (processed and smoked meats, many cheeses, certain fruits and nuts) in high levels
It is a potent releaser of norepinephrine, which we don't have to worry about because we have a lot of MAO in GI tract and liver
68
What should foods high in tyramine be avoided in patients taking MAO inhibitors?
If they eat foods high in tyramine, they will absorb it since MAO is not there in GI tract and liver
This would cause release of norepinephrine in the body and increase risk of arrhythmia
69
Cocaine
Indirect adrenergic agonists
Uptake inhibitor
Local anesthetic and CNS effects
Acts at prejunctional receptor transporter at sympathetic neuronal varicosity, stopping it from working
Accumulate norepinephrine in neuronal cell junction
CNS effects are reason for it s abuse potential
In periphery, is similar to what amphetamine does: increase in heart rate, increase in force of contraction, increase in blood pressure, increase in risk of arrhythmia
70
Tricylic antidepressants
Indirect adrenergic agonist
Uptake inhibitor
Does similar things to block reuptake of norepinephrine, just like cocaine
71
Mixed adrenergic agonists
Act like epinephrine (bind to all of the α and β receptors) but also act like amphetamine (increase release of norepinephrine)
So, are part direct acting and part indirect acting
72
Ephedrine
A mixed adrenergic agonist
(α, β)
Sometimes used as a drug for hypotensive crises (given to elevate BP)
Can be used as a bronchodilator or to treat incontinence
Mostly concerned about this b/c it appears in lots of food supplements
73
Phentolamine type
Non-selective α adrenergic antagonist
α1, α2
74
What is phentolamine used for?
Sometimes used in hospital to quickly lower BP
Causes vasodilation in arteries and arterioles, as well as veins
Shifts the fraction of blood to the venous side, lowering venous return to the heart
75
Is phentolamine used chronically to treat hypertension?
No because patients who take this have severe orthostatic hypertension (when they stand up, get dizzey and might faint)
76
Prazosin type
Selective α adrenergic antagonist
α1
77
What is prazosin used for?
To chronically treat hypertension
| Lowers both systolic and diastolic pressure, just like in phentolamine
78
What is first dose effect of prazosin?
Only see orthostatic hypertension after first dose of drug; don't know why this is
79
What is epinephrine reversal when prazosin is administered?
In a cardiac emergency, if given epinephrine to patient who has many other α1 receptors already blocked by the prazosin, the epinephrine just binds to the β2 receptor with little binding to the α1 receptor, which vauses vasodilation (opposite effect of what you want to see when treating pt for cardiac emergency)
80
Why is there increased heart rate seen with administration of phentolamine?
As a result of blocking α2, get elevated norepinephrine around heart
End up seeing increase in heart rate, but systolic pressure doesn't go up bc of drop in stroke volume due to decrease in venous return since the phentolamine has caused vasodilation in arteries and veins
81
What can be given instead of epinephrine to a pt taking prazosin who has a cardiac emergency?
Norepinephrine or dopamine
| Anything that won't bind at β2 receptor and will instead compete at α1 receptor
82
What are α1 antagonists considered?
Second line drugs for treatment of hypertension
83
Tamsulosin type
Selective α adrenergic antagonist
α1A
84
What is tamsulosin used for?
α1A receptors are located on smooth muscle that forms capsule around the prostate gland
With benign prostatic hyperplasia, the prostate starts to grow and pressure builds up because there is a capsul of smooth muscle around it
This puts pressure on the urethra, making it hard to urinate
Tamsulosin blocks the α1A receptors on the capsul of smooth muscle, causing it to relax which relieves some of the pressure on the urethra as a result of the hyperplasia
85
Propranolol type
non-selective (first generation) β adrenergic antagonist
β1, β2
86
What are the uses of beta blockers?
Hypertension
Angina - Decreases work that heart does, so oxygen demand to heart is reduced
Arrhythmias - Have to give very high dose to see this effect
Myocardial infarction - Best circumstance is to give beta blocker during heart attack to reduce work of heart/oxygen consumption of heart by slowing it down and reducing force of contraction
Glaucoma - Reduces formation of aqueous humor
Migraines
87
How do beta blockers work?
