Tài liệu Color Atlas of Pharmacology (Part 10): Nicotine pptx

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108 Nicotine

Ganglionic Transmission

Whether sympathetic or parasympa-

thetic, all efferent visceromotor nerves

are made up of two serially connected

neurons The point of contact (synapse)

between the first and second neurons

occurs mainly in ganglia; therefore, the

first neuron is referred to as pregan-

glionic and efferents of the second as

postganglionic

Electrical excitation (action poten-

tial) of the first neuron causes the re-

lease of acetylcholine (ACh) within the

ganglia ACh stimulates receptors locat-

ed on the subsynaptic membrane of the

second neuron Activation of these re-

ceptors causes the nonspecific cation

channel to open The resulting influx of

Nat leads to a membrane depolariza-

tion If a sufficient number of receptors

is activated simultaneously, a threshold

potential is reached at which the mem-

brane undergoes rapid depolarization in

the form of a propagated action poten-

tial Normally, not all preganglionic im-

pulses elicit a propagated response in

the second neuron The ganglionic syn-

apse acts like a frequency filter (A) The

effect of ACh elicited at receptors on the

ganglionic neuronal membrane can be

imitated by nicotine; i.e., it involves nic-

otinic cholinoceptors

Ganglionic action of nicotine If a

small dose of nicotine is given, the gan-

glionic cholinoceptors are activated The

membrane depolarizes partially, but

fails to reach the firing threshold How-

ever, at this point an amount of re-

leased ACh smaller than that normally

required will be sufficient to elicit a

propagated action potential At a low

concentration, nicotine acts as a gan-

glionic stimulant; it alters the filter

function of the ganglionic synapse, al-

lowing action potential frequency in the

second neuron to approach that of the

first (B) At higher concentrations, nico-

tine acts to block ganglionic transmis-

sion Simultaneous activation of many

nicotinic cholinoceptors depolarizes the

ganglionic cell membrane to such an ex-

tent that generation of action potentials

is no longer possible, even in the face of

an intensive and synchronized release

of ACh (C)

Although nicotine mimics the ac-

tion of ACh at the receptors, it cannot

duplicate the time course of intrasynap- tic agonist concentration required for appropriate high-frequency ganglionic activation The concentration of nicotine in the synaptic cleft can neither build up as rapidly as that of ACh released from nerve terminals nor can nicotine be eliminated from the synaptic cleft as quickly as ACh

The ganglionic effects of ACh can be blocked by tetraethylammonium, hexamethonium, and other substances (ganglionic blockers) None of these has in-

trinsic activity, that is, they fail to stim-

ulate ganglia even at low concentration; some of them (e.g., hexamethonium) actually block the cholinoceptor-linked ion channel, but others (mecamyla- mine, trimethaphan) are typical receptor antagonists

Certain sympathetic preganglionic neurons project without interruption to the chromaffin cells of the adrenal medulla The latter are embryologic homo- logues of ganglionic sympathocytes Ex- citation of preganglionic fibers leads to

release of ACh in the adrenal medulla,

whose chromaffin cells then respond with a release of epinephrine into the blood (D) Small doses of nicotine, by in- ducing a partial depolarization of adre-

nomedullary cells, are effective in liber-

ating epinephrine (pp 110, 112)

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First neuron Preganglionic Second neuron postganglionic

-70 mV

Acetylcholine

= |—

1411111110) U11 Impulse frequency 11 —L 1)

A Ganglionic transmission: normal state

-55 mV Persistent depolarization

vo

Ganglionic activation

=>

JILU11111U)

Low concentration

Nicotine

B Ganglionic transmission: excitation by nicotine

-30 mV

Depolarization High concentration

Nicotine

Ỷ

Ganglionic blockade

C Ganglionic transmission: blockade by nicotine

Adrenal medulla

oO

@

CC

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D Adrenal medulla: epinephrine release by nicotine

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110 Nicotine

Effects of Nicotine on Body Functions

At a low concentration, the tobacco al-

kaloid nicotine acts as a ganglionic stim-

ulant by causing a partial depolarization

via activation of ganglionic cholinocep-

tors (p 108) A similar action is evident

at diverse other neural sites, considered

below in more detail

Autonomic ganglia Ganglionic

stimulation occurs in both the sympa-

thetic and parasympathetic divisions of

the autonomic nervous system Para-

sympathetic activation results in in-

creased production of gastric juice

(smoking ban in peptic ulcer) and en-

hanced bowel motility (“laxative” effect

of the first morning cigarette: defeca-

tion; diarrhea in the novice)

