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Daddy Pharm > Cholinergics > Flashcards

Cholinergics Flashcards

1
Q

cholinergic agonist may also be called

A

Parasympathomimetic

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2
Q

Cholinergic receptors

A

nicotinic (ganglionic & NMJ; CNS also)

muscarinic (all over; mostly smooth muscle & glands)

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3
Q

Parasympathomimetic vs cholinergic agonists

A

Parasympathomimetic: primarily at muscarinic

cholinergic agonist: can act at NMJ (nicotinic) as well without being a parasympathomimetic

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4
Q

Anticholinesterase/Cholinesterase antagonist

A

Cholinesterase: breaks down ACh

increases duration of ACh in synapse
acts as cholinergic agonist/cholinomimetic

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5
Q

ACh is the primary NT in…

A

the parasymp. NS

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6
Q

Where is ACh found?

A

post synaptic jxn sites
muscarinic receptors
nicotinic receptors (NM system)

preganglionic sites:
nicotinic & muscarinic receptors of the ganglia

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7
Q

ACh synthesis location

A

in the cholinergic nerve terminal cytoplasm

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8
Q

ACh synthesis process

A

Choline Acetyltransferase (ChAT) on the precursors choline (Ch) and acetyl-coenzyme A (acetyl-CoA)

acetylate choline = ACh

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9
Q

Choline is provided mainly through

A

reuptake
via high-affinity Na co-transport pumps
on nerve terminal membrane

requires energy & Na

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10
Q

Choline that cannot be reuptaken/reused
___% is able to be repackaged

A

escapes reuptake carriers and is lost
metabolism to lesser extent

80%

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11
Q

De Novo synthesis

A

De Novo: “from scratch”
makes up for the 20% choline loss

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12
Q

Where do we get the materials for De Novo synthesis?

A

primarily choline-containing phospholipids
(internal & external membranes of cellular structures; ie terminal)

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13
Q

phosphatidylcholine

A

stripped from membrane
converted to choline
choline used to make ACh

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14
Q

Acetyl-CoA is synthesized from

A

pyruvate or acetate
acetylating coenzyme A in mitochondria

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15
Q

Limitations of De Novo synthesis

A

unable to produce enough Ch to keep up with transmitter needs

only provides enough Ch to make up for amounts lost in the synapse/not brought back via re-uptake

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16
Q

Acetylcholine (ACh) Release

A

released first on nerve terminal depolarization

non-vesicular released first
then vesicular ACh

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17
Q

Newly synthesized ACh exists in…

A

the cytoplasm

can be in vesicles, in pools, or in storage attached to other compounds

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18
Q

T/F
Vesicular ACh is the first ACh that can act in the synapse.

A

False
non-vesicular, as this is released first

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19
Q

Vesicles contain ___ quanta. 1 quanta contains…

A

1 vesicle = 1 quanta
1 quanta = 5,000 – 50,000 molecules of ACh

other compounds in here as well

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20
Q

vesicles are produced in…

A

the nerve terminal mainly

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21
Q

Hwo do we package the ACh into vesicles?

A

ACh is taken from cytoplasm & transported across the neurotransmitter vesicle membrane by a carrier-mediated process

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22
Q

What happens when the action potential reaches the nerve terminal?

A

Calcium channels open:
depolarizes nerve terminal
calcium into cytoplasm
↓
triggers a much larger calcium release from the sarcoplasm.
↓
vesicles fuse with the inner wall of the nerve terminal
↓
exocytosis

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23
Q

normal amount of ACh released on a single stimulation

A

several hundred vesicles
aka millions of ACh molecules
(5k – 50k molecules of ACh per vesicle)

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24
Q

can disrupt ACh release

A

Hemicholinium-3 (HC-3): eventually depletes ACh

Vesamicol: cannot package ACh

Botulinium Toxin (BoTox): irreversible inhibition of ACh release

Black Widow Spider Venom: overstimulates → depletion

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25
Q

Hemicholinium-3 (HC-3)

A

inhibits high-affinity uptake carriers of Ch

eventual depletion of ACh in terminal
-Ch will be metabolized more
-De Novo synthesis cannot keep up

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26
Q

What happens if ACh is depleted?

A

cannot pass signal

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27
Q

Vesamicol

A

inhibits ACh transport system on the vesicles
↓
decreased amount of ACh in vesicles
↓
decreasing available ACh for transmission

cannot package ACh

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28
Q

Botulinium Toxin (BoTox)

A

a toxin produced by Clostridium sp.

-binds to nerve terminal
-blocks ACh vesicles from fusing with internal terminal cell wall & exocytosis

-irreversible inhibition of ACh release from terminal

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29
Q

Botox cosmetic use

A

decrease facial fine wrinkles
relaxes the muscles around the wrinkle

Small amount injected around the wrinkle, which leaves the muscles unable to contract.

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30
Q

Black Widow Spider Venom

A

binds to nerve terminal (similar to BoTox)
but
instead of blocking release, triggers exocytosis of ACh vesicles

initial overstimulation via cholinergic transmission
↓
blockade (ACh depletion)

-early severe stomach cramping
-potential fatality d/t respiratory paralysis.

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31
Q

T/F
the GIT has a large [ ] of muscarinic receptors.

