Benzodiazepines Benzodiazepines modify affective re- sponses to sensory perceptions; specifi- cally, they render a subject indifferent towards anxiogenic stimuli, i.e., anxio- lytic action. Furthermore, benzodiaze- pines exert sedating, anticonvulsant, and muscle-relaxant (myotonolytic, p. 182) effects. All these actions result from augmenting the activity of inhibi- tory neurons and are mediated by spe- cific benzodiazepine receptors that form an integral part of the GABA A re- ceptor-chloride channel complex. The inhibitory transmitter GABA acts to open the membrane chloride channels. Increased chloride conductance of the neuronal membrane effectively short- circuits responses to depolarizing in- puts. Benzodiazepine receptor agonists increase the affinity of GABA to its re- ceptor. At a given concentration of GABA, binding to the receptors will, therefore, be increased, resulting in an augmented response. Excitability of the neurons is diminished. Therapeutic indications for benzo- diazepines include anxiety states asso- ciated with neurotic, phobic, and de- pressive disorders, or myocardial in- farction (decrease in cardiac stimula- tion due to anxiety); insomnia; prean- esthetic (preoperative) medication; epileptic seizures; and hypertonia of skeletal musculature (spasticity, rigid- ity). Since GABA-ergic synapses are con- fined to neural tissues, specific inhibi- tion of central nervous functions can be achieved; for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose produc- ing respiratory depression, is greater than 100 and thus exceeds that of bar- biturates and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication can be treated with a spe- cific antidote (see below). Since benzodiazepines depress re- sponsivity to external stimuli, automo- tive driving skills and other tasks re- quiring precise sensorimotor coordina- tion will be impaired. Triazolam (t 1/2 of elimination ~1.5–5.5 h) is especially likely to impair memory (anterograde amnesia) and to cause rebound anxiety or insomnia and daytime confusion. The severity of these and other adverse reactions (e.g., rage, violent hostility, hallucinations), and their increased frequency in the elderly, has led to curtailed or suspended use of triazolam in some countries (UK). Although benzodiazepines are well tolerated, the possibility of personality changes (nonchalance, paradoxical ex- citement) and the risk of physical de- pendence with chronic use must not be overlooked. Conceivably, benzodiaze- pine dependence results from a kind of habituation, the functional counterparts of which become manifest during absti- nence as restlessness and anxiety; even seizures may occur. These symptoms reinforce chronic ingestion of benzo- diazepines. Benzodiazepine antagonists, such as flumazenil, possess affinity for ben- zodiazepine receptors, but they lack in- trinsic activity. Flumazenil is an effec- tive antidote in the treatment of ben- zodiazepine overdosage or can be used postoperatively to arouse patients se- dated with a benzodiazepine. Whereas benzodiazepines possess- ing agonist activity indirectly augment chloride permeability, inverse agonists exert an opposite action. These sub- stances give rise to pronounced rest- lessness, excitement, anxiety, and con- vulsive seizures. There is, as yet, no therapeutic indication for their use. 226 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 227 A. Action of benzodiazepines Anxiolysis plus anticonvulsant effect, sedation, muscle relaxation Diazepam R 1 = Cl R 2 = CH 3 R 3 = R 4 = H Benzo diaz epine R 4 N N R 1 R 3 O R 2 Inhibition of excitation Hyper- polari- zation GABA GABA-gated Cl - -channel Cl - Benzodiazepines Unopposed excitation Normal GABA-ergic inhibition Enhanced GABA-ergic inhibition GABA-ergic neuron Benzodiazepine receptor GABA-receptor Chloride ionophore GABA= !-amino- butryc acid Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Pharmacokinetics of Benzodiazepines All benzodiazepines exert their actions at specific receptors (p. 226). The choice between different agents is dictated by their speed, intensity, and duration of action. These, in turn, reflect physico- chemical and pharmacokinetic proper- ties. Individual benzodiazepines remain in the body for very different lengths of time and are chiefly eliminated through biotransformation. Inactivation may en- tail a single chemical reaction or several steps (e.g., diazepam) before an inactive metabolite suitable for renal elimina- tion is formed. Since the intermediary products may, in part, be pharmacologi- cally active and, in part, be excreted more slowly than the parent substance, metabolites will accumulate with con- tinued regular dosing and contribute significantly to the final effect. Biotransformation begins either at substituents on the diazepine ring (diaz- epam: N-dealkylation at position 1; midazolam: hydroxylation of the methyl group on the imidazole ring) or at the diazepine ring itself. Hydroxylated mid- azolam is quickly eliminated following glucuronidation (t 1/2 ~ 2 h). N-de- methyldiazepam (nordazepam) is bio- logically active and undergoes hydroxy- lation at position 3 on the diazepine ring. The hydroxylated product (oxaze- pam) again is pharmacologically active. By