Anda di halaman 1dari 15

Jan Kirchhof

Pharmacology

UMF Targu Mures

Pharmacology Lippincotts 5th Edition UMF Targu Mures 2012/13


Unit II, Chapter 3 The Autonomic Nervous System (ANS)
overview

autonomic drugs: drugs that produce primary therapeutic effect by mimicking/altering function of ANS
o act by stimulation or blocking of ANS

introduction to the nervous system

PNS
o

efferent division
somatic/voluntary efferent system
sk. mm. motor system
autonomic/involuntary/visceral/vegetative system regulates bodily functions (sm. mm., cardiac mm., glands)
preggl. neuron(soma in CNS, emerges from braistem/SC) postganglionic neuron(soma in ggl., AX unmyelinated) effector organ
o sympathetic neurons (thoracolumbar division)
preggl. neuron (emerges from T1-L2)
short/highly branched AX(interaction with many postggl. nn. activation of many effector organs simultaneously)
syn. with postggl. nn. in ggl., adrenal medulla (exception)
postggl. neuron (soma mainly in ggl. of truncus symphaticus, long AX)
o parasympathetic neurons (craniosacral division)
preggl. neuron (emerges from brainstem (CN III/VII/IX/X(90% vagus)) + S2-S4)
long/mainly unbranched(one-to-one connection discrete response) AX
postggl. neuron (soma in ggl. near effector organs, short AX)
o enteric neurons (guts brain, independent from CNS, modulated by ParaSNS + SNS)
innervates GIT, pancreas, gallbladder motility, exo-/endocrine secr., GITs microcirc.
o afferent division (sensory input, modulate efferent division through reflex arcs/neural pathways)
ANS afferent neurons: imp. in reflex regulation (e.g. baroceptor reflex)
functions of SNS
o not essential for life, but imp. to handle some situations
o continually active (e.g. vascular tone) + adjustment in stress (trauma, fear, hypoglycemia, cold, exercise)
o effects of SNS stimulation
HR, ionotropy, BP, energy mobilization, altered Q(blood flow)(sk. mm./heart, skin/viscera), dilation of pupils/bronchioles
GIT(motility + tone, sphincter contr.), bladder(relaxation of detrusor, contr. of trigone + sphincter), sexual organs(ejaculation, relaxation of uterus)
adrenal medulla(secr. A, NA), kidney(renin(1 incr., 1 decr.)), saliv. glands(thick, viscous secr.)
o fight or flight response
direct SNS activation discharge at complete system (diffuse) + adrenal medulla (Adrenaline + NA)
functions of PSNS
o essential for life, maintenance of homeostasis (digestion, elimination of wastes)
o action is often opposed to SNS, dominant over SNS in rest + digest situation
o discrete(exception: plexus myentericus: 1 preggl. n. interacts with 8000 postggl. nn.) discharges to affect spec. organs
role of CNS in control of autonomic functions
o afferent sensory input/feedback CNS(e.g. hypothalamus, medulla oblongata, SC) integration efferent reflex impulses by ANS
o reflex arcs: afferent sensory arm + efferent motor arm (mostly unconsciousness)
o emotions/strong feelings (rage, fear, pleasure) can modify ANSs action
ANS innervation
o dual(SNS + PSNS) innervation: main mechanism, usually one predominating system
o only SNS innervation:
adrenal medulla, kidney, pilomotor mm., sweat glands, BP control mainly by SNS
somatic nervous system
o single motor neuron(CNS sk. mm.): fast response(myelinated/no ggl.), highly branched(motor unit formation)

chemical signaling between cells

types of NTs: NA, ACh, DA, 5-HT, HA(histamine), GABA most commonly involved in therapeutically useful drugs
NA, ACh: primary chem. signals of ANS
most syn. vesicles contain also cotransmitters (e.g. adenosine) modulate transmission process (/NT effect)

Jan Kirchhof

Pharmacology

UMF Targu Mures

ACh
o cholinergic
NA/E
o adrenergic
o some symp. postggl. neurons release ACh, postggl. renal sm. mm. is innervated by DA
cholinergic + adrenergic drugs act by stim./blocking recc. of ANS
ANS:
pregg. neurons NT
postggl. neurons rec.
postggl. neurons NT
o sympathetic:
ACh
nicotinic rec.
NA (/ACh(e.g. sweat glands))
o symp. adrenal medulla: ACh
nicotinic rec.
humoral A(80%) + NA(20%)
o parasympathetic:
ACh
nicotinic rec.
ACh
o somatic nerv. system
single neuron
no ggl.
ACh (single neuron)

effector organs rec.


adrenergic recc.
adrenergic recc.
muscarinic rec.
nicotinic rec.

Jan Kirchhof

Pharmacology

UMF Targu Mures

Unit II, Chapter 4 Cholinergic Agonists


cholinergic neuron

ACh as NT: autonomic ggl., adrenal medulla, parasym. postggl. neurons, symp. postgl. sweat glands, somatic system mm.
EXKURS: Alzheimers patient: significant loss of cholinergic neurons in temp. lobe + entorhinal cortex drugs: AChEsterase inhibitor
neurotransmission at cholinergic neurons
o synthesis
+
choline-Na coupled transport(energy dependent, rate limiting step in synth., inhibited by hemicholinium) into neuron
choline + acetylCoA(from mitochondria by pyruvate oxidation/FA oxidation) choline acetyltransferase ACh(ester)
o ACh storage in vesicles
ACh storage(active transport with H+ efflux) in presyn. vesicles(organized in beadlike structures (varicosities) along nerve terminal)
mature vesicle contains ACh, ATP(cotransmitter at prejunctional purinergic recc. to inhibit release of ACh/NA), proteoglycan
o release
see neurophysiology, botulinum toxin blocks ACh release, black widow spider venom causes total ACh release
o ACh rec. binding
postsynaptic, presynaptic(at releasing neuron or other targeted presyn. recc.)
o NT degradation in syn. cleft
rapid signal termination: ACh hydrolyzing by AChE(butyryl/pseudo-ChE found in plasma, but no role in synapse) choline + acetate
o choline, acetate recycling
+
choline-Na coupled high affinity reuptake in neuron

