Farmacologia sistemului

nervos central
Anxiolitice, sedative, hipnotice
 Cuplarea receptor neurotransmitator - efector
A. Activare receptor (canal ionic)
- N-AChR, NMDAR -  Na+, Ca++
- GABA, glicina – hiperpolarizare (Cl-)

A. Activare receptor cuplat cu proteine G –

activare canal ( - direct;  - indirect)

B. Dimerizare – TK

C. Activare receptor cytoplasmic – expresie

canal
 Eliberarea, actiunea si inactivarea neurotransmitatorului (NT)
1. Depolarizare – deschidere canale Ca++
voltaj-operate – influx Ca++
2. Exocitoza vezicule sinaptice
neurotransmitator ( Ca++ - sinaptotagmina
– ancorare - fuziune – exocitoza)
3. Cuplare NT – canal ionic
4. Cuplare NT – GPCR
5. Receptori NT presinaptici -  sau 
eliberarea NT
6. Recaptare NT presinaptica (NET, SERT, DAT)
7. Degradare NT (ACh, peptide)
8. Captare si metabolism in cellule gliale (Glu)
9. Membrana veziculara – recaptata prin
endocitoza clathrin-mediate
10. Neuropeptide si proteine – granule cu
nucleu dens
11. Eliberare la situsuri distincte – stimulare
repetitiva
 Neurotransmitatori – Aminoacizi - GABA
• Actiune inhibitorie interneuroni cerebral, inhibitie presinaptica medulara (?)
• Receptori
• GABA-A – canal Cl- ligand operat (ionotropic)
• Benzodiazepine, barbiturice, etanol, steroizi anestetici,
anestezice volatile, propofol)

• GABA-B – GPCR (metabotropic)

•  AC,  K+,  Ca++
• Presinaptic – autoreceptori – inhiba elib. GABA

• GABA-C – canal Cl- ligand op. (retina, maduva, colliculi

superiori, hipofiza)
• GABA – activ X 10 GABA-C vs. GABA-A
 Neurotransmitatori – Aminoacizi
• Glicina
• Inhibitor (~ GABA-R)
• GlyR (-Ala, taurina)
• Antag: cafeina
• Glutamat si aspartat
• Excitatori – ubicuitar cerebral
• Receptori – ionotropic/
metabotropic
• Receptori
• NMDA (N-metil-D-aspartate) –
plasticitate sinaptica
• Non- NMDA – depolarizare rapida la
sinapse glutamatergice
• AMPA ( - amino-3-hidroxi-5 metil-4
izoxazol-propionic acid)
• Kainat (acid kainic)
Excitotoxicitatea semnalizarii prin glutamat
(ischemie-reperfuzie)
 Neurotransmitatori
• Acetilcolina
• NAChR – Na++/Ca++ - depolarizare
• MAChR – 5 subtipuri
• Catecolamine
• Dopamina
• Nigrostriat
• Mezocortical (n. ventral tegmental – n. accumbens, amigdala, hippocampus, cortex)
• Tuberoinfundibular – n. arcuat – hipofiza
• D1R, D5R – Gs – AC – cAMP – PKA
• D2R, D3R, D4R -  AC, Ca++, K+
• Noradrenalina
• Hipotalamus, limbic, amigdala, hippocampus, l. coeruleus
• 1 – Gq – PLC; 2 – Gi - AC (presynaptic – autoreceptori inhibitori –
clonidine);  - Gs - AC
• Adrenalina –
• formatia reticulata bulbara
 Neurotransmitatori
• Serotonina (5-HT)
• 9 nuclei – rafeu (punte, trunchi sup.)
• Input serotoninergic: N. suprachiasmatic, corpuscul geniculat, amigdala,
hippocampus
• 5HT1R (A-F) - AC, can K+, Ca++
• 5HT1A – anxietate
• 5HT2 (A,B,C) – Gq- PLC
• Neocortex, tubercul olfactiv
• Antidepresive
• LSD – rafeu (agonist partial)
• 5HT3 – canale ionice ligand- activate
• Area postrema, NTS
• Emeza, antinociceptie
• 5HT4 – Gs – AC – cAMP
• Coliculi, hipocampus
 Neurotransmitatori
• Histamina
• Hipotalamus ventral
• H1R – glial, vascular
• Gq – PLC – Ca++
• Antihistaminice - somnolenta
• H2R
• Gs – AC
• H3R
• Gi -  AC
• H4R – cel. hematopoietice
Peptide
• Sinteza – RER
• Propeptid – clivaj – transport centripet
• Antagonisti (ex. morfina)
 Alte substante neuroreglatoare
• Canabinoizi
•  -9 tetrahidrocanabinol – THC – marijuana
• Euforie, perceptie senzoriala alterata
• Receptori
• CB1 (CNS)
• CB2 (periferie, lucocite, splina)
• Liganzi endogeni – derivati Ac. Arahidonic
• Anadamida
• Gi -  AC – inhibitie eliberare glutamate
• Purine – ATP, UDP, UTP
• Co-transmitatori – adrenergici
• Receptori : P1, P2
• Metaboliti AA, NO, CO, citokine
Hipnotice si sedative
 Notiuni generale
• Sedativ – scade activitatea, reduce agitatia, produce calmare
• Hipnotic – produce somnolenta si faciliteaza instalarea si mentinerea starii de
somn similar EEG somnului natural (din care poate fi usor trezit)
• Sedarea – effect secundar al multor medicamente care nu sunt deprimante SNC –
i.e. – nu induc anestezie chirurgicala in absenta altor deprimante SNC
(benzodiazepine)
• Medicamente sedativ-hipnotice non-benzodiazepin-receptor – deprimante SNC
dependente de doza: Calmare, somnolenta – somn (hipnoza farmacologica) –
pierderea constientei – coma – anestezie chirurgicala – depresie
cardiovascular/respirator (proprietati similare cu anestezicele generale si alcoolii
alifatici – etanol)
• Efectul deprimant central dependent de doza – doua stadia clare
• Anestezie chirurgicala (stimuli durerosi nu provoaca raspuns comportamental sau
autonomic)
• Moarte prin depresie a neuronilor bulbari
• Alti indici – f. cognitiva, ataxie, analgezie, antiepileptic – necorelate cu doza-efect
 Istoric