A

True
GI motility is stimulated by muscarinic receptors

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32
Q

Where can AChase be found?

A

-in synapse
-bound into postsynaptic membrane
-surface of postsynaptic membrane
-pre-synaptic membrane

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33
Q

True AChase is found…

A

-postsynaptic membrane of cholinergic neurons
-on RBCs

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34
Q

Vmax

A

maximum velocity
how quickly the enzyme can produce

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35
Q

True AChase when acting on ACh will…

A

break 10s of thousands of ACh per second

HIGH VMAX

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36
Q

How do we increase ACh activity at the post syn membrane?

A

fire neuron frequently
multiple pulses of ACh
can more constantly stimulate pst syn receptor.

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37
Q

T/F
As soon as we stop firing the pre-synaptic neuron, the post-synaptic activity of ACh stops.

A

True

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38
Q

ACh is broken down into __ & __. Which are used for…

A

ACh → choline + acetic acid

choline: reuptake by nerve terminal, re-acetylated to make more ACh

acetic acid: can enter Krebbs cycle

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39
Q

T/F
Choline can interact act an ACh receptor but has less activity than ACh.

A

True
produces practically no post-synaptic activity

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40
Q

Ch vs. ACh
potency

A

Ch approximately 10,000 times less than ACh

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41
Q

T/F
Choline can be obtained through other places than phosphatidylcholine of the membrane.

A

True
carriers can take Ch into nerve terminal

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42
Q

T/F
Intake of supplemental choline can increase transmission and alleviate certain disorders.

A

False
not very effective

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43
Q

A cholinoreceptor could be…

A

(means its a cholinergic receptor)

could be nicotinic or muscarinic

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44
Q

A2 adrenoceptor

A

norepi

heteroreceptor
(innervated by separate neuron that releases the compound this receptor reacts to)

stimulates cell to block further release

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45
Q

autoreceptor vs heteroreceptor

A

autoreceptor: reacts w/ compound released from nerve terminal

heteroreceptor: on nerve terminal but responds to NT released from elsewhere

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46
Q

The presynaptic A2 adrenoceptor acts as a (autoreceptor/heteroreceptor). This allows…

A

heteroreceptor

sympathetic system can shut off parasymp. so both are not firing at once

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47
Q

The receptor allowing the release of ACh is a (nicotinic/muscarinic) (hetero/auto)receptor.

A

muscarinic
autoreceptor

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48
Q

Components of the ACh structure

A

ester
(rapid hydrolysis by esterases)

quat amine
(permanent + charge; covalent bond)

2 C spacer between these groups

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49
Q

Natural components that the muscarinic and nicotinic receptors react to

A

-Muscarinic – Muscarine – from mushroom Amanita muscaria

-Nicotinic – Nicotine – from tobacco plant

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50
Q

T/F
Nicotine cannot stimulate muscarinic receptors well & muscarine cannot stimulate nicotinic receptors well.

A

True
react properly only to their respective compounds they’re based on

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51
Q

Muscarinic Receptor family

A

(M1 – M5)

M1: autonomic ganglia & CNS
M2: supraventricular heart region
M3: smooth muscles, glands, vascular endothelial cells

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52
Q

T/F
Even when referring to the same receptor (ie: M1), it will not be identical across humans.

A

True
very similar but not identical

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53
Q

Role of M1 receptor

A

autonomic ganglia
modulate signal

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54
Q

Role of M2 receptor

A

supraventricular regions of heart
(control regions: SA & AV nodes)

controls heart rate

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55
Q

Which muscarinic receptor controls heart rate?

A

M2

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56
Q

95% of muscarinic receptors

A

M3

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57
Q

Muscarinic Receptors
M 1, 3 & 5

A

coupled to phospholipase C via G protein

activation:
splits phosphatidylinositol polyphosphates
(from cell membrane)
↓
inositol 1, 4, 5 triphosphate (IP3) & Diacylglycerol (DAG)

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58
Q

IP3
(inositol 1, 4, 5 triphosphate)

A

water soluble

in cytoplasm: acts on IP3 receptors on the SR, increasing Ca++ release which can then act in cell

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59
Q

Diacylglycerol (DAG)

A

(lipid soluble)
stays in cell membrane

along with increased Ca++, activates protein kinase C (PKC) which can then control many other enzyme activities

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60
Q

kinase fxn

A

cleaves proteins, activating enzymes

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61
Q

T/F
M1 and M3 normally mediate inhibtory responses.

A

False
excitatory

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62
Q

ACh action on most blood vessels causes ___ via ___ receptors

A

vasodilation
M3

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63
Q

Why is vasodilation considered an excitatory effect?

A

via M3r

increased Ca++
↓
activates Nitric Oxide Synthetase
↓
increases Nitric Oxide
(diffuses from endothelial cells to smooth muscles of vasculature)
↓
activates guanylate cyclase (in cytoplasm)
↓
increase cGMP
↓
relaxation of vascular smooth muscles

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64
Q

M2 & M4 receptors mediate mainly ____ effects via ____.

A

inhibitory
G proteins

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65
Q

M2 & M4
MoA

A

(mainly inhibitory)

-inhibit adenyl cyclase (decreased cAMP)
-trigger membrane K+ channels = hyperpolarization = inhibits SA node automaticity = ↓HR

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66
Q

Which M receptors decrease cAMP?

