Kaplan Pharmacology - Section 2 - Autonomic Pharmacology

Front 1

What is the role of the ANS?

Back 1

Being responsible for automatic, unconscious bodily functions such as:

(1) Control of HR
(2) Control of BP
(3) GI functions
(4) Genitourinary functions

Front 2

What is a ganglia?

Back 2

A relay station for PANS and SANS (between CNS and end organ).

Front 3

What is an important anatomic difference between SANS and PANS?

Back 3

Ganglia in the SANS lie in two paraventral chains adjacent to the vertebral column. Most ganglia of PANS are located in the organs innervated.

Front 4

Mention the major receptor types and their locations for the ANS and somatic system.

Back 4

(1) N_N: Cell bodies in ganglia of PANS, SANS, adrenal medulla
(2) N_M: Skeletal muscle motor end plate
(3) M (1-3): All organs and tissues innervated by postganglionic nn. of PANS and on thermoregulatory sweat glands innervated by the SANS.

Front 5

Dopamine (DA) activates what receptors and where?

Back 5

D1, causing vasodilation in renal and mesenteric vascular beds.

Front 6

BP is a function of what?

Back 6

BP = TPR x CO

Front 7

What branch of the ANS are involved in the autonomic (neural) control of BP via feedback mechanisms?

Back 7

Both.

Front 8

Changes in mean blood pressure are detected by ____________.

Back 8

baroreceptors

Front 9

Baroreceptors relay information to?

Back 9

cardiovascular centers in the brain stem controlling PANS and SANS outflow.

Front 10

Describe sequence of events from an increase in mean blood pressure.

Back 10

Baroreceptor discharge to cardiovascular centers, increased PANS activity leading to bradycardia and decreased SANS activity leading to decreased heart rate, force of contraction and vasoconstriction.

Front 11

How can you block the baroreceptor reflex?

Back 11

You can block the ganglionic synapse with N_N receptor antagonists. Muscarinic antagonist can block reflex bradycardia. β1-antagonist can block reflex tachycardia.

Front 12

Reflex bradycardia occurs through this receptor.

Back 12

M2

Front 13

Reflex tachycardia occurs through this receptor.

Back 13

β1

Front 14

What hormonal feedback loop is important in regulating BP?

Back 14

Renin-Angiotensin-Aldosterone system

Front 15

What makes the hormonal feedback system for BP respond?

Back 15

Hypotension only. It decreases renal blood flow.

Front 16

A patient is treated with an antihypertensive drug. What compensatory mechanisms in the body will kick in to reinstate homeostasis?

Back 16

(1) ANS (neural)
• Baroceptor reflex → Tachycardia
(2) Endocrine feedback loop
• RAAS → Water, Na+ retention

Front 17

(1) What is this called?
(2) How would a increased/decreased in BP look?
(3) How would a increased/decreased HR look?

Back 17

Front 18

What happens with SANS stimulation of the pupil?

Back 18

α1 stimulation → Mydriasis through radial muscle contraction.

Remember: Gq coupled → Increased intracellular Ca++ (proportional to contractile force)

Front 19

What happens with PANS stimulation (receptor and intracellularly) of the pupil?

Back 19

M3 on sphincter and ciliary muscle.

This is Gq coupled, increasing calcium and miosis through sphincter muscle contraction. Ciliary muscle contraction relaxes suspensory ligaments of the lens and causes accomodation of the lens to view near objects.

Front 20

These receptors induce H+ secretion in the stomach when stimulated by ACh.

(1) What receptor is this?
(2) What is it coupled to intracellularly?

Back 20

(1) M1
(2) Gq, similarly to M3 in the eye for example.

("Gq increases Ca++, an important intracellular signal for exocytosis").

Front 21

What happens to the eye if you use a muscarinic antagonist?

Back 21

1. Mydriasis
2. Cycloplegia (paralysis of accomodation, you now accomodate to far vision)

Front 22

What is cycloplegia?

Back 22

Paralysis of accomodation, seen with muscarinic antagonism.

Front 23

Blocking the PANS and stimulating the SANS can both cause mydriasis, how do you differentiate between the two?