cholinergic recc. (cholinoceptors)

muscarinic recc.
o affinity: muscarine > ACh >> nicotine
o GPCR, 5 subclasses: M1-3 (functionally characterized), M4-5
o signal transduction:
M1, M3: Gq:
subunit: PLC: PIP2 IP3( IC Ca2+ stim./inhib. of enzymes hyperpol., secr., contr.) + DAG(+ Ca2+ PKC phosphorylation)
M2:
Gi:
subunit: AC cAMP PKA
subunit: KACh channel activation neg. chronotropic/ionotropic effect
o location:
PNS ggl., autonomic effector organs, neurons (M1-5)
gastric parietal cells (M1), cardiac cells/sm. mm. (M2), bladder/exocrine glands/sm. mm. (M3)
o muscarinic agonists/antagonists
pirenzepine (tricyclic anticholinergic)
affinity: M1 (mainly), M2 (low)
application: gastric/duodenal ulcers(alternatively to H+ pump inhibitors)
o questionable due to side effect: reflex tachycardia in fast infusion (M2 blockage)
darifenacin (competitive musc. rec. antagonist)
affinity: M3 (mainly)
application: treatment of overactive bladder
nicotinic recc.
o affinity: nicotine(low conc. stim. rec., high conc. blocks rec.) > ACh >> muscarine(may stim. in high doses)
+
o ligand-gated ion (Na ) channel(5 subunits): NM (NMJ recc.), NN (other recc.) recc.
o location: CNS, adrenal medulla, autonomic ggl., NeuroMusc.Junction
o nicotinic agonists/antagonists
hexamethonium block autonomic ggl. NN recc.
tubucurarine
block NMJ NM recc.

Jan Kirchhof

Pharmacology

UMF Targu Mures

direct-acting cholinergic agonists

cholinergic agonists/choline-/parasym.-mimetics ACh mimicking agents, little spec. limits usefulness


2 groups: esters (choline esters(including ACh)/synthetic esters of choline(e.g. carbachol, bethanechol)) + naturally occurring alkaloids
acteylcholine
o action:
short duration (rapid inactivation by cholinesterases), multiple diffuse action no therapeutic importance
HR, CO
ACh mimics cardiac vagal stim.(normal vagal activity releases ACh at SAN)
BP (indirectly) M3 rec.(endothelial cell) NO(diffuses in sm. mm.) PKG hyperpol. + PDE3 inhibition vasodilation
rec. is physiologically unimp., rec. blocked by atropine (no vasodilation)
other actions
salivary/intestinal/bronchiolar secretion
contr. of mm. detrusor urinae( expulsion of urine)
contr. of mm. ciliaris ( near vision)/mm. sphincter pupillae( miosis used locally in ophthalmic surgery)
diarrhea, diaphoresis(profuse sweating), nausea
Betanechol (ester)
o action
1h duration inactivated by hydrolysis of esterases, but not by AChE
strong muscarinic/no nicotinic action
mainly sm. mm., bladder, GIT
bladder: mm. detrusor vesicae contr., mm. trigone + sphincter relax. P to empty, capacity urine expulsion
o application
neurogenic atony, atonic bladder(postpartum/postoperative/non obstructive) stimulation in urinary retention, megacolon
o adverse effects
generalized cholinergic stim.: sweating, salivation, flushing, BP, nausea, abdominal pain, diarrhea, bronchospasm
atropine sulfate: against cardiovasc. + bronchoconstr. responses
Carbachol (ester)
o action
long duration inactivated by hydrolysis of esterases (very slow rate), poor substrate for AChE
muscarinic/nicotinic action
st
nd
ggl.-stimulating activity: profound effect on cardiovasc. system + GIT 1 system stimulation, 2 system depression
nicotinic action: release of A/NA from adrenal medulla
o application
systemic use: rarely (high potency, rec. non-selectivity, long duration)
local ophthalmological use: glaucoma miosis(onset in 10-20min), Pintraocular (lasts for 4-8h), contr. of ciliary mm.
o adverse effects
in local administration little/no side effects (no systemic penetration)
Pilocarpine (alkaloid)
o action
long duration stable to hydrolysis by AChE
muscarinic action, far less potent than ACh/derivates, uncharged(can cross BBB, enter CNS)
one of most potent secr. stimulators (sweat, tears, saliva)
not used because non-selectivity
o application
primarily used in ophthalmology
primarily local ophthal. use: cornea fast miosis, contr. of ciliary mm. spasm of accommodation fixed vision
atropine (opposing effect, or vice versa(use pilorcarpine to reverse mydriasis of atropine))
local ophthalmological use: glaucoma(in closed or open angle): drug of choice in emergency
effect in opening Schlemms canal(by trabecular mesh around) drainage(aqueous humor) immediate Pintraocular
timing: onset in few minutes, duration of 4-8h
o echothiphate(organophosphate, AChE inhibition)
same effect, longer duration
o CA inhibitors(e.g. acetazolamide), -blocker(e.g. timolol)
for chronic glaucoma, not in emergency
in xerostomia(from irradiation of head/neck), Sjgrens sdr.(dry mouth, no tears, give oral pilocarpine (or cevimeline (also non-spec.)): salivation
o adverse effects
poisoning: CNS disturbance(can cross BBB), exaggerated parasym. effects(e.g. profuse sweating/salivation, similar to eating inocybe mushrooms)
treatment: atropine(can cross BBB) counteracts pilocarpine toxicity