A

M2 M4

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67
Q

Stimulation of which M receptor would decrease HR?

A

M2 & M4

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68
Q

M1

A

Late EPSP in ganglia

blocked by Atropine

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69
Q

N2 vs M1
in ganglia

A

N2 is inital stimulation

M1 modulates that stimulation; slower, more consistent, and longer duration

both together = longer overall stimulation

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70
Q

M2

A

Cardiac mainly

↓ SA automaticity
↓ AV nodal conduction

result: ↓HR

blocked by Atropine (like M1)

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71
Q

Atropine blocks which M receptors?

A

M1 M2 M3

may block 4 & 5 but still unclear

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72
Q

M3

A

mainly at neuroeffector junctions
(glands, smooth muscles)

salivation, urination, defecation, pupillary constriction, bronchoconstriction

blocked by Atropine (like M1)

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73
Q

M4

A

mainly in CNS (striatum)

? mainly inhibitory autoreceptors

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74
Q

M5

A

salivary glands
some CNS (substantia nigra)

Exact importance unclear.

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75
Q

Nicotinic Receptors
Endogenous ligand (neurotransmitter)

A

ACh

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76
Q

Nicotinic Receptors
Two primary types (several subtypes)

A

Nm (N1): NMJ

Nn (N2): autonomic ganglia & neurons

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77
Q

Nm (N1)

A

neuromuscular (NMJ)
Blocked by d-tubocurarine (non-depolarizing)
& decamethonium (depolarizing)

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78
Q

Nn (N2)

A

“neuronal”
autonomic ganglia & neurons

Blocked by hexamethonium (non-depolarizing)

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79
Q

unlike muscarinic receptors, the nicotinic receptors are…

A

ion channels; pentameric; ligand gated ionophore

muscarinic: tied to phospholipase C & enzyme control systems

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80
Q

T/F
Nm (N1) receptors are voltage-gated, while Nn (N2) receptors are ligand-gated.

A

False
Nm (N1) & Nn (N2) are both ligand-gated, pentameric ionphores

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81
Q

Nicotinic Receptors
ACh sites & requirements

A

Simultaneous binding of TWO molecules of ACH is required to open channel.

Binding sites in pockets between certain subunits.

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82
Q

Nm (N1) & Nn (N2)
are ionophores that allow passage of which ion(s)?

A

Na+ (or Ca++)

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83
Q

What the hell am I looking at

A

shows similarities between subunits and other ionphores
structures are almost identical

-amine
-disulfide bridge
-M1,2,3,4 receptor
-Carbox. acid attached to M4

A1 subunit: has extra disulfide bridge

all probably came from 1 ionophore

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84
Q

Ganglionic receptors are (nicotinic/muscarinic)

A

nicotinic

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85
Q

Ganglionic receptors
location

A

symp NS
parasymp NS
neuromuscular junctions

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86
Q

Ganglionic nicotinic receptor antagonist

A

Trimethaphan (Arfonad)

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87
Q

Neuromuscular Nicotinic receptors are stimulated by

A

Nicotine and ACh

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88
Q

D-tubocurarine (Tubarine)

A

non-depolarizing nicotinic antagonist

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89
Q

almost irreversible antagonist of nicotinic receptors

A

α-bungarotoxin (from snake venom)

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90
Q

initially stimulate receptor, then block

A

Neuromuscular depolarizing blockers (Decamethonium and Succinylcholine (Anectine)

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91
Q

Autoreceptors

A

-shuts off further release of ACh
-pre synaptic membrane

-mainly muscarinic (M1, M2, M4,??)

-nicotinic autoreceptors increase rather than inhibit ACh release (feed forward)

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92
Q

Heteroreceptors

A

innervation on nerve terminal by another type of receptor (A2r on cholinegic nerve terminals)

controls release via another system

receptor may not be innervated but can react to circulating neurotransmitter

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93
Q

How does the symp NS control the eye?

A

contracts radial muscles
iris is pulled open
more light into eyes
see better in the dark

dilates the eye

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94
Q

(Sympathetic NS)
Dilation of eye
physiologic effects

A

obstructs canal of schlemm
(outflow channel for aqueous humor which is cont. produced in eye)

block trabecular network
(group of BV vessels)

↑IOP
happens in glaucoma

95
Q

Aqueous humor

A

continuously produced in eye

canal of schlemm:
allows it to flow out of eye
picked up by BV
reabsorbed back into body

96
Q

Parasymp. NS
Eye effects

A

thru CN 3, a branch goes to ciliary muscle (ciliary body)

sphincter muscle with circular-shaped fibers

PNS stimulation contracts fibers, which constrict the eye opening

97
Q

suspensory ligaments

A

suspend the lens so it stays behind pupil
tied onto ciliary muscle

ciliary muscle tightens = shpincter draws inward
releases tension on suspensory ligaments
lens is not pulled as tight
becomes more spherical

98
Q

Parasymp stimulation gives the lens which shape?

