Drugs and Nervous System

8/8/2019 Drugs and Nervous System

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NERVOUS SYSTEM Drugs and Poisons

Chem 377

1

Drugs and

The Nervous System




Chem 377

2

stimulus response

cells & tissues

muscle cells

secretory cells

information storage

integration

by sensory cells (nerves)

(receptors) (effectors)




Chem 377

3

axon

dendrite

cell body

preganglionic

synapse

postganglionic

synapse

neuroeffector

cell CNS

action potential (AP)




Chem 377

4




Chem 377

5

Schwanncell

unmyelinated nerve cell

myelinated nerve cell

Schwann cells in the CNS

Oligodendrocite cells in the PNS

saltatory conductance

node to node

node ofRanvier




Chem 377

6myelinated nerve cell (Schwann cell)




Chem 377

7

potential

in

millivolts

0

-70resting state

Na+ gate

opening

K+ gate

opening

Na+ /K+ pump

operating

Action Potential

The action potential is

propagated down the

length of a nerve cell.

time

Generation of the Action Potential

intracellular environment of the nerve

cell membrane

cell membrane

[Na+] [K+]

This ion inbalance is maintained by the Na+-K+ ATPase pump.

The intracellular side of the membrane is ~70mv lower in potentialthat the extracellular side.

-70mv

extracellular environment




Chem 377

8

CH3

RO

CH3

OH

O

The group of activecompounds are knownas the cardiac glycosides.

If R= carbohydrate thenDigitoxin or Digitalin

Digitoxigenin R=H

The Digitalis Alkaloids

Toxins Affecting the Na+-K+ Pump

Sources: foxglove, purple foxglove, fairy gloves

LD50(guinea pigs, cats): 60.0, 0.18 mg;kg

The therapeutic dose is close to the toxic dose.

Sy mptoms: anorexia, nausea, salivation, vomiting,

headache, drowsiness, disorientation, delirium,

hallucinations; can be fatal.

Uses: cardiac stimulant (Cry stodigin®, Lanoxin®,

Digibind®)

pharmacokinetics: half-life 1.5 days

60% excreted through the kidneys, 30% by the liver

inotropic agent - causes more efficient contraction of the heart

used to treat congestive heart failure




Chem 377

9

Ca2+

Na+

C(CH2)3NCH2CH2

OCH3

OCH3

CH3O

CH3O

CN

CH(CH3)2

initial dose - 5-10 mg

LD50 (mice, rats): 16, 8 mg/kg(i.v .)

Calan®, Isotopin®, Cordilox®,Vasolan®

verapamil

NCH3 CH3

CH3OC COCH3

NO2

O

H

O

initial dose - 10 mg

LD50 (mice, rats): 494, 1022 mg/kg (oral)

4.2, 15.5 mg/kg (i.v.)

Adalat®, Procardia®

nifedipine

Calcium channel blockers

intracellular environment of the nerve

cell membrane

cell membrane

extracellular environment

[Ca2+]

Ca2+

ATPaseNa+/Ca2+

Exchange

gates Ca2+

Na+




Chem 377

10

Multiple Sclerosis

myelin degeneration (demyelination)

multiple sclerotic plaques

presence of antibodies and killer T-cells of immune system

Incidence

U.S. - 300,000 (could be classified as an orphan condition)

prevalent in temperate climates

mainly females, ages 20-45 years

usually chronic; sometimes acute

Symptoms

muscle weakness

lack of coordination

difficulty in vision

spasticity

vertigo

facial numbness

tremor

emotional lability




Chem 377

11

Toxins affecting the action potential

Na+

-channel blockers

NN

OOH2N

HOHO

OH

CH2OH

HO

H

H

Sources: flora inhabiting puffer fish (roe, liv er,

skin), some newts, octopi and frogs,

gobys, the California salamander

LD50 (mice): 10 mg/kg (i.p.)

Sy mptoms: spreading paralysis

Antidote: none (60% fatality )

Uses: Puffer fish is a Japanese delicacy .

A chef must be licensed to prepare puffer

fish. Some thrill seekers wil l prepare it

improperly to see how far they can go.

tetrodotoxin

+

“...that voodoo, that you do, to me...”