Jan Kirchhof

Pharmacology

UMF Targu Mures

indirect-acting cholinergic agonists: AChE inhibitors (reversible)

AChE(in pre-/postsyn. membr. splits ACh no action) inhibitors(short/intermed. acting): prolonged t1/2 AChendog. ACh accumulation at all cholinergic synapses
Edrophonium
o action
10-20 min short-acting(rapid renal elimation) agent, reversible AChE binding(no AChE action), only peripheral action
o application (limited due to other agents)
diagnosis of myasthenia gravis(autoimmune disease, Ig destruction of NMJ NM recc.)
edrophonium IV inject. rapid muscle strength may cause cholinergic crisis use atropine as antidote
evaluation of cholinesterase inhibitor therapy (differentiate betw. cholinergic (NMJ overstim.) + myasthenic(NMJ overinhib.) crisis
reverse non-depolarizing neuromusc. blockers after surgery
Physostigmine
o action
2-4h intermed.-acting agent, revers. relat. stable AChE binding cholinergic activity at all recc.(ANS, musc., nic., NMJ, CNS)
o application
atony of intestine/bladder: motility
local ophthalmological use: used in glaucoma(but pilocarpine > effective): miosis, spasm of accommodation, Pintraocular
treatment in anticholinergic drug OD (e.g. atropine, phenothiazines, tricyclic antidepressants)
o adverse effects (rare, but in high doses)
convulsion(CNS effect), bradycardia, CO, hypotension, paralysis of sk. mm.(as final result of ACh accumulation at NMJ)
Neostigmine
o action
0.5-2h intermed.-acting agent, revers. relat. stable AChE binding
poorly GIT absorbance, no CNS entering, greater(compared to physostigmine) sk. mm. effect (contr. before paralysis)
o application
antidotic stimulation of bladder/GIT (antidote for tubocurarine/other competitive NeuroMusc. blockers)
symptomatic treatment of myasthenia gravis (preserving endog. ACh)
o adverse effects
general cholinergic stim. (salivation, flushing, hypotension, nausea, abdominal pain, diarrhea, bronchospasm)
contraindication: GIT/bladder obstruction, peritonitis, inflamm. bowel disease
Pyridostigmine, ambenonium
o action
3-6h/4-8h intermed.-acting agents
o application
chronic management of myasthenia gravis
o adverse effects
similar to neostigmine
Tacrine, Donepezil, Rivastigmine, Galantamine
o application
delay progression of Alzheimers disease (tacrine replaced due to hepatotoxicity)
o adverse effects
GIT distress

Jan Kirchhof

Pharmacology

UMF Targu Mures

indirect-acting cholinergic agonists: anticholinesterases (irreversible)

synthetic organophosphates, bind AChE covalently, long lasting ACh at site of release, many toxic agents( military nerve agents, insecticides)
Echothiophate
o mechanism of action
covalent AChE binding aging(alkyl group loss) impossible reactivation(by e.g. pralidoxime) irreversible AChE inactivation
AChE restoration by de novo synthesis
o application
local ophthal. use: chronic treatment of open-angle glaucoma(not first-line agent in glaucoma): intense miosis, Pintraocular
risk of cataracts (limited use)
o adverse effects
generalized cholinergic stimulation
paralysis of motor fct. (e.g. breathing difficulties)
convulsions
high doses atropine: reverse of many muscarinic/some central effects

toxicology of AChE inhibitors

used as agricultural insecticides, for suicidal/homicidal purpose toxicity manifested as nicotinic + muscarinic signs peripherally/totally
reactivation of AChE
o pralidoxime
no CNS entering
reactivates AChE before aging reverses echothiopate effects(except on in CNS), effectiveness in newer agents(aging in seconds)
weak AChE inhibitor properties
other treatment
o atropine
prevent muscarinic side effects(e.g. saliva/bronchial secr., bronchoconstr., bradycardia)
o diazepam
persistent convulsions of cholinergic stimulants
o pay attention to: free airways, O2 supply, artificial respiration

Jan Kirchhof

Pharmacology

UMF Targu Mures

Unit II, Chapter 5 Cholinergic Antagonists


general

common adverse effect: blurred vision, confusion, mydriasis, constipation, urinary retention

antimuscarinic agents

select. musc.(parasym. + few sym. effector organs) blockers(no nicot. block no action on NMJs/auton. ggl.), most useful cholinergic antagonists, clinically beneficial
other antimuscarinic drugs: some antihistaminics, antidepressants
Atropine
o action
4h duration(7-14d in topical administration e.g. eyes), central/peripheral ACh competitive action, high affinity for muscarinic recc.
diff. effector organ sensitivity to atropine (greatest inhib. effect: bronchial tissue + secr. of sweat/saliva)
eye
total cholinergic block persistent mydriasis(pupil dilation), light unresponsiveness, cycloplegia(no near vision focus)
o dangerous rise in Pintraocular for narrow-angle glaucoma patients
o favored drugs in ophthalmic examination: tropicamide, -adrenergic drug (e.g. phenylephrine)
GIT
GIT activity: antispasmodic(atropine + scopolamine are most potent drug for this effect)
gastric motility, almost no effect on HCl secr.(but by pirenzepine (M1-antagonist) HCl secr., no other effect in low doses)
spasm reducing doses have non acceptable side effects (saliva secr., ocular accommodation, micturition)
urinary system
hypermotility used in childrens enuresis(involuntary emptying), -adrenergic agonists(fewer side effects, more effective)
cardiovascular
dose:
bradycardia(M1 block on inhib. presyn. neuron incr. ACh release) (+ little mouth dryness, no sweating)
(min 1mg) dose: HR(M2 block on SAN), normal BP (+ palpitations, mouth dryness, mydriasis, blurred near vision)
toxic dose:
cutaneous vessel dilation (+ hallucinations, delirium, coma)
secretions
block of salivary(high atropine sensitivity, xerostomia (dry oral mucosa))/sweat(body temp. dangerous in children/elderly)/lacrimal glands
o application
ophthalmic
topical administ.: mydriasis(phenylephrine is preferred), cycloplegia(no accomm. interference) refractive error measures
o eye pain (sudden Pintraocular) in narrow-angle glaucoma
o replaced by shorter-acting(6-24h) antimuscarinics (cyclopentolate, tropicamide)
antispasmodic
relaxation of GIT, bladder
antidote for cholinergic agonists
in AChE inhibitor(e.g. physostigmine)/anticholinesterases(insecticides, mushroom poisoning) OD importance of CNS entering
antisecretory
block of upper/lower resp. tract secr. prior to surgeries
o adverse effects
dose dependent: peripheral:
dry mouth, blurred vision(sandy eyes), tachycardia, urinary retention, constipation
CNS:
restlessness, confusion, halluc., delirium depression, circ./resp. collapse, death
danger for elderlies(glaucoma attack, urinary retention), children(rapid body temp.)
atropine toxicity give doses ChE inhibitors
o pharmacokinetics
easy absorption, partially liver metabolization, mainly urine elimination, 4h t 1/2
Scopolamine
o action
longer duration than atropine, peripherally like atropine, centrally(CNS) greater action than atropine(already at therapeutic doses)
prevents motion sickness, blocks short-term memory, sedates(not in atropine), excitement(in higher doses), euphoria(risk of abuse)
o application
prevention of motion-sickness(one of most potent, use prophylactically), short-term memory block, amnesic action(additive in anesthetic)
o adverse effects, pharmacokinetics
like atropine

Jan Kirchhof

Pharmacology

UMF Targu Mures

Ipratropium, Tiotropium
o application
inhalatory administration: tiotropium once daily, ipratropium up to 4 times daily
bronchodilators(no CNS entering, isolated pulmonary effect) in bronchospasm (COPD), chronic bronchitis, emphysema
pending for asthma in patients cannot take adrenergic agonists
Tropicamide, Cyclopentolate
o action
6h(tropicamide)/24h(Cyclopentolate) duration(shorter than atropine)
o application
local ophthalmological use(similar to atropine) for mydriasis + cycloplegia
Benztropine, Trihexyphenidyl
o action
centrally acting
o application
in Parkinson(replaced by levodopa/carbidopa)
antiparkinson adjunct(Zusatzstoff): treat all types of syndromes (e.g. antipsychotic-induced extrapyramidal symptoms)
Darifenacin, Fesoterodine, Oxybutynin, Solifenacin, Tolterodine, Trospium chloride
o action
atropine like drugs
o application
overactive urinary bladder disease (musc. bladder recc. block Pintravesicular, capacity(bladder), contr. (bladder) frequ.
o adverse effects:
dry mouth, constipation, blurred vision (better tolerance with oxybutynin transdermal patches)

ganglionic blockers

action on ANS(parasym./sym.) ggl.(block of nicotinic rec., some ion channels), no effect on NMJ selective block of total ANS output
drug categories: nicotine, non-depolarizing competitive antagonists rarely used therapeutically, but in experimental pharmacology
o non-depolarizing blockers: knowing predominant tone of given organ system predict physiological response
e.g. sym. predom. organ system block
e.g. vasodilation (by blocking arterioles sym. tone)
e.g. parasym. predom. organ system block e.g. bladder/GIT atony, cycloplegia, xerostomia, tachycardia
nicotine (for exact mechanism see chapter 10)
o action
dose dependent: depolarization of ANS ggl.
first effect:
ggl. stimulation NT release (sym. + parasym. effects) BP/HR/peristalsis/secretion
o DA(pleasure, appetite suppression), NA(pleasure, appetite suppression), ACh(arousal, cogn. enhancement), Glu(learning, memory enhancement),
5-HT(mood modulation, appetite suppression), -endorphin(anxiety/tension), GABA(anxiety/tension)
second effect (doses): ggl. paralysis BP/musc. activity GIT + bladder
o application, adverse effect
poison, many unwanted actions, no therapeutic benefit, harmful to health
mecamylamine
o competitive nicotinic ggl. blocker, replaced by agents with fewer side effects