Back 23

With α1-agonists, there is mydriasis but without cycloplegia (solely dependent on PANS).

Front 24

Acetylcholine can stimulate what receptor types?

Back 24

Muscarinic and nicotinic

Front 25

Hemicholinium does what?

Back 25

Blocks the reuptake of choline into cholinergic nerves close to their neuroeffector junctions.

Front 26

What enzyme condensates Choline and Acetyl-CoA to produce ACh?

Back 26

Choline Acetyl Transferase

Front 27

Botulinum toxin does what?

Back 27

Binds synaptobrevin, preventing ACh release into the neuromuscular junction.

Front 28

Choline is accumulated in cholinergic presynaptic nerve endings via an active transport mechanism linked to a ____ pump.

Back 28

Na+

Front 29

Botulinum toxin is used medically and cosmetically for what?

Back 29

(1) Blepherospasm
(2) Strabismus
(3) Hyperhydrosis
(4) Dystonia
(5) Wrinkles

Front 30

Some cholinergic nerve endings have presynaptic autoreceptors for ____ that on activation may elicit a negative feedback of transmitter release.

Back 30

ACh

Front 31

What do we call inhibitory drugs that have Acetylcholine Esterase as a target?

Back 31

Indirect-acting cholinomimetics

Front 32

Reversible AChE inhibitors include?

Back 32

(1) Edrophonium
(2) Physostigmine
(3) Neostigmine, Pyridostigmine
(4) Donepezil, Tacrine

Front 33

Irreversible AChE inhibitors include?

Back 33

(1) Echothiophate
(2) Malathion
(3) Parathion

Front 34

There are three major muscarinic responses in the body, list them.

Back 34

(1) Heart: Decreased heart rate
(2) Secretions: Increased all types of secretions
(3) Smooth muscle: Contraction

Front 35

What muscarinic receptors are found in the eye?

Back 35

Sphincter - M3
Ciliary muscle - M3

Front 36

What muscarinic receptors are found in the heart?

Back 36

SA node - M2
AV node - M2

Front 37

What muscarinic receptors are found in the lungs?

Back 37

Bronchioles - M3
Glands - M3

Front 38

What muscarinic receptors are found in the GI tract?

Back 38

Stomach - M3
Glands - M1
Intestine - M3

Front 39

What muscarinic receptors are found in the bladder?

Back 39

M3
• Detrusor → Contracts
• Trigone/sphincter → Relaxes

The result is voiding and urinary incontinence.

Front 40

What muscarinic receptors are found in sphincters in the body?

Back 40

M3
• Causes relaxation EXCEPT LES which contracts.

Front 41

What muscarinic receptors are found in glands?

Back 41

M3
• Causes secretion → Sweat (thermoregulatory), salivation, lacrimation

Front 42

What happens when the PANS stimulates blood vessels through innervation?

Back 42

There is no PANS innervation of blood vessels.

Front 43

What muscarinic receptors are found in blood vessels?

Back 43

M3 (however NOT innervated)
• Dilation via NO production by endothelium.

Front 44

Stimulation of autonomic ganglia will result in what action in blood vessels?

Back 44

Vasoconstriction. Vessels are solely innervated by the SANS.

Front 45

What is special about the adrenal medulla and what does it do?

Back 45

It acts like a specialized ganglion. It is innervated by the SANS and just like postganglionic neuron receives ACh stimulation via their N_N receptors, however, instead of extending axons to an end-organ, it just releases E into the blood.

Front 46

Where do we find N_N receptors?

Back 46

(1) Adrenal medulla
(2) Autonomic ganglia

Front 47

Where are N_M receptors found? What is the result of stimulation?

Back 47

Neuromuscular junction. Stimulation leads to twitching or hyperactivity of skeletal muscle.

Front 48

An important property of N receptors is [...]

Back 48

N receptors desensitize very quickly upon excessive stimulation.

Front 49

Blood vessels are dominated by the ___________ while the GI tract is dominated by the ___________.

Back 49

SANS; PANS

Front 50

What happens in the GI tract if you "tickle" the autonomic ganglia?

Back 50

GI tract is dominated by the PANS, so ganglionic stimulation causes increased motility and secretions.

