RX318: Exam 2

krdoll

muscarine

cholinomimetic alkaloid

pilocarpine

muscarinic cholinomimetic alkaloid

used for glaucoma

nicotine

cholinomimetic alkaloid

lobeline

cholinomimetic alkaloid

direct-acting drugs

work on both muscarinic and nicotinic receptors

receptor agonists

alkaloid and choline esters

provocholine (methacholine)

choline ester

inhalation (asthma challenge- diagnostic test)

carbachol

choline ester

topical to treat glaucoma

bethanechol

choline ester

oral- increases bowel and bladder tone and motility

indirect-acting drugs

work on both nicotinic and muscarinic receptors

blocks AChE, increases ACh

can be reversible or irreversible

neostigmine

AChEI

increases transmission at NMJ and increases parasympathetic tone

diseases/conditions: myasthenia gravis, Lambert-Eaton syndrome, glaucoma, abdominal distention

carbaryl

AChEI

physostigmine

AChEI

increases parasympathetic tone

used to treat glaucoma and abdominal distention

edrophonium

AChEI

pyridostigmine

AChEI

increases transmission at NMJ

used to treat myasthenia gravis and Lambert-Eaton syndrome

ambenonium

AChEI

increases transmission at NMJ

used to treat myathenia gravis and Lambert Eaton syndrome

donepezil

AChEI

increases central cholinergic activity

used to treat Alzheimer's disease

galantamine

AChEI

increases central cholinergic activity

used to treat Alzheimer's disease

atropine

nonselective muscarinic antagonist- equal ability to block M1, M2, M3

decreases parasympathetic activity

uses:
-mydriasis for opthamalogical exams
-reverse sinus bradycardia or cholinergically mediated AV block
-decrease salivation/secretions during surgery
-muscarinic poisoning
-diarrhea

hyoscyamine (levo-isomer of atropine)

nonselective muscarinic antagonist

uses:
-for abdominal cramps (intestinal or bladder)
-longer duration of action than dicyclomine

scopolamine (hyoscine)

nonselective muscarinic antagonist

uses:
-has greater CNS penetration
-antimuscarinic activity useful for motion sickness
-vestibular inputs to vomiting center

tiotropium (long-acting, Spiriva) and ipratropium (short-acting, Atrovent)

antimuscarinics for chronic respiratory disease

quarternary ammonium, useful in COPD and asthma

produces bronchodilation

inhaled to limit distribution

pirenzepine

selective M1 antagonist used to treat peptic ulcers

decreases gastric acid secretion

dicyclomine

selective M1 antagonists used to treat GI motility and secretion

quarternary N+ , low CNS penetration

trihexylphenidyl

selective M1 antagonists

used for Parkinson's disease

symptoms of tremor and muscle rigidity result from overactive cholinergic signaling in brain

nitrogen is part of ring system

darifeniacin

selective M3 antagonists

treatment for overactive bladder

solifenacin

selective M3 antagonist

treatment for overactive bladder

methoscopolamine

antimuscarinic

used to treat peptic ulcers

quarternary N+, CNS penetration

glycopyrrolate

antimuscarinic

used to treat GI motility and secretion (peptic ulcer)

in inhalation formula in COPD

oxybutynin

antimuscarinic

used for treatment for overactive bladder

not as selective for M3 receptor

tolteridine

antimuscarinic

treatment for overactive bladder

not as selective for M3 receptor

metabolized in the body to 5-hydroxymethyltolteridine

benztropine

antimuscarinic

used to treat Parkinson's disease

symptoms of tremor and muscle rigidity from overactive cholinergic cholinergic signaling in brain

diphenoxylate

antimuscarinic used to treat diarrhea

vasovagal attack

excessive neurotransmission of vagal innervation to the heart, resulting in a rapid drop in heart rate and blood pressure, decreased blood flow to the brain and fainting

carotid sinus syncope

constriction of the carotid artery in the neck

non-depolarizing NMJ blockers MOA

competitive antagonist of nAChR (selective for muscle subtype)

non-depolarizing NMJ blockers clinical uses

skeletal muscle relaxant during anesthesia
initial motor weakness to flaccid paralysis
exhibit sequential paralysis of muscle

tubocurarine

non-depolaring NMJ blocker

long duration of action

pancuronium

non-depolarizing NMJ blocker

long duration of action

rocuronium

non-depolarizing NMJ blocker

intermediate duration of action

veracuronium

non-depolarizing NMJ blocker

intermediate duration of action

mivacurium

non-depolarizing NMJ blocker

short duration of action

Sugammadex

can reverse neuromuscular blockade increased by rocuronium and vecuronium

adverse effects: may decrease the effectiveness of hormonal contraceptive drugs

depolarizing NMJ blockers MOA

cause persistant opening of nAChR channel

initially (phase 1): generalized disorganized contraction of muscles fibers (fasciculation)
eventually (phase 2): flaccid paralysis