virtue of their long half-lives, diaze- pam (t 1/2 ~ 32 h) and, still more so, its metabolite, nordazepam (t 1/2 50–90 h), are eliminated slowly and accumulate during repeated intake. Oxazepam undergoes conjugation to glucuronic ac- id via its hydroxyl group (t 1/2 = 8 h) and renal excretion (A). The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for in- duction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area) because they permit maintenance of steady plasma levels with single daily dosing. Midazolam enjoys use by the i.v. route in preanesthetic medication and anesthetic combination regimens. Benzodiazepine Dependence Prolonged regular use of benzodiaze- pines can lead to physical dependence. With the long-acting substances mar- keted initially, this problem was less ob- vious in comparison with other depen- dence-producing drugs because of the delayed appearance of withdrawal symptoms. The severity of the absti- nence syndrome is inversely related to the elimination t 1/2 , ranging from mild to moderate (restlessness, irritability, sensitivity to sound and light, insomnia, and tremulousness) to dramatic (de- pression, panic, delirium, grand mal sei- zures). Some of these symptoms pose diagnostic difficulties, being indistin- guishable from the ones originally treat- ed. Administration of a benzodiazepine antagonist would abruptly provoke ab- stinence signs. There are indications that substances with intermediate elim- ination half-lives are most frequently abused (violet area in B). 228 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 229 B. Rate of elimination of benzodiazepines A. Biotransformation of benzodiazepines Midazolam Diazepam as glucuronide Active metabolites Inactive Oxazepam Nordazepam Triazolam Brotizolam Oxazepam Lormetazepam Bromazepam Flunitrazepam Lorazepam Camazepam Nitrazepam Clonazepam Diazepam Temazepam Prazepam Applied drug Active metabolite Plasma elimination half-life Hypnagogic effect Abuse liability Anxiolytic effect 0 20 30 40 50 6010 >60 h Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Therapy of Manic-Depressive Illness Manic-depressive illness connotes a psychotic disorder of affect that occurs episodically without external cause. In endogenous depression (melancholia), mood is persistently low. Mania refers to the opposite condition (p. 234). Pa- tients may oscillate between these two extremes with interludes of normal mood. Depending on the type of disor- der, mood swings may alternate between the two directions (bipolar de- pression, cyclothymia) or occur in only one direction (unipolar depression). I. Endogenous Depression In this condition, the patient experienc- es profound misery (beyond the observer’s empathy) and feelings of se- vere guilt because of imaginary miscon- duct. The drive to act or move is inhibit- ed. In addition, there are disturbances mostly of a somatic nature (insomnia, loss of appetite, constipation, palpita- tions, loss of libido, impotence, etc.). Al- though the patient may have suicidal thoughts, psychomotor retardation pre- vents suicidal impulses from being car- ried out. In A, endogenous depression is illustrated by the layers of somber col- ors; psychomotor drive, symbolized by a sine oscillation, is strongly reduced. Therapeutic agents fall into two groups: ¼ Thymoleptics, possessing a pro- nounced ability to re-elevate de- pressed mood e.g., the tricyclic anti- depressants; ¼ Thymeretics, having a predominant activating effect on psychomotor drive, e g., monoamine oxidase inhib- itors. It would be wrong to administer drive-enhancing drugs, such as amphet- amines, to a patient with endogenous depression. Because this therapy fails to elevate mood but removes psychomo- tor inhibition (A), the danger of suicide increases. Tricyclic antidepressants (TCA; prototype: imipramine) have had the longest and most extensive therapeutic use; however, in the past decade, they have been increasingly superseded by the serotonin-selective reuptake inhibi- tors (SSRI; prototype: fluoxetine). The central seven-membered ring of the TCAs imposes a 120° angle between the two flanking aromatic rings, in contradistinction to the flat ring system present in phenothiazine type neuroleptics (p. 237). The side chain nitrogen is predominantly proto- nated at physiological pH. The TCAs have affinity for both re- ceptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal re- uptake of norepinephrine (p. 82) and se- rotonin (p. 116) is inhibited, with a re- sultant increase in activity. Muscarinic acetylcholine receptors, !-adrenocep- tors, and certain 5-HT and hista- mine(H 1 ) receptors are blocked. Inter- ference with the dopamine system is relatively minor. How interference with these trans- mitter/modulator substances translates into an antidepressant effect is still hy- pothetical. The clinical effect emerges only after prolonged intake, i.e., 2–3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adap- tive processes (such as downregulation of cortical serotonin and "-adrenocep- tors) are ultimately responsible. In healthy subjects, the TCAs do not im- prove mood (no euphoria). Apart from the antidepressant ef- fect, acute effects occur that are evident also in healthy individuals. These vary in degree among individual substances and thus provide a rationale for differ- entiated clinical use (p. 233), based upon the divergent patterns of interfer- ence with amine transmitters/modula- tors. Amitriptyline exerts anxiolytic, sedative and psychomotor dampening effects. These are useful in depressive patients who are anxious and agitated. In contrast, desipramine produces psychomotor activation. Imipramine 230 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 231 A. Effect of antidepressants Amphetamine Immediate Week 9 Week 7 Week 5 Week 3 Endogenous depression Imipramine 5HT or NA Inhibition of re-uptake Deficient drive Normal mood Normal drive M, H 1 , ! 