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CNS part 1

  1. Sedative, hypnotics & anxiolytic drugs Dr. Karun Kumar Senior Lecturer Dept. of Pharmacology
  2. Sedative • A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced • Sedation refers to decreased responsiveness to any level of stimulation; is associated with some decrease in motor activity and ideation • Slowly acting drugs with flatter dose-response curves
  3. Hypnotic • A drug that induces and/or maintains sleep, similar to normal arousable sleep • This is not to be confused with ‘hypnosis’ meaning a trans-like state in which the subject becomes passive and highly suggestible • Quicker onset, shorter duration and steeper dose- response curves • A hypnotic at lower dose may act as sedative • Most important use  Insomnia
  4. Classification
  5. Uses of barbiturates 1. Phenobarbitone in epilepsy 2. Thiopentone in anaesthesia
  6. Adverse effects 1. Side effects  Hangover, mental confusion, impaired performance and traffic accidents 2. Idiosyncrasy  In an occasional patient barbiturates produce excitement 3. Hypersensitivity  Rashes, swelling of eyelids, lips, etc. 4. Tolerance and dependence  Tolerance develops on repeated use. Barbiturates have considerable abuse liability
  7. Interactions 1. Barbiturates induce the metabolism of Warfarin, steroids (including contraceptives), Tolbutamide, Griseofulvin, Chloramphenicol, Theophylline. 2. Additive action with other CNS depressants (Alcohol, antihistamines, opioids, etc.) 3. Sodium valproate increases plasma concentration of Phenobarbitone 4. Phenobarbitone competitively inhibits as well as induces Phenytoin and Imipramine metabolism: complex interaction 5. Phenobarbitone decreases absorption of Griseofulvin from the g.i.t.
  8. Why Benzodiazepines ? 1. They have a high therapeutic index 2. Hypnotic doses do not affect respiration or cardiovascular functions 3. BZDs have practically no action on other body systems. Only on i.v. injection the BP falls and cardiac contractility decreases 4. BZDs cause less distortion of sleep architecture 5. BZDs do not alter disposition of other drugs by microsomal enzyme induction
  9. 6. They have lower abuse liability: tolerance is mild, psychological and physical dependence, drug seeking and withdrawal syndrome are less marked 7. A specific BZD antagonist flumazenil is available which can be used in case of poisoning
  10. Site of action • Benzodiazepines act preferentially on midbrain ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental functions) • Muscle relaxation is produced by a primary medullary site of action • Ataxia is due to action on cerebellum
  11. Mechanism of action • BZDs act by enhancing presynaptic/postsynaptic inhibition through a specific BZD receptor which is an integral part of the GABAA receptor–Cl¯ channel complex • The binding site for GABA is located on the β subunit, while the α/γ subunit interface carries the BZD binding site • The modulatory BZD receptor increases the frequency of Cl¯ channel opening induced by submaximal concentrations of GABA
  12. • BZDs also enhance GABA binding to GABAA receptor • The GABAA antagonist Bicuculline antagonizes BZD action in a noncompetitive manner • BZDs do not themselves increase Cl¯ conductance; have only GABA facilitatory but no GABA mimetic action
  13. Adverse effects • Side effects of hypnotic doses  Dizziness, vertigo, ataxia, disorientation, amnesia, prolongation of reaction time—impairment of psychomotor skills (should not drive) • Hangover is less common • Weakness, blurring of vision, dry mouth and urinary incontinence are sometimes complained • Tolerance to the sedative effects develops gradually, but there is little tendency to increase the dose
  14. • Cross tolerance to alcohol and other CNS depressants occurs • The dependence producing liability of BZDs is low • They are weak reinforcers (less pleasurable) and seldom abused alone • Withdrawal syndrome is generally mild • Drug seeking behavior is not prominent
