Faculty of dentistry Second year CND Course CNS Drugs Dr. Ali Awadallah

Transcription

1 Faculty of dentistry Second year CND Course CNS Drugs Dr. Ali Awadallah

2 Drugs that act upon the central nervous system (CNS) influence the lives of everyone, everyday. Drugs that affect the CNS can selectively relieve pain, reduce fever, suppress disordered movement, induce sleep or arousal, and reduce the desire to eat, or allay the tendency to vomit.

3 Selectively acting drugs can be used to treat anxiety, mania, depression, or schizophrenia and do so without altering consciousness. In addition to their use in therapy, drugs acting on the CNS are used without prescription to increase one s sense of well-being.

4 Caffeine, alcohol, and nicotine are socially accepted drugs in many countries, and their consumption is practiced worldwide. Because some of the drugs in this group are addictive and cause severe personal, social, and economic dysfunction, societies have found it necessary to control their use and availability.

5 It is generally accepted that transmission at most, if not all, synapses in the mammalian CNS is mediated by chemical agents called neurochemical (neurohumoral) transmitters. Neurotransmitters are released by presynaptic terminals and produce rapid excitatory or inhibitory responses in postsynaptic neurons.

6 Central neurotransmitters (1) Amino acids: A- Neutral amino acids: glycine & Gamma - Amino Butyric Acid (GABA): The neutral amino acids are inhibitory and increase membrane permeability to chloride ions, thus mimicking the IPSP (inhibitory postsynaptic potential).

7 B- Acidic Amino Acids: (Glutamate) Glutamate and aspartate are found in very high concentrations in brain, and both aminoacids have extremely powerful excitatory effects on neurons in virtually every region of the CNS.

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9 (2) Acetylcholine: Certain neurodegenerative diseases, especially dementia and Parkinsonism are associated with abnormalities in chollinergic pathways. Acetylcholine has mainly excitatory effects "mediated by either nicotinic (ligand gated channels) or muscarinic (G-protein-coupled) receptors. Some muscarinic receptors are inhibitory.

10 (3) Monoamines: Monoamines include the catecholamines (dopamine and norepinephrine) and 5- hydroxytryptamine. a) Noradrenaline: The catecholamine hypothesis of affective disorders suggested that depression results from a functional deficiency of noradrenaline in certain parts of the brain, while mania results from an excess.

11 b) Dopamine: Parkinson's disease is a disorder of motor control, associated with a deficiency of dopamine in the nigrostriatal pathway. Many antipsychotic drugs are D2 - receptor antagonists, whose major side-effect is to cause movement disorders, probably associated with block of D2 - receptors in the nigrostriatal pathway.

12 There is some evidence that schizophrenia in human is associated with dopaminergic hyperactivity. Dopamine has an inhibitory effect on prolactin release. Dopamine acts on the chemoreceptor trigger zone to cause nausea and vomiting.

13 C) 5-hydroxytryptamine (serotonin): There is evidence that 5-HT, as well as noradrenaline, may be involved in the control of mood. 5-HT exerts an inhibitory effect on transmission in the pain pathway, both in the spinal cord and in the brain, and there is a synergistic effect between 5-HT and analgesics such as morphine. Other functions of 5-HT include the control of food intake, regulation of body temperature, blood pressure and sexual function.

14 (4) Histamine: H1, H2 and H3- receptors "all of which are typical G-protein coupled receptors" are widespread in the brain "histamine produces either excitatory or inhibitory effects". The role of histamine in the CNS is poorly understood. Blocking H1-receptors causes sedation (the main side-effect of histamine antagonists used to treat allergies), and also has an anti-emetic effect.

15 Neurotransmitters in CNS: 1. Inhibitory neurotransmitters: GABA, Glycine and Dopamine. 2. Excitatory neurotransmitters: Glutamate and Aspartate. 3. Neurotransmitters Mediate both inhibitory as well as excitatory effects: Acetylcholine, Noradrenaline and Serotonin (5-HT)

16 Inhibitory postsynaptic potential (IPSP) When an inhibitory transmitter binds and interacts with specifi c receptors on postjunctional membrane, the membrane permeability to K+ or Cl increases. Excitatory postsynaptic potential (EPSP) When an excitatory neurotransmitter binds and interacts with the specific receptors on the postjunctional membrane, the membrane permeability to cations (Na, K) increases.