Although stimulation of parasym-

pathetic cardioinhibitory neurons

would tend to lower heart rate, this re-

sponse is overridden by the simultane-

ous stimulation of sympathetic cardio-

accelerant neurons and the adrenal me-

dulla Stimulation of sympathetic

nerves resulting in release of norepi-

nephrine gives rise to vasoconstriction;

peripheral resistance rises

Adrenal medulla On the one hand,

release of epinephrine elicits cardiovas-

cular effects, such as increases in heart

rate und peripheral vascular resistance

On the other, it evokes metabolic re-

sponses, such as glycogenolysis and li-

polysis, that generate energy-rich sub-

strates The sensation of hunger is sup-

pressed The metabolic state corre-

sponds to that associated with physical

exercise — “silent stress”

Baroreceptors Partial depolariza-

tion of baroreceptors enables activation

of the reflex to occur at a relatively

smaller rise in blood pressure, leading

to decreased sympathetic vasoconstric-

tor activity

Neurohypophysis Release of vaso-

pressin (antidiuretic hormone) results

in lowered urinary output (p 164)

Levels of vasopressin necessary for va-

soconstriction will rarely be produced

by nicotine

Carotid body Sensitivity to arterial

pCO) increases; increased afferent input

augments respiratory rate and depth Receptors for pressure, temperature, and pain Sensitivity to the corre- sponding stimuli is enhanced

Area postrema Sensitization of chemoceptors leads to excitation of the medullary emetic center

At low concentration, nicotine is al-

so able to augment the excitability of the motor endplate This effect can be manifested in heavy smokers in the form of muscle cramps (calf muscula- ture) and soreness

The central nervous actions of nicotine are thought to be mediated largely

by presynaptic receptors that facilitate transmitter release from excitatory aminoacidergic (glutamatergic) nerve terminals in the cerebral cortex Nico- tine increases vigilance and the ability

to concentrate The effect reflects an enhanced readiness to perceive external stimuli (attentiveness) and to respond

to them

The multiplicity of its effects makes nicotine ill-suited for therapeutic use

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A.Effects of nicotine in the body

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112 Nicotine

Consequences of Tobacco Smoking

The dried and cured leaves of the night-

shade plant Nicotiana tabacum are

known as tobacco Tobacco is mostly

smoked, less frequently chewed or tak-

en as dry snuff Combustion of tobacco

generates approx 4000 chemical com-

pounds in detectable quantities The

xenobiotic burden on the smoker de-

pends on a range of parameters, includ-

ing tobacco quality, presence of a filter,

rate and temperature of combustion,

depth of inhalation, and duration of

breath holding

Tobacco contains 0.2-5% nicotine

In tobacco smoke, nicotine is present as

a constituent of small tar particles It is

rapidly absorbed through bronchi and

lung alveoli, and is detectable in the

brain only 8 s after the first inhalation

Smoking of a single cigarette yields peak

plasma levels in the range of 25-50

ng/mL The effects described on p 110

become evident When intake stops,

nicotine concentration in plasma shows

an initial rapid fall, reflecting distribu-

tion into tissues, and a terminal elimi-

nation phase with a half-life of 2h Nic-

otine is degraded by oxidation

The enhanced risk of vascular dis-

ease (coronary stenosis, myocardial in-

farction, and central and peripheral is-

chemic disorders, such as stroke and

intermittent claudication) is likely to be

a consequence of chronic exposure to

nicotine Endothelial impairment and

hence dysfunction has been proven to

result from smoking, and nicotine is

under discussion as a factor favoring

the progression of arteriosclerosis By

releasing epinephrine, it elevates plas-

ma levels of glucose and free fatty acids

in the absence of an immediate physio-

logical need for these energy-rich me-

tabolites Furthermore, it promotes

platelet aggregability, lowers fibrinolyt-

ic activity of blood, and enhances coag-

ulability

The health risks of tobacco smoking

are, however, attributable not only to

nicotine, but also to various other ingre-

dients of tobacco smoke, some of which

possess demonstrable properties

Dust particles inhaled in tobacco smoke, together with bronchial mucus, must be removed from the airways by the ciliated epithelium Ciliary activity, however, is depressed by tobacco smoke; mucociliary transport is impair-

ed This depression favors bacterial in- fection and contributes to the chronic bronchitis associated with regular smoking Chronic injury to the bronchi-

al mucosa could be an important causa- tive factor in increasing the risk in smokers of death from bronchial carcinoma

Statistical surveys provide an im- pressive correlation between the number of cigarettes smoked a day and the risk of death from coronary disease or

lung cancer Statistics also show that, on cessation of smoking, the increased risk

of death from coronary infarction or other cardiovascular disease declines over 5-10 years almost to the level of

non-smokers Similarly, the risk of de-

veloping bronchial carcinoma is re- duced

Abrupt cessation of regular smoking is not associated with severe physical withdrawal symptoms In general, subjects complain of increased nervous-

ness, lack of concentration, and weight

gain

carcinogenic

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N

Nicotiana

tabacum

"Tar"