  15. Interactions 1. BZDs synergise with alcohol and other CNS depressants leading to excessive impairment 2. Concurrent use with sod. valproate has provoked psychotic symptoms 3. Drug interactions due to microsomal enzyme induction are not significant 4. Their action can be prolonged by CYP3A4 inhibitors like Ketoconazole, Erythromycin and others 5. Cimetidine, Isoniazid and Oral contraceptives also retard BZD metabolism
  16. Non-benzodiazepine hypnotics • Produce hypnotic amnesic action with only weak antianxiety, muscle relaxant and anticonvulsant effects • They have lower abuse potential than hypnotic BZDs • Given their shorter duration of action, they are being preferred over BZDs for the treatment of insomnia
  17. Uses 1. As hypnotic  When indicated, BZDs or the newer non-BZDs like Zolpidem, Zaleplon are the hypnotic of choice • Dentists are likely to need to prescribe a hypnotic either to ensure sleep night before the dental procedure in an apprehensive patient, or to supplement analgesics before and after dental surgery • A longer acting BZD, like Diazepam, is mostly preferred
  18. Other uses 1. As anxiolytic and for day-time sedation 2. As anticonvulsant, especially emergency control of status epilepticus, febrile convulsions, tetanus, etc. 3. As centrally acting muscle relaxant for muscular spasms
  19. 4. For preanaesthetic medication, i.v. anaesthesia and conscious sedation 5. Alcohol withdrawal in dependent subjects 6. Along with analgesics, NSAIDs, spasmolytics, antiulcer and as adjuvants to treat ‘gas’ or nonspecific dyspeptic symptoms
  20. Ethyl Alcohol (Pharmacological actions) 1. Local actions  Mild rubefacient and counterirritant when rubbed on the skin. By evaporation it produces cooling. Alcohol is an astringent—precipitates surface proteins and hardens the skin. By precipitating bacterial proteins it acts as an antiseptic 2. CNS  Alcohol is a neuronal depressant. Hesitation, caution, self-criticism and restraint are lost first. Mood and feelings are altered; anxiety may be allayed
  21. • ‘Hangover’ (headache, dry mouth, laziness, disturbed mood, impaired performance) may occur the next morning • Chronic alcohol abuse damages brain neurones, causes shrinkage of brain • Any measurable concentration of alcohol produces a measurable slowing of reflexes: driving is dangerous
  22. Other actions 1. Vasodilatation, flushing, tachycardia 2. Resp. centre depressed (at high conc.) 3. Heat loss is greater in cold 4. GERD is worsened 5. Cirrhosis of liver (chronic alcoholism) 6. Small to moderate alcohol ↓ CAD risk 7. Urine flow may ↑ (ADH inhibition) 8. Impairment of sexual performance 9. Hyperglycaemia followed by hypoglycaemia
  23. Contraindications 1. Peptic ulcer, hyperacidity and gastroesophageal reflux patients (alcohol increases gastric secretion and relaxes LES) 2. Epileptics: seizures may be precipitated 3. Severe liver disease patients 4. Unstable personalities: they are likely to abuse it and become excessive drinkers 5. Pregnant women  “Foetal alcohol syndrome” (Intrauterine and postnatal growth retardation, ↓ IQ, microcephaly, cranio-facial and other abnormalities, and immunological impairment→ ↑ susceptibility to infections)
  24. Effects of alcohol
  25. Toxicity 1. Moderate drinking  Nausea, vomiting, flushing, hangover, traffic accidents 2. Acute alcoholic intoxication  Hypotension, gastritis, hypoglycemia, respiratory depression, collapse, coma and death 3. Chronic alcoholism  Physical dependence occurs only on heavy and round-the-clock drinking (if alcohol is present in the body continuously). Psychic dependence often occurs even with moderate drinking
  26. Dental implications 1. Alcoholics have higher incidence of heavy dental plaque, calculus deposits, chronic periodontitis, and tooth loss due to poor oral hygiene 2. Dentists while prescribing Metronidazole or certain Cephalosporins for periodontal infections should warn patients not to drink 3. Concurrent use of NSAIDs and alcohol should be prohibited
  27. Disulfiram aversion therapy
  28. Clinical uses 1. As antiseptic and disinfectant 2. Rubefacient & counterirritant for sprains, joint pains, etc. 3. Rubbed into the skin to prevent bedsores 4. Astringent action of alcohol is utilized in antiperspirant and aftershave lotions 5. Low concentrations as appetite stimulant & carminative 6. To treat methanol poisoning