1 Blockade of receptors Ach NA Effects on synaptic transmission by inhibition of amine re-uptake and by receptor antagonism Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. occupies an intermediate position. It should be noted that, in the organism, biotransformation of imipramine leads to desipramine (N-desmethylimipra- mine). Likewise, the desmethyl deriva- tive of amitriptyline (nortriptyline) is less dampening. In nondepressive patients whose complaints are of predominantly psy- chogenic origin, the anxiolytic-sedative effect may be useful in efforts to bring about a temporary “psychosomatic un- coupling.” In this connection, clinical use as “co-analgesics” (p. 194) may be noted. The side effects of tricyclic antide- pressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances. These effects develop acutely. Antagonism at musca- rinic cholinoceptors leads to atropine- like effects such as tachycardia, inhibi- tion of exocrine glands, constipation, impaired micturition, and blurred vi- sion. Changes in adrenergic function are complex. Inhibition of neuronal cate- cholamine reuptake gives rise to super- imposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of ! 1 -receptors may lead to orthostatic hypotension. Due to their cationic amphiphilic nature, the TCA exert membrane-stabi- lizing effects that can lead to distur- bances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appe- tite. Maprotiline, a tetracyclic com- pound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasyn- aptic concentrations of norepinephrine by blocking presynaptic ! 2 -receptors, rather than reuptake. Moreover, it has less pronounced atropine-like activity. Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is con- sidered comparable to that of estab- lished antidepressants. Added advan- tages include: absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse ef- fects include: overarousal, insomnia, tremor, akathisia, anxiety, and distur- bances of sexual function. Moclobemide is a new representa- tive of the group of MAO inhibitors. In- hibition of intraneuronal degradation of serotonin and norepinephrine causes an increase in extracellular amine levels. A psychomotor stimulant thymeretic ac- tion is the predominant feature of MAO inhibitors. An older member of this group, tranylcypromine, causes irre- versible inhibition of the two isozymes MAO A and MAO B . Therefore, presystem- ic elimination in the liver of biogenic amines, such as tyramine, which are in- gested in food (e.g., aged cheese and Chianti), will be impaired. To avoid the danger of a hypertensive crisis, therapy with tranylcypromine or other nonse- lective MAO inhibitors calls for strin- gent dietary rules. With moclobemide, this hazard is much reduced because it inactivates only MAO A and does so in a reversible manner. 232 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 233 Serotonin Dopamine Anxiolysis ! 1 -Blockade Parasympatho- lytic activity Indication Amitriptyline Patient: Depressive, anxious, agitated 50-200 mg/d t 1/2 = 9-20h Imipramine Depressive, normal drive 75-200 mg/d t 1/2 = 15-60h Desipramine Depressive, lack of drive and energy 20-40 mg/d t 1/2 = 48-96h Fluoxetine 300 mg/d t 1/2 = 1-2h Moclobemide A. Antidepressants: activity profiles 5-HT-Receptor M-Cholinoceptor !-Adrenoceptor D-Receptor Norepinephrine Acetylcholine 50-150 mg/d t 1/2 = 30-40h Patient: Patient: Patient: Patient: Drive, energy Depressive, lack of drive and energy Depressive, lack of drive and energy Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. II. Mania The manic phase is characterized by ex- aggerated elation, flight of ideas, and a pathologically increased psychomotor drive. This is symbolically illustrated in A by a disjointed structure and aggres- sive color tones. The patients are over- confident, continuously active, show progressive incoherence of thought and loosening of associations, and act irre- sponsibly (financially, sexually etc.). Lithium ions. Lithium salts (e.g., acetate, carbonate) are effective in con- trolling the manic phase. The effect be- comes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li + serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At high- er values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin (p. 164) leads to polyuria and thirst. Thyroid function is impaired (p. 244), with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemi- cally, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and po- tassium. Apart from interference with transmembrane cation fluxes (via ion channels and