Antidepressants. Antianxiety, Psychostimulants and Psychodyleptics

1. Antidepressants. Antianxiety, Psychostimulants and Psychodyleptics Anton Kohút

2. Depression is pervasive mood altering ilnesses affecting energy, sleep, appetite, libido and the ability to function

3. Antidepressants.

4. Depression Symptoms: • depression • intensive feelings of sadness • hopelessness • inability to experience pleasure in usual activities • mania • enthusiasm • rapid though and speech paterns • it is an affective disorders characterized by changes in mood (depression or mania) • - about 10% of population - experience with depression • woman:man ratio - 2:1

6. Depression is due to a decrease of noradrenaline, serotonine,Mania is due to oposite changes,The bases of the treatment of depression is increase of Na and 5-HT.

7. ? • first great theory - role of monoamine neurotransmitters (NE, 5-HT) • defficiency of neurotransmitters - depression • simplistic theory • problem - timming of antidepressant effect on neurotransmitts is far from the timing of the antidepressant effect on mood • newer theories - role of neurotransmitter receptors • disturbancies in signal transducion

8. Classification of antidepressants 1. Tricyclic antidepressants (TCAs) • Imipramine, Nortriptyline, Amitriptyline, Doxepin Clomipramine Desipramine 2. Monoamine oxidase inhibitors (MAOIs) • Phenelzine, Tranylcypromine 3. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) • Fluoxetine, Fluvoxamine, Sertraline, Paroxetine 4. Reversible monamine oxidase inhibitors (RIMAs) • Moclobemide

9. New antidepressants 5. Norepinephrine Reuptake Inhibitors (NRI) -Reboxetine 6. Norepinephrine and Dopamine Reuptake Inhibitors (NDRI)- Bupropion 7. Serotonin / norepinephrine reuptake inhibitors - Venlafaxine 8. Noradrenergic and Specific Serotoninergic Antidepressants (NaSSA)–Mirtazapine, Mianserine 9. Serotonin-2A antagonists/serotonin reuptake inhibitors • Trazodone 10. Serotonin-2A antagonists/norepinephrine reuptake inhibitors • Nefazodone

10. Classification of antidepressive drugs

11. TCAs prevent the re-uptake of NA and 5-HT from the synaptic cleft This re-uptake blockade leads to the accumulation of 5-HT and NA in the synaptic cleft Tricyclic antidepressants (TCAs)

12. Tricyclic antidepresants (TCA) • inhibition of re-uptake  increase of NE, 5-HT • also blockade of M, H1 1 receptors • 2-3 weeks for antidepressive action • many years  drug of choice • M-receptors dry mouth, urine retention, constipation, blurred vision • M+1-receptors - tachycardia, hypertension, postural hypotension, • H1-receptors  sedative effects, body weight gain

13. 1. Anticholinergic -mucosal dryness -constipation -urinary retention -confusion -blurred vision -aggravation of glaucoma 2. Anti alpha adrenergic - orthostatic hypotension 3. Antihistaminic -sedation 4. Quinidine-like - cardiac arrhytmias and block Side effects of TCAs

14. Selective Serotonin Reuptake Inhibitors (SSRI) • inhibiion of 5-HT re-uptake • increase of 5-HT  effect on postsynaptic 5-HT and 5-HT1A presynaptic receptors • stimulation of 5-HT1A receptors „down-regulation“  lower effect on 5-HT release from presynaptic neurons • inhibition of NE reuptake  • blockade of 1, H1 alebo M- receptors  cardotoxic, hypotensive, sedative effects • most often prescribed antidepressants today • SEROTONINE SYNDROME – combination of SSRI + MAO - lifethreating consequences  tremor, convulsions, abdominal pain, diarhea, hypertension, tachycardia, cardiovacular colaps

15. . Fluoxetine • in depresion of different etiology PK • food prolongs time of absorpion • 95% to plasma albumine • metabolised in the liver  major metabolite (norfluoxetine)  simmilar effect as a fluoxetine Side effects • lower incidence and intensity GIT - nausea, anorexia, CNS - insomnia, tremor, headache, vertigo CVS - orthostatic hypotension