  29. Interactions 1. Alcohol synergises with anxiolytics, antidepressants, antihistaminics, hypnotics, opioids → marked CNS depression with motor impairment can occur: Chances of accidents increase 2. Individuals taking a sulfonylurea, cefoperazone, or metronidazole have experienced bizarre, somewhat disulfiram-like reactions when they consume alcohol
  30. 3. Acute alcohol ingestion inhibits, while chronic intake induces metabolism of Tolbutamide, Phenytoin and some other drugs 4. Hypoglycaemic action of insulin and sulfonylureas is enhanced by alcohol ingestion 5. Aspirin and other NSAIDs cause more gastric bleeding when taken with alcohol 6. Formation of toxic metabolite of Paracetamol (NAPQI) is increased in chronic alcoholics
  31. Antiepileptic drugs • Seizure  Paroxysmal abnormal discharge at high frequency, from an aggregate of neurons in cerebral cortex • Epilepsy  Condition characterized by recurrent episodes of such seizures • Convulsions  Involuntary, violent and spasmodic or prolonged contractions of skeletal muscle
  32. Classification of seizures 1. Generalized (Both cerebral hemispheres involved) 1. Generalised tonic-clonic seizures 2. Absence seizures 3. Atonic seizures 4. Myoclonic seizures 5. Infantile spasms (Hypsarrhythmia) 2. Partial (Restricted to a discrete area belonging to 1 cerebral hemisphere only) 1. Simple partial seizures 2. Complex partial seizures 3. Simple partial or complex partial seizures secondarily generalized
  33. Generalized seizures 1. Generalised tonic-clonic seizures (GTCS, major epilepsy, grand mal)  Commonest, lasts 1–2 mins. usual sequence is aura—cry— unconsciousness—tonic spasm of all body muscles—clonic jerking followed by prolonged sleep and depression of all CNS functions 2. Absence seizures (minor epilepsy, petit mal)  Prevalent in children, lasts about 1/2 min. Momentary loss of consciousness, patient apparently freezes and stares in one direction, no muscular component or little bilateral jerking
  34. 3. Atonic seizures (Akinetic epilepsy)  Unconsciousness with relaxation of all muscles due to excessive inhibitory discharges. Patient may fall 4. Myoclonic seizures  Shock-like momentary contraction of muscles of a limb or the whole body 5.Infantile spasms (Hypsarrhythmia)  Seen in infants. Intermittent muscle spasm and progressive mental deterioration
  35. Partial seizures 1. Simple partial seizures (SPS, cortical focal epilepsy)  lasts 1/2–1 min; Convulsions are confined to a group of muscles or localized sensory disturbance depending on the area of cortex involved in the seizure, without loss of consciousness 2. Complex partial seizures (CPS, temporal lobe epilepsy, psychomotor)  Attacks of bizarre and confused behaviour and purposeless movements, emotional changes lasting 1–2 min along with impairment of consciousness
  36. 3. Simple partial or complex partial seizures secondarily generalized  The partial seizure occurs first and evolves into generalized tonic-clonic seizures with loss of consciousness
  37. Classification
  38. Phenobarbitone • Enhancement of GABAA receptor mediated synaptic inhibition appears to be most important mechanism • Phenobarbitone has specific anticonvulsant activity • The higher anticonvulsant: hypnotic ratio of phenobarbitone may be due to its minimal effect on Ca2+ channels and glutamate release compared to hypnotic barbiturates
  39. • With continued use of Phenobarbitone sedation wanes off but not anticonvulsant action • The major drawback of Phenobarbitone as an antiepileptic is its sedative action • Long term administration (as needed in epilepsy) may produce additional side effects like— behavioral abnormalities, diminution of intelligence, impairment of learning and memory, hyperactivity in children, mental confusion in older people
  40. Phenytoin (Adverse effects) • Plasma level monitoring needed (0 order k.) • Hypertrophy of gums • Enzyme induction • Neutropenia and other hypersensitivity reactions • Young girls beware ! Causes hirsutism, coarsening of facial features and acne • Teratogenic • Osteomalacia
