assoc. prof. iv. lambev www.medpharm-sofia.eu medical university of sofia, faculty of medicine...

Download Assoc. Prof. Iv. Lambev www.medpharm-sofia.eu Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology Antidepressants

Post on 16-Dec-2015

218 views

Category:

Documents

1 download

Embed Size (px)

TRANSCRIPT

  • Slide 1
  • Slide 2
  • Assoc. Prof. Iv. Lambev www.medpharm-sofia.eu Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology Antidepressants Mood stabilizers Psychostimulants Nootropic drugs CNS stimulants (Abstract)
  • Slide 3
  • Depression is a heterogeneous disorder. A simplified classification based on presumed origin is as follows: (1) brief reactive or secondary depression (most common), occurring in response to real stimuli such as grief, illness, etc; (2) major depression (melancholic and recurrent depression) a genetically determined biochemical disorder manifested by an inability to experience ordinary pleasure or to cope with ordinary life events; (3) manic-depressive depression (depression associated with bipolar affective disorder ) Pharmacologic treatment of depressions is very important, although a continuing role for electroconvulsive therapy for severe forms of life-threatening depression is also noted.
  • Slide 4
  • manic
  • Slide 5
  • Depression is one of the most common psychiatric disorders. At any given moment, about 35% of the population is depressed, and an estimated 10% of people may become depressed during their lives. The symptoms of depression are often subtle and unrecognized both by patients and by physicians. Patients with vague complaints that resist explanation as manifestations of somatic disorders and those who might be simplistically described as neurotic should be suspected of being depressed. Soon after the introduction of reserpine (1948), it became apparent that the drug could induce depression by inhibiting the neuronal storage of amine neurotransmitters 5-HT and NE. Reserpine-induced depression and depleted stores of amine neuro- transmitters. It was reasoned, depression must be associated with decreased functional amine-dependent synaptic transmission.
  • Slide 6
  • Slide 7
  • NA (noradrenaline) = NE (norepinephrine)
  • Slide 8
  • Rauwolfia serpentina (a small indian shrub) Reserpine Ajmaline
  • Slide 9
  • Pathogenesis of depression The idea that depression must be associated with decreased functional amine-dependent synaptic transmission provided the basis for amine hypothesis of depression. By extension, drugs that increased amine function in appropriate synaptic areas would relieve depression. The amine hypothesis has provided the major experimental models for the discovery of new antidepressants. All currently available antidepressants, except bupropion, are classified as having their primary actions on the metabolism, reuptake, or selective receptor antagonism of 5-HT, NA, or both.
  • Slide 10
  • The effects of DA, 5-HT and NE on the brain functions (NE) (DA) (5-HT)
  • Slide 11
  • Raised neurotransmitter concentrations produce immediate alterations in postsynaptic receptor activation, leading to changes in second messenger (intracellular) systems and to gradual modifications in cellular protein expression. Antidepressants increase a cyclic AMP response-element binding ( CREB ) protein which in turn is involved in regulating the transcription of genes that influence survival of other proteins including brain derived neurotrophic factor ( BDNF ) which exerts effects on neuronal growth. The role of BDNF in depression is supported by the observation that stress both reduces its expression and impairs neurogenesis.
  • Slide 12
  • Slide 13
  • The monoamine hypothesis of depression is an oversimplification (only deficieny of NA, 5-HT, and DA) of a complicated picture. Other systems that are implicated in the etiology of depression (and which provide potential targets for drug therapy) include the hypothalamo-pituitarythyroid axis and the hypothalamo-pituitary-adrenal axis (HPA). The finding that 50% of depressed patients have elevated plasma cortisol concentrations constitutes evidence that depression is associated with increased HPA drive.
  • Slide 14
  • Slide 15
  • Structural relationships between various tricyclic antidepressants (TCAs). Their structures are similar to phenothiazines.
  • Slide 16
  • Selective serotonin reuptake inhibitors (SSRIs).
  • Slide 17
  • Pharmacokinetics The antidepressants are generally well absorbed after oral administration. Steady-state plasma concentrations of TCAs show great individual variation but correlate with therapeutic effect. Antidepressants in general are inactivated princi- pally by metabolism by hepatic cytochrome P450 enzymes (2D6 and 3A4). Other cytochrome enzymes are CYP 1A2 inhibited by the SSRI fluvoxamine, and induced by cigarette smoking, caffeine and the atypical antipsychotics (clozapine and olanzapine).
