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MCS > Autonomic Pharmacology > Flashcards

Autonomic Pharmacology Flashcards

1
Q

What is constrictor muscle of the eye under the control of?

A

Under parasympathetic control; has muscarinic receptors

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2
Q

When constrictor muscle contracts, what occurs?

A

Pupil constricts (miosis)

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3
Q

What is dilator muscle of the eye under the control of?

A

Sympathetic control; has α1 receptors

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4
Q

What could you do in order to dilate the pupils?

A

Muscarinic antagonists

α1 agonists

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5
Q

What are the 2 parts to the ciliary muscle?

A

Radial ciliary muscle and longitudinal muscle

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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

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7
Q

What is the ciliary muscle under control of?

A

Mostly the parasympathetic division

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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

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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

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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

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11
Q

What kind of drug assists in draining aqueous humor in glaucoma patient?

A

Muscarinic agonist

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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

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13
Q

Parasympathetic and sympathetic physiology of heart

A

Sympathetic
β1: increase in rate and force
Parasympathetic
Muscarinic: decrease in rate and force

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14
Q

In normal, healthy individuals, what controls systolic and diastolic pressure?

A

Systolic by heart

Diastolic by blood vessels

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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)

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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

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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

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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

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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

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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
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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
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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

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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

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24
Q

What does sympathetic input in both GI tract and bladder cause?

A

Suppresses urination, digestion, and defecation

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25
Q

What does parasympathetic input in both GI tract and bladder cause?

A

Promotes urination, digestion, and defecation

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26
Q

Parasympathetic and sympathetic physiology of uterus

A

Sympathetic
α1: increase contractions
β2: decrease contractions

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27
Q

Parasympathetic and sympathetic physiology of salivary glands

A

Sympathetic
α1, β2: increase viscous secretions
only occurs in extremely fearful situations

Parasympathetic
Muscarinic: increase watery saliva

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28
Q

Where is norepinephrine stored? How does it get there?

A

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)

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29
Q

What terminates the action of the norepinephrine?

A

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

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30
Q

What occurs to remaining 5% of norepinephrine that is not taken up by prejunctional neuronal uptake?

A

Extraneuronal uptake occurs at the effector cell

Inside effector cells, there are 2 enzymes that break up norepinephrine: COMT and MAO

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31
Q

Epinephrine type

A

Direct acting adrenergic agonist (non-selective)

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32
Q

What receptors does epinephrine act on?

A

α1, α2, β1 and β2

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33
Q

What are the cardiovascular effects of epinephrine?

A

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

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34
Q

Is epinephrine given orally? Why or why not?

A

No because catecholamines are not effective after oral administration since we have lots of MAO in out GI tract and in our liver

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35
Q

What are the pulmonary effects of epinephrine?

A

Binding to the β2 receptors causes bronchodilation

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36
Q

What are the metabolic effects of epinephrine?

A

Binds to the β2 receptors of hepatocytes, causing hepatocytes to break down glycogen and release glucose into the blood

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37
Q

What are the indications for epinephrine?

A

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

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38
Q

What are the direct acting, selective (α, β) adrenergic agonists?

A

Norepinephrine (α1, α2, β1)
Dopamine (α1, β1)
Dobutamine (α1, β1, β2)

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39
Q

Norepinephrine type

A

A direct acting, selective (α, β) adrenergic agonist

α1, α2, β1

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40
Q

What is most common use of norepinephrine?

A

Most common use is as a vasoconstrictor w/ local anesthetics

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41
Q

Why is norepinephrine not normally used in a cardiac emergency?

A

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

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42
Q

Dopamine type

A

Direct acting, selective (α, β) adrenergic agonist

α1, β1

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43
Q

What is dopamine used for?

A

Cardiac emergency

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44
Q

What is added benefit of using dopamine during a cardiac emergency?

A

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

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45
Q

Dobutamine type

A

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

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46
Q

What is dobutamine used for?

A

Used as a β1 to get heart going

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47
Q

Phenylephrine type

A

Direct acting, selective (α) agonist

α1

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48
Q

What is phenylephrine used for?

A

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

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49
Q

Clonidine type

A

Direct acting, selective (α), adrenergic agonist

α2

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50
Q

What is clonidine used for?

A

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

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51
Q

What are the side effects of clonidine?

A

Dry mouth and sedation

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52
Q

Brimonidine type

A

Direct acting, selective (α) adrenergic agonist

α2

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53
Q

What is brimonidine used for?

A

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

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54
Q

Isoproterenol type

A

Direct acting, selective (β) adrenergic agonist

β1, β2

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55
Q

What is isoproterenol used for?

A

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

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56
Q

Albuterol type

A

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

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57
Q

What is albuterol used for?

A

Used in treatment of asthma

Can be inhaled to get bronchodilation

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58
Q

What is a potential problem in using β2 agonists in treatment of asthma?

A

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

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59
Q

Terbutaline type

A

Direct acting, selective (β) adrenergic agonist

β2

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60
Q

What is terbutaline used for?

