Drugs acting on ANS part 2

Benztropine is used with other antiparkinson agents to treat

treat Parkinson and antipsychotic induced extrapyramidal symptoms

antimuscarinic agents used for

overactive bladder

examples of antimuscarinic agents for overactive bladder

Oxybutynin, darifenacin tolterodine (Detrol, Detrol LA)

overactive bladder meds are

synthetic atropine like drugs with antimuscarinic actions

mechanism of action for antimuscarinic agents

They work by competitively blocking muscarinic (M3) receptors in the bladder, increasing bladder capacity and
reducing frequency of bladder contractions
Darifenacin is more selective M3 muscarinic receptor antagonist

therapeutic uses for antimuscarinic agents

used for management of overactive bladder and urinary incontinence
oxybutynin is also used in patients with neurogenic bladder

pharmokinetics for antimuscarinic agents

-they have a long half life, which allows for once daily administration
- oxybutynin is also available in a transdermal patch and topical gel formulation
- these drugs are hepatically metabolized by the cytochrome P450 system

adverse effects of antimuscarinic agents

similar to atropine

benztropine therapeutic uses

treatment of parkinson
management of antipsychotic induced extrapyramidal effects

darifenacin, oxybutynin, trospium therapeutic uses

treatment of overactive urinary bladder

cyclopentolate, tropicamide and atropine uses

in ophthalmology to produce mydriasis and cycloplegia prior to refraction

atropine uses

treat spastic disorders of the GI tract
treat organophosphate poisoning
suppress respiratory secretions prior to surgery
treat bradycardia

scopolamine uses

prevent motion sickness

ipratropium and tiotropium uses

treatment of COPD

ganglionic blockers act on

nicotinic receptors of both parasympathetic and
sympathetic autonomic ganglia.

ganglionic blockers are not effective

as a neuromuscular antagonist

ganglionic blockers block

the entire output of the ANS at the nicotinic receptor

ganglionic blockers are rarely used

therapeutically, but often helpful in experimental pharmacology

nicotine is a component of

cigarette smoke

depending on the dose nicotine does what

depolarizes autonomic ganglia resulting first in stimulation and then in paralysis of all ganglia

the stimulatory effects of ganglionic blockers are

complex and result from increased release of neurotransmitters

Nicotine releases

dopamine, NE, acetylcholine, glutamate, serotonin, beta-endorphin, GABA

dopamine with nicotine releases

pleasure, appetite suppression

norepinephrine with nicotine releases

arousal, appetite suppression

acetylcholine with nicotine releases

arousal, cognitive enhancement

glutamate with nicotine releases

learning, memory enhancement

serotonin with nicotine releases

mood modulation, appetite suppression

beta endorphin with nicotine releases

reduction of anxiety and tension

GABA with nicotine releases

reduction of anxiety and tension

neuromuscular blocking agents block

cholinergic transmission between motor nerve endings and the nicotinic receptors on skeletal muscle

neuromuscular blocking agents possess some chemical similarities to ACh and act either as

antagonists (nondepolarizing) or as agonists (depolarizing) at the receptors on the endplate of the NMJ

therapeutic uses for neuromuscular blocking agents

Are clinically useful to facilitate rapid intubation when needed due to
respiratory failure in critically ill patients
-Used to facilitate endotracheal intubation and provide complete
muscle relaxation during surgery
- Increase the safety of anesthesia by allowing patients to recover
quickly and completely due to lower anesthetic doses.

nondepolarizing (competitive) blockers for neuromuscular bocking agents- the first known NMB was

curare

tubocurarine has been replaced agents with fewer adverse effects such as

pancuronium, rocuronium and vecuronium

mechanism of action at low doses for NMB agents

competitively block ACH at nicotinic receptors
compete with ACh at the receptor without stimulating it, preventing depolarization of the muscle cell membrane and inhibiting muscular contraction

competitive action for NMB agents can be overcome by administration of

cholinesterase inhibitors, such as neostigmine and edrophonium which increase concentration of ACh in NMJ

mechanism of action for NMB agents at high doses block

the ion channels of the motor end plate

mechanism of action for NMB agents at high doses leads to further weakening of neuromuscular transmission

reducing the ability of cholinesterase inhibitors to reverse the actions of the nondepolarizing blockers

mechanism of action for NMB agents at high doses- with complete blockade the muscle

does not respond to direct electrical stimulation

actions for high doses of NMB agents- the muscles recover in what manner

reverse

for high doses the mechanism of action, what is the order the muscles contract

the face and eye paralyze first
then the fingers, limbs, neck and trunk
then intercostal muscles and lastly diaphragm

Sugammadex

a selective relaxant-binding agent that terminates the action of both rocuronium and vecuronium and can be used to speed recovery

all NMBs are injected how and why

intravenously or occasionally intramuscularly, bc these agents possess two or more quaternary amines in their structure that prevent absorption from the gut

pharmacokinetics for NMB penetrate membranes how

very poorly and do not enter cells or cross the blood brain barrier

cholinesterase inhibitors for NMB are drugs that overcome * and examples are \___

Drugs such as neostigmine, physostigmine, pyridostigmine, and
edrophonium can overcome the action of nondepolarizing NMBs

if the NMB has entered the ion channel, cholinesterase inhibitors are not

as effective in overcoming the blockade

aminoglycoside antibiotics for NMB examples and what do they do

Drugs such as gentamicin and tobramycin synergize with competitive
blockers, enhancing neuromuscular blockade.