16. MAO inhibitors (IMAO) • first antidepressive agents used clinically • "clasical" (e.g. tranylcypromine) irreverzible, nonselective inhibition of MAO-A and MAO-B • for antidepressive effects - inhibition of MAO-A • 2-3 weeks for antidepressive action • use of "clasical" MAOI is now limited - side effects, interactions (food, drugs) • tyramine (contained in some foods - chees, red wine, beer) is normally inactivated by MAO-B in the gut • MAO inhibitors elevated tyramine  tyramine causes release of stored catecholamines • tachycardia, hypertension, • headache, cardiac arrhythmias • patients must avoid tyramine-containing foods

17. RIMA (Reversible Inhibitors of MAO-A) Moclobemide • specific inhibition of MAO-A (reversible) • inhibition of deamination of 5-HT, NE, D PK • good absorption in GIT • 50% bound to plasma albumine • 95% excreted in urine as an inactive metabolites Side effects • insomnia, nausea, headache, dizziness, desorientation, nervousness • effect on CVS in combination with tyramine - less important

18. New antidepressants

19. Norepinephrine Reuptake Inhibitors (NRI) Reboxetine • introduced in 1997 • inhibition of NE re-uptake • minimal effect on 5-HT a D • depression, narcolepsy, panic fear • 98% bound to 1 acid glycoproteine Side effects • well tolerated • obstipation, dry mouth, urine retention, insomnia, tachycardia

20. Norepinephrine and Dopamine Reuptake Inhibitors (NDRI) Bupropion • weak inhibitor of D and NE re-uptake • major metabolite - strong NE re-uptake inhibitor • suitable for patients with intolerability or low response to SSRI • suitable to supress withdrawal symptoms in nicotine-dependent people • contraindicate in epileptic patients - proconvulsive effect

21. Serotonin and Norepinephrine Reuptake Inhibitors (SNRI) • action similar to TCA - NE and 5-HT re-uptake inhibition • no effects on M, H1 and 1-adrenergic receptors Venlafaxine • low doses  5-HT, moderate doses  NA, high doses  D • metabolised in the liver - O-desmethylvenfalaxine - active metabolit Side effects • nausea, constipation, somnolece, nervousness, headache • serotonine syndrome

22. Noradrenergic and Specific Serotoninergic Antidepressants (NaSSA) • blockade of 2-receptorov  release of NE a 5-HT Mirtazapine • high affinity to 2-receptors • antagonist of 5-HT2, a 5-HT3 and h1-receptors Side effects • somnolence, dry mouth, increase of apetite, body weight gain, constipation, serotonine syndrome Mianserine • selective antagonist of presynaptic 2-adrenergic receptors • partial effect on 1, 5-HT2, 5-HT3 h1- receptorov • main metabolites  biological activity Side effects • hypersensitivity, nausea, tremor

23. Utilization of antidepressants

24. Edvard Munch

25. Anxietyunpleasant state of tension, apprehension, or uneasiness. Disorders involving anxiety are the most common mental disturbances

26. Causes of Anxiety 2). Drug-Induced: • Stimulants • Amphetamines, cocaine, TCAs, caffeine. • Sympathomimetics • Ephedrine, epinephrine, pseudoephedrine phenylpropanolamine. • Anticholinergics\Antihistaminergics • Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin. • Dopaminergics • Amantadine, bromocriptine, L-Dopa, carbid/levodopa. 3). Drug Withdrawal: • BDZs, narcotics, BARBs, other sedatives, alcohol.

27. Anxiolytics • Benzodiazepines (BZDs). • Barbiturates (BARBs). • 5-HT1A receptor agonists. • 5-HT2A, 5-HT2C & 5-HT3 receptor antagonists. If ANS symptoms are prominent: • ß-Adrenoreceptor antagonists. • 2-AR agonists (clonidine).