Nitrosamines, acrolein,

polycyclic hydrocarbons e.g., benzopyrene heavy metals

Sum of noxious

|

\

sS a

Platelet Damage to Damage to Inhibition of aggregation vascular bronchial mucociliary

endothelium epithelium transport

Duration |of

Fibrinolytic Epinephrine t Years exposure Months

activity }

fatty acidst bronchitis

L_ Coronary disease = L_ Bronchial carcinoma

FT Annual deaths/1000 people T1 TT Annual cases/1000 people 7

5

4

x S

| § § Lu

0 É -10 20 -40 >40 0£ ha 15-40 >40 4

Number of cigarettes per day

A Sequelae of tobacco smoking

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114 Biogenic Amines

Biogenic Amines — Actions and

Pharmacological Implications

Dopamine A As the precursor of nore-

pinephrine and epinephrine (p 184),

dopamine is found in sympathetic (adre-

nergic) neurons and adrenomedullary

cells In the CNS, dopamine itself serves

as a neuromediator and is implicated in

neostriatal motor programming (p 188),

the elicitation of emesis at the level of

the area postrema (p 330), and inhibi-

tion of prolactin release from the anteri-

or pituitary (p 242)

Dopamine receptors are coupled to G-

proteins and exist as different subtypes

D,-receptors (comprising subtypes D,

and Ds) and D2-receptors (comprising

subtypes D2, D3, and D4) The aforemen-

tioned actions are mediated mainly by

Dz receptors When given by infusion,

dopamine causes dilation of renal and

splanchnic arteries This effect is mediat-

ed by D, receptors and is utilized in the

treatment of cardiovascular shock and

hypertensive emergencies by infusion of

dopamine and fenoldopam, respective-

ly At higher doses, @1-adrenoceptors

and, finally, a-receptors are activated, as

evidenced by cardiac stimulation and

vasoconstriction, respectively

Dopamine is not to be confused with do-

butamine which stimulates o- and p-ad-

renoceptors but not dopamine receptors

(p 62)

Dopamine-mimetics | Administra-

tion of the precursor L-dopa promotes

endogenous synthesis of dopamine (in-

dication: parkinsonian syndrome,

p.188) The ergolides, bromocriptine,

pergolide, and lisuride, are ligands at D-

receptors whose therapeutic effects are

probably due to stimulation of D2 recep-

tors (indications: parkinsonism, sup-

pression of lactation, infertility, acrome-

galy, p 242) Typical adverse effects of

these substances are nausea and vomit-

ing As indirect dopamine-mimetics, (+)-

amphetamine and ritaline augment do-

pamine release

Inhibition of the enzymes involved

in dopamine degradation, catechol-

amine-oxygen-methyl-transferase

(COMT) and monoamineoxidase (MAO),

is another means to increase actual available dopamine concentration

(COMT-inhibitors, p 188), MAOs-inhibi-

tors, p 88, 188)

Dopamine antagonist activity is the hallmark of classical neuroleptics The antihypertensive agents, reserpine (ob- solete) and a-methyldopa, deplete neuronal stores of the amine A common adverse effect of dopamine antagonists or depletors is parkinsonism

Histamine (B) Histamine is stored

in basophils and tissue mast cells It plays arole in inflammatory and allergic reactions (p.72, 326) and produces

bronchoconstriction, increased intestinal peristalsis, and dilation and in-

creased permeability of small blood ves-

sels In the gastric mucosa, it is released

from enterochromaffin-like cells and stimulates acid secretion by the parietal

cells In the CNS, it acts as a neuromod-

ulator Two receptor subtypes (G-pro-

tein-coupled), H; and Hp, are of thera-

peutic importance; both mediate vascular responses Prejunctional H3 receptors exist in brain and the periphery Antagonists Most of the so-called H,-antihistamines also block other receptors, including M-cholinoceptors and

D-receptors H)-antihistamines are used

for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, cle-

mastine, dimethindene, mebhydroline

pheniramine); as antiemetics (mecli-

zine, dimenhydrinate, p 330), as over-

the-counter hypnotics (e.g., diphenhydramine, p 222) Promethazine represents the transition to the neuroleptic phenothiazines (p 236) Unwanted ef-

fects of most Hj-antihistamines are las-

situde (impaired driving skills) and atro- pine-like reactions (e.g., dry mouth, con- stipation) At the usual therapeutic dos-

es, astemizole, cetrizine, fexofenadine,

and loratidine are practically devoid of

sedative and anticholinergic effects H2- antihistamines (cimetidine, ranitidine,

famotidine, nizatidine) inhibit gastric

acid secretion, and thus are useful in the

treatment of peptic ulcers

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Dopaminergic neuron

HO

wo À cụ chrang

Dopamin

Receptors

Dopamine

A Dopamine actions as influenced by drugs

CH2—GH2—NHz2

„5 H-Receptors

DR}

xã”