• Din atichitate – alcool, laudanum

• Sec. XIX – bromura – sedative hypnotic
• Cloral hidrat, paraldehida, uretan, sulfonal
• 1903 – barbital; 1912 – fenobarbital - ~50 commercial inainte de 1960
• Sedativ-hipnotic-anestezic vs. antiepileptic – anticonvulsivante non-sedative
• Clorpromazina, meprobamate – animale
• Clordiazepoxid – 1950 – inceputul epocii benzodiazepine
• Efect anxiolytic vs. deprimant SNC
• Risc redus de depresie SNC fatala
• Benzodiazepinele inlocuiesc barbituricele pentru effect sedativ-hipnotic
 Benzodiazepine

• Stimuleaza legarea GABA la receptor GABA-A – cresc permeabilitatea Cl- la

actiunea GABA
• Situs de legare eterogen – dependent de structura subunitatilor canal
GABA-activat
• Scop: selectivitate pentru subtipuri de receptori GABA – ex. Compusii “Z”
• Mecanisme de actiune distincte si situsuri de actiune diferite (subunitati
specific GABA-A)
• Efecte (general): sedativ-hipnotic, miorelaxant, anxiolitic si anticonvulsivant
 Benzodiazepine

• “Benzodiazepine” –
• A – inel benzenic
• B – inel diazepinic (7 atomi, 2N, poz.1,4)
• C – 5-aril
• Pe langa benzodiazepine – numerosi compusi
actioneaza pe aceleasi situsuri de legare SNC
- imidazopyridine (zolpidem)
- imidazochinolone
- ciclopirolone (Eszopiclone)
 Benzodiazepine – proprietati farmacologice

• Actiuni SNC: Sedare, hipnoza, scaderea anxietatii, miorelaxare, amnezie

anterograda, anticonvulsivanta
• Actiuni periferice: vasodilatatie coronariana, blocare neuromusculara
• Agonisti
• Completi
• Partiali
• Inversi (efect opus in absenta agonistilor benzodiazepine-like)
• Antagonist: flumazenil (inel “C” modificat keto “=0”) – competitive situs
legare
• Modele animale: neofobie, stimuli aversivi
• Diferenta de concentratie: effect motor vs. efect antisupresiv = sedativ hypnotic vs
anxiolitic
 Benzodiazepine – proprietati farmacologice