28. Benzodiazepines

29. Benzodiazepines (BZD)Mechanism of action

31. BDZ receptors

32. Actions  Reduction of anxiety  Sedative and hypnotic actions  Anticonvulsant  Muscle relaxant (relax spasticity of ckeletal muscle). Pharmacokinetic aspects  Are well absorbed from GIT,  They bind strongly to plasma protein, have high lipid solubility, fast cross blood-brain-barrier: rapid onset of action  The effect of long-acting increases with the age. Therapeutic uses  Anxiety  anxiety that accompaniges some forms of depression.  Muscular disorders-muscle spasm, spasticity from degenerative disorders,  Seizures- grand mal epilepic seizures,  acute treatment of alcohol withdrawal  Sleep disorders. Side effects  Disturbance of intellectual functioning and motor activity impairs manual skils,  Potential for dependence and withdrawal syndrome. Benzodiazepines

33. Properties of Benzodiazepines • BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence. • BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics. • BDZs depress the turnover rates of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in various brain nuclei. • Keep in mind that with formation of active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect.Prototype drug is diazepam (Valium), which has active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr). • Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects. • All of these drugs and their metabolites are excreted in urine.

34. Metabolizmus BDZ From Katzung, 1998

35. I. Benzodiazepines a. Used as anxiolytics: alprazolam, chlordiazepoxid, diazepam, lorazepam b. Used as hypnotics: flurazepam, nitrazepam, temazepam Long – acting(1-3 days): diazepam, nitrazepam, flurazepam Intermediate acting(10 20 hours): alprazolam, lorazepam Flumazenyl –BDZ antagonist II. Other Anxiolytic drugs ( buspirone (5-HT1A agonist), Classification of anxiolytic and hypnotic drugs

36. Buspirone • “second generation anxiolytics” • has strong anxiolytic properties • almost no sedative effect, drowsiness or hypnosis • minimal amnesia and dementia • does not potentiate other sedatives • no abuse potential • it is 5-HT1A agonist • has both antianxiety and antidepressant effects • used for a variety of conditions • metabolized very quickly, grapefruit juice increases effect • slow onset of action

38. Jennifer Glasgow

39. Hypno-sedative drugsThey produce a pronounce, graded, dose-dependent depression of the central nervous system.

40. Hypno-sedative drugs terminology Sedation can bedefinedas a supression of responsiveness to a constant level of stimulation, with decreased spontaneous activity Hypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with most sedative drugs simply increasing the dose.

41. Hypno-sedatives • generation – barbiturates (obsolete) • generation – benzodiazepines(BDZs) • generation – zolpidem, zaleplon

42. Hypnotics a.Barbiturates . - Long acting (1-2 days) : phenobarbital. - Intermediate acting (3-8 hours): amobarbital, aprobarbital, pentobarbital,. - Ultrashot acting (20 minutes): thiopental b. Other sedatives and hypnotics Antihistamines Ethanol

43. Barbiturates • In the elderly and in those with limited hepatic function, dosages should be reduced. • Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes. • Strong physiological dependence may develop upon long-term use. • Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression.

44. Toxicity/Overdose • Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions. • Drugs with long-half lives have mildest withdrawal. • Drugs with quick onset of action are most abused. • No medication against overdose with BARBs. • Contraindicated in patients with porphyria.

45. WITHDRAWAL CONTROL SLEEP PER NIGHT (%) NIGTHS OF DRUG DOSING Sedative/Hypnotics Tolerance and excessive rebound occur in response to barbiturate hypnotics. REM NREM III and IV 1 2 3

46. Respiratory Depression BARBS Coma/ Anesthesia BDZs Ataxia RESPONSE Sedation Anticonvulsant Anxiolytic DOSE

47. Miscellaneous Drugs • Buspirone • Chloral hydrate • Hydroxyzine • Meprobamate (Similar to BARBS) • Zolpidem (BZ1 selective) • Zaleplon (BZ1 selective)

48. Zolpidem • Structurally unrelated but as effective as BDZs. • Minimal muscle relaxing and anticonvulsant effect. • Rapidly metabolized by liver enzymes into inactive metabolites. • Dosage should be reduced in patients with hepatic dysfunction, the elderly and patients taking cimetidine.