A

more spherical; lose tension = can bend light more (can focus in oncloser objects)

(vs. disc shape)

99
Q

sympathetic stimulation of eye

A

blocks ciliary muscle from contracting
loosen ciliary muscle & it dilates
pulls on suspensory ligaments
lens assumes flatter shape

flatter lens is good for bending light at longer distance = see farther

100
Q

ability to focus your eyes

A

accommodation

101
Q

Choline esters

A

Acetylcholine (Miochol-E)
Methacholine (Provocholine)
Carbachol (Miostat)
Bethanechol

102
Q

Choline esters
Acetylcholine (Miochol-E)

A

short t½ (secs in blood; d/t plasma AChase).

ophthalmic for glaucoma or surgery i.e., cataracts, or for eye exam

causes miosis

moA:
-contractions sphincter muscles of the iris & ciliary muscles → accommodation for near vision

-stimulate ciliary muscles, opening traebeclear network and increasing aqueous humor outflow.

103
Q

T/F
Plasma cholinesterase is as equally active as true acetylcholinesterase.

A

False
less active

104
Q

Choline esters
Methacholine (Provocholine)

A

-β-methyl group gives more muscarinic activity
-longer duration than ACh (less well hydrolyzed by AChE)

given by inhalational route

diagnose airway hyperreactivity in asymptomatic asthmatics

adverse reactions – headache, dizziness, pruritus

NOTE: - keep emergency meds and equipment ready due to asthmatic type reaction

105
Q

Choline esters
Methacholine (Provocholine)
considerations

A

keep emergency meds and equipment ready due to asthmatic type reaction

106
Q

Choline esters
Carbachol (Miostat)

A

resistant to AChE hydrolysis due to carbamyl group
nicotinic & muscarinic effects

antiglaucomic, miosis induction for surgery/exam

much longer duration than ACh (6 – 8 hours in eye)

adverse reactions:
stinging/burning of eye, corneal clouding
may cause systemic effects
(salivation, GI cramps, N/V in sensitive persons)

107
Q

carbamyl group

A

provides esters w/ resistance to hydrolysis by normal esterases

108
Q

T/F
Ophthalmic medications can cause systemic effects

A

True
esp if they are not metabolized right away

109
Q

Choline esters
Bethanechol
structure & metab

A

β-methyl group + carbamyl group
further enhances doA

muscarinic mainly
slow hydrolysis
Not destroyed by AChE (at least very slowly)

bad PO absorption
Onset 30-90 min
DoA: 1H PO, 2H subQ

110
Q

Choline esters
Bethanechol
uses

A

Tx:
-urinary retention (primary use)
-stimulate GI motility
-counteract anticholinergic fx of tricyclic antidepressants.

-paraplegics (direct acting & CNS pathway not needed)
-Drug of choice for post partum & post op urinary retention

111
Q

Choline esters
Bethanechol
moA & SEs

A

-Minimal CV effects

-bladder: stimulates detrusor muscle, which decreases bladder capacity and triggers urination
-relaxes urinary sphincters (urination)

-GIT: ↑ peristalsis, motility
↑ peristalsis & ↓ sphincter tone = poop

112
Q

Alkaloids

A

Pilocarpine (Isopto Carpine) (Salagen tabs)
Muscarine
Arecholine

113
Q

Alkaloids
Pilocarpine (Isopto Carpine) (Salagen tabs)
use

A

alkaloid from Pilocarpus microphyllus

ESP sweat glands & eyes – glaucoma
miotic for exam/surgery

Occusert: ocular slow-release system for glaucoma

Salagen Tabs: Sjogren’s syndrome Sx
(AI Dz; exocrine glands; dry eyes, mouth, skin; fatigue, aching joints).

114
Q

Alkaloids
Pilocarpine (Isopto Carpine) (Salagen tabs)
moA & doA

A

directly stimulates muscarinic receptors

open-angle glaucoma: contracts ciliary muscle, increasing outflow of aqueous humor

closed angle glaucoma: miosis opens angle of anterior chamber – allowing aqueous humor to exit

PO: stimulates glandular secretions, including salivary flow

Duration:
PO: 3-5H

(ophthalmic)
solution: 4 – 14H
gel: 18 – 24H

115
Q

Alkaloids
Muscarine

A

from Amanita muscaria
muscarinic agonist only

poisoning treated with Atropine
(poisoning rare; not very potent)

116
Q

Alkaloids
Arecholine

A

from Betel nut, which is chewed by many populations in Africa and East Indies

no therapeutic use

CNS effects similar to nicotine and habit forming

117
Q

Acetylcholinesterase Inhibitors
primary forms

A

-True acetylcholinesterase
(primarily RBCs, pre & post-synaptic)

-Pseudocholinesterase/plasma cholinesterase/butyrylcholinesterase
(plasma & many other sites)

118
Q

ACh vs butyrylcholinesterase
structure

A

ACh: 2 C ester

butyrylcholinesterase: 4 C ester

119
Q

T/F
butyrylcholinesterase and acetylcholinesterase are equally active towards ACh.