17 Manifestations of CNS depression and stimulation CNS depression CNS stimulation Drowsiness Excitement Sedation Euphoria Hypnosis Insomnia Disorientation Tremors Confusion Twitching Unconsciousness Convulsions Coma Coma Death Death

18 Sedative-Hypnotic Drugs Anxiety is the most commonly observed symptom in mental illness but also occurs in normal individuals. Normal anxiety is of short duration, usually event related, not under conscious control, and is characterized by dis-satisfaction, somatic complaints, or apprehension, some research indicates that anxiety is a conditioned fear response.

19 Severe stress often induces increased muscle tension, autonomic nervous system dysfunction, irritability and fatigue. When these symptoms persist and impair normal activities, they are considered pathological and require treatment. Patients suffering significant anxiety over extended periods may have an inherited predisposition.

20 A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state. Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with most sedative drugs simply by increasing the dose.

21 Sedative is a drug that reduces excitement and calms the person. Hypnotic is a drug that produces sleep resembling normal sleep.

22 Classification of anxiolytic and hypnotic drugs: 1- Benzodiazepines: This is the most important group used as anxiolytic and hypnotic agents. E.g. Diazepam. 2-5-HT1A-receptor agonists (e.g. buspirone): These agents, recently introduced, are anxiolytic but not appreciably sedative.

23 3- Barbiturates: Long acting: Phenobarbitone, mephobarbitone. Short acting: Pentobarbitone, secobarbitone. Ultra-short acting: Thiopentone,methohexitone. These are now largely obsolete, superseded by benzodiazepines. Their use is now confined to anaesthesia and the treatment of epilepsy.

24 4- Beta-adrenoceptor antagonists (e.g. Propranolol): These are used to treat some forms of anxiety, particularly where physical symptoms, such as sweating, tremor and tachycardia, are trouble some. Their effectiveness depends on block of peripheral sympathetic responses rather than on any central effects. They are sometimes used by actors and musicians to reduce the symptoms of stage fright.

25 5- Miscellaneous: Other drugs (e.g. chloral hydrate, meprobamate and paraldehyde); They are no longer recommended. Sedative antihistamines such as diphenhydramine, are sometimes used as sleeping pills, particularly for wakeful children.

26 Benzodiazepines: Mechanism of action Benzodiazepines facilitate action of gamma-aminobutyric acid (GABA) they potentiate inhibitory effects of GABA.

27 Pharmacological actions and therapeutic uses 1. Sedation and hypnosis: Benzodiazepines decrease time required to fall asleep (sleep latency). 2. Anticonvulsant: Diazepam, lorazepam, clonazepam, clobazam, etc. have selective anticonvulsant effect. 3. Diagnostic (endoscopies) and minor operative procedures: Intravenous BZDs are used because of their sedative amnesic analgesic and muscle-relaxant properties.

28 4. Preanaesthetic medication: These drugs are used as preanaesthetic medication because of their sedative amnesic and anxiolytic effects. 5. Antianxiety (anxiolytic) effect: Some of the BZDs (diazepam, oxazepam, alprazolam, lorazepam) 6. Muscle relaxant (centrally acting): They reduce skeletal muscle tone by inhibiting polysynaptic reflexes in the spinal cord. 7. To treat alcohol-withdrawal symptoms. 8. Conscious sedation

29 Adverse effects Benzodiazepines have a wide margin of safety. They are generally well tolerated. The common side effects are drowsiness, confusion, blurred vision, amnesia, disorientation, tolerance and drug dependence. Withdrawal after chronic use causes symptoms like tremor, insomnia, restlessness, nervousness and loss of appetite.

30 Epilepsy: Antiepileptic drugs (Antiseizure drugs) Epilepsy is a very common disorder, affecting 0.5-1% of the population. Epileptic seizures often cause transient impairment of consciousness, leaving the individual at risk of bodily harm and often interfering with education and employment. Therapy is symptomatic in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available.

31 Antiseizure drugs (Antiepileptic drugs): Mechanism of action: Mechanisms appear to be important in the action of anticonvulsant drugs include: 1- Enhancement of GABA action "mediated inhibition": e.g. a- Direct action on the GABA receptor chloride channel e.g. "benzodiazepines, barbiturates". b- Drugs act on the reuptake or metabolism of GABA: e.g. "gabapentin, tiagabine, and vigabatrin".