  • Slide 18
  • Several of these drugs produce active metabolites which prolong their action (e.g. fluoxetine is metabolized to norfluoxetine, t 1/2 200 h). The meta- bolic products of certain TCAs are antidepressants too, e.g. nortriptyline (from amitriptyline), desipramine (from imipramine). Half-lives of TCAs and SSRIs are long (> 15 h). Around 7% of the Caucasian population have very limited CYP 2D6 enzyme activity. Such poor metabolizers may find standard doses of tricyclic antidepressants intolerable and it is often worth starting at a very low dose.
  • Slide 19
  • Clinical indications The major indication is to treat depression, but a number of other uses have been established by clinical experience. Antidepressants may benefit most forms of anxiety disorder (panic disorder, generalized anxiety disorder, post-traumatic stress, obsessive-compulsive disorder, and social phobia), migraine. SSRIs are effective in milder cases of the eating disorder bulimia nervosa, particularly fluoxetine (in higher doses than are required for depression). Antidepressants appear to be ineffective in anorexia nervosa.
  • Slide 20
  • SSRIs (selective serotonin reuptake inhibitors) are used in: panic disorders chronic anxiety depression bulimia neurosa (fluoxetine in higher doses)
  • Slide 21
  • Schematic representation of the time course of panic treatments Adapted from Bennett and Brown (2003)
  • Slide 22
  • Mode of use The action of TCAs in ameliorating mood is usually absent in the first 2 weeks of therapy and at least 4 weeks must elapse to constitute an adequate trial. Where a minimal response is noted in this period, it is reasonable to extend the trial to 6 weeks to see if further benefit is achieved. Dose titration is often necessary. By contrast, patients may experience unwanted drug effects immediately on starting treatment (and they should be warned), but such symptoms often diminish with time. TCAs are given either in divided doses or, for the more sedative compounds, as a single evening dose.
  • Slide 23
  • SSRIs have advantages over tricyclics in simplicity of introduction and use. Dose titration is often unnecessary since the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not required and administration is by a single morning or evening dose. Patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs. Venlafaxine is licensed for treatment-resistant depression by gradual dose titration. There is some need for dose titration when using MAOIs.
  • Slide 24
  • Side effects of TCAs Anticholinergic (atropine-like): dry mouth, blurred vision, accommodation disturbances, increased ocular pressure, con- stipation, urinary retention, sweating, adynamic ileus (very rare). CNS: dizziness, tiredness, confusion, tremor, insomnia, seizures, exacerbation of psychotic symptoms. CVS: postural hypotension, sinus tachycardia, arrhythmia. Blood: leucopenia, agranulocytosis, thrombocytopenia, Haemolytic anaemia. Other ADRs: impaired respiration, libido changes, tinnitus, GI complaints, liver function disturbances, increased body weight.
  • Slide 25
  • TCAs Interactions:Potential Results MAOIs hyperthermia, palpitations, excitation Adrenomimetics hypertension, hyperthermia, tachycardia Alcohol effect of alcohol may be increased Clonidine, Methyldopa decreased hypotensive effects T3, T4 enhanced potential for CV toxicity Physostigmine antagonism Anticholinergics additional anticholinergic activity Neuroleptics inhibition of metabolism of antidepressants Levodopa overreaction of levodopa Lithium the therapeutic response is increased in some cases and suppressed in others
  • Slide 26
  • Precautions: close supervision, especially in early phase of treatment ( suicide risk of TCAs ). The possibility of unmasking a latent psychosis should be considered. A switch into a manic or hypomanic condition may occur ( switch process ). Caution should be exercised in CVD, history of urinary retention, narrow-angle glaucoma, and thyroid disease. Side-effects of SSRIs (mainly during the 1 st and 2 nd weeks of treatment): CNS: head- ache, restleness; CVS: bradycaria; GIT: nausea, diarrhoea The serotonin syndrome is a rare but dangerous complication with features restlessness, tremor, hperthermia, convulsions, coma and death. Risk is increased by co-administration with MAOIs, the antimigraine drug sumatriptan, and St. Johns Wort.
  • Slide 27
  • Slide 28
  • Side-effects of MAOIs (Moclobemide) CNS: insomnia, restlessness, confusion, dizziness. CVS: arrhythmia, tachycardia, palp

Recommended

View more >