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Pharmacology > Lecture 11 (EXAM 3) > Flashcards

Lecture 11 (EXAM 3) Flashcards

1
Q

RECAP: What are the direct-acting muscarinic agonists

A

-choline esters

-alkaloids

DRUGS covered: Atropine, Homatropine, Pirenzepine, Scopalamine, Ipratropium, Tiotropium, Pamine, Homapine, Robinul, Pirenzepine, Darifenacin, Oxybutynin, Tolterodine

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2
Q

Function of Muscarinic Blockers

A

-competitive (binds and unbinds) antagonists of ACh at muscarinic receptors

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3
Q

What are the 3 origins of muscarinic blockers?

A

-Natural alkaloids, eg. Atropine
-Semisynthetic, eg. Homatropine
-Synthetics, eg. Pirenzepine

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4
Q

What is the consequence of blocking muscarinic receptors?

A

-Anti-parasympathetic (Anticholinergic)
-sympathetic effect bc of autonomic tone

-Tachycardia, Hypertension (mild), Bronchodilation, Constipation, Urinary retention, Mydriasis, and cycloplegia (blurred vision), Dry mouth, Drowsiness, Anti-emetic

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5
Q

Which effect opposites antimuscarinic effects?

A

SLUDGE (muscarinic)

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6
Q

What are the prototypes of Anti-parasympathetic drugs?

A

Atropine and Scopolamine
(From Atropos Belladonna- pretty lady –> Mydriatic effects (dilate pupils))

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7
Q

What are the Dose-related effects of Atropine?

A

0.5 mg low dose: paradoxical effect -> Slight cardiac slowing; some dryness of mouth, inhibition of sweating

1mg: tachycardia, very dry mouth, fully dilated pupils; some blurring of vision

10 mg: EXTREME: RED, HOT, DRY, and MAD
ataxia (affect coordination, balance, and speech), restlessness and excitement; hallucinations, delirium, coma

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8
Q

Pharmacologic use of antimuscarinic drugs

A

-Anti-diarrheal, IBS, and gastric ulcers -> Donnatal, Lomotil
-Cardiovascular support: stop salivation and make airways free in unconscious patients
-Preoperative antisecretory agent: stop urinating, airways open, mouth dry
-Mydriatic agent for eye exams
-Respiratory disorders (asthma, COPD)
-Promote urinary retention (urinary incontinence)
-Nerve gas protectant

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9
Q

What are the active forms of Atropine and Scopolamine?

Different effects

A

Atropine: L-hyoscyamine: cardiac stimulation and antisecretory, Minor CNS effects, Paradoxical bradycardia at lower doses

Scopolamine: L-hyoscine: cross the BBB -> Drowsiness and antinausea, weak cardiac stimulant

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10
Q

What is Ipratropium (Atrovent) (anticholinergic) used for and why doesn’t it cross the BBB?

Atropine-like

A

-Inhaler for bronchodilation
-it has a charged Nitrogen, which prevents it from crossing the BBB

-most notable side effect: dry mouth bc inhaling through the mouth

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11
Q

What is Tiotropium (Spiriva) (anticholinergic) used for?

A

-Inhalant for COPD
-longer T1/2 -> 72 hr, can be measured with FEV1
-binds M3 receptor
-efficacious for asthma

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12
Q

What is the FEV1?

A

-Volume that patient can breathe out within 1 sec
-with COPD the volume that is exhaled is less

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13
Q

Which receptor does Tiotropium (Spiriva) bind to?

A

M3

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14
Q

Other muscarinic drugs:

A

Methscopolamine bromide (Pamine)
– Quart. Amm. Tx GI spasms

Homatropine Methylbromide (Homapin)
– Quart. Amm. Tx GI spasms, irritable bowel

Glycopyrrolate (Robinul): injectable anti-vagal drug with general
anesthesia -> vagus nerve is a big part of the parasympathetic NS (abdominal, lungs,…) - also to treat excessive drooling (sialorrhea) (oral drug)

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15
Q

Receptor subtype selective agent #1

A

Pirenzepine (Gastrozepine)
-selective for M1, M4
-does not cross the BBB
-never approved in the USA
-investigated for diabetic peripheral neuropathy (neural damage)

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16
Q

Receptor subtype selective agent #2

A

Darifenacin (Enablex) often in older women
-Tx of urinary and fecal incontinence
-some selective for M3
-muscarinic receptors cause muscle contraction to squeeze out the urine -> blocked by the drug to stop the urine

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17
Q

Receptor subtype selective agent #3

A

Oxybutynin (Ditropan) - Anti-muscarinic
– Papaverine*-like (opiod-like effect), relaxes smooth muscles -> Anti-spasmodic
– Relaxes detrusor mm

18
Q

Receptor subtype selective agent #4

A

Tolterodine (Detrol)
-similar to Oxybutynin, with less efficacy, fewer side effects

19
Q

What are the effects of CNS-targeted antimuscarinics?