Lower both systolic and diastolic pressure, but we're not sure how they work
Blocking at β1 receptor reduces systolic pressure
Blocking at β2 receptors on blood vessels would cause vasoconstriction, but in reality get vasodilation and decrease in diastolic pressure which doesn't make sense
Could work in CNS to reduce diastolic pressure or could block release of renin from kidneys; overall, still unknown
88
What are some potential issues in use of non-selective (first generation) beta blockers?
Asthmatics - don't want to block β2 receptor because that will cause bronchoconstriction
Insulin-dependent diabetics - Don't want to block the β2 receptor since they no longer produce any glucagon, which is usually fine since there is epinephrine, but if the blocker is there, epinephrine is no longer working in addition to glucagon not being there
Sudden withdrawal - If beta blocker is abruptly stopped, have twice as many β1 receptors and heart is working very hard. Have to slowly taper off to allow for β1 receptors to allow number of receptors in heart to go back to normal
89
Timolol type/use
Non-selective (first generation) β adrenergic antagonist
β1, β2
Used to treat glaucoma; applied topically because it doesn't irritate the eye
90
Metoprolol type
Selective (second generation) β adrenergic antagonist
β1
91
What is metoprolol used for?
Will lower both systolic and diastolic pressure
Can be used cautiously in asthmatics and insulin-dependent diabetics
Still have to be cautious because they are selective, not specific, to β1 receptors and if at too high of a dose will start to bind β2 receptors
92
Labetalol type
β adrenergic antagonist with additional actions (third generation)
α1 antagonist
β receptor partial agonist (acts as a competitive antagonist to the full agonist at the β receptors, which is norepinephrine)
93
What is labetalol used for?
Lowers systolic and diastolic pressure
94
Reserpine
Indirect adrenergic antagonist
Depletor
95
What is reserpine used for?
Treat hypertension
Is a very old drug that is sometimes still used today (not common)
96
How does resperine work?
Blocks the entry of norepinephrine into the storage vesicle in the sympathetic varicosity
Over time, as norepinephrine is released and taken back up into the cell, it can't go back into the neuronal varicosity and ends up being broken down by MAO
After a couple weeks of the drug, norepinephrine levels go down throughout the sympathetic nervous system, which lowers the systolic and diastolic BP
97
What are the adverse side effects of reserpine?
Sleep disruption, headaches, nausea
Also get depletion or reduction of dopamine from dopaminergic neurons in the brain
Patients can develop symptoms of Parkinson's disease
98
What enzyme produces acetylcholine in cytosol?
Choline acetyl transferase
99
Is there an autoregulatory receptor in cholinergic effector junction?
Yes, a muscarinic autoregulatory
100
How is action of the acetylcholine terminated?
At effector cell junction, there is enzyme called acetylcholinesterase which will break down acetylcholine into acetate and choline, which terminates action of acetylcholine (as opposed to reuptake seen w/ epinephrine and norepinephrine)
101
Botulinum toxin
A poison but also used as a drug
Prevents the cholinergic storage vesicle from fusing w/ the cell membrane - stops the release of acetylcholine
Can paralyze muscle b/c it prevents acetylcholine from contacting neuromuscular junction and muscle thus can't contract
102
What is botulinum toxin used for?
Pts with cerebral palsy so they can have better control over their movements
Cosmetic purposes
103
Black widow spider venom
Causes explosive release of acetylcholine
| All of the cholinergic storage vesicles will fuse with membranes, causing massive release of acetylcholine
104
Anticholinesterases
Inhibit acetylcholinesterase, so you accumulate levels of acetylcholine
These act as indirect agonists
105
What are the cholinegic receptor subtypes?