calcium channel blockers for NMB examples and do what

diltiazem
may increase the neuromuscular blockage of competitive blockers

depolarizing agents Succinycholine (Quelicin) work by

depolarizing the plasma membrane of the muscle fiber. they are more resistant to degradation by AChE and can persistently depolarize the muscle fibers

mechanism of action for NMB

persists at high concentration in the synaptic cleft, remaining attached to the receptor for a longer time and providing sustained depolarization of the muscle cell cuaing paralysis

phase 1 for mechanism of action for NMB for depolarizing agents

first causes opening of the Na channel associated with nicotinic receptors, which results in depolarization of the receptor. this leads to transient twitching of the muscle

phase 2 for mechanism of action for NMB agents for depolarizing agents

continued binding renders the receptor incapable of transmitting further impulses.
continuous depolarization gives way to gradual repolarization as the Na channel closes or is blocked
this causes a resistance to depolarization and flaccid paralysis

therapeutic uses for NMB agents

useful when rapid endotracheal intubation is required due to its rapid onset of action
electroconvulsive shock treatment

pharmacokinetics for NMB agents

succinylcholine is injected intravenously
its brief duration of action results from redistribution and rapid hydrolysis by plasma cholinesterase
drug effects rapidly disappear upon discontinuation

adverse effects for NMB gents

hyperthermia
apnea
hyperkalemia

apnea adverse effects for NMB agent

-Prolonged apnea due to paralysis of the diaphragm.
-Succinylcholine should be used cautiously or not at all In patients with electrolyte imbalances receiving digoxin
or diuretics (such as heart failure patients).

hyperkalemia for adverse effects for NMB agents

-Succinylcholine increases potassium release from intracellular stores.
-This may be particularly dangerous in burn patients, patients with massive tissue damage or in patients with
renal failure.

Atropine is available as

generic

cyclopentolate is available as

generic, cyclogyl, others

darifenacin is available as

generic, enablex

ipratropium is available as

generic, atrovent

oxybutynin is available as

generic, ditropan, gelnique, others

Scopolamine is available as for
oral
ophthalmic
transdermal

generic
isopto hyoscine
transderm scop

tropicamide is available as

generic, mydriacyl ophthalmic, others

nicotine is available as

nicoderm, nicorette, nicotrol

adrenergic agonists are drugs that activate

adrenergic receptors

adrenergic agonists are termed

sympathomimetics bc they mimic NE

adrenergic neurons release

NE as the primary transmitter

adrenergic neurons are found in

CNS and in sympathetic nervous system

adrenergic neurons serve as

links between ganglia and the effector organs

neurotransmission at adrenergic neurons involves the following steps

synthesis
storage
release
receptor binding of norepinephrine
removal of the neurotransmitter from the synaptic gap

potential fates of recaptured norepinephrine

• Taken up into synaptic vesicles via the amine transporter system and be sequestered for release by another action potential, or
• It may persist in a protected pool in the cytoplasm or
• Norepinephrine can be oxidized by monoamine
oxidase (MAO) present in neuronal mitochondria.

alpha adrenoreceptors show a weak response to

isoproterenol

alpha adrenoreceptors are responsive to naturally occurring catecholamines

norepi and epi

alpha adrenoreceptors rank order of potency and affinity

epi \> norepi\> isoproterenol

alpha adrenoreceptors are divided into two subtypes

alpha 1 and 2
based on their affinities for alpha agonists and antagonists

alpha 1 receptors have a higher affinity for

phenylephrine

clonidine binds to what receptor

alpha 2

alpha 1 receptors are present where

on the postsynaptic membrane of the effector organs

alpha 1 receptors mediate many classic effects involving

constriction of smooth muscle

activation of alpha 1 receptors initiates a series of reactions through

G protein activation of phospholipase C

second messenger for alpha 1 receptor

inosital 1,4,5 triphosphate (IP3) and (DAG) diacylglycerol

IP3 initiates the release of Ca2+ from endoplasmic reticulum into

the cytosol and DAG turns on other proteins within the cell

alpha 2 receptors are located primarily on

presynaptic sympathetic and presynaptic parasympathetic nerve endings and control the release of norepi

stimulation of alpha 2 receptors causes

feedback inhibition and inhibits further release of NE from the stimulated adrenergic neuron

the inhibitory action of alpha 2 receptors serves as

a local mechanism for modulating norepi output when there is high sympathetic activity

alpha 2 receptors are also referred to as

inhibitory autoreceptors

following activation of alpha2 receptors there is inhibition of

adenylyl cyclase followed by a fall in the levels of intracellular cAMP

alpha one receptor is divided into

apha 1 A, B, C and D

alpha 2 receptor is divided into

alpha 2A, B and C

tamsulosin is a selective alpha 1A antagonist that is used to treat

benign prostatic hyperplasia

alpha 1 type
agonist
antagonist
G protein
effects

phenylephrine
prazosin
Gq
increase IP3. DAG, common to all

alpha 1A
antagonist

Tamsulosin

alpha 2
agonist
antagonist
G protein
effects

clonidine
yohimbine
G
decrease cAMP common to all

alpha 2A
agonist

oxymetazoline

alpha 2B and 2C
antagonist

prazosin

beta adrenoreceptors are responses of beta receptors that are characterized by

a strong response to isoproterenol, with less sensitivity to epi and norepi

for beta receptors the rank of order of potency

isoproterenol \> epi\> norepi

the beta adrenoreceptors can be subdivided into

B1, 2 3 based on their affinities for adrenergic agonists and antagonists

binding of a neurotransmitter at any of the three types of beta receptors results in

activatin of adenylyl cyclase and increased concentration of cAMP within the cell