A

False
butyrylcholinesterase is less active (still very active tho)

120
Q

function of AChE in the synapse

A

destroy acetylcholine and prevent overstimulation of cholinergic receptors

121
Q

AChE Structure

A

multiple forms
-simple chains (oligomers, dimers or tetramers)
-multiple chains that form a more complex structure

anionic site: attract & hold ACh’s (+) quat amine
esteratic site: serine group; splits ACh into choline and acetic acid

122
Q

Acetylcholinesterase is a member of the large group of enzymes in the body known as ____

A

esterases

123
Q

true AChE is bound to…

A

outer surface of the plasma membrane
or
basement membrane of the synapse

124
Q

Which part of AChE’s structure cleaves the ester on ACh?

A

esteratic site

lines up thanks to spacing & the anionic site, which holds the quat amine group (+)

125
Q

AChE
has a anionic site that attracts & holds the ____ of ACh in place so that the ester group is directed to a ____ site.

A

anionic site holds quaternary amine group of ACh

ACh ester group → esteratic site on AChE

126
Q

AChE
esteratic site contains a ___ group which provides….

A

serine
the site’s esteratic functions; splits ACh → choline & acetic acid.

127
Q

The ___ site on AChE splits ACh into __ & __.

A

esteratic site (has serine group)

choline
acetic acid

128
Q

Acetylcholinesterase Inhibitors (AChE-I’s)
fxn

A

block enzymatic degradation of ACh by AChE

allows released ACh to act longer at the cholinergic receptor sites

129
Q

AChE-I’s
act as ____ in the autonomic system
act as _____ in the somatic system

A

parasympathomimetics (increase ACh doA)

neuromuscular stimulants

130
Q

Besides their potential clinical uses, specific AChE-I’s have been widely used as ….

A

insecticides
(i.e. clorpyrifos (Dursban), diazinon (Spectracide), carbaryl (Sevin)

“war gas”
(i.e. sarin, soman, tabun)

131
Q

Soman

A

AChE-I
so toxic that <1 drop on the skin is fatal

132
Q

How does war gas work?

A

irreversible bonding

overstimulates cholinergic system
produce too much secretions
“drown”

133
Q

What gives the anionic site its negative charge?

A

various AAs

serine hydroxy group (OH) reacts with O on esteratic group

134
Q

How acetic acid and choline are formed

A

acetic acid
1) serine hydroxy group (OH) reacts with O on esteratic group

2) bond breaks & no longer tightly held to AChE

3) ester bonded to serine; water places OH back on serine

4) releases acetic acid

choline
water molecules knock mlcl off anionic site

135
Q

Water is also known as a

A

nulceophile

136
Q

Acetylcholinesterase Inhibitors

A
137
Q

Which AChEI has tautomer forms?

A

Physostigmine

double bond will move
can be Quat amine at times

138
Q

Which is attached to AChE longer?
ACh
AChEIs

A

AChEIs
not as quickly broken down (vs ACh)

139
Q

Which AChEI is a true competitive inhibitor?

A

Edrophonium
only acts on anionic site
doesnt interact at esteratic site

140
Q

Edrophonium vs the other girls

A

only acts on anionic site

does not form carbamate group (N + ester) which bonds to esteratic site
they will leave this structure at the serine site
(they dont come off easily)

true competitive inhibitor

‘edro is not like the ester girls”

141
Q

AChE-I’s
2 classifications based on their AChE binding

A

Reversible agents
Irreversible agents

142
Q

AChE-I Reversible agents
MoA
example

A

do not permanently bind to AChE

A) simple H or ionic binding at the site
B) longer & stronger inhibition d/t covalent bond at serine/esteratic site

i.e. the carbamate types: neostigmine (Bloxiverz)
slowly removed by nucleophilic attack of water molecules (rejuvenates AChE)

143
Q

carbamylated enzyme

A

enzyme attached to carmabae w/ a serine OH group

water can break but needs higher energy
reversible but takes longer

144
Q

T/F
the reaction that created a carbamylated enzyme cannot be reversed.

A

False
takes longer but is reversible

145
Q

AChE is rejuvinated once….

A

carbamate group removed
H reattached to serine group

done by nucleophilic attack by water

146
Q

Organophosphates are….

A

Irreversible Acetylcholinesterase Inhibitors

147
Q

Irreversible Acetylcholinesterase Inhibitors
drug class/types examples

A

organophosphates, insecticides, war gas

148
Q

Irreversible Acetylcholinesterase Inhibitors
MoA

A

long-term or permanent covalent bonds to serine esteratic site

strong!
nucleophilic attack by water ineffective

‘aging’: covalent bond of OPs is further strengthened with time

149
Q

“Aging”

what this program is doing to me…lol

A

irreversible AChEIs: OPs

-covalent bond of OPs is further strengthened with time
-‘R’ group on the phosphoryl group splits off

150
Q

half-aging times

A

varies per OP

most toxic = minutes
less toxic = days

151
Q

T/F
In order for a AChEI to render AChE incapable, it must “age” the enzyme.

A

False
‘aged’ or not, the enzyme is incapable of further hydrolysis of ACh

152
Q

Once ‘aged’ the only way to restore normal function is to ______ (which takes up to ____).

A

re-synthesize the enzyme

six weeks for complete regeneration

153
Q

Treatment for OP poisoning

A

anticholinergic agent, Atropinem
(block overstimulation by excess ACh)

Pralidoxime (2-PAM, Protopam)
enzyme reactivator
only works if OP has not ‘aged’

154
Q

T/F
Pralidoxime cannot restore the phosphorylated enzyme to normal if the attached OP is ‘aged’.