Chem 377

12

ON

O

N N

N

H2N

NH2

H

H

OHOH

H2N

H

saxitoxin

+

+

Sources: dinoflagellates(protozoa) of the

genusGinoyaulax - the "red tide"-

shellfish feed upon these planktonic algae

and become s torage depots for the toxin

LD50(mice) : 263g/kg(oral)

(humans) about 1-4 mg total

Sy mptoms: paraly sis

Antidote: none

HN

CO2H

CH3

HO2C

HO2C

H3Cdomoic acid

binds to kainate receptors

Chondra armata

SXT

paralytic shellfish poisoning




Chem 377

13

N

CH3CH2

OCH3

OCH3

CH3OCH2

HO

OHOCH3

OC

OH

OCCH3

O

O

Sources: Aconitum napellus, Ranunculaceae

LD50 (mice): 1 mg/kg (oral)

Sy mptoms: heart arrhythmia

Use: arrow poison

aconitine




Chem 377

14

H3C OC

O

NN

CH3

H3C

CH3

H

O

O

H3C

HO

HO

Source: skin of Columbian

frog Phyllobatus

aurotaenia

LD50(mice): 1 mg/kg (i.v.)

Use: arrow poison

batrachotoxin

N CH2CH

OHH

CHC CH

CHCCHCH

histrionicotoxins

N

C H3

C H2C H3

H

pumiliotoxin C

NHOCH2C H2

C H2C H C H C C H

gephyrotoxin

C H3

OH

C H C H

C H3

C H2C HC H3CHCHC

OH C H3

OH pulmiliotoxin B




Chem 377

15

Scorpion toxins

Sea anemones

Predatory cone snails

conotoxins

30-78 amino acid polypeptides

persistent activation of Na+channels




Chem 377

16

Mass of a large sensory neuron 10-6 gram

Diameter of a neuron4 microns to 100 microns

(motor neuron in cord)

15 feetLength of a giraffe primary afferentaxon (toe to neck)

Typical number of sodium pumps1,000 pumps/square micron ofmembrane surface

Total number of sodium pumps for asmall neuron 1 million

Density of sodium channels300 per square micron in the giantsquid axon

Number of voltage-gated sodium

channels in unmyelinated axon

100-200 per square micron

Number of voltage-gated sodiumchannels at each node

1000-2000 per square micron

Number of voltage-gated sodiumchannels between nodes

25 per square micron

Neuron Factoids




Chem 377

17

Number of synapses for a “typical”

neuron1,000 to 10,000

Thickness of neuronal membrane 5 nanometers

Conduction velocity of action potential 0.6-120 m/s (1.2-250 miles/hr)

Typical synaptic cleft distance 20-40 nanometers across

Diameter of synaptic vesicle 50 nanometers

Number of neurotransmittermolecules in one synaptic vesicle

5,000

Axonal transport rate Slow 0.2-4mm/day

(actin, tubulin)

Intermediate 15-50mm/day

(mitochondrial protein)

Fast 200-400mm/day

(peptides, glycolipids)

Neuron Factoids




Chem 377

18

From http://www.dreisen.com/anatomy_of_a_neuron.htm




Chem 377

19

Autonomicinvoluntary

v isceral motor andsensory systems, smoothmuscle, glands

Somatic

Voluntary

reflex as well asconscious action,muscles

CNS

(central

nervous

system)

PNS

(peripheral

nervous

system)anatomical

distinctions

functional

distinctions

Parasympathetic

vegetative

Sympatheticfight or flight

chemical distinctions




Chem 377

20

SNS Effects PNS Effects

Organ or Tissue

The Autonomic NervousSystem

EYES

HEART RATE

BLOOD PRESSURE

BLOOD GLUCOSE

BRONCHIOLES

RBC PRODUCTION

SWEAT GLANDS

SALIVA

PERISTALSIS

DIGESTION

Dilated

Increased

Dilated

Increased

Elevated

Increased

Stimulated

Thick Secretion

Inhibited

Inhibited

Contracted

Decreased

Constricted

Decreased

Normal

Normal

Normal

Watery Secretion

Normal

Stimulated




Chem 377

21

receptors

synaptic vesicles

postsynaptic

membrane

presynaptic

membrane

The Synapse (synaptic cleft)

Action Potential

dendrite axon

50-200 A

Action Potential

CH3

CH3COCH2CH2N CH3

CH3

O

acetylcholine (Ach)

HO

HO

CHCH2NH(2)