A

Used to treat unusual movements in Schizophrenia patients - by blocking muscarinic receptors in the brain

Anti-parkinson’s, anti-extrapyramidal effects (motor nerves - unusual movements)

-Newer antipsychotics tend to have some anti-cholinergic effects and less extrapyramidal effects

20
Q

Drugs with anticholinergic effects

A

OTC antihistamines

Prescription antihistamines

Tricyclic Antidepressant

21
Q

Drugs with significant anticholinergic side effects

A

Antipsychotics:
chlorpromazine (Thorazine), thioridazine (Mellaril)

Benzodiazepines:
Alprazolam (Xanax)

22
Q

Example Exam Question

A patient taht takes Antipsychotic with anticholinergic side effect, is he likely to have constipation?

A

Yes, because Parasympathetic block, and sympathetic increased -> stops urination

23
Q

Why is Scopolamine dangerous for patients exposed to high temperatures?

EXAM !!

A

-To treat sea-sickness
-Risk of heat stroke bc sweating is blocked

24
Q

What is the MOA of indirect cholinergic agonists (=work like the protagonist)?

A

Inhibit ACh esterase (AChE)
-> increases ACh concentration in the synaptic cleft ->
results in the receptors being stimulated, a lot

25
Q

Which receptors are affected by indirect cholinergic agonists?

A

Muscarinic and nicotinic receptors
doesn’t differentiate between the two

26
Q

MOA of drugs that treat Glaucoma?

A

Blocks AChE at muscarinic receptors -> more ACh present -> stimulating muscles in the eye that promote fluid drainage, which lower intraocular pressure

  • Echothiophate (Phospholine Iodide)
  • Diisopropylfluorophosphate (DFP)
27
Q

MOA to treat Myasthenia Gravis?

A

-Ab destroy nicotinic receptors on skeletal muscle -> muscle weakness

-MOA: drugs inhibit ACh and increase the number of ACh in the synaptic cleft -> sensation of getting strength back

-it doesn’t cross the BBB because of charged nitrogen

28
Q

How are patients tested for Myasthenia Gravis?

A

With Edrophonium (Tensilon) - Tensilon test

-if the patient’s strength increases shortly after they take Tensilon, the test is positive
if it gets worse -> no drastic consequence bc the drug has a short half-life

29
Q

How to test for overdosing or underdosing of cholinergic agonists?

A

perform the Edrophonium (Tensilon) test again

-if strength comes back again the doe was too low -> bc Tensilon will increase ACh level again

if the strength gets worse, the dose was too high -> Tensolin will compete with the drug, and lower its effect -> getting weaker
WHY does the strength goes bock from overdose???

30
Q

How do cholinergic Agonists (AChE blockers) help in Alzheimer’s disease?

A

With centrally acting drugs that are uncharged and don’t cross the BBB

-reduce symptoms of Alzheimer, but doesn’t cure the disease
-but they still work in the periphery, e.g. promotes urinating

31
Q

Centrally Acting cholinergic Agonists (AChE blockers)

A

Physostigmine (Antilirium)
Tacrine (Cognex)
Donepezil (Aricept)
Galantamine (Reminyl)

-mostly used as Bug poison
-nerve gas (Sarin, VX)

32
Q

2 forms of AChE in the body

A

True AChe in the synapsis

-Pseudocholinesterase (Butyrylcholinesterase) in the blood, produced in the liver (test for exposure to bug poison -> it will be reduced in the blood if exposed to bug poison)

33
Q

What is a side effect of the increase of ACh by inhibiting AChE in the muscle?

A

fasciculations (muscle twitching) -> loss of control -> then paralysis
-also uncontrolled urination, defecation, …

34
Q

How does AChE interact with ACh in the breakdown process (MOA)?

A

Step1: Electrostatic interaction with charged Nitrogen and anionic pocket
Step2: a covalent bond between carbon and Serine (pocket 2)
Step 3: unstable ACh breaks into Choline and acetate (bound to Serin)
Step 4:acetate is prone to hydrolysis and will produce Acetic acid and recovering of the enzyme in its native state

35
Q

What is the rate-limiting step in ACh breakdown?

A

The reaction is so fast (AChE is covered with many active sites) that the amount of ACh (how fast ACh gets to the enzyme) determines the rate of the reaction

36
Q

What are the 3 classes of AChE?

A

-Quaternary Amines such as edrophonium (charged N+) -> short-acting

-neostigmine and physostigmine (Carbamates) – intermediate to long-acting

-Organophosphates such as diisopropyl fluorophosphate (DFP)
very long-acting

37
Q

Why are Quarternary amines short-acting?

A

REVERSIBLE REACTION

Because of the weak ionic bond between the anionic pocket and charged N+ (half-life: minutes)

38
Q

Intermediate-acting of carbamates

A

REVERSIBLE REACTION of N+ and anionic pocket
+ carbamate forming a covalent bond with Serine -> spontaneous breakdown through H2O (takes time)

39
Q

long-acting Organophosphates

A

-Phosphorylation of the Serine residue in AChE, Flourin dissociates
-permanently bound when one isopropyl leaves -> enzyme not functional anymore

-permanent deactivation of AChE can be prevented when administered before the leaving group leaves (within hours) by administering Pralidoxime (2-PAM)

40
Q

Why are Organophosphates so effective?

A

Because they are so lipophilic and distribute very well within the body
nicotinic effects: Muscle weakness, fasciculation (twitching), paralysis
(SLUDGE - Salvation, Lacrimation, Urination, Defecation)
Atropine blocks peripheral organs

Pharmacology (14 decks)

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