A

True
Once ‘aged’, even its strong nucleophilic attack cannot restore

155
Q

Symptomology of AChE-I toxicity

A

salivation, lacrimation, urination, defecation (SLUDGE)
sweating
miosis

(cholinergic crisis)

156
Q

T/F
reversible AChEIs don’t have to interact with the anionic site

A

False
this applies to irreversible

157
Q

When reacting with AChE,
reversible AChEIs form ____
irrereversible AChEIs form ____

A

reversible carbamylated enzyme

phosphorylated enzyme

158
Q

Why can’t Pralidoxime rejuvenate AChE after the OP ages it?

A

the way the bond breaks does not leave an OH group to allow its nucleophile attack
the structure is now “locked”

must resynthesize (6 weeks)

159
Q

(AChEI Irreversible Agents)
Echothiophate (Phospholine)

A

miotic used for glaucoma & diagnosis
organophosphate class
⚠️ asthmatic & cardiac pts

Ophthalmic: initial stinging/burning
Long-term use: cataract risk

160
Q

(AChEI Irreversible Agents)
Malathion

A

topical (lotion, shampoo)
external parasites (head lice)

OP class
one of the least toxic of the OPs
very potent insecticide

Must be converted to malaoxon (active)
faster in insects
humans eliminate a lot before its converted

poisoning only on ingestion or aspiration
Advantage: kills the eggs (nits) (vs pyrethroid agents)

Potential poisoning Tx: atropine + pralidoxime.

161
Q

(AChEI Reversible Agents)
Physostigmine (Eserine) (Antilirium)

A

Isolated from the Calabar bean
(poison in West African natives in witchcraft trials)

ophthalmic & IV

mainly open-angle glaucoma
Alzheimer’s disease (limited success)

tertiary compound
crosses BBB better than Neostigmine (a quat)

162
Q

(AChEI Reversible Agents)
Neostigmine (Bloxiverz)
uses

A

PO & IV

IV:
-MG acute episodes & diagnosis
-antagonize Non-DNMB (tubocurarine)
-post-op urinary retention & abdominal distention (but bethanechol is better)

163
Q

(AChEI Reversible Agents)
Neostigmine
moA

A

Action at different muscle groups depends on:
-sensitivity of the muscle group
-distributes to that site

some direct NM nicotinic stimulation

164
Q

Physostigmine use in TCA OD

A

(occasionally)
treat toxic anticholinergic effects i

not recommended d/t seizure potential

165
Q

Physostigmine MoA

A

Potentiates the effects of ACh at:
peripheral nicotinic & muscarinic sites
CNS mainly muscarinic

166
Q

Physostigmine
normal response to IV

A

↑ skeletal muscle tone
↑ GI tone & motility
bradycardia
↑ sweat & salivary gland
bronchoconstriction
miosis
↓IOP (widens trabecular network =↑ outflow aq. humor)

167
Q

Physostigmine @ high doses

A

acts directly at neuromuscular & ganglionic nicotinic receptors as a depolarizing blocker.

168
Q

Physostigmine
metab & doA

A

Rapidly hydrolyzed by cholinesterase

IV doA: 1-2H
ophthalmic doA: 12 – 36H

169
Q

Neostigmine (Bloxiverz) vs pyridostigmine

A

both quats
neo has shorter HL

170
Q

preferred agent for MG diagnosis

A

edrophonium
due to its extremely short half-life

171
Q

T/F
Neostigmine & physostigmine have the same moA & ultimate effect

A

False
same moA
but
Neo is a quat., so no CNS effects.

172
Q

Neostigmine
absorption
onset
metab

A

PO: 1% – 2% absorbed
onset: 2 – 4H

IV Onset:10 – 30 min

Elimination: primarily liver microsomal enzymes
some excreted unchanged in the urine

173
Q

Reversible Agents
Pyridostigmine (Mestinon)
routes and use

A

regular & SR PO

Myasthenia Gravis Tx

174
Q

Reversible Agents
Pyridostigmine (Mestinon)
absorption

A

PO: poor

very variable person to person

175
Q

Reversible Agents
Pyridostigmine (Mestinon)
Excretion

A

mainly unchanged via kidneys

some liver microsomal enzymes & cholinesterases

176
Q

Pyridostigmine vs Neostigmine

A

both quats

pyridostigmine:
-longer doA & onset
-fewer muscarinic effects (more specific to NMJ)

177
Q

Reversible Agents
Edrophonium (Enlon)
onset & duration

A

rapid onset: 30 – 60 seconds
short doA: 5 – 10 minutes

IM
onset: 2 – 10 min
duration: 5 – 30 min

178
Q

Available in parenteral form only since it has a very short duration in the body

A

Edrophonium (Enlon)

179
Q

Edrophonium (Enlon)
structure
moA

A

Structurally different! not a carbamate

Binds to anionic site by ionic & H bonding
bond easily broken = short duration

rapid renal elimination (unchanged)

180
Q

Treating OP poisoning
“treat until full atropinized”

A

eyes cannot dilate any more
10 mg Q30-60 min

181
Q

Edrophonium
for reversal

A
  • NDNMB reversal: risky d/t short duration
    -with atropine: treat resp depression from curare
182
Q

Edrophonium
uses

A

-drug of choice for MG diagnosis
(not treatment b/c short half-life)
-allows potential benefits/risks of AChE-I therapy

183
Q

T/F
Edrophonium is the drug of choice for MG diagnosis and treatment.