A

Treatment of asthma

Suppress uterine contractions in premature labor

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61
Q

How do indirect acting adrenergic agonists work?

A

Act by elevating levels of endogenous norepinephrine in the effector junction by a number of mechanisms

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62
Q

How do indirect acting adrenergic agonists that are releasers work?

A

Reverse prejunctional reuptake of norepinephrine; so, norepinephrine is pumped out into the cell junction
Transporter in storage vesicle is reversed as well

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63
Q

Amphetamine type

A

Indirect acting adrenergic agonist

Releaser

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64
Q

What is amphetamine used for?

A

ADHD
Nacrolepsy
Chronic fatigue syndrome
These therapeutic actions occur in CNS and are unrelated to ANS (so details were not discussed)

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65
Q

What are risks associated w/ amphetamine?

A

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
Q

Methylpenidate

A

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
Q

Tyramine

A

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
Q

What should foods high in tyramine be avoided in patients taking MAO inhibitors?

A

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
Q

Cocaine

A

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
Q

Tricylic antidepressants

A

Indirect adrenergic agonist

Uptake inhibitor

Does similar things to block reuptake of norepinephrine, just like cocaine

71
Q

Mixed adrenergic agonists

A

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
Q

Ephedrine

A

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
Q

Phentolamine type

A

Non-selective α adrenergic antagonist

α1, α2

74
Q

What is phentolamine used for?

A

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
Q

Is phentolamine used chronically to treat hypertension?

A

No because patients who take this have severe orthostatic hypertension (when they stand up, get dizzey and might faint)

76
Q

Prazosin type

A

Selective α adrenergic antagonist

α1

77
Q

What is prazosin used for?

A

To chronically treat hypertension

Lowers both systolic and diastolic pressure, just like in phentolamine

78
Q

What is first dose effect of prazosin?

A

Only see orthostatic hypertension after first dose of drug; don’t know why this is

79
Q

What is epinephrine reversal when prazosin is administered?

A

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
Q

Why is there increased heart rate seen with administration of phentolamine?

A

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
Q

What can be given instead of epinephrine to a pt taking prazosin who has a cardiac emergency?

A

Norepinephrine or dopamine

Anything that won’t bind at β2 receptor and will instead compete at α1 receptor

82
Q

What are α1 antagonists considered?

A

Second line drugs for treatment of hypertension

83
Q

Tamsulosin type

A

Selective α adrenergic antagonist

α1A

84
Q

What is tamsulosin used for?

A

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
Q

Propranolol type

A

non-selective (first generation) β adrenergic antagonist

β1, β2

86
Q

What are the uses of beta blockers?

A

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
Q

How do beta blockers work?

A

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
Q

What are some potential issues in use of non-selective (first generation) beta blockers?

A

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
Q

Timolol type/use

A

Non-selective (first generation) β adrenergic antagonist

β1, β2

Used to treat glaucoma; applied topically because it doesn’t irritate the eye

90
Q

Metoprolol type

A

Selective (second generation) β adrenergic antagonist

β1

91
Q

What is metoprolol used for?

A

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
Q

Labetalol type

A

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
Q

What is labetalol used for?

A

Lowers systolic and diastolic pressure

94
Q

Reserpine

A

Indirect adrenergic antagonist

Depletor

95
Q

What is reserpine used for?

A

Treat hypertension

Is a very old drug that is sometimes still used today (not common)

96
Q

How does resperine work?

A

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
Q

What are the adverse side effects of reserpine?

A

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
Q

What enzyme produces acetylcholine in cytosol?

A

Choline acetyl transferase

99
Q

Is there an autoregulatory receptor in cholinergic effector junction?

A

Yes, a muscarinic autoregulatory

100
Q

How is action of the acetylcholine terminated?

A

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
Q

Botulinum toxin

A

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
Q

What is botulinum toxin used for?

A

Pts with cerebral palsy so they can have better control over their movements

Cosmetic purposes

103
Q

Black widow spider venom

A

Causes explosive release of acetylcholine

All of the cholinergic storage vesicles will fuse with membranes, causing massive release of acetylcholine

104
Q

Anticholinesterases

A

Inhibit acetylcholinesterase, so you accumulate levels of acetylcholine
These act as indirect agonists

105
Q

What are the cholinegic receptor subtypes?

A

Nicotinic - activated by nicotine, sodium channel, muscle type (Nm), neuronal type (Nn)

Muscarinic - activated by muscarine, coupled through G proteins, M1 - M5

106
Q

Cholinergic stimulation

A

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
Q

Cholinergic blockade

A

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
Q

Acetylcholine type

A

Direct-acting cholinergic agonist

Choline ester

109
Q

What is acetylcholine (drug) used for?

A

Sometimes used to induce accomodation

110
Q

Why is acetylcholine not a very good drug?

A

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
Q

Carbachol type

A

Direct-acting cholinergic agonist

Choline ester

112
Q

What is carbachol used for?

A

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
Q

Why is carbachol an exception to the rule of not giving agonists of muscarinic receptors to pts with asthma?

A

Is used topically to treat glaucoma

Ok as long as pt understands that these are only meant for eyes

114
Q

Bethanecol type

A

Direct acting cholinergic agonist

Choline ester

115
Q

Why is bethanceol a better drug than acetylcholine?

A

Is not broken down by cholinesterases and has no nicotinic activity

116
Q

What is bethanecol used for?

A

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
Q

Pilocarpine type

A

Direct acting cholinergic agonist

Alkaloid

Has negligible nicotinic activity

118
Q

What is pilocarpine used for?

A

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
Q

Why isn’t pilocarpine used to treat paralytic ileus?

A

Wasn’t presented that way by drug company to FDA, so doesn’t have FDA approval for treatment of paralytic ileus

120
Q

What are the adverse effects of direct acting cholinergic agonists?

A

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
Q

Anticholinesterases

A

Cholinergic agonists that inhibit acetylcholinesterase

122
Q

How does acetylcholinesterase work?

A

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
Q

Edrophonium type

A

Cholinergic agonist

Anticholinesterase

Non-covalent, rapidly reversible inhibitor

124
Q

Donepezil type

A

Cholinergic agonist

Anthicholinesterase

Non-covalent, rapidly reversible inhibitor

125
Q

What is donepezil used for?

A

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
Q

How does donepezil work?

A

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
Q

Carbamates

A

Cholinergic agonists
Anticholinesterase
Covalent inhibitors of acetylcholinesterase

128
Q

How do carbamates work?

A

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
Q

Physostigmine type

A

Cholinergic agonist
Anticholinesterase
Covalent inhibitor - carbamate

130
Q

What is physostigmine used for?

A

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
Q

Neostigmine type

A

Cholinergic agonist
Anticholinesterase
Covalent inhibitor - carbamate

132
Q

What is neostigmine used for?

A

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
Q

Carbaryl type

A

Cholinergic agonist
Anticholinesterse - carbamate
A pesticide, not a drug

134
Q

What does carbaryl do when ingested?

A

People who ingest carbaryl can develop cholinergic crisis bc acetylcholine accumulates in various locations through body bc these pesticides inhibit acetylcholinesterase

135
Q

Organophosphates

A

Cholinergic agonist

Anticholinesterase - slowly reversible inhibitors

136
Q

Echothiophate type

A

Organophosphate
Cholinergic agonist
Anticholinesterase - slowly reversible inhibitors

137
Q

What is echothiophate used for?

A

Used for glaucoma (topically applied only once every 4 days bc inhibition of acetylcholinesterase is that long-lasting)

138
Q

How do organophosphates work?

A

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
Q

What is aging of organophosphates?

A

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
Q

Is reactivation possible w/ aging of organophosphates?

A

No

Acetylcholinesterase is permantently inhibited

141
Q

Parthion type

A

Cholinergic agonist
Anticholinesterase - slowly reversible inhibitor
Organophosphate
Is a pesticide

142
Q

How can pts poisoned w/ organophosphates be treated?

A

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
Q

Can 2-PAM be used for carbamate poisoning?

A

No, only for organophosphate poisoning

Only makes carbamate poisoning worse (don’t know why this occurs)

144
Q

Soman type

A

Cholinergic agonist
Anticholinesterase - slowly reversible inhibitor
Organophosphate
Nerve gas (chemical warfare)

145
Q

What does soman do?

A

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
Q

What do soldiers do to protect against nerve gas (soman) attack?

A

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
Q

Atropine type

A

Cholinergic blocker
Muscarinic blocker
Natural alkaloid

148
Q

What effects does atropine have?

A

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
Q

What can atropine be used to treat?

A

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
Q

Scopolamine type

A

Cholinergic blocker
Muscarinic blocker
Natural alkaloid

151
Q

What is scopolamine used for?

A

To suppress motion sickness (in CNS)

152
Q

Ipratropium type

A

Cholinergic blocker
Muscarinic blocker
Synthetic quaternary amine

153
Q

What is ipratropium used for?

A

Treat asthma

Can be inhaled and will block muscarinic receptors, cause bronchodilation, and reduce mucus production

154
Q

Benztropine type

A

Cholinergic blocker
Muscarinic blocker
Synthetic tertiary amine

155
Q

What is benztropine used for?

A

Used to treat Parkinson’s disease

For reasons that we don’t understand, will suppress tremors in early stages of Parkinson’s disease

156
Q

Ganglionic blockers

A

Cholinergic blocker
Will block ganglia in both sympathetic and parasympathetic divisions
Are complicated and have lots of action

157
Q

Mecamylamine

A

Cholinergic blocker

Ganglionic blocker

158
Q

What does mecamylamine do?

A

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
Q

What does mecamylamine do in eyes?

A

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
Q

What does mecamylamine do in arteries and arterioles?

A

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
Q

What does mecamylamine do in heart?

A

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
Q

What is biggest problem w/ administering mecamylamine?

A

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

MCS (7 decks)

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