  41. • Interference with folate absorption leads to megaloblastic anemia • Neurological manifestations at higher doses  Ataxia, vertigo, nystagmus, diplopia
  42. Uses • Less commonly used now because side effects are frequent and marginal overdose causes steep rise in plasma concentration, producing neurotoxicity. 1. Generalized tonic-clonic, simple and complex partial seizures. It is ineffective in absence seizure 2. Trigeminal neuralgia  second choice drug to carbamazepine
  43. Interactions 1. Phenobarbitone competitively inhibits phenytoin metabolism, while by enzyme induction both enhance each other’s degradation— unpredictable overall interaction 2. Carbamazepine and phenytoin induce each other’s metabolism 3. Valproate displaces protein bound phenytoin and decreases its metabolism  Plasma level of unbound phenytoin increases
  44. 4. Chloramphenicol, Isoniazid, Cimetidine and Warfarin inhibit phenytoin metabolism  Can precipitate its toxicity 5. Phenytoin induces microsomal enzymes and increases degradation of steroids (failure of oral contraceptives), Doxycycline, Theophylline
  45. Fosphenytoin • Water soluble prodrug of Phenytoin has been introduced to overcome the difficulties in i.v. administration of Phenytoin, which it has replaced for use in status epilepticus. • On i.v. injection it is less damaging to the intima • While Phenytoin cannot be injected in a drip of glucose solution (because it gets precipitated), fosphenytoin can be injected with both saline and glucose
  46. Carbamazepine • First line antiepileptic drug for focal seizures and trigeminal neuralgia • Manic depressive illness and acute mania  As an alternative to Lithium • Carbamazepine produces dose-related neurotoxicity  sedation, dizziness, vertigo, diplopia and ataxia. Vomiting, diarrhoea, worsening of seizures are also seen with higher doses • Hypersensitivity reactions are rashes, photosensitivity, hepatitis, lupus like syndrome and rarely agranulocytosis, aplastic anemia
  47. Lupus like syndrome • Autoimmune disorder caused by a reaction to certain medications • Symptoms are muscle and joint pain sometimes with swelling;flu-like symptoms of fatigue and fever • SHIP drugs are responsible 1. Sulfonamides incl. dapsone and PAS 2. Hydralazine 3. Isoniazid 4. Procainamide
  48. Interactions • Carbamazepine is an enzyme inducer; can reduce efficacy of Haloperidol, oral contraceptives • Metabolism of Carbamazepine is induced by Phenobarbitone, Phenytoin, Valproate and vice versa • Erythromycin, Fluoxetine, Isoniazid inhibit metabolism of carbamazepine
  49. Oxcarbazepine • Newer congener of carbamazepine • Toxic effects due to the epoxide metabolite are avoided • Drug interactions and auto induction of own metabolism are less marked, because it is a weak enzyme inducer • Risk of hepatotoxicity is estimated to be lower than carbamazepine; but that of hyponatremia is more • Indications are the same as for carbamazepine, but it may be better tolerated • Dose to dose it is 1½ times less potent
  50. Valproic acid (Sodium valproate) • Valproate appears to act by multiple mechanisms: 1. A phenytoin-like frequency-dependent prolongation of Na+ channel inactivation. 2. Weak attenuation of Ca2+ mediated ‘T’ current (Ethosuximide like) 3. Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation (by GABA- transaminase) 4. Blockade of excitatory NMDA type of glutamate receptor
  51. Uses • Drug of choice for 1. Generalised tonic clonic seizures 2. Absence seizures 3. Myoclonic seizures 4. Atonic seizures • Alternative/adjuvant drug for SPS and CPS. • Mania and bipolar illness  As alternative to Lithium
  52. Adverse effects • Vomiting • Alopecia • Liver toxicity • Pancreatitis • Rash • Obesity • Agranulocytosis • Teratogenic (Neural tube defects in offspring)
  53. • E (dEntist)  Dentist may face excess bleeding while executing a dental procedure as Valproate causes increased bleeding tendency • E  Epigastric pain
  54. Interactions 1. Valproate increases plasma levels of Phenobarbitone and lamotrigine by inhibiting their metabolism 2. It displaces Phenytoin from protein binding site and decreases its metabolism → Phenytoin toxicity 3. Valproate inhibits hydrolysis of active epoxide metabolite of Carbamazepine 4. Concurrent administration of Clonazepam and valproate is contraindicated because absence status may be precipitated 5. Foetal abnormalities are more common if Valproate and Carbamazepine are given concurrently