A

False
drug of choice for MG diagnosis
(not treatment b/c short half-life)

184
Q

T/F
Edrophonium
Few nicotinic effects are seen in challenge dosing with this drug due to the short duration of action

A

False
muscarinic effects (salivation, bradycardia)

185
Q

AChEIs Reversible Agents
Donepezil (Aricept)

A

piperidine-type reversible ChE-I

mild-moderate Alzheimer’s
(only improves earlier stages)

binds by H bonding (easily reversed)

186
Q

memories are tied to…

A

ACh release in certain areas of the brain

187
Q

(Alzheimers drugs)
Donepezil (Aricept) vs Tacrine

A

Donepezil:
-doesnt have hepatotoxicity risk
-fewer peripheral effects (greater affinity for CNS cholinesterase)
-longer HL (higher CNS affinity & slower elimination)

188
Q

T/F
Most of the AChE-I’s show little selectivity between true AChE and pseudo ChE

A

True
exception is donepazil (more selective for true AChE)

189
Q

Donepezil (Aricept)
absorption

A

almost 100%

190
Q

Donepezil (Aricept)
metab

A

P450 system
donepezil → 2 active + 2 inactive metabolites
HLoE: parent + active metabolites = 70 Hrs

191
Q

Rivastigmine (Exelon)

A

reversible AChEI
improve thinking & memory in Alzheimer’s

192
Q

Galantamine (Razadyne)

A

reversible AChEI
cognitive loss d/t Alzheimer’s

acts as a reversible, competitive antagonist of AChE

193
Q

acts as a reversible, competitive antagonist of AChE

A

Galantamine (Razadyne)

194
Q

Cholinergic Antagonists

A

block ACh at muscarinic receptors
can be tertiary or quat

compounds penetrate different tissues at different concentrations (compound’s effect varies at therapeutic doses)

195
Q

Advantage of blocking true AChE and not pseudoChE

A

maintain many normal metabolic pathways

196
Q

Quats have higher ___________ ratio

A

ganglionic blocking to antimuscarinic activity

197
Q

CNS penetration of
Atropine
Scopolamine
Ipratropium

A

Atropine (tert): poor CNS penetration
Scopolamine (tert): penetrates CNS better than Atropine

Ipratropium (Quat): little, if any, CNS activity

198
Q

other drug classes w/ anticholinergic effects

A

H1-blockers
phenothiazines
TCA’s
carbamazepine (Tegretol)

watch for anticholinergic SEs with these!

199
Q

Anticholinergics were a mainstay for ulcer therapy until

A

cimetidine (70’s)

200
Q

Anticholinergic toxicity symptoms

A

hot as a hare (hyperthermia d/t decreased sweating)
blind as a bat (mydriasis & cycloplegia)
mad as a hatter (CNS stimulation)
dry as a bone (xerostomia)

tachycardia
constipation
confusion
urinary retention

Some nicotinic activity seen with some compounds, but not a major concern

201
Q

Cholinergic Antagonists
Tertiary Agents

A

Atropine (USP)
Scopolamine (Transderm Scop)
Benztropine mesylate (Cogentin)
Dicyclomine (Bentyl)
Darifenicin (Enablex)
Tolterodine (Detrol)
Homatropine
Cyclopentolate (Cyclogyl)
Tropicamide (Mydriacyl)

202
Q

Cholinergic Antagonists
Quaternary Agents

A

Glycopyrrolate (Robinul)
Ipratropium (Atrovent HFA)
Tiotropium (Spiriva)

203
Q

Cholinergic Antagonists
Atropine
derived from…
which forms are in/active

A

belladonna plant
(l-hyoscyamine is active, d form is not)

204
Q

Cholinergic Antagonists
Atropine
uses

A

Prototype of its class
-brady🩷
-pre-op decrease secretions
-mydriatic for eye exam
-No longer for Parkinson’s disease

☆ Important in AChE-I toxicity to counteract excessive ACh (ex. Reversal of neuromuscular blockade)

205
Q

Cholinergic Antagonists
Atropine
moA

A

-competitive inhibitor & autonomic postganglionic cholinergic receptors (muscarinic)
-in SNS at sweat glands

206
Q

Cholinergic Antagonists
Atropine
dose dependent effects

A

therapeutic doses: Does not block at NMJ
-Low doses: paradoxical ↓HR
-higher doses: restlessness, hallucinations (abuse potential), disorientation

207
Q

Sites most/least receptive to atropine

A

most= Salivary, bronchiole, sweat glands

eye & heart

GI tract

208
Q

Which causes greater CNS depression?
atropine
scopolamine

A

scopolamine
drowsiness, euphoria, etc

209
Q

T/F
Atropine is a potent bronchodilator & decreases bronchial secretions, making it useful for asthmatics.

A

False
side effects limit this use

(although it is a potent bronchodilator & decreases bronchial secretions)

210
Q

Atropine HL

A

~12H

211
Q

Scopolamine (Transderm Scop)
uses

A

-motion sickness (blocks output from vestibular nuclei in inner ear → vomiting center)
-Parkinsonism
-Truth drug in WWII (twilight sleep & lowers inhibitions)
-preop ↓ bronchial secretions

⚠️High incidence CNS depression @ therapeutic doses

212
Q

Atropine vs Scop
potentcy

A

Scop: More potent on iris, ciliary body, secretions

atropine: more potent at heart, bronchial and GI smooth muscles

213
Q

Scopolamine (Transderm Scop)

A

8H

214
Q

Scopolamine (Transderm Scop)
be cautious of ____ at therapeutic doses

A

⚠️High incidence CNS depression @ therapeutic doses

215
Q

Scopolamine (Transderm Scop)
derived from

A

Naturally occurring alkaloid (belladonna plant)

216
Q

(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)

A

Oral and parenteral forms available

217
Q

(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
uses

A

Parkinsonian syndromes, including antipsychotic induced extrapyramidal symptoms
(M1 antagosim)

218
Q

(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
structure

A

Synthetic muscarinic antagonists (structure similar to atropine)

219
Q

(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
moA

A

Synthetic muscarinic antagonist

-antihistamine & LA effects
-Blocks CNS muscarinic receptors (M1)
(↓ excessive cholinergic activity seen in Parkinsonism)
-blocks dopamine reuptake (prolongs dopamine activity)
-direct smooth muscle antispasmodic action

220
Q

Do we expect to see CNS stimulation from Benztropine mesylate (Cogentin)?

A

crosses BBB, but minimal CNS stimulation

221
Q

(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
DD effects

A

small doses: minor CNS depressant

larger doses: atropine-like CNS stimulation

Tolerance to effects in prolonged use (especially in Parkinson’s disease)

Therapeutic effects ~ 2 - 3 days

222
Q

Benztropine mesylate (Cogentin)
how long until we see the therapeutic effects?

A

2 - 3 days

223
Q

(Cholinergic Antag; Tert)
Dicyclomine (Bentyl)

A

(little CNS activity)
-antispasmodic in IBS (antimuscarinic effects and direct action on smooth muscles in GI tract)

-Limited effects on salivary glands, sweat glands, or cardiovascular system

224
Q

(Cholinergic Antag; Tert)
Darifenicin (Enablex)
moA & use

A

-overactive bladder & urgency
-Competitive agent
-More potent at M3 receptors

225
Q

(Cholinergic Antag; Tert)
Darifenicin (Enablex)
metab & SEs

A

-98% protein bound (mostly alpha-1-acid)
-P-450 metabolism 97% (CYP2D6 and CYP3A4)

⚠️ hepatic insufficiency & P-450 inhibitors (clarithromycin)

Major SE’s: dry mouth, dry eyes, constipation, UTI’s

226
Q

(Cholinergic Antag; Tert)
Tolterodine (Detrol)

A

-overactive bladder

SE’s: blurred vision, dry mouth, dizziness, constipation

Metab: CYP3A4 (interacts w/ Ketaconazole, macrolide antibiotics, cyclosporine (3A4 inhibitors) requiring dosage reduction)

227
Q

Meds metab by CYP3A4 interacts w/ …

A

Ketaconazole, macrolide antibiotics, cyclosporine (3A4 inhibitors)

reduce dose

228
Q

for Overactive Bladder (OAB)

A

Tolterodine (Detrol)
Darifenicin (Enablex)
fesoterodine (Toviaz)
flavoxate
oxybutynin (Ditropan XL)
solifenacin (Vesicare)

229
Q

(Cholinergic Antag; Tert)
Homatropine
Cyclopentolate (Cyclogyl)
Tropicamide (Mydriacyl)

A

Structurally similar to atropine

-ophthalmic: mydriasis & cycloplegia for diagnosis
- temporary stinging/burning
~increase intraocular pressure

❌ glaucoma or a sensitivity to anticholinergics

230
Q

Contraindicated in patients with glaucoma or a sensitivity to anticholinergics

A

Homatropine
Cyclopentolate (Cyclogyl)
Tropicamide (Mydriacyl)

231
Q

(cholinergic antag; Quat)
Glycopyrrolate (Robinul)
uses

A

-GI antispasmotic
-treat bronchospasms

-pre-op: decrease salivary, GI, pulmon secretions
-decrease risk of acid aspiration
-block the effects of surgical vagal stimulation
-block muscarinic effects of reversal

No CNS effects- can’t treat OP toxicity

232
Q

(cholinergic antag; Quat)
Ipratropium (Atrovent HFA)
uses

A

Structurally similar to atropine, but is a quat

-oral inhalation or nasal spray

-bronchodialator (COPD better than albuterol, but not other β2 adrenergic agonists)
-acute asthma attacks
-Nasal spray: rhinorrhea d/t colds/allergies

233
Q

(cholinergic antag; Quat)
Tiotropium (Spiriva)

A

Structurally similar to atropine, but is a quat

-oral inhalation (powder)
-bronchodialator (better than albuterol in COPD)

Daddy Pharm (13 decks)

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