H4-Receptors

Vasodilation Bronchoconstriction Bowel peristalsis + permeability +

“H+-Antihistamines”

Diphenhydramine Chlorpromazine

hypnotic,

antiemetic action

Ach Roeper ml

B Histamine actions as influenced by drugs

Parietal cell

Acetylcholine

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116 Biogenic Amines

Inhibitors of histamine release: One

of the effects of the so-called mast cell

stabilizers cromoglycate (cromolyn)

and nedocromil is to decrease the re-

lease of histamine from mast cells (p

72, 326) Both agents are applied topi-

cally Release of mast cell mediators can

also be inhibited by some H, antihista-

mines, e.g., oxatomide and ketotifen,

which are used systemically

Serotonin

Occurrence Serotonin (5-hydroxytrypt-

amine, 5-HT) is synthesized from L-

tryptophan in enterochromaffin cells of

the intestinal mucosa 5-HT-synthesiz-

ing neurons occur in the enteric nerve

plexus and the CNS, where the amine

fulfills a neuromediator function Blood

platelets are unable to synthesize 5HT,

but are capable of taking up, storing,

and releasing it

Serotonin receptors Based on bio-

chemical and pharmacological criteria,

seven receptor classes can be distin-

guished Of major pharmacotherapeutic

importance are those designated 5-HTj,

5-HT>, 5-HTa, and 5-HTy, all of which are

G-protein-coupled, whereas the 5-HT3

subtype represents a ligand-gated non-

selective cation channel

Serotonin actions The cardiovascu-

lar effects of 5-HT are complex, because

multiple, in part opposing, effects are

exerted via the different receptor sub-

types Thus, 5-HT2, and 5-HT7 receptors

on vascular smooth muscle cells medi-

ate direct vasoconstriction and vasodi-

lation, respectively Vasodilation and

lowering of blood pressure can also oc-

cur by several indirect mechanisms: 5-

HTiq receptors mediate sympathoinhi-

bition (— decrease in neurogenic vaso-

constrictor tonus) both centrally and

peripherally; 5-HT2, receptors on vas-

cular endothelium promote release of

vasorelaxant mediators (NO, p 120;

prostacyclin, p 196) 5-HT released from

platelets plays a role in thrombogenesis,

hemostasis, and the pathogenesis of

preeclamptic hypertension

Ketanserin is an antagonist at 5-

HT 2, receptors and produces antihyper-

tensive effects, as well as inhibition of

thrombocyte aggregation Whether 5-

HT antagonism accounts for its antihypertensive effect remains questionable, because ketanserin also blocks a-adrenoceptors

Sumatriptan and other triptans are antimigraine drugs that possess agonist

activity at 5-HT, receptors of the B, D

and F subtypes and may thereby allevi- ate this type of headache (p 322) Gastrointestinal tract Serotonin released from myenteric neurons or en-

terochromaffin cells acts on 5-HT3 and 5-HT4 receptors to enhance bowel mo-

tility and enteral fluid secretion Cisa- pride is a prokinetic agent that promotes propulsive motor activity in the stomach and in small and large intes- tines It is used in motility disorders Its mechanism of action is unclear, but stimulation of 5HT4 receptors may be important

Central Nervous System Serotoni- nergic neurons play a part in various

brain functions, as evidenced by the ef-

fects of drugs likely to interfere with serotonin Fluoxetine is an antidepressant that, by blocking re-uptake, inhibits in- activation of released serotonin Its activity spectrum includes significant psy- chomotor stimulation, depression of ap- petite, and anxiolysis Buspirone also has anxiolytic properties thought to be mediated by central presynaptic 5-HT1a receptors Ondansetron, an antagonist at the 5-HT3 receptor, possesses striking effectiveness against cytotoxic drug-in-

duced emesis, evident both at the start

of and during cytostatic therapy Trop- isetron and granisetron produce analo- gous effects

Psychedelics (LSD) and other psy- chotomimetics such as mescaline and psilocybin can induce states of altered

awareness, or induce hallucinations and

anxiety, probably mediated by 5-HT2, receptors Overactivity of these receptors may also play a role in the genesis

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Psychedelic

Antiemetic

CH2 ` Hạ

N

Antidepressant

Emesis

lô

F

A Serotonin receptors and actions

Tiêu đề	Nicotine
Tác giả	Lỹllmann
Trường học	Thieme
Chuyên ngành	Pharmacology
Thể loại	Tài liệu
Năm xuất bản	2000
Thành phố	Thieme

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