OH CH3

norepinephrine (NE) epinephrine - E

HO

HO

C H2C H2NH2

dopamine (DA)NH

CH2CH2NH2HO

serotonin (5-hydroxy tryptamine - 5-HT)




Chem 377

22

postsy naptic

receptor

SYNAPTIC CLEFT

ACTION POTENTIAL

ACTION POTENTIAL

presynaptic

receptor

sy naptic

vesicles

12

34

5

6

8

7c

7b

7a

1 biosynthesis of NT 6 the NT-receptor complex triggersgeneration of the AP

2 storage of NTs in synaptic vesicles 7a NT dissociates from receptor andeither

diffuses away,3 arrival of AP trigger fus ion of ves icle

with synaptic membrane and7b is enzymatically broken down, or

4 release of neurotransmitter 7c taken back up into the presynapticending.

5 NT diffuses to postsynaptic membranewhere it combines with a receptor.

8 The NT may also bind withpresynaptic receptors as a regulatorydevice for NT release.




Chem 377

23

From http://www.dreisen.com/anatomy_of_a_neuron.htm




Chem 377

24

AP

axon

synapticvesicles

presynaptic membrane

postsynaptic membrane

synapse

postsynaptic receptorsdirect ion channels




Chem 377

25

CH3C SCoA

O

HOCH2CH2N CH3

CH3

CH3

CH3COCH2CH2N CH3

O CH3

CH3acetylcholine

esterase (Achase)

+

choline acetyl

transferase (CAT)

acetyl coenzyme A choline acetylcholine

H3NCHCOO-+

CH2CH2CH2NHC=NH2+

NH2arginine

NADPH

O2

nitric oxide

synthase

H3NCHCOO-+

CH2CH

2CH

2NHC=O

NH2

+ NADP+

N O

+

citrulline

N

N

N

NH

H3C O

O

H3C

SO

O

N

N

CH3

sildenafilVIAGRA®

PDE-5 inhibitor




Chem 377

26

CH2CHCOH

O

NH2

Dietary Protein

L-Phenylalaninean essential amino acid

HO CH2CHCOH

O

NH2

L-Tyrosinea nonessential amino acid

HO

HO

CH2CHCOH

O

NH2Dihydroxyphenylalanine

(L-DOPA)

HO

HO

CH2CH2NH2

Dopamine (DA)

HO

HO

CHCH2NH2

HONorepinephrine (N E)

HO

HO

CHCH2NHCH3

HO

phenylalanine

hydroxylase

tyrosine

hydroxylase

dopamine b -

hydroxylase

monoamine oxidase

(MAO)

catecholamine-O-

methyl transferase

(COMT)

L-aromatic amino acid

decarboxylase

DOPA-decarboxylase

phenylethanolamine-N-

methyl transferase

Synthesis ofCatecholamines




Chem 377

27

parasympathetic system sympathetic system

nicotinic

receptors

muscarinic

receptors

nicotinic

receptors

acetylcholine

acetylcholine

acetylcholine

norepinephrine

adrenergic

receptors

CHOLINERGIC

CHOLINERGIC

ADRENERGIC




Chem 377

28axonal synaptic area




Chem 377

29

INACTIVE

protein kinase

cAMP cAMP cAMP

catalytically ACTIVE

protein kinase

cAMP-regulatory

subunit complexes

The cAMP Stimulated Activation of a Protein Kinase

ex tracellular intracellular

Rs

Ri

stimulatory

receptors

inhibitory

receptors

Gs protein

Gi protein

adenylate cyclase

intracellular

Rs

Gs protein

adenylate cyclase

extracellular Neurohormone

receptor

complex

ATP

cAMP + PPi

G- Protein Complex and Generation of Cyclic AMP (cAMP)




Chem 377

30

cAMP cAMP

phosphodiesterase

AMP AMP

Reassociation of Inactive Complex

after Phosphodiesterase Cleavage

N

N N

N

NH2

OHO-P-O-P-O-PO

O O O

N

N N

N

NH2

O

N

N N

N

NH2

O

OHOH

O

O

P

O OH

O

O

HOPO

OHOH

O

O

(AMP)

5'-Adenosine

Monophosphate (cAMP)

Cyclic Adenosine

3',5'-monophosphate

O O- - -

Adenosine

Triphosphate

ATP

- i+ PP

adenylate

cyclase

-

phosphodiesterase

H2O

Drugs and Nervous System

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