32 2- Inhibition of sodium channel function: e.g. phenytoin, carbamazepine, and lamotrigine; it may also contribute to the effects of phenobarbital, valporate, and topiramate. 3-Inhibition of voltage-activatedca2+channel: e.g. ethosuximide, dimethadione "used for absence seizures". 4- Reduction of excitatory glutamatergic neuron transmission: e.g. AMPA receptor blockade probably contributes to the effect of phenobarbital and topiramate, and NMDA receptor blockade probably contributes to the effect of remacemide "an investigational drug".

33 Antipsychotic Drugs The term 'Psychosis' denotes a variety of mental disorders. Antipsychotic drugs are used mainly in the treatment of schizophrenia and other behavioural emergencies, acute mania but they are also used for other psychosis illnesses. Antipsychotic drugs are also known as neuroleptic drugs anti-schizophrenic drugs, or major tranquillisers.

34 Classification of Antipsychotic Drugs Main categories are: 1. Typical antipsychotics or classical or conventional: (e.g. chlorpromazine, haloperidol, fluphenazine, thioridazine, flupenthixol, clopenthixol). They mainly block dopamine (D2) receptors in the limbic system and mesocortical areas.

35 2. Atypical antipsychotics: (e.g. clozapine, risperidone, sulpiride, Olanzapine). Block 5-HT2A receptors in mesolimbic system.

36 Affective Disorders: Antidepressant Agents Affective disorders are characterized primarily by changes of mood (depression or mania) rather than by thought disturbances. Depression: Depression is the most common manifestation, and it may range from a very mild condition, bordering on normality, to severe depressionsome times called psychotic depression accompanied by hallucinations and delusions.

37 Antidepressant Drugs: Antidepressant drugs fall into the following categories: 1. Tricyclic antidepressants (TCA): e.g. imipramine, amitriptyline. These are nonselective (or in some cases noradrenalineselective) inhibitors of monoamine uptake. 2. Selective 5-HT uptake inhibitors (SSRIs): e.g. fluoxetine, fluvoxamine, paroxetine, sertraline.

38 3- Monoamine oxidase inhibitors (MAOI): e.g. phenelzine, tranylcypromine, which are non-selective with respect to the MAO-A and B subtypes, clorgyline, moclobemide, which are MAO-A selective. 4- Atypical antidepressant. *** Electro convulsive therapy (ECT) which is effective, and usually acts more rapidly than antidepressant drugs.

39 Clinical indications of antidepressant drugs: The major indication for these drugs is to treat depression, but a number of other uses have been established by clinical experience and controlled trials: 1- Depression. 2- Panic disorder imipramine, SSRIs. 3-Obssessive-compulsive disorders SSRIs: fluoxetine, clomipramine. 4- Enuresis TCA, imipramine. 5- Chronic pain TCA, phenothiazines are also sometimes used in combination.

40 6- Other indication: - Certain antidepressants have been shown to be effective for eating disorders, especially bulimia (fluoxetine). - Attention deficit disorder (imipramine, desipramine). - SSRIs show efficacy in social phobia, and combined serotonin and norepinephrine uptake inhibitors are effective in generalized anxiety disorder.

41 Pharmacologic management of parkinsonism Parkinson's disease (PD) is a progressive disorder of movement that occurs mainly in the elderly. The chief symptoms are: The normally high concentration of dopamine in the basal ganglia of the brain is reduced in Parkinsonism. The intrinsic cholinergic neurons of the corpus striatum are also involved in PD. Acetylcholine release from the striatum is strongly inhibited by dopamine, and it is suggested that hyperactivity of these cholinergic neurons (associated with the lack of dopamine) leads to the symptoms of PD.

42 Drug treatment of Parkinson's Disease include: 1-Drugs that replace dopamine (e.g. levodopa, usually used concomitantly with peripherally acting dopa decarboxy inhibitors, e.g. carbidopa, benserazide). 2-Drugs that mimic the action of dopamine (e.g. bromocriptine, pergolide, lisuride).

43 3- MAO-B inhibitors (e.g. selegiline). 4- Drugs that release dopamine (e.g. amantadine). 5- Acetylcholine antagonists (e.g. benztropine) "used to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia).