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Flashcards in Autonomic Pharmacology Deck (134):
0

Where is ACh secreted ?

1. In all of the parasympathetic synapses (between pre and postganglionic and between postgan. and organs).
2. In the preganglionic neurons of SANS.
3. In some post ganglionic neurons of SANS - sweat glands, Piloerector, muscles.
4. In the neuromuscular junction.

1

Where do we find nicotine receptors (type n)?

In all of the synapses between preganglionic and postganglionic neurons in the ANS.

2

Where do we find nicotine receptors type M?

In the neuromuscular junction where ACh binds.

3

What receptors are mainly responsible for the whole body secretions?

M receptors (in both SANS and PANS).

4

What is the main advantage of epinephrine in comparison with norepinephrine ?

Epinephrine is released into the blood circulation, hence it can go to all receptors. Norepinephrine can go only to the receptors that are innervated.

5

What is true abou β2 receptors?

They are NOT innervated, hence they cannot bind to norepinephrine (released in neural terminals) but to epinephrine (released in blood).
Even IV injection of norepinephrine cannot activate these receptors. (Chemical structure).

6

In the pupil, SANS or PANS controls the radial + sphincter muscle?

SANS - radial muscle
PANS - sphincter muscle

7

What receptors do we find in the radial and what in the sphincter muscle?

Radial - α1
Sphincter - Μ

8

How can you identify if a patient is on muscarinic blockers or α1 agonists (or vice versa) by examining the eye?

By looking in the ciliary muscle, which is innervated by the PANS (m receptors).
In muscarinic stimulation we have accommodation (near vision).
In muscarinic antagonism we have cycloplegia (accommodation to far vision).
With α1-agonists we have no cycloplegia.

9

Blurred vision is a hallmark of muscarinic or α1-agonist drug?

Muscarinic drug

10

What is the difference between direct and indirect acting drugs?

The direct acting drugs bind to the receptors, in contrast to the indirect drugs that function somewhere in the nerve terminal or the synapse.

11

What is the effect of hemicholine?

It decreases the uptake of choline by the nerve terminal in order to recreate Ach.

12

What is the effect of botulinum toxin?

It binds to synaptobrevin and suppresses Ach release. It causes muscle paralysis.

13

Where is botulinum toxin used?

1. Blepharospasm
2. Dystonia
3. Strabismus
4. Hyperhydrosis

14

Where are ?

1. Eye sphincter
2. Ciliary muscle
3. Lung bronchioles
4. Glands

15

What effect has the muscarinic receptor activation in the eye sphincter, ciliary muscle, lung bronchioles and glands (M3 receptors)?

1. Eye sphincter : contraction - miosis
2. Ciliary muscle : contraction - accommodation to near vision.
3. Lung bronchioles : contraction - bronchospasm
4. Glands : secretion

16

Where are M2 receptors mainly ?

1. Heart SA node
2. AV node

17

What response cause muscarinic receptor activation in the SA and AV node?

1. HR down
2. Conduction of velocity DOWN
3. No effects on ventricles - purkinje system

18

What muscarinic receptors do we find in stomach, GI glands, intestine, bladder and GI sphincters?

M3 everywhere except Glands of GI system where we find M1 receptors.

19

What receptors are in the sweat glands and endothelium of blood vessels?

M3

20

What happens with stimulation of M3 receptors in the vascular endothelium?

Stimulation of NO synthase. Vasodilation.

21

Is the vascular endothelium innervated?

No. The indirect agonists have no effect on the vascular endothelium.

22

What category of G-proteins is used by M1,M2,M3 receptors?

M1 and M3 - Gq coupled
M2 - Gi coupled

23

Do Nn and Nm receptors have 2nd messengers?

No, they are ligand-gated channels receptors.

24

How quickly do the nicotine receptors desensitized?

Very rapidly, in seconds.

25

Mention 3 basic muscarinic agonists (direct-acting cholinomimetics).