Jan Kirchhof

Pharmacology

UMF Targu Mures

neuromuscular blockers

blocking action at NMJ recc. antagonistic action (non-depol. type), agonistic action (depol. type)
nd
o 2 group of drugs: central mm. relaxants control spastic mm. tone
diazepam(binds GABA recc.), dantrolene(direct action: interferes sarcoplasmic Ca2+ release), baclofen(action on CNS GABA recc.)
clinical use: surgery (total mm. relaxation, no need of higher anesthetics), orthopedic surgery, tracheal intubation
non-depolarizing (competitive) blockers
o new agents present safety of anesthesia(dose for mm. relaxation fast post-surgical recovery; doses resp. paralysis, cardiac depression, recovery time)
o mechanism of action
low doses
interaction(competitive with ACh) with nic. recc. prevent: ACh binding to rec.; mm. cell depol.; mm. contr.
overcome action by ACh conc.: e.g. by ChE inhibitors duration of neuromusc. block (used in anesthesia)
incomplete block: electrical stim. mm. responds depends on extent of blockade
high doses
additional end-plate ion channel block: NMJ transmission weakening, ability of reversion by AChE inhibitor
complete block: electrical stim. no mm. respond
o actions
mm. paralysis (mm. are diff. sensitive to comp. blockers, most sensitive mm. are paralysed first + recover last)
order in decr. sensitivity: facial, eye mm. fingers limbs, neck, trunk mm. intercostal mm. diaphragm
some agents release HA (e.g. atrocurium) BP, flushing, bronchoconstr.
o application
adjuncts in anesthesia for mm. relaxation, orthopedic surgery (e.g. correct fractures, dislocations), tracheal intubation
o pharmacokinetics, advantages, adverse effects
IV injection(minimal oral absorption, poor membr./BBB crossing), choice of drug due to onset(O in min)/duration(D in min)/side effects
tubocurarine(O = 2, D = 38; prototype agent from first found drug curare, replaced due to side effects)
pancuronium(O = 3, D = 86; unchanged excretion in urine)
atracurium(O = 2, D = 40; releases HA, degredation in plasma to laudanosine (can cause seizures) (replaced by cisatracurium(less side effects))
cisatracurium(O = 3, D = 90; used in patients with multisystem organ failure (hepato/reno-independent metabolisms), for mech. ventilation of critical patients)
vecuronium(O = 2, D = 44), rocuronium(O = 1, D = 43) (amino steroids(degraded in liver, longer duration in hepatic disease excreted in bile))
o drug interactions
ChE inhibitors
ACh conc. can overcome action of non-depol. blockers(if blockers
dont enter ion channel), depolarizing block(in dose)
halogenated hydrocarbon anesthetics(e.g. halothane)
sensitize/stabilize NMJ to NMJ blockers
2+
aminoglycoside antibiotics(e.g. gentamicin, tobramycin)
compete with Ca ACh releasesynergize with comp. blockers
calcium-channel blockers
NMJ block of comp. + depol. blockers
depolarizing agents (succinylcholine(only drug used today))
o mechanism of action
agent binds NM rec.(like ACh, but resistant to AChE (duration depends on diffusion from endplate + hydrolysis by plasma pseudo-ChE) persistent conc. continual stim.)
+
NM rec. Na channel opening (phase 1) depol. transient switching (fasciculations) continual binding
+
Na channel closes/blocks gradual repol. depol. resistance (phase 2) flaccid(schlaff) paralysis
o actions
fast onset(1.1 min), short(8 min.) duration(redistribution + fast hydrolysis (plasma pseudo-ChE, not by AChE)
prolonged effect/paralysis: genetic defect in pseudo-ChE, continual infusion(effects disappear in discontinuation)
diff. paralyzing sequence compared to non-depol. agents, but resp. mm. paralyzed last
initial effect: ggl. block, fascilitations(cause mm. pain) (dose non-depol. agents prior to depol. agents fascilitations)
weak HA releasing action
o application
IV injection
useful in endotracheal intubation in patient with gastric content (avoid aspiration) due to rapid onset + short duration
electroconvulsive shock treatment
o adverse effects
hyperthermia: halothane(anesthetic) + succinyl-Ch can cause malignant hyperthermia(mm. rigidity, metab. acidosis, tachycardia, hyperpyrexia)
treatment: fast cooling + dantrolene(blocks sarcoplasmic Ca2+ release heat production, relaxing mm. tone)
apnea: genetic defect of plasma ChE prolonged apnea(due to diaphragmatic paralysis + rapid K+ release)
+
hyperkalemia: succinyl-Ch IC K release(dangerous in prior IC K+ loss (burns, massive tissue damage))
dont mix succinyl-Ch + digoxin/diuretics in electrolyte imbalance
mm. pain, Pintraocular/intragastric