Front 51

These cholinergic receptors are Gq coupled and what happens upon stimulation of the receptors?

Back 51

M1 (stomach) and M3 (widespread)

Increases phospholipase C activity, cleaving PIP2 into IP3 and DAG. IP3 mobilizes Ca++ from ER. Ca++ and DAG activate protein kinase C.

Front 52

What cholinergic receptors are Gi coupled and how do they work?

Back 52

M2 receptors, found in the heart (SA, AV node). It makes sense that it would be inhibitory, decreasing cAMP and causing negative chrono- and dromotropy.

Front 53

What second messengers are generated upon stimulation of N_N and N_M receptors?

Back 53

No 2nd messengers. Stimulation causes activation (opening) of Na/K channels.

Front 54

List drugs that are direct-acting cholinomimetics.

Back 54

(1) ACh
(2) Bethanechol
(3) Methacholine
(4) Pilocarpine

Front 55

What is another word synonymous with cholinomimetics?

Back 55

Muscarinic/Nicotinic agonists

Front 56

What is another word synonymous with muscarinic agonists?

Back 56

Cholinomimetics

Front 57

Clinical use of bethanechol?

Back 57

Rx:
• Ileus (tarmslyng, tarmgikt) postoperatively or neurogenic.
• Urinary retention in diabetic nephropathy or BPH.

Front 58

Clinical use of methacholine?

Back 58

Dx of asthma. It induces bronchial hyperreactivity.

Front 59

Clinical use of pilocarpine?

Back 59

Rx:
• Glaucoma (topically)
• Xerostomia

Front 60

To what degree can these different drugs resist Acetylcholinesterase degradation?

(1) ACh
(2) Bethanechol
(3) Methacholine
(4) Pilocarpine

Back 60

(1) Highly hydrolyzed (+++)
(2) Resistant
(3) Somewhat (+)
(4) Resistant

Front 61

What cholinergic receptors are stimulated with these drugs?

(1) ACh
(2) Bethanechol
(3) Methacholine
(4) Pilocarpine

Back 61

(1) M and N
(2) M
(3) M > N
(4) M

("Methacholine er Metta med M")

Front 62

What is another term synonymous with Acetylcholinesterase Inhibitors?

Back 62

Indirect-Acting Cholinomimetics

Front 63

What is the rational for clinical use of AChE inhibitors in Alzheimer's?

Back 63

ACh neurons in Meynert's nucleus may degenerate in Alzheimers due to neuropathy (neurofibrillary tangles, amyloid plaques).

Front 64

These drugs are Indirect-Acting Cholinomimetics (Acetylcholinesterase Inhibitors).

Back 64

(1) Edrophonium
(2) Physostigmine
(3) Neostigmine, Pyridostigmine
(4) Donepezil, Tacrine
(5) Organophosphates

Front 65

Clinical use of edrophonium?

Back 65

• Dx of Myasthenia Gravis
• Used to differentiate myasthenia from cholinergic crisis

Front 66

Clinical use of Physostigmine?

Back 66

• Rx: Glaucoma
• Rx: Antidote in atropine overdose (enters CNS)

Front 67

Clinical use of Neostigmine and Pyridostigmine?

Back 67

• Rx: Ileus
• Rx: Urinary retention
• Rx: Myasthenia gravis
• Rx Reversal of nondepolarizing NM blockers (curare)

Front 68

Clinical use of Donepezil and Tacrine?

Back 68

• Rx: Alzheimers

Front 69

Clinical use of Organophosphates?

Back 69

• Rx: Glaucoma (Echothiophate)

Front 70

What is the nature of the drugs found in insecticides and nerve gas?

Back 70

AChE Inhibitors (irreversible)

Insecticides: Malathion, Parathion
Nerve gas: Sarin

Front 71

Describe characteristics of AChE Inhibitors.

Back 71

(1) Edrophonium - Ultra short acting
(2) Physostigmine - Tertiary amine (enters CNS)
(3) Neo-, Pyridostigmine - Quaternary amines (no CNS entry)
(4) Donepezil, Tacrine - Lipid soluble (CNS entry)
(5) Organophosphates - Lipid-soluble, irreversible inhibitors

Front 72

How do human vs insects metabolize organophosphate insecticides?