  55. Divalproex (Semisodium valproate) • Coordination compound of valproic acid with sodium valproate (1:1) • Oral absorption is slower, but bioavailability is the same • Gastric tolerance may be better • Indications are similar to Valproate
  56. Clonazepam • BZD with prominent anticonvulsant properties (potentiates GABA induced Cl- influx) • At large doses, high frequency discharges are inhibited akin to Phenytoin • Pharmacokinetics  Oral abs. is good. 85% bound to plasma proteins, completely metabolized in liver and excreted in urine; t½ averages 24 hours • A/E  Sedation and dullness. Motor disturbances and ataxia are dose-related adverse effects • Uses  Absence seizures. Also useful adjuvant in myoclonic and akinetic epilepsy
  57. Clobazam • Less sedative and longer acting than Diazepam • Anxiolytic & is useful in partial, secondarily generalized tonic-clonic as well as absence and atonic seizures, including some refractory cases • Sedation and psychomotor retardation are less prominent, but side effect profile is similar to other BZDs • MOA  Acts by facilitating GABA action • Use  Adjuvant to other antiepileptic drugs like phenyt., CBMZ or valproate in refractory epilepsy
  58. Lamotrigine • Blocks voltage sensitive Na+ & N-type Ca2+ channels • Broad-spectrum antiepileptic • Add-on/monotherapy in refractory cases of partial seizures and GTCS • Absence and myoclonic or akinetic epilepsy cases have also been successfully treated • S/E  Sleepiness, dizziness, diplopia, ataxia and vomiting. Rash may be a severe reaction, particularly in children, requiring withdrawal
  59. Gabapentin • Enhances GABA release, but does not act as agonist at GABAA receptor • Added to a 1st line drug, ↓ seizure frequency in refractory partial seizures with or without general. • Gabapentin and its newer congener Pregabalin exert a specific analgesic effect in neuropathic pain • 1st line drug for pain due to diabetic neuropathy, postherpetic & other neuralgias • Some prophylactic effect in migraine • S/E  Sedation, tiredness, dizziness & unsteadiness
  60. Topiramate • Broad spectrum anticonvulsant drug acting by :- 1. Prolongation of Na+ channel inactivation 2. Activation of GABAA receptor 3. Inhibition of AMPA receptors for Glutamate • Monotherapy or supplementing primary antiepileptic drug in refractory SPS, CPS, GTCS, myoclonic epilepsy • A/E  Impairment of attention, sedation, ataxia, word finding difficulties, poor memory, weight loss, paresthesias and renal stones.
  61. Treatment of epilepsies • Antiepileptic drugs suppress seizures, but do not cure the disorder • The aim of drugs is to control and totally prevent all seizure activity at an acceptable level of side effects • The cause of epilepsy should be searched in the patient; if found and treatable, an attempt to remove it should be made • Some general principles of symptomatic treatment with antiepileptic drugs are 
  62. 1. Choice of drug and dose is according to the seizure type(s) and need of the individual patient 2. Initiate treatment early, because each seizure episode increases the propensity to further attacks. Start with a single drug, preferably at low dose, gradually increase dose till full control of seizures or side effects appear. If full control is not obtained at maximum tolerated dose of one drug, substitute another drug. Use combinations when all reasonable monotherapy fails.
  63. 3. A single tonic-clonic seizure in a subject with no predisposing factor for development of epilepsy (history of head injury, family history of epilepsy, neurological abnormality, abnormal EEG or brain scan) may not merit initiation of antiepileptic therapy 4. Therapy should be as simple as possible. A seizure diary should be maintained. 5. All drug withdrawals should be gradual (except in case of toxicity). Prolonged therapy (may be life-long, or at least 3 years after the last seizure) is needed. Stoppage of therapy may be attempted in selected cases.