pumps), a lithium effect of major significance appears to be mem- brane depletion of phosphatidylinositol bisphosphates, the principal lipid sub- strate used by various receptors in transmembrane signalling (p. 66). Blockade of this important signal trans- duction pathway leads to impaired abil- ity of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal trans- duction initiated by formation of the ag- onist-receptor complex. Rapid control of an acute attack of mania may require the use of a neuro- leptic (see below). Alternate treatments. Mood-sta- bilization and control of manic or hy- pomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifed- ipine, nimodipine). Effects are delayed and apparently unrelated to the mecha- nisms responsible for anticonvulsant and cardiovascular actions, respective- ly. III. Prophylaxis With continued treatment for 6 to 12 months, lithium salts prevent the re- currence of either manic or depressive states, effectively stabilizing mood at a normal level. 234 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals 235 A. Effect of lithium salts in mania Day 8 Day 6 Day 4 Day 2 Normal state Depression Mania H Na K Rb Cs Be Mg Ca Sr Ba Li + Normal state Mania Lithium Day 10 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. [...]... effects Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 240 Psychopharmacologicals Psychotomimetics (Psychedelics, Hallucinogens) Psychotomimetics are able to elicit psychic changes like those manifested in the course of a psychosis, such as illusionary distortion of perception and hallucinations This experience may be of dreamlike... causes a delayed and selective degeneration of forebrain 5-HT nerve terminals Although development of psychological dependence and permanent psychic damage cannot be considered established sequelae of chronic use of psychotomimetics, the manufacture and commercial distribution of these drugs are prohibited (Schedule I, Controlled Drugs) Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved... neuroleptanalgesia (p 216) by means of the butyrophenone droperidol in combination with an opioid; tranquilization of overexcited, agitated patients; treatment of delirium tremens with haloperidol; as well as the control of mania (see p 234) It should be pointed out that neuroleptics do not exert an anticonvulsant action, on the contrary, they may lower seizure thershold Lüllmann, Color Atlas of Pharmacology © 2000... to terms and conditions of license Psychopharmacologicals Week 3 after start of therapy Neuroleptics Phenothiazine type: Chlorpromazine Butyrophenone type: Week 5 Haloperidol Week 7 Sedation Week 9 Autonomic disturbance due to atropine-like action Movement disorders due to dopamine antagonism Antiemetic effect A Effects of neuroleptics in schizophrenia Lüllmann, Color Atlas of Pharmacology © 2000 Thieme... 2000 Thieme All rights reserved Usage subject to terms and conditions of license Psychopharmacologicals C2H5 O C N C2H5 N Lysergic acid diethylamide 0.0001 g/70 kg CH3 HN A Psychotomimetic effect of LSD in a portrait artist Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 241 ...236 Psychopharmacologicals Therapy of Schizophrenia Schizophrenia is an endogenous psychosis of episodic character Its chief symptoms reflect a thought disorder (i.e., distracted, incoherent, illogical thinking; impoverished intellectual content; blockage of ideation; abrupt breaking of a train of thought: claims of being subject to outside agencies that control... strongly sedating When esterified with a fatty acid, both fluphenazine and haloperidol can be applied intramuscularly as depot preparations Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license Psychopharmacologicals 239 1 Triflupromazine Clozapine Trifluoperazine Flupentixol 15 – 20 mg/d 2 – 10 mg/d 30 – 150 mg/d 25 – 200 mg/d 10 50 40%... complete normalization often cannot be achieved because of the persistence of negative symptoms Nonetheless, these changes are significant because the patient experiences relief from the torment of psychotic personality changes; care of the patient is made easier and return to a familiar community environment is accelerated The conventional (or classical) neuroleptics comprise two classes of compounds with... delosis = revelation) implying expansion of consciousness The contents of such illusions and hallucinations can occasionally become extremely threatening (“bad” or “bum trip”); the individual may feel provoked to turn violent or to commit suicide Intoxication is followed by a phase of intense fatigue, feelings of shame, and humiliating emptiness The mechanism of the psychotogenic effect remains unclear... incoherence of ideation is symbolically represented at the top left (A) and the normal psychic state is illustrated as on p 237 (bottom left) Neuroleptics After administration of a neuroleptic, there is at first only psychomotor dampening Tormenting paranoid ideas and hallucinations lose their subjective importance (A, dimming of flashy colors); however, the psychotic processes still persist In the course of . 226 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals. 228 Psychopharmacologicals Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Psychopharmacologicals