Nicotinic - activated by nicotine, sodium channel, muscle type (Nm), neuronal type (Nn)
Muscarinic - activated by muscarine, coupled through G proteins, M1 - M5
106
Cholinergic stimulation
Nicotinic:
Neuromuscular endplate - contraction (get muscular fasiculations or twitching)
```
Muscarinic:
Iris - miosis
Ciliary muscle - accomodation
Exocrine glands - increased secretion
Bronchi - constriction
GI tract - contraction and peristalsis
Bladder - constriction
Heart - decreased rate and force
Blood vessels - vasodilation (muscarinic receptors are on endothelial cells of blood vessels, which leads to production of NO which causes relaxation is mooth muscle and thus vasodilation)
```
107
Cholinergic blockade
Nicotinic:
Neuromuscular endplate - paralysis
Ganglia - complex
```
Muscarinic:
Iris - mydriasis
Ciliary muscle - cycloplegia (can't undergo accommodation)
Exocrine glands - decreased secretions
GI tract - relaxation
Bladder - relaxation
Heart - increased rate and force
Blood vessels - no effect
```
108
Acetylcholine type
Direct-acting cholinergic agonist
Choline ester
109
What is acetylcholine (drug) used for?
Sometimes used to induce accomodation
110
Why is acetylcholine not a very good drug?
Very rapidly down by cholinesterases (acetylcholinesterase and pseudocholinesterase)
Acetylcholinesterase is found in many tissues but is in very high concentration in RBCs
Pseudocholinesterase is also found in many tissues but is in very high concentrations in plasma
These 2 together in blood keep endogenous acetylcholine out of blood
If you give intravenous dose of acetylcholine, it will be broken down very quickly
Also, acetylcholine has both muscarinic and nicotine receptors - will activate receptors at the ganglia and the neuromuscular junction
111
Carbachol type
Direct-acting cholinergic agonist
Choline ester
112
What is carbachol used for?
Applied topically to eye for glaucoma - causes contraction of radial longitudinal ciliary muscle
Is a better drug than acetylcholine bc it is not broken down by cholinesterases (still has nicotinic activity and shouldn't be given systemically)
113
Why is carbachol an exception to the rule of not giving agonists of muscarinic receptors to pts with asthma?
Is used topically to treat glaucoma
| Ok as long as pt understands that these are only meant for eyes
114
Bethanecol type
Direct acting cholinergic agonist
Choline ester
115
Why is bethanceol a better drug than acetylcholine?
Is not broken down by cholinesterases and has no nicotinic activity
116
What is bethanecol used for?
Treatment of paralytic ileus (condition that occurs when peristalsis stops in small intestines) and bladder atony (detrusor muscle loses ability to contract)
These conditions occur due to infection, surgery, or due to no reason. Most frequently occur in infants and elderly
Bethanechol jumpstarts peristalsis and the detrusor muscles
117
Pilocarpine type
Direct acting cholinergic agonist
Alkaloid
Has negligible nicotinic activity
118
What is pilocarpine used for?
Can be given orally, injected, or put topically in eye to treat glaucoma
Most frequent use is to treat zerostomia (dry mouth) since salivary glands have muscarinic receptors
119
Why isn't pilocarpine used to treat paralytic ileus?
Wasn't presented that way by drug company to FDA, so doesn't have FDA approval for treatment of paralytic ileus
120
What are the adverse effects of direct acting cholinergic agonists?
Annoyances to pts due to activation of muscarinic receptors other than those at target sites for that pt (someone treated for bladder atony may have excessive salivation)
If someone overdoses (taking high levels), there is syndrome called cholinergic crisis - pts with symptoms that they have too much acetylcholine in their periphery: characterized by symptoms that are represented by SLUD (salivation, lacrimation, urination, defecation)
Bronchiolar smooth muscle contraction - difficulty breathing or burning sensation in chest
121
Anticholinesterases
Cholinergic agonists that inhibit acetylcholinesterase
122
How does acetylcholinesterase work?
Has a hydroxyl group on serine at the active center of the enzyme
When a molecule of acetylcholine comes into contact w/ acetylcholinesterase, the acetylcholine acetylates the hydroxyl group of the serine
Water molecule then comes along and pulls off the acetyl group from the oxygen
Get acetyl and choline
123
Edrophonium type
Cholinergic agonist
Anticholinesterase
Non-covalent, rapidly reversible inhibitor
124
Donepezil type
Cholinergic agonist
Anthicholinesterase
Non-covalent, rapidly reversible inhibitor
125
What is donepezil used for?
Treatment of Alzheimer's
Pts with Alzheimer's were found to be deficient in acetylcholine (as measured by cholineacetyltrasnferase)
Donepezil inhibits acetylcholinesterase and elevates acetylcholine levels in the brain, suppressing some of the effects of Alzheimer's disease if it is given during the early stages
126
How does donepezil work?
Reversibly binds to some amino acids located at the active site of acetylcholinesterase, close to the serine hydroxyl group
While the donepezil is there, it prevents acetylcholine from getting close to the hydroxyl group
Donepezil molecule won't be there for long, but once it dissociates, another molecule will be there to take its place
127
Carbamates
Cholinergic agonists
Anticholinesterase
Covalent inhibitors of acetylcholinesterase
128
How do carbamates work?
When it comes into contact w/ acetylcholinesterase, it carbamalates the oxygen of the serine hydroxyl group, forming a covalent bond
Water will come off and pull off the carbamate to reform acetylcholinesterase
However, this takes minutes to hours depending on the structure of the carbamate (unlike when water reactivaates acetylated enzyme and it occurs in a fraction of a second)
During the time when the intermediate exists, the enzyme is inhibited
129
Physostigmine type
Cholinergic agonist
Anticholinesterase
Covalent inhibitor - carbamate
130
What is physostigmine used for?
Used topically to treat glaucoma
Can be taken orally, but it penetrates the blood-brain barrier and gets into brain (don't want to inhibit acetylcholinesterases of brain if don't have to)
131
Neostigmine type
Cholinergic agonist
Anticholinesterase
Covalent inhibitor - carbamate
132
What is neostigmine used for?
Can be given systemically b/c it doesn't cross the brain-blood barrier
Used in combination w/ bethanecol to treat paralytic ileus or bladder atony
Also used to treat mysasthenia gravis , which is a collection of autoimmune disorders where antibodies are produced to different parts of the nicotinic receptor at the neuromuscular junction; most common form of this involves antibody binding to nicotinic receptor and blocking acetylcholine from binding; neostigmine will inhibit acetylcholinesterase in different locations of the body and increase levels of acetylcholine so that it can outcompete the antibodies for nicotinic receptors at neuromuscular junction
133
Carbaryl type
Cholinergic agonist
Anticholinesterse - carbamate
A pesticide, not a drug
134
What does carbaryl do when ingested?
People who ingest carbaryl can develop cholinergic crisis bc acetylcholine accumulates in various locations through body bc these pesticides inhibit acetylcholinesterase
135
Organophosphates
Cholinergic agonist
| Anticholinesterase - slowly reversible inhibitors
136
Echothiophate type
Organophosphate
Cholinergic agonist
Anticholinesterase - slowly reversible inhibitors
137
What is echothiophate used for?
Used for glaucoma (topically applied only once every 4 days bc inhibition of acetylcholinesterase is that long-lasting)
138
How do organophosphates work?
When it comes in contact w/ acetylcholinesterase, phosphorylate the oxygen of the serine hydroxyl group
Water molecule molecule can pull off the phosphate group to reactivate acetylcholinestease, but this reaction w/ water takes hours to days to occur, depending on the structure of the organophosphate
139
What is aging of organophosphates?
Doesn't occur w/ all organophosphates
Side chains of organophosphates are usually aklyls - methyl or propyl or something attached
With some organophosphates, when they phosphorylate the serine hydroxyl group, one of those alkyl side chains can spontaneously break off and are left w/ just a hydroxyl group there
140
Is reactivation possible w/ aging of organophosphates?
No
| Acetylcholinesterase is permantently inhibited
141
Parthion type
Cholinergic agonist
Anticholinesterase - slowly reversible inhibitor
Organophosphate
Is a pesticide
142
How can pts poisoned w/ organophosphates be treated?
Given 2-PAM, which is a reactivator that pulls off the phosphate group off the enzyme faster than water
2-PAM doesn't work when aging has occurred
143
Can 2-PAM be used for carbamate poisoning?
No, only for organophosphate poisoning
| Only makes carbamate poisoning worse (don't know why this occurs)
144
Soman type
Cholinergic agonist
Anticholinesterase - slowly reversible inhibitor
Organophosphate
Nerve gas (chemical warfare)
145
What does soman do?
Behaves like other organophosphates but has some important differences:
1) very, very potent - will inhibit nearly all acetylcholinesterase in body at fairly low concentrations in blood
2) volatile - designed so exposure is through inhalation; allows for widespread exposure when they are dispersed into the air
3) age instantly - organophosphate ages immediately, so there is no chance for antidote that will lead to reactivation
146
What do soldiers do to protect against nerve gas (soman) attack?
Administer a carbamate that is similar to physostigmine, which binds to acetylcholinesterase and causes symptoms of cholinergic crisis, but protects against having soman bind
Muscarinic antagonists are also in antidote for nerve gas
147
Atropine type
Cholinergic blocker
Muscarinic blocker
Natural alkaloid
148
What effects does atropine have?
Heart - decreases parasympathetic tone; heart will increase rate and force of contraction
Eye - dilator muscle becomes dominant and pupils will dilate; will cause cycoplegia
Salivary glands - used in oral surgery to stop too much saliva from being produced
Respiratory system - cause bronchodilation and reduce mucus production (treat asthma)
Intestines - antispasmodic agent; will reduce peristalsis
Bladder - used for urinary urge incontinence (sudden need to urinate and have to do so very quickly; found in elderly) since atropine causes relaxation of detrusor muscle
149
What can atropine be used to treat?
Cholinergic crisis - will block excess acetylcholine at muscarinic site
Also can be given to someone w/ carbamate poisoning (since they wouldn't be given reactivator)
150
Scopolamine type
Cholinergic blocker
Muscarinic blocker
Natural alkaloid
151
What is scopolamine used for?
To suppress motion sickness (in CNS)
152
Ipratropium type
Cholinergic blocker
Muscarinic blocker
Synthetic quaternary amine
153
What is ipratropium used for?
Treat asthma
| Can be inhaled and will block muscarinic receptors, cause bronchodilation, and reduce mucus production
154
Benztropine type
Cholinergic blocker
Muscarinic blocker
Synthetic tertiary amine
155
What is benztropine used for?
Used to treat Parkinson's disease
| For reasons that we don't understand, will suppress tremors in early stages of Parkinson's disease
156
Ganglionic blockers
Cholinergic blocker
Will block ganglia in both sympathetic and parasympathetic divisions
Are complicated and have lots of action
157
Mecamylamine
Cholinergic blocker
| Ganglionic blocker
158
What does mecamylamine do?
Will block ganglia
In tissues that have dual input, in order to figure out what the drug effect will be, have to ask what tone is dominant and take opposite of dominant effect
159
What does mecamylamine do in eyes?
In eyes, contrusor and dilator have dual input
Parasympathetic tone is dominant when resting (effect is constriction of pupils)
So, mecamylamine will cause dilationof pupils
160
What does mecamylamine do in arteries and arterioles?
Only have sympathetic innervation to arteries and arterioles
If this is blocked, cause vasodilation and there is decreased return to the heart
Both systolic and diastolic pressure will go down
161
What does mecamylamine do in heart?
Dominant tone in heart is parasympathetic
Heart will speed up w/ mecamylamine
Systolic pressure won't increase bc stroke volume goes down (since decreased return to heart)
162
What is biggest problem w/ administering mecamylamine?
Causes severe orthostatic hypotension
| Only ok to be used in hospital bed bc it lowers BP pretty quicky, but not a good drug to be used in an active person