depolarizing NMJ blockers clinical use

skeletal muscle relaxant during anesthesia

need to be administered by experienced clinicians

rapid onset, short duration

succinylcholine

stimulate all AChR, including nicotinic and muscarinic

can cause bradycardia, hyperkalemia, increase intragastric pressure- emesis, muscle pain (myalgia)

cholinesterase inhibitors are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia

irreversible AChE inhibitors

will permanently bind to AChE

organophosphorus compounds- esters or thiols derived from phosphoric type acids

reversible AChE inhibitors

can be removed from AChE enzyme

compound with carbamate, quarternary or tertiary ammonium group

used to treat myasthenia gravis, Alzheimer's, bladder distention, glaucoma

2-PAM

an antidotal therapy to poisoning with organophosphorus compounds

must be used before aging

antimuscarinic drugs MOA

take advantage of hydrophobic pockets between transmembrane domains

don't need to bind as tightly as acetylcholine, just take up space

structure activity relationship

relationship of chemical structure of a drug compared to the biological activity it produces

structure of an antimuscarinic

two lipophilic groups, usually rings
a hydrogen, hydroxyl, hydroxymethyl, or carboxamide
an ester, ether, or carbon
some distance between the ring substituted carbon and amine nitrogen (tertiary or quarternary)

solanaceous alkaloids

atropine, scopolamine

scopolamine

gets into the CNS more than atropine because it has a lower pKa

used as a CNS depressant for treatment of motion sickness

mydriatics and cycloplegics (dilate pupils and blur vision)

homatropine, tropicamide, cyclopentate

used in opthamology exams

antispasmodics

dicyclomine

used to treat intestinal cramping

ipratropium bromide

SAMA bronchodilator

atropine derivative but has a 4N

tiotropium bromide

ultra LAMA bronchodilator

scopolamine derivative with 4N
epoxide contributes to potency

aclidinium bromide

LAMA bronchodilator

quiniclidine ring
M3 selective

glycopyrrolate bromide

LAMA bronchodilator

used as preanesthetic and intraoperative antimuscaricinic, reduces drooling, and used for hyperhydrosis

absorption is low but enough where it works

revefencin

ultra LAMA

for maintenance therapy of COPD

bulky amine group takes advantage of additional binding sites on receptor
has a linker

flavoxate

used for treatment of overactive bladder - relaxes detrussor muscle

tropsium chloride

used for treatment of overactive bladder - relaxes detrussor muscle

4N- wont cross the BBB, absorption is lowered

sympathomimetic

drugs that produce sympathetic-like effects

catecholamines

structure of dopamine, norepinephrine, and epinephrine compounds

have a catechol and amine group

all synthesized from tyrosine

reserpine

inhibits loading of vesicles with dopamine, NE, Epi

inhibits uptake into storage vesicle step

guanethidine

replaces NE in vesicles

inhibits release of neurotransmitter step

cocaine

inhibits removal of norepinephrine, allowing released NE to remain in the synaptic cleft

amphetamine

inhibits removal of norepinephrine

a substrate of DAT/NET, competitively inhibits DA/NE transport

also interferes with VMAT and impedes the filling of synaptic vesicles

direct-acting agonists

receptor agonist

indirect-acting agonists

agents that block reuptake, block metabolism of NE, or promote the release of NE

mixed-action agonists

stimulate adrenoreceptors directly and enhance the release of norepinephrine from the adrenergic neuron

catechol-o-methytransferase (COMT)

degrades norepinephrine - widely distributed enzyme particularly important in metabolism of catecholamines in the liver

monoamine oxide (MAO)

degrades norepinephrine - localized to the outer surface of mitochondria

receptors in eye

a2, b2

receptors in salivary glands

a1, a2

receptors in trachea and bronchioles

b2

receptors on heart

b1, b2

receptors on kidney

a1, b1

receptors on ureters and bladder

a1, b2, b3

receptors on blood vessels (skeletal muscle)

b2, a1

receptors on blood vessels (skin, mucous membranes, splanchnic area)

a1

alpha receptor affinity

epinephrine\>norepinephrine\>>isopreternol

beta receptor affinity

isopreternol\>epinephrine\>norepinephrine

epinephrine binding

beta\>alpha

norepinephrine binding

alpha\>beta

isopreterenol binding

beta\>>>alpha

phenylephrine

a1-selective agonist

clonidine

a2 selective agonist

dobutamine

b1-selective agonist

albuterol

b2-selective agonist

cardiovascular effect of epinephrine

increases rate and force of cardiac contraction
decreases peripheral resistance

systolic blood pressure is increased, diastolic is decreased

cardiovascular effects of norepinephrine

induces reflex bradycardia
constricts all blood vessels, causing increased peripheral resistance

norepinephrine causes systolic and diastolic increase

cardiovascular effects of isoproterenol

causes vasodilation but strongly increases cardiac force and rate

significant decrease in peripheral resistance

markedly decreased diastolic pressure, moderate increased systolic

propranolol

nonselective beta blocker

metoprolol

selective b1 blocker

atenolol

selective b1 blocker

pinodolol

partial beta agonist

acebutolol

partial beta agonist

penbutolol

partial beta agonist

carvedilol

alpha and beta blocker