Jan Kirchhof

Pharmacology

UMF Targu Mures

Unit II, Chapter 6 Adrenergic Agonists


adrenergic neurons

adrenergic neurons: release primarily NA, located in CNS + SNS


action of adrenergic drugs: adrenergic neurons, adrenergic recc.(pre-, postsyn.)
neurotransmission at adrenergic neurons
o NA synthesis
tyrosine transport(Na+ cotransporter) in axoplasm
tyrosine hydroxylation(tyrosine hydroxylase) to DOPA(dihydroxyphenylalanine) rate limiting step in NA formation
DOPA decarboxylation(DOPA decarboxylase) to DA(dopamine)
o NA storage in vesicles
DA transport(amine transporter system, also involved in reuptake) in syn. vesicle transporter blocked by: reserpine
DA hydroxylation(DA -hydroxylase) to NA (adrenal medulla: NA methylation to A A + NA storing in chromaffin cells)
vesicle content: DA, NA, ATP, DA -hydroxylase, + other cotransmitters
o NA release
see neurophysiology, guanethidine and bretylium blocks release
o rec. binding
o NA removal
reuptake(driven by Na+/K+ ATPase; prim. mech. for effect termination) reuptake block by tricyclic antidepressants: imipramine, cocaine
vesicle reuptake(amine transporter system); persistence in cytoplasmic protected pool; oxidation(MonoAmineOxidase from mitoch.)
diffusion out of syn. cleft (entering general circulation)
metabolization(postsyn. cell membr. assoc. catechol O-methyltransferase (COMT)) to O-methylated derivatives in syn. cleft
o urinary excretion of inactive metabolites(vanillylmandelic acid, metanephrine, normetanephrine) (metabolized by MAO or COMT)
adrenergic recc. (adrenoceptors)
o receptors
affinity: A NA >> isoproterenol(synthetic agonist)
1 rec.
loc.:
postsyn. membr. of effector organ constr. of sm. mm
protein: Gq (PLC IP3 + DAG)
ligand: higher affinity to phenylephrine than 2
2 rec.
loc.:
presyn. nerve endings, pancreatic -cells pancreas, certain vasc. sm. mm.
protein: Gi (AC cAMP)
ligand: higher affinity to clonidine than 1
effect: feedback inhibition at presyn. membr. of NT release autonomic activity regulation
o sym./parasym.(NA diffuses there) neurons: NA(inhibitory autorec. fct.)/ACh(inhibitory heterorecc. fct.) release
further subdivision
1A, 1B, 1C, 1D, 2A, 2B, 2C explains drugs selectivity
o 1A (primarily loc. in urinary tract + prostate gland) antagonist tamsulosin: treatment in benign prostate hyperplasia
o receptors
affinity: isoproterenol > A > NA
subgroups spec. affinities: 1 (affinity: A = NA), 2 (affinity: A > NA predom. tissues(e.g. sk. mm. vasc.) are espec. responsive to hormonal (A) effects)
protein: Gs (AC cAMP) (for all subtypes 1, 2, 3)
o rec. distribution in adrenergically innervated organs/tissues
rec. type predominance(e.g. sk. mm. vasc.: 2 (predom.) + 1) or single rec. type innervation(e.g. heart: 1)
o characteristic responses mediated by adrenoceptors
1
vasoconstr. (espec. in skin, abdominal viscera), Rperipheral, BP, mydriasis, closure of bladders int. sphincter
2
NA release, ACh release, insulin release
1
cardiac stim. (chronotropy, ionotropy), lipolysis, renin release
2
sm. mm. relax.(vasodil. (sk. mm. vasc.), R periph., bronchodil., uterine sm. mm. relax.), glycogenolysis(mm., liver), glucagon release
3
lipolysis
o receptor desensitization
prolonged catecholamine exposure rec. responsiveness (desensitization)
sequestration of rec. receptor becomes unavailable for ligand interaction
down-regulation (destruction/synth.)
inability to couple to G proteins (because rec. has been phosphorylated at cytoplasmic side)

10

Jan Kirchhof

Pharmacology

UMF Targu Mures

characteristics of adrenergic agonists

most adrenergic agents: -phenylethylamine derivates


o substitutions (on benzene ring(no./loc. of OH groups), ethylamine side chain(substitute on amino N (larger substitute affinity))
derivate variety, diff. abilities(/ affinity, entering CNS, etc.)
catecholamines
o sympathomimetic amines with 3,4-dihydroxybenzene A, NA, isoproterenol, DA
o high potency
catechol derivates(3,4-dihydroxybenzene) have highest directly activating + recc. potency
o rapid inactivation
COMT(postsyn., gut wall), MAO(intraneuronally, liver, gut wall) inactivation(orally: ineffective; parenterally: short action before inactivation)
o poor CNS penetration
polar OH groups almost no CNS entry, but some CNS clinical effects (anxiety, tremor, headache)
non-catecholamines
o phenylephrine(A analogue, but 3-monohydroxybenzene), ephedrine(no OH at benzene, but methyl group at -carbon), amphetamine
o agents lack catechol hydroxyl groups no COMT/poor MAO inactivation longer t1/2
o lipophilic properties of many non-catecholamines (no polar OH groups) better CNS entry
substitutions on amine N
o nature/bulk of substituent on amine N: imp. in selectivity ( affinity: isoproterenol(CH-(CH3)2 substitute) > A(CH3 substitute) > NA(no substitute))
mechanism of action of adrenergic agonists
o direct-acting agonists
A, NA, isoproterenol, phenylephrine
direct action on adrenoceptors(resemble SNS/adrenal medulla effects)
o indirect-acting agonists
amphetamine, cocaine, tyramine
NA reuptake block(uptake blockers)/induced NA release from cytopl. pools/vesicles(agent is taken up in presyn. neuron affects NT release)
o mixed-action agonists
ephedrine, pseudoephedrine(stereoisomer)
direct action + indirect action via NA release
adverse effects of adrenergic agonists
o arrhythmias, headache, hyperactivity, insomnia, nausea, tremors

11

Jan Kirchhof

Pharmacology

UMF Targu Mures

direct-acting adrenergic agonists

binding adrenoceptors, no interaction with presynaptic neuron


adrenalin
o action
interaction with , recc. dose predom. (vasodil.), dose predom. (vasoconstr.)
cardiovascular effect (main site of effect)
heart: pos. ionotropic (1), pos. chronotropic (1) CO myocardial O2 demands
kidney: renin release (1) (activation of RAAS)
vessels: constriction of arterioles in skin, mucosa, viscera ()
dilation of vessels of liver, sk. mm. (2) decr. renal blood flow
systolic BP, slightly diastolic BP (Rperipheral)
respiratory effect
powerful bronchodilation(action on bronchial sm. mm.) (2) relieve of all known allergic-/HA-induced bronchoconstr.
o anaphylactic shock
lifesaving
o acute asthmatic attack relieve of dyspnea (labored breathing), VolumeTidal
o inhibition of allergic mediator release (e.g. HA from mast cells)
hyperglycemic effect
hepatic glycogenolysis (2), glucagon release (2), insulin release (2)
lipolytic effect
agonistic action on adipose tissue ( effect(Gs: AC cAMP hormone sensitive lipase TG hydrolysis FA + glycerol))
o biotransformation
metabolization by MAO/COMT(S-adenosylmethionine cofactor) metanephrine, vanillylmandelic acid in urine
o application
bronchospasm
primary drug in emergency bronchoconstr. ( resp. exchange) (e.g. in acute asthma/anaphylactic shock)
o subcut. administ.(can be repeated in few hours) improved resp. exchange in few min
o chronic asthma treatment: selective 2 agonists (e.g. albuterol) longer duration, min. cardiac effect
anaphylactic shock
drug of choice in type I hypersensitivity reactions due to allergens
cardiac arrest
restore cardiac rhythm in cardiac arrest regardless the cause
local anesthetics/controlled local vasoconstriction
1:100000 A solutions injection site vasoconstr., anesthetic persists at inj. site anesthetic duration
topical use to stop mucosal capillary bleeding by vasoconstriction
o pharmacokinetics
fast onset, short duration (rapid degradation)
administration: intramusc.(preferred route, rapid absorption), IV(emergency case, most rapid onset), subcut., endotracheal tube, inhalation
o adverse effects
CNS disturbances
e.g. anxiety, fear, tension, headache, tremor
hemorrhages
elevated BP cerebral hemorrhage
cardiac arrhythmias
espec. in combination with digoxin(heart glycoside)
pulmonary edema
o interactions
hyperthyroidism:
hyperthyr.(vasc. adrenoceptor prod. hypersens. response) + Acardiovasc. effectA dose for patients
cocaine:
cocaine(catecholamine reuptake blocker) + A cardiovasc. action
DM:
endogenous stored Glc release insulin demand
-blockers:
no rec. effect, restricted rec. effect Rperipheral BP
inhalation anesthetics: agents sensitize heart to A tachycardia

12

Jan Kirchhof

Pharmacology

UMF Targu Mures

noradrenalin
o action

in therapeutic doses: recc. most affected


cardiovasc. actions
vasoconstr.
o vasoconstr.(NA > A, no 2 vasodil. in sk. mm. etc.) of most vessels(including kidney (1)
Rperipheral BP(syst. (vasoconstr. preload) + diast.)
barorec. reflex litte/no cardiac stimulation
o BP baroceptor reflex vagal activity reflex bradycardia counteracts local cardiac NA action
atropine pretreatment
o atropine(blocks vagal transmission) + NA tachycardia
o application (NA may be called levarterenol)
shock: Rvascular BP
not used in: asthma(weak 2 effect), combination with anesthetic(NA is potent vasoconstr. extravasation along inj. site)
o pharmacokinetics
IV(rapid onset, duration: 1-2 min after infusion end), subcut.(poor absorption), orally(ineffective)
o adverse effects
similar to A
skin blanching(becoming pale)/sloughing(Hutung) along injected vein (due to extreme vasoconstr.)
NA induced impaired circulation give phentolamine (-rec. antagonist))
isoproterenol
o actions
mainly 1/2 stim.(insignificant stim.) -non-selectivity drawback, rare therapeutic use
cardiovasc.
intense cardiac stim. (as active as A useful in AV block, cardiac arrest) pos. chronotropic, pos. ionotropic CO
sk. mm. arteriole dilation (2) Rperipheral
cardiac stim.: (moderately)syst. BP, distol. BP BP(MAP)
others: glycemia (), lypolysis () not clinically significant
o application
cardiac emergency stim. (e.g. AV block, cardiac arrest)
o pharmacokinetics
marginal substrate for COMT, stable to MAO
o adverse effect
similar to A
dopamine
o action
naturally in CNS(basal ggl.)/adrenal medulla
acts on adrenergic (/) + dopaminergic (D1 (Gs)/D2 (Gi)) recc.
D recc.: in renal/splachnic vasc./presyn. adrenergic nn.(D2 inhibits NA release), not affected by / blockers
cardiovascular
doses: 1 activation vasoconstr.
doses: 1 activation cardiac stim. (pos. ionotropic, pos. chronotropic)
renal/visceral
D1/D2 activation: renal/splachnic artery dilation Qrenal/visceral
o application
drug(as continues infusion) of choice for cardiogenic/septic shock
vasoconstr. (1) Rperipheral
BP (cardiac 1) CO
+
Qrenal/splachnic GFR Na diuresis (sup. to NA(Qrenal renal shutdown), SNS also comprises renal fct.)
hypotension, severe congestive heart failure (mainly in patients with Rperipheral, oliguria)
o adverse effects
DA OD nausea/hypertension/arrhyth. (similar to sym. stim.) fast metaboliz.(MAO/COMT homovanillic acid) short effects

13

Jan Kirchhof

Pharmacology

UMF Targu Mures

fenoldopam
o action
st
racemic mixture(equal amounts left/right handed entantiomers of chiral molecule R-isomer is active), extensive 1 -pass metabolism, IV t1/2 10 min
peripheral D1 agonist, moderate 2 agonist
o application
severe hypertension in hospitalized patients: fast vasodilation (acts on coronary artt., renal arterioles, mesenteric artt.)
o adverse effects
headache, flushing, dizziness, nausea, vomiting, tachycardia (due to vasodil.)
dobutamine (synth. direct acting catecholamine)
o action
1 agonist in racemic mixture: CO, few vasc. effects
o application
acute congestive heart failure/post-surgical inotropic support
CO, hardly incr. myocardial O2 demand(major advantage over other symphatomimetics)
o adverse effects
similar to A, tolerance in prolonged use
be careful in atrial fibrillation (agent causes AV conduction)
oxymetazoline
o action, application
acts on 1/2 recc.: topical administration direct vasc. rec. stimulation vasoconstr. Q congestion
mainly for eyes(relief eye redness), nose(decongestant (abschwellend) nasal sprays, all 12h)
o adverse effects
absorption in syst. circulation(regardless route of administr.) nervousness, headache, trouble sleeping
nasal administration nasal mucosa burning, sneezing, rebound congestion( rec. no., predom. effect?), dependence
phenylephrine
o action
acts mainly on 1 rec., COMT resistant(no catechol)
vasoconstr. BP(syst. + diast.), no direct cardiac effect, induced reflex bradycardia in parental use
o application
topical use: nasal mucosa(nasal decongestant (all 4h) vasoconstr.), ophthalmic solutions(mydriasis)
for raising BP, termination of supraventricular(atria/AV junction) tachycardia
o adverse effects
doses: hypertensive headache, cardiac irregularities
clonidine
o action
2 agonist, central action inhibition of sym. vasomotor centers sym. outflow
o application
in essential hypertension: lowering BP(by CNS action sym. activity)
minimize withdrawal effects from opiates/tobacco smoking/benzodiazepines
o adverse effects
lethargy, sedation, constipation, xerostomia effects in progressed therapy/doses
avoid abrupt discontinuance rebound hypertension
metaproterenol
o COMT resistant(chemic. similar to isoproterenol, but no catecholamine), use due to longer acting more selective 2 available agonists
albuterol, terbutaline
o action
short acting 2 agonists
o application
mainly for bronchodilation (by metered-dose inhaler)
terbutaline: off-label-use as uterine relaxant suppress premature labor
o adverse effects
excessive 2 activ. tremor(tolerance develops: start with dose, wait for tolerance to dose), restlessness, apprehension(Besorgnis), anxiety
syst. administr.: 1 effects tachycardia/arrhythmia, espec. in underlying cardiac disease
cardiovascular effects in combination with MAOInhibitors (2 week gap betw. MAOI + 2 agonists)

14

Jan Kirchhof

Pharmacology

UMF Targu Mures

salmeterol, formoterol
o action
long acting 2 selective agonists
o application, adverse effects
long acting bronchodilation(one metered-dose inhalation 12h bronchodilation (< 3h for albuterol), salmeterol has delayed onset)
mono-therapy not recommended, efficacious in corticosteroid combination
agents of choice in nocturnal asthma in symptomatic patients with other asthma medication
inhaled 2 agonists are dangerous in excess OD death

indirect-acting adrenergic agonists

indirect postsyn. effect induce NA release from presyn. terminals, inhibit NA reuptake potentiate endogenous NA effects
amphetamine
o action
indirect-acting adrenergic drug (blocking NA uptake, induce release of stored catecholamines)
central stimulation (often mistaken by drug abuses as only action)
peripheral action: BP (vascular 1 + cardiac agonistic action)
similar drugs: dextroamphetamine, methamphetamine, methylphenidate, dexmethylphenidate similar effects + use
o application, adverse effects
central effect: treatment of hyperactivity in children, narcolepsy(Schlafkrankheit), appetite control
avoid use in pregnancy adverse effects on fetal development
tyramine
o induces NA release, centrally active
o clinically not used, found in fermented food(aged cheese, Chianti wine), tyrosine metabolism byproduct MAO oxidation in GIT
using MAOI serious vasopressor episodes
cocaine
o Na+/K+ ATPase block(unique among local anesthetics) no NA reuptake(on adrenergic neurons) NA accumulation
sym. activity, A/NA effect potentiation, duration of action: small catecholamine dose effects
o central stimulation (drug of abuse), BP (vascular 1 + cardiac agonistic action)

mixed-action adrenergic agonists

induce NA release presynaptically + activate adrenergic recc. postsynaptically


ephedrine, pseudoephedrine
o induce NA release, stimulate / recc. wide variety of adrenergic actions (similar to A, less potent)
o long duration(no catechols poor for COMT, MAO), excellent oral absorption, can enter CNS(pseudoephedrine has less CNS effects)
ephedrine
o action
vasoconstriction, cardiac stimulation BP(syst. + diast.)
bronchodilation (potent/fast than A/isoproterenol)
mild CNS stimulation alertness, fatigue, insomnia
improved athletic performance
excretion: mainly unchanged urinary elimination
o application, adverse effects
used for asthma prevention (replaced by new agents)
use: potent/side effect newer agents
ban of ephedrine-containing herbal supplements life threatening cardiovasc. reactions
pseudoephedrine
o action, application, adverse effects
excretion: incomplete hepatic metabolism urinary elimination
mainly oral use: treatment of nasal/sinus/eustachian tube congestion
illegal conversion to metamphetamine restrictions for pseudoephedrine containing products

15

Anda mungkin juga menyukai