1. Bethanechol
2. Methacholine
3. Pilocarpine
4. Ach

26

Does Ach has a clinical use?

No, because of short half life.

27

What is the effect of AChE on Ach, bethanechol, methacholine and pilocarpine?

1. Ach : very high hydrolysis
2. Bethanechol : no hydrolysis
3. Methacholine : hydrolysis
4. Pilocarpine : no hydrolysis

28

What is the clinical use of bethanechol?

In postoperative/neurogenic conditions - ileus, urinary retention (side effects from anesthesia).

29

What is the clinical use of methacholine?

Bronchial hyperactivity for diagnostic purposes.

30

What is the clinical use of pilocarpine?

Glaucoma (topical) - xerostomia.

31

Mention 7 acetylcholinesterase inhibitors (indirect-acting cholinomimetics).

1. Edrophonium
2. Physostigmine
3. Neostigmine
4. Pyridostigmine
5. Donapezil
6. Tacrine
7. Organophosphates

32

What is the main characteristic and clinical use of edrophonium?

Short acting.
For diagnosis of myasthenia - used to differentiate myasthenia from cholinergic crisis.

33

What is the characteristic and clinical use of physostigmine?

Tertiary amine (enters CNS).
Glaucoma - antidote in atropine overdose.

34

What is the characteristic and clinical use of neostigmine and pyridostigmine?

Quarternary amines (no CNS entry)
Ileus - urinary retention - myasthenia (neostigmine) - reversal of nondepolarizing NM blockers (pyridostigmine).

35

What is the clinical use and characteristic of donepezil and tacrine?

Lipid soluble (CNS entry)
Alzheimer's disease.

36

What is the characteristic and clinical use of organophosphates?

Lipid soluble, irreversible inhibitors
Glaucoma (echothiophate)

37

In what main forms organophosphates present?

1. Malathion
2. Parathion
3. Sarin (nerve gas)

38

What are the active forms of malathion and parathion?

Malaoxon and paraoxon - activation by P450

39

What are the symptoms of acute toxicity from excessive muscarinic stimulation (toxicity of AchE inhibitors)?

1. Diarrhea
2. Urination
3. Miosis
4. Bradycardia
5. Bronchoconstriction
6. Lacrimation
7. Salivation
8. Sweating
9. CNS stimulation

40

What is the principal M antagonist?

Atropine

41

What are the nicotinic effects of acute toxicity of AchE inhibitors?

1. Skeletal muscle excitation - paralysis
2. CNS stimulation

42

How we manage acute toxicity of AchE inhibitors ?

1. Muscarinic effects : atropine
2. Regeneration of AchE : pralidoxime (2-PAM)
3. Time-dependent aging requires use of 2-PAM ASAP.

43

What happens in chronic toxicity of AchE inhibitors?

1. Peripheral neuropathy causing muscle weakness and sensory loss.
2. Demyelination not due to AchE inhibition.
(Mimics MS)

44

How much time must pass for the hydrolysis of an organophosphate binded to AchE to take place (making it irreversible, even with pralidoxime)?

6-8 hours (with nerve gases (sarin) is 2-3 mins!!).

45

What are the pharmacological effects of atropine?

1. Decreased secretions
2. Mudriasis and cycloplegia
3. Hyperthermia (with resulting vasodilation)
4. Tachycardia
5. Sedation
6. Urinary retention and constipation
7. Behavioral excitation and hallucination

46

Mention other classes of drugs with anti muscarinic pharmacology.

1. Antihistamines
2. Tricyclic antidepressants
3. Antipsychotics
4. Quinidine
5. Amantadine
6. Meperidine

47

What are the 3 C's of overdose by muscarinic antagonists?

1. Cardiotoxicity
2. Convulsion
3. Coma

48

What is the antidote for atropine overdose?

Physostigmine

49

Mention 6 M blockers.

1. Atropine
2. Tropicamide
3. Ipratropium
4. Scopolamine
5. Benzotropine
6. Trihexyphenidyl

50

What is the clinical use of atropine?

Antispasmodic, anti secretory, management of AChE inhibitor OD, antidiarrheal, in ophthalmology (but long action).

51

What is the clinical use of Tropicamide?

Ophthalmology (topical use)

52

What is the clinical use of Ipratropium?

1. Asthma and COPD
2. No CNS entry
3. No change in mucus viscosity

53

What is the clinical use of scopolamine?

1. Used in motion sickness
2. Causes sedation and short term memory block

54

What is the clinical use of benzotropine and trihexyphenidyl?

1. Lipid soluble (CNS entry) used in parkisonism.
2. Used in acute extra pyramidal symptoms induced by antipsychotics.

55

What is the half life of atropine ?

24-36 hours

56

Mention 2 principal nicotinic receptor antagonists (ganglion blocking agents).

1. Hexamethonium
2. Mecamylamine

57

What is the main effect of ganglion blocking agents?

Wipe out the entire ANS.

58

What are the major effects of hexamethonium and mecamylamine?

1. Reduce the predominant autonomic tone.
2. Prevent baroreceptor reflex changes in heart rate.

59

Are hexamethonium and mecamylamine used clinically?

No!

60

What is the biochemical pathway of norepinephrine ?

Tyrosine - hydroxylation to dopa - decarboxylation to dopamine - dopamine β hydroxylation to norepinephrine.

61

What is the major role of MAO enzymes?

To control the mobile pool of norepinephrine.

62

What are the main categories of indirect acting adrenergic (NE released) drugs?

1. Methyl-P-tyrosine
2. MAO inhibitors
3. Releasers
4. Reuptake blockers
5. α2 agonists and antagonists
6. Reserpine
7. Guanethidine

63

What is the role of methyl-p-tyrosine?

It blocks tyrosine Hydroxylase, decreasing synthesis of NE.

64

What is the role of MAO inhibitors?

Increasing the mobile NE pool.

65

What interaction occurs between MAO inhibitors and releasers?

Increasing tremendously the amount of NE in the adrenergic synapse.

66

Where are the α2 receptors located ?

Presynaptically

67

What is the major role of α2 receptors ?

Negative feedback on the synthesis and release of NE.

68

Where is the site of action of reserpine and guanethidine?

On the level of exocytosis of NE.

69

Where α1 receptors are mainly found?

In smooth muscle.

70

Where are mainly α1 receptors?

1. Radial muscle
2. Arterioles (skin, viscera)
3. Veins
4. Bladder trigone and sphincter
5. Make sex organs
6. Liver
7. Kidney

71

What are the principal responses of α1 receptor activation?

1. Mydriasis
2. Contraction of the arterioles - increased TPR - increased diastolic pressure - increased afterload.
3. Contraction of veins - increased venous return - increased preload.
4. Urinary retention
5. Ejaculation
6. Glycogenolysis
7. Decreased renin release

72

Where in general are α2 receptors are found?

1. Prejunctional nerve terminals
2. Platelets
3. Pancreas

73

What responses occur with stimulation of α2 receptors?

1. Decreased transmitter release and NE synthesis.
2. Aggregation of platelets
3. Decreased insulin secretion

74

Where are β1 receptors?

1. SA node
2. AV node
3. Atrial and ventricular muscle
4. His-Purkinje
5. Kidney

75

What response occur after stimulation of β1 receptors?

1. HR up
2. Conduction velocity up
3. Force of contraction up
4. Oxygen consumption up
5. Automaticity and conduction velocity up
6. Renin release up

76

Where are β2 receptors?

1. Blood vessels (all)
2. Uterus
3. Bronchioles
4. Skeletal muscle
5. Liver
6. Pancreas

77

What response elicit β2 receptor stimulation?

1. Vasodilation - decreased TPR - decreased diastolic - decreased afterload.
2. Relaxation (uterus)
3. Dilation (bronchioles)
4. Glycogenolysis - contractility (skeletal muscle)
5. Glycogenolysis + gluconeogenesis + lipolysis (liver)
6. Insulin secretion (pancreas)

78

What is the effect of α1 agonists on heart rate and blood pressure?

1. TPR up
2. BP up
3. Potential reflex bradycardia (baroreceptor reflex)
4. No change in PULSE pressure
5. Cardiac output may be DOWN but also offset by UP venous return.

79

Mention two principal α1 agonists.

1. Phenylephrine
2. Methoxamine

80

What is the action of phenylephrine?

Nasal decongestant and ophthalmologic use (Mydriasis without cycloplegia).

81

What is the action of methoxamine?

Paroxysmal atrial tachycardia through basal reflex.

82

Is methoxamine used today?

No!

83

What is the action of α2 agonists?

1. Stimulate prejunctional receptors in the CNS to decrease sympathetic outflow.
2. Primary use is in mild to moderate hypertension.

84

Mention two principal α2 agonists.

1. Clonidine
2. Methyldopa

85

What are the effects of β1 stimulation?

1. HR up
2. SV up
3. CO up
4. PULSE pressure up

86

What are the effects of β2 stimulation?

1. TPR down
2. BP down

87

What is the principal non selective β agonist?

Isoprotenerol (β1=β2)

88

What are the effects of isoprotenerol?

1. Bronchospasm
2. Heart block
3. Bradyarrythmias
4. Side effects : angina, flushing and arrhythmias.

89

What is the principal β1 agonist?

Dobutamine

90

What is the clinical use of Dobutamine?

Congestive heart failure

91

Mention 4 selective β2 agonists.

1. Salmeterol
2. Albuterol
3. Terbutaline
4. Ritodrine

92

What is the major use of salmeterol, albuterol and terbutaline?

Asthma

93

What is the main use of ritodrine?

Prevention of premature labor.

94

To what receptors does norepinephrine bind ?

α1, α2, β1.

95

To what receptors does epinephrine bind ?

All adrenergic receptors.

96

What is the MAIN FACT about norepinephrine ?

NE CAN NEVER LOWER THE BP!!!

97

What happens with administration of low dose epinephrine (like isoprotenerol)?

1. HR, SV, CO, PULSE pressure UP (action on β1).
2. TPR, BP DOWN (action on β2).

98

What happens with medium administration of epinephrine (like Dobutamine) ?

1. The same as with lower dose.
2. TPR, BP UP (action on α1).
3. No change in BP - physiological antagonism.

99

What happens with high dose of epinephrine?

1. Same as with medium dose, but now α1 predominates.
2. Potential reflex bradycardia.

100

What are the β2 specific effects of epinephrine?

1. Smooth muscle relaxation (e.g. Bronchodilation).
2. Glycogenolysis
3. Gluconeogenesis
4. Mobilization and use of fat

101

What is the epinephrine reversal?

Use of α1 blocker to reverse hypertension to hypotension in a patient receiving too much epinephrine.

102

What are the main uses of norepinephrine and epinephrine ?

1. Cardiac arrest
2. Adjunct to local anesthetic
3. Hypotension
4. Anaphylaxis (epinephrine only)
5. Asthma (epinephrine only)

103

What is the major action of releasers (indirect acting adrenergic receptor agonists)?

Displace norepinephrine from the mobile pool.

104

What is the classic drug interaction of releasers?

With MAOA inhibitors (hypertensive crisis).

105

When a patient is on MAOA inhibitors, what are the possible interactions?

1. Tyramine - With eating cheese and drinking wine.
2. Ephedrine
3. Amphetamines
DEATH BY HYPERTENSIVE CRISIS!!!

106

Mention two basic reuptake inhibitors (indirect acting adrenergic receptors agonists).

1. Cocaine
2. Tricyclic antidepressant (in part)

107

What are the major effects of α receptor antagonists?

1. TPR down
2. Mean BP down
3. May cause reflex tachycardia and salt - water retention.

108

What are the principal uses of α receptor antagonists?