  64. 6. Dose regulation may be facilitated by monitoring of steady state plasma drug levels 7. When women on antiepileptic therapy conceive, antiepileptic drugs should not be stopped. Lamotrigine has widest spectrum (GTCS, typical Absence, atypical absence, myoclonic, atonic, focal seizures) and is preferred drug in pregnancy. Prophylactic folic acid supplementation in 2nd and 3rd trimester along with vit. K in the last month of pregnancy is recommended, particularly in women receiving antiepileptic drugs to minimize neural tube defects and bleeding disorder respectively in the neonate
  65. Dental implications 1. Dentists have to recognize and manage Phenytoin induced gum hypertrophy 2. In an epileptic patient, dental procedure should be carried out only after ensuring that the patient is under adequate anticonvulsant drug cover and has taken his/her medication 3. In the event of a patient developing an attack of GTCS during dental procedure, the first priority is to prevent injuries due to biting or fall. Ensure that the patient is secure on the flat dental chair or floor
  66. • Any denture or instrument should be immediately removed from the mouth • The head should be turned to the side to prevent the tongue from falling back and obstructing the airway • Give oxygen through a face mask to support respiration if any sign of cyanosis is seen • Do not attempt to stop convulsive movements by restraining the patient • In case the seizures do not stop or recur within 10- 20 minutes, management is as for status epilepticus
  67. Status epilepticus • When seizure activity occurs for >30 min, or 2 or more seizures occur without recovery of consciousness  Status epilepticus • Recurrent tonic-clonic convulsions without recovery of consciousness in between is an emergency; fits have to be controlled as quickly as possible to prevent death and permanent brain damage
  68. Management of status epilepticus 1. Maintain patent airway 2. Dextrose [20-50 ml of 50% soln.] injected i.v. (If seizure is due to hypoglycemia) 3. Lorazepam 4 mg injected i.v. over 2 mins., repeated once after 10 min if required, is the first choice drug now 4. Diazepam 10 mg injected i.v. at 2 mg/min 5. Fosphenytoin 100–150 mg/min i.v. infusion to a maximum of 1000 mg (15–20 mg/kg) under continuous ECG monitoring is a slower acting drug which should be given if the seizures recur or fail to respond 20 min after onset, despite Lorazepam / Diazepam
  69. 4. Phenytoin sodium should be used only when fosphenytoin is not available 5. Phenobarbitone sodium 50–100 mg/min i.v. injection to a maximum of 10 mg/kg is another slower acting drug which can be used as alternative to fosphenytoin 6. Refractory cases may be treated with i.v. Midazolam/ Propofol/ Thiopentone anaesthesia, with or without curarization 7. General measures, including maintenance of airway (intubation if required), oxygenation, fluid and electrolyte balance, BP, normal cardiac rhythm, euglycaemia and care of the unconscious must be taken
  70. Parkinsonism • P  Pill rolling tremors • A  Akathisia (inability to sit still) • R  Rigidity • K  Kinesias (akinesia, bradykinesia) • I  Instable (stooped) posture • N  No arm swinging in rhythm with legs • S  Sialorrhoea (drooling or excessive salivation) • O  Oculogyric crisis (Eyes are held fixed for a variable length of time)
  71. • N  Nervous depression • I  Involuntary tremors • S  Seborrhoea • M  Masked facial expression • Parkinsonism applies for a disease state having the above features whereas Parkinson’s Disease is restricted to primary or idiopathic Parkinsonism
  72. Classification
  73. Antiparkinsonian Drugs • Levodopa  Levodopa has a specific salutary effect in PD • More than 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver). • DA thus formed is further metabolized, and the remaining acts on heart, blood vessels, other peripheral organs and on CTZ • About 1–2% of administered levodopa crosses to the brain, is taken up by the surviving dopaminergic neurones, converted to DA which is stored and released as a transmitter.
  74. Actions 1. CNS  Levodopa hardly produces any effect in normal individuals. Marked symptomatic improvement occurs in parkinsonian patients. Hypokinesia and rigidity resolve first, later tremor as well. Secondary symptoms of posture, gait, handwriting, speech, facial expression, mood, self care and interest in life are gradually normalized. 2. CVS  The peripherally formed DA can cause tachycardia by acting on β adrenergic receptors. Postural hypotension is quite common.
  75. 3. CTZ  The DA formed peripherally gains access to the CTZ without hindrance—elicits nausea and vomiting by stimulating D2 receptors 4. Endocrine  DA acts on pituitary mammotropes to inhibit prolactin release
  76. Adverse Effects 1. Nausea and vomiting 2. Postural hypotension  Care should be taken by the dentist that patients on levodopa therapy do not sit up and leave the dental chair abruptly from a reclining position 3. Cardiac arrhythmias 4. Exacerbation of angina 5. Alteration in taste sensation 6. Abnormal movements  Orofacial dyskinesia
  77. 7. Behavioural effects  Range from mild anxiety, nightmares, etc. to severe depression, mania, hallucinations, mental confusion or frank psychosis. • Levodopa is contraindicated in patients with psychotic illness. 8. Fluctuation in motor performance  After 2–5 years of therapy, the level of control of parkinsonian symptomatology starts showing fluctuation. ‘End of dose’ deterioration develops into rapid ‘switches’ or ‘on-off’ effect. With time ‘all or none’ response develops, i.e. the patient is alternately well and disabled.