Back 72

Front 73

What is the acute toxicity that results from organophosphate exposure? (General)

Back 73

Excessive muscarinic and nicotinic stimulation.

Muscarinic
• Diarrhea
• Urination
• Miosis
• Bradycardia
• Bronchoconstriction
• Lacrimation
• Salivation
• Sweating
• CNS stimulation

Nicotinic
• Skeletal mm. excitation (twitching, fasciculations) followed by desensitization with paralysis.
• CNS stimulation

Front 74

Excessive muscarinic (M2) stimulation of the heart may result in?

Back 74

Increased PR interval with possibility of AV block.

Front 75

How is organophosphate poisoning managed?

Back 75

Regenerate AChE with Pralidoxime (2-PAM)

Rx of M: Atropine

Front 76

How much time do you have from time of exposure to organophosphates until the time when AChE are truly irreversibly inhibited?

Back 76

6-8 hours (couple of minutes for sarin)

Front 77

How do irreversibly acting cholinomimetics work?

Back 77

They phosphorylate the esteratic site on AChE, at serine hydroxyl groups. After some time, "aging" occurs where the R- portion of the drug disattaches from the P- part, which is now bound irreversibly to the enzyme. 2-PAM can be used before aging occurs.

Front 78

What are symptoms of chronic exposure to irreversibly acting cholinomimetics?

Back 78

• Peripheral neuropathy causing mm. weakness and sensory loss
• Demyelination not due to AChE inhibition

"Mimics MS"

Front 79

What type of drug is atropine?

Back 79

Muscarinic antagonist ("Prototype")

Front 80

Atropine is a ___________ (tertiary/quaternary) amine.

Back 80

tertiary; it enters the CNS

Front 81

List effects of atropine in order of increasing dose.

Back 81

(1) Decreased secretions (salivary, bronchiolar, sweat)
(2) Mydriasis and cycloplegia
(3) Hyperthermia (with vasodilation)
(4) Tachycardia
(5) Sedation
(6) Urinary retention, Constipation
(7) Behavioral excitation, Hallucinations

Front 82

What are some other classes of drugs with antimuscarinic pharmacology (outside of atropine)?

Back 82

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

Front 83

Treatment of acute intoxication with atropine?

Back 83

Physostigmine and symptomatic treatment.

Front 84

Clinical uses of atropine?

Back 84

(1) Antispasmodic
(2) Antisecretory
(3) Management of AChE inhibitor OD
(4) Antidiarrheal
(5) Ophthalmology

Front 85

List muscarinic antagonists.

Back 85

(1) Atropine
(2) Tropicamide
(3) Iptratropium
(4) Scopolamine
(5) Benztropine, Trihexyphenidyl

Front 86

Clinical uses of tropicamide?

Back 86

Ophthalmology (topical)

Front 87

Clinical uses of ipratropium?

Back 87

Asthma and COPD (inhalational) - no CNS entry, no change in mucus viscosity

Front 88

Clinical uses of scopolamine?

Back 88

Used in motion sickness, causes sedation and short term memory block (anterograde)

Front 89

Clinical uses of benztropine and trihexyphenidyl?

Back 89

Lipid-soluble (CNS entry) used in parkinsonism and in acute extrapyramidal symptoms induced by antipsychotics.

Front 90

Talk on ANS dominance.

Back 90

For effector tissues with dual innervation, PANS is dominant. These include the SA and AV nodes of the heart, pupil, GI and GU muscles and sphincters. SANS is dominant only in terms of vascular tone and thermoregulatory sweat glands.

Front 91

These drugs are ganglion blocking agents.

Back 91

Hexamethonium and mecamylamine.

Front 92

What is the effect og ganglion blockade on vessels, heart, eye, GI, bladder and glands?