• Toleranta : aparent selectiva

•  effect sedativ, miorelaxare, anticonvulsivant
•  effect anxiolytic
• Efect EEG somn
• Scad latent instalarii
• Scad trezirile si timpul in stadiul 0
• Scurteaza stadiul 1
• Scurteaza stadiile 3,4 dar si REM dar cresc frecventa REM
• Cresc timpul total de somn si stadiul 2
 Benzodiazepine – tinte moleculare

• Receptor GABA - eterogen

• pentamer
• 16 subunitati (7 familii)
• Situs de legare diferit de GABA – interfata 
• Nu activeaza GABA-A direct
• Efect allosteric – modulare effect GABA
• Cresc frecventa de deschidere a canalului (nu durata – barbiturice)
• Modulare allosterica legare GABA – BZD
• In absenta agonistului BZD, antagonistul nu modifica efectul GABA
 Benzodiazepine – efecte electrice in vivo

• Benzodiazepinele – depeind de prezenta GABA (profil de siguranta )

• Efecte sedative si comportamentale

• Potentarea cailor GABAergice care regleaza neuroni monoaminergici care mediaza
efectele inhibitorii ale fricii si pedepsei asupra comportamentului

• Miorelaxare si anticonvulsivant
• Potentarea circuitelor gabaergice inhibitoare la niveluri diferite
• Cai recurente axo-somatice
 Benzodiazepine – efecte sistemice
• Respiratia
• Doze hipnotice – fara effect la subiecti normali
• La doze mai mari (preanestezic) -  ventilatia alveolara – acidoza respiratorie prin scaderea
stimularii hipoxice – atentie BPOC
• Apnee in timpul anesteziei sau in asociere cu opioizi
• Asistarea respiratory este necesara la intoxicatii cu BZD doar in asociere cu alte deprimante
centrale (frecvent: alcool).
• Efect myorelaxant la caile aeriene superioare – agravare episoade de apnee de somn –
posibila contraindicatie
• Cardiovascular
• Minore la normali cu exceptia intoxicatiilor
• Scad presiunea arteriala si cresc frecventa cardiac (consecinta scaderii lucrului cardiac si DC
– diazepam;  rezistenta periferica – midazolam)
• Tract digestiv
• Scad secretia acida gastrica nocturna
 Benzodiazepine – efecte sistemice
• Respiratia
• Doze hipnotice – fara effect la subiecti normali
• La doze mai mari (preanestezic) -  ventilatia alveolara – acidoza respiratorie prin scaderea
stimularii hipoxice – atentie BPOC
• Apnee in timpul anesteziei sau in asociere cu opioizi
• Asistarea respiratory este necesara la intoxicatii cu BZD doar in asociere cu alte deprimante
centrale (frecvent: alcool).
• Efect myorelaxant la caile aeriene superioare – agravare episoade de apnee de somn –
posibila contraindicatie
• Cardiovascular
• Minore la normali cu exceptia intoxicatiilor
• Scad presiunea arteriala si cresc frecventa cardiac (consecinta scaderii lucrului cardiac si DC
– diazepam;  rezistenta periferica – midazolam)
• Tract digestiv
• Scad secretia acida gastrica nocturna
 Benzodiazepine – cinetica
• Predominant lipofile
• Pe baza t1/2
• Actiune ultra scurta
• Scurta (<6 h) : triazolam, zolpidem, eszopiclone
• Intermediar (6-24h): estazolam, temazepam
• Lung (>24h) : flurazepam, diazepam, quazepam
• Legare protein plasmatice 70-99%
• Conc. LCR = concentratie plasmatica libera
• Distributie – rapida in organe perfuzate (creier) – redistributie muschi/grasime –
important pentru sedarea nocturna
• Trec bariera placentara si se secreta in lapte matern
• Metabolism hepatic CYP 3A4 (inhibitori: eritromicina, ketoconazole, suc grapefruit),
2C19
• Metabolism
• Modificare substituent pozitia 1 diazepina
• Hidroxilare poz. 3 – activare
• Glucuronidare - inactivare
 Benzodiazepine – cinetica
• Hipnoticul ideal:
• Instalare rapida a actiunii la administrare la culcare, effect sustinut nocturn, fara
activitate reziduala la trezire
• Ex: triazolam
• Principii terapeutice
• Majoritatea BZD pot fi utilizate intersanjabil
• Anticonvulsivante – t1/2 lung
• Hipnotice – eliminare rapida
• Anxiolitice – t ½ lung
COMPOUND (TRADE NAME) ROUTES OF ADMINISTRATIONa EXAMPLES OF THERAPEUTIC COMMENTS t1/2, hoursc USUAL SEDATIVE-HYPNOTIC
USESb DOSAGE, mgd

Alprazolam (XANAX)
Chlordiazepoxide (LIBRIUM,
others)
Clonazepam (KLONOPIN)
Oral Anxiety disorders, agoraphobia Withdrawal symptoms may be 12±2 —
especially severe
Oral, IM, IV Anxiety disorders, management Long-acting and self-tapering 10±3.4 50-100, qd–qide
of alcohol withdrawal, anesthetic because of active metabolites
premedication
Oral Seizure disorders, adjunctive Tolerance develops to 23±5 —
treatment in acute mania and anticonvulsant effects
certain movement disorders

Clorazepate (TRANXENE, others) Oral Anxiety disorders, seizure Prodrug; activity due to formation 2.0±0.9 3.75-20, bid–qide
disorders of nordazepam during absorption
Diazepam (VALIUM, others) Oral, IM, IV, rectal Anxiety disorders, status Prototypical benzodiazepine 43±13 5-10, tid–qide
epilepticus, skeletal muscle
relaxation, anesthetic
premedication
Estazolam (PROSOM) Oral Insomnia Contains triazolo ring; adverse 10–24 1-2
effects may be similar to those of
triazolam
Flurazepam (DALMANE) Oral Insomnia Active metabolites accumulate 74±24 15-30
with chronic use
Lorazepam (ATIVAN) Oral, IM, IV Anxiety disorders, preanesthetic Metabolized solely by conjugation 14±5 2-4
medication
Midazolam (VERSED) IV, IM Preanesthetic and intraoperative Rapidly inactivated 1.9±0.6 —f
medication
Oxazepam (SERAX) Oral Anxiety disorders Metabolized solely by conjugation 8.0±2.4 15-30, tid–qide

Quazepam (DORAL) Oral Insomnia Active metabolites accumulate 39 7.5-15

with chronic use
Temazepam (RESTORIL) Oral Insomnia Metabolized mainly by 11±6 7.5-30
conjugation
Triazolam (HALCION) Oral Insomnia Rapidly inactivated; may cause 2.9±1.0 0.125-0.25
disturbing daytime side effects
 Benzodiazepine – efecte adverse
• Ameteala, prelungirea timpului de reactie, neccordonare motorie, confuzie,
amnezie anterograde
• Somnolenta diurna
• Cefalee, vertij, greata, dureri epigastrice, diaree

• Efecte adverse psihologice

• Cosmaruri, anxietate, iritabilitate, tahicardie
• Amnezie, euforie, halucinatii, hipomanie – dezinhibitie
• Paranoia, depresie, ideatie suicidara

• Abuz si dependenta
• Flunitrazepam – “date rape drug”
• Dependenta – exacerbarea problemei initiale + iritabilitate, disforie
• Coma apare doar in asociere cu alti deprimanti SNC (etanol)
 Noi agonisti benzodiazepinici
• Compusi “Z”
• Zolpidem (Ambien ®), Zaleplon (Sonata ®), Zopiclone (Imovane ®), Eszopiclone
(Lunesta®)
• Agonisti sit benzodiazepinic GABA-A; structura chimica diferita
• Inlocuiesc treptat benzodiazepinele in tratamentul insomniei
• Instalarea somnului + mentinerea somnului
 Flumazenil - antagonist
• Antagonist competitiv
• Administrare : i.v
• T ½ ~ 1h
• Indicatii:
• Supradozare benzodiazepine
• Restabilirea efectelor sedative – therapeutic
• Poate precipita convulsii si alte simptome de sevraj la utilizatori dependent,
pe termen lung
 Cogeneri Melatonina
• Ramelteon (sintetic) – agonist MT1, MT2

• Melatonina
• N Suprachiasmatic – ritm circadian – max. seara
• MT1 (instalarea somnului), MT2 (modificarea ritmului circadian)
Barbituricele
 Barbituricele
• Mecanisme de actiune SNC
• Dozele sub-anestezice suprima raspunsurile polisinaptice
• Reduc facilitarea si cresc inhibitia
• Inhibitie postsinaptica (cortical, cerebelos, s. nigra, thalamus)
• Inhibitie presynaptic – medular
• Celular
• Cresc legarea GABA la GABA-A; stimuleaza legarea BZD
• Potenteaza curentii de Cl- (durata) chiar si in absenta GABA (!)
• Legare subunitati 
• Reduc depolarizarea indusa de glutamate (AMPA)
• Doze mari – inhiba curenti Na+ voltaj-dependent
• Efecte: sedare – anestezie
• Indice therapeutic scazut
• Toleranta
• farmacodinamica – incrucisata cu toate deprimantele SNC (incl. alcool)
• farmacocinetica
 Barbituricele - efecte
• Sistem nervos periferic
• Scad neurotranmisia ganglionara (nAChR) – hipotensiunea
• Amplifica efectul curarizantelor
• Respiratia
• Scad stimularea hipoxica si ritmicitatea
• Apare la doze x3 fata de cele care induc somnul
• Reflexele protectoare sunt mentinute: tuse, stranut, sughit, laringospasm (complicatie
frecventa a anesteziei)
• Cardiovascular
• Doze sedativ hipnotice – effect minim (PA, FC scad)
• Semnificativ la IC, soc hypovolemic
•  ventilatie/perfuzie la PEP
•  debit sangvin renal si cerebral
• Aritmii ventriculare
• Hepatic
• Acut: inhiba metabolizarea
• Cronic: inductie enzimatica – cresc metabolizarea (inclusive proprie – toleranta)
 Barbituricele - cinetica
• Sedativ – hypnotic – oral
• saruri Na+ - absorbtie rapida
• Efect intarziat de prezenta alimentelor gastric
• i.m. – profund – necroza
• i.v. – anesthetic
• Distributie
• Redistributie dupa i.v – scadere concentratie (5-15 min) – mentinerea
anesteziei
• Metabolism
• Aproape complet hepatic inainte de eliminare renala
• Excretia renala – crescuta de diureza osmotica si alcalinizare
Majoritatea barbituratilor se acumuleaza la doze repetate
 Barbituricele – efecte adverse
• Persistenta
• Depresie SNC reziduala
• Vertij, greata, varsaturi, diaree
• Excitatie
• Excitatia paradoxala
• Aparenta – betie
• Agitatie – delir – in prezenta durerii (cresc perceptia durerii)
• Hipersensibilitate
• R. alergice – facial, dermatita eritematoasa (dermatita exfoliativa – rar,
fenobarbital)
• Interactiuni
• Cu alte deprimante SNC (alcool – frecvent)
• Majoritatea – inductie metabolism: vit. D, K; h. steroizi; contraceptive
 Barbituricele – intoxicatie

• Frecvent suicidar; accidental

• X 10 doza hipnotica
• Depresie respiratorie severa – insuf. Pulmonara
• Colaps cardiovascular – bolus (inaintea anesteziei)
• Prezentare: coma, depresie respiratory, soc c-v
• Tratament
• Suportiv (eliminare, support hemodynamic, fc. Renala)
 Alte sedativ - hipnotice
• Paraldehida – polimer acetaldehida – puternic irritant
• Cloral hidrat (tricolor-acetaldehida) – metabolism la tricloroetanol
• Meprobamat – ester bis-carbamate
• Anxiolitic, dar utilizat si ca hypnotic
• Similar cu BZD – nu produce anestezie dar depresie cardiorespiratory
• Potential de abuz (carisoprodol – miorelaxant)
• Etomidat – anestezic i.v.
• Clomethiazol – sedativ, miorelaxant, anticonvulsivant
• Hipnoza la varstnici si institutionalizati; sevraj la alcool
• Propofol – extrem de lipofil – inductie si mentinere anestezie
• Diphenhydramine – antihistaminic – singurul OTC (USA) sedativ –
efect rezidual
 Principii in managementul insomniei
• Benzodiazepine si compusii Z sunt preferabilibarbituricelor
• Index therapeutic mai mare
• Mai putin toxice la supradozare
• Efecte mai mici asupra arhitecturii somnului
• Potential mai scazut de abuz
• Compusi cu t ½ scurt
• Probleme la adormire, fara anxietate diurna
• Varstnici
• - Trezire timpurie, anxietate rebound, episoade amnestice
• Compusi cu t ½ mai lung
• Anxietate diurna cu toleranta la effect persistent sedativ
• Depresie (evitarea trezirii timpurii)
• - deficiente cognitive diurne acut sau tardive (acumulare)