1. Hypertension
2. Pheochromocytoma (nonselective α blocker)
3. Benign prostatic hyperplasia (BPH, selective α1 blocker)

109

Mention 2 non selective α blockers.

1. Phentolamine (competitive inhibitor)
2. Phenoxybenzamine (noncompetitive inhibitor)

110

Mention 4 major selective α1 blockers.

1. Prazosin
2. Doxazosin
3. Terazosin
4. Tamsulosin

111

Mention 2 selective α2 blockers.

1. Yohimbine
2. Mirtazapine

112

Prior to surgery, what is the drug of choice for pheochromocytoma?

Phenoxybenzamine

113

What are the principal effects of β blockers?

On β1 :
1. HR, SV, CO down
2. Renin release down
3. Aqueous humor production down (eye)
On β2 :
1. May precipitate bronchospasm (asthma patients) and vasospasm (in patients with vasospastic disorders).
2. Metabolic effects.

114

What is the best way to reduce β blocker overdose?

With glucagon

115

Is there a clinical use of β2 blockers?

No!!!

116

Mention 6 principal β blockers.

1. Acebutolol
2. Atenolol
3. Metoprolol
4. Pindolol
5. Propranolol
6. Timolol

117

Which one of the 6 β blockers is β1 selective?

1. Acebutolol
2. Atenolol
3. Metoprolol

118

Which one of the 6 β blockers can cause sedation?

1. Acebutolol
2. Metoprolol
3. Pindolol
4. Propranolol (very much)
5. Timolol (very)

119

Which one of the 6 β blockers can cause raise in blood lipids?

1. Atenolol
2. Metoprolol
3. Propranolol
4. Timolol

120

What means that a drug is β1 selective (clinically)?

1. Cardioselectivity
2. Safer in asthma, diabetes, peripheral vascular diseases.

121

Which one of the 6 β blockers has intrinsic sympathomimetic activity?

1. Acebutolol
2. Pindolol

122

What means for a β blocker to have ISA?

1. It mimics NE.
2. Acts like a partial agonist.

123

What are the general uses of β blockers ?

1. Angina, hypertension, post-MI (all)
2. Antiarrythmics (class II : propranolol, acebutolol, esmolol)
3. Glaucoma (timolol + betaxolol)
4. Migraine, thyrotoxicosis, performance anxiety, essential tremor (propranolol)

124

Why we use propranolol in hyperthyroidism?

Because it is the only β blocker that inhibits deiodinase.

125

Mention two β blockers that have α1 activity.

1. Labetalol
2. Carvedilol
(Uses in CHF)

126

Mention a β blocker with K+ channel blockade activity.

Sotalol
(Use as antiarrythmic - class III)

127

What happens in open-angle glaucoma?

Chronic condition with IOP (intra ocular pressure) due to decreased reabsorption of aqueous humor, leading to progressive (painless) virtual loss, if left untreated, blindness.

128

What is the drug treatment in open-angle glaucoma?

1. β blockers : decrease formation of fluid by ciliary epithelial cells.
2. Muscarinic activators : improve drainage through the canal of Schlemm.

129

What happens in closed-angle glaucoma?

Acute (painful) or chronic (genetic) condition with increased IOP due to blockade of the canal of Schlemm.

130

What is the emergency drug prior to surgery?

1. Cholinomimetics
2. Carbonic anhydrase inhibitors
3. Mannitol

131

What are the principal drugs in glaucoma treatment?

1. Pilocarpine
2. Echothiophate
3. Timolol
4. Latanoprost

132

What is the mechanism of action of pilocarpine and echothiophate in glaucoma treatment?

1.Activation of M receptors causes contraction of the ciliary muscle.
2. Increases the flow through the canal of Schlemm
(Echothiophate is an organophosphate - AchE inhibitor - increase outflow)

133

What is the mechanism of action of timolol in the glaucoma treatment?

1. Block actions of NE at ciliary epithelium.
2. Decrease aqueous humor formation.

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