Back 92

(1) Arterioles - SANS (predominant) - Vasodilation, Hypotension
(2) Veins - SANS - Dilation, Decreased preload, Decreased CO
(3) Heart - PANS - Tachycardia
(4) Iris - PANS - Mydriasis
(5) Ciliary m. - PANS - Cycloplegia
(6) GI - PANS - Decreased tone and motility leading to constipation
(7) Bladder - PANS - Urinary retention
(8) Salivary glands - PANS - Xerostomia
(9) Sweat glands - SANS - Anhydrosis

Front 93

True or false: Ganglionic blocking drugs do not prevent changes in HR elicited directly by beta1-agonists or M2-agonists.

Back 93

True

Front 94

What is the result of ganglion blockade when you administer a drug to a patient that produces hypotension?

Back 94

The vasomotor center cannot relay stimuli via baroceptor reflex to the heart, so any reflex changes in HR is cancelled.

Front 95

Describe catecholamine synthesis in adrenergic nerves.

Back 95

Tyrosine to Dopa with the help of Tyrosine Hydroxylase (Vit C) to Dopamine with the help of DOPA Decarboxylase to NE with the help of Vesicular dopamine beta-hydroxylase. NE is stored in vesicles.

Front 96

What molecule prevents transport of tyrosine into adrenergic nerves?

Back 96

Methyl-p-tyrosine

Front 97

MAO inhibitors do what?

Back 97

Inhibit MAO-A which normally degrade the NE mobile pool. Result is a larger NE pool.

Front 98

What type of drug prevents reuptake of NE into the adrenergic nerve terminal?

Back 98

Reuptake blockers

Front 99

What is the role of reserpine and guanethidine?

Back 99

Prevent exocytosis of NE-vesicles.

Front 100

What receptor can modulate release of NE from adrenergic terminals?

Back 100

Alpha2-receptors working through Gi proteins to inhibit the production and release of NE into the synaptic cleft.

Front 101

What is the rate limiting step in the synthesis of NE?

Back 101

Tyrosine hydroxylase step.

Front 102

______ (beta/alpha) receptors are usually more sensitive to activators than _____ (beta/alpha) receptors. What is the significance of this?

Back 102

beta; alpha

Since beta is more sensitive than alpha, administering drugs that have both effects will cause a beta-dominant response at low dosages while alpha responses will predominate at higher doses.

Front 103

Where do we have α1-receptors? What is the result of stimulation in each organ.

Back 103

• Eye (radial) - Mydriasis
• Arterioles (skin, viscera) - Contraction, Increased TPR, Increased diastolic P, Increased afterload
• Veins - Contraction, Increased preload, Increased systolic P
• Bladder trigone and sphincter - Contraction with urinary retention
• Male sex organs - Vas deferens - Ejaculation
• Liver - Increased glycogenolysis
• Kidney - Decreased renin release

Front 104

What is the result of stimulation of β1, α1 and D1 in the kidney?

Back 104

α1 - Decreased renin release
β1 - Increased renin release
D1 - Vasodilation

Front 105

Where do we find α2 receptors and what is the response as a result of stimulation of the receptor?

Back 105

• Prejunctional n. terminals - Decreased transmitter release, Decreased NE synthesis
• PLTs - Aggregation
• Pancreas - Decreased insulin secretion

Front 106

Where do we find β1 receptors and what is the response as a result of stimulation of the receptor?

Back 106

• Heart
- SA node → Increased HR
- AV node → Increased conduction velocity
- Atrial & Ventricular muscle → Increased force of contraction with oxygen consumption, Increased conduction velocity
- His-Purkinje → Increased automaticity and conduction velocity
• Kidney - Increased renin release

Front 107

Where do we find β2 receptors and what is the response as a result of stimulation of the receptor?

Back 107

• Blood vessels (all) → Vasodilation, Decreased TPR, Decreased Diastolic pressure, Decreased afterload
• Uterus → Relaxation
• Bronchioles → Dilation
• Skeletal muscle → Increased glycogenolysis
• Liver → Increased glycogenolysis
• Pancreas → Increased insulin secretion

Front 108

True or false: β2 is mostly innervated.

Back 108

False. It's mostly NOT innervated.

Front 109

Where do we find D1 receptors (outside of the CNS) and what is the response as a result of stimulation of the receptor?

Back 109

Renal, mesenteric, coronary vasculature - Causes vasodilation in kidney with increased RBF, increased GFR and increased Na+ secretion.