  78. Adverse Effects of Levodopa
  79. Interactions 1. Pyridoxine  Abolishes the therapeutic effect of levodopa by enhancing its peripheral decarboxylation 2. Phenothiazines, Butyrophenones, Metoclopramide reverse the therapeutic effect of levodopa by blocking DA receptors 3. Antihypertensive drugs  Postural hypotension caused by levodopa is accentuated
  80. Peripheral decarboxylase inhibitors • Carbidopa and benserazide are extracerebral dopa decarboxylase inhibitors; they do not penetrate blood-brain barrier and do not inhibit conversion of levodopa to DA in the brain. • Administered along with levodopa, they increase its t½ in the periphery and make more of it available to cross blood-brain barrier and reach its site of action
  81. Benefits of the combination 1. The plasma t½ of levodopa is prolonged and its dose is reduced to approximately 1/4th. 2. Systemic concentration of DA is reduced, nausea and vomiting are not prominent 3. Cardiac complications are minimized. 4. Pyridoxine reversal of levodopa effect does not occur. 5. ‘On-off’ effect is minimized 6. Degree of improvement may be higher
  82. Problems not resolved 1. Involuntary movements 2. Behavioral abnormalities 3. Excessive day time sleepiness in some patients 4. Postural hypotension
  83. Dopaminergic agonists • The DA agonists can act on striatal DA receptors even in advanced patients who have largely lost the capacity to synthesize, store and release DA from levodopa • Longer acting, can exert subtype selective activation of DA receptors involved in parkinsonism and not share the concern expressed about levodopa of contributing to dopaminergic neuronal damage by oxidative metabolism
  84. Ropinirole and Pramipexole • First choice drugs for Parkinsonism (preferred over levodopa); selective D2/D3 receptor agonists with negligible affinity for D1 and nondopaminergic receptors • The therapeutic effect as supplementary drugs to levodopa in advanced cases of PD as well as side effect profile is similar to bromocriptine, but they are better tolerated with fewer GI symptoms • Side-effects are nausea, dizziness, hallucinations, and postural hypotension and episodes of day time sleep
  85. Side effects of Dopaminergic agonists
  86. Selegiline • It is a selective and irreversible MAO-B inhibitor • MAO-A and MAO-B  Present in peripheral adrenergic structures and intestinal mucosa • MAO-B  Brain and blood platelets • Unlike nonselective MAO inhibitors, Selegiline in low doses (10 mg/day) does not interfere with peripheral metabolism of dietary amines; Accumulation of CAs and hypertensive reaction does not develop
  87. Adverse Effects • Postural hypotension • Nausea • Confusion • Accentuation of levodopa induced involuntary movements and psychosis
  88. Interactions • Selegiline interacts with pethidine possibly by favouring its metabolism to norpethidine which causes excitement, rigidity, hyperthermia, respiratory depression. • It may also interact with tricyclic antidepressants and selective serotonin reuptake inhibitors
  89. Central anticholinergics • Act by reducing the unbalanced cholinergic activity in the striatum of Parkinsonian patients • Only drugs effective in drug (phenothiazine) induced parkinsonism • Sialorrhoea is controlled by their peripheral action • Trihexyphenidyl is the most commonly used drug • Xerostomia caused by them may aggravate dental caries

Hinweis der Redaktion

  1. a person's inherent qualities of mind and character
  2. Impaired balance or coordination
  3. Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug
  4. Since CYP 3A4 isoenzyme plays important role in metabolism
  5. indigestion
  6. Korsakoff psychosis is a late complication of persistent Wernicke encephalopathy and results in memory deficits, confusion, and behavioral changes
  7. Aldehyde syndrome  flushing, burning sensation, throbbing headache, perspiration, uneasiness, tightness in chest, dizziness, vomiting, visual disturbances, mental confusion, postural fainting and circulatory collapse. inhibition of aldehyde dehydrogenase with disulfiram is irreversible: synthesis of fresh enzyme is required for return of activity
  8. causing the contraction of skin cells and other body tissues.
  9. a sudden attack or outburst of a particular emotion or activity.
  10. Tonic-clonic seizures involve both tonic (stiffening) and clonic (twitching or jerking) phases of muscle activity. Tonic-clonic seizures may start with a simple partial seizure or aura. The person may experience changes in sensation, mood or emotion leading up to the tonic-clonic seizure. An 'aura' is the term that some people use to describe the warning they feel before they have a tonic clonic seizure.
  11. An involuntary eye movement which may cause the eye to rapidly move from side to side, up and down or in a circle, and may slightly blur vision Megaloblastic anemia is a condition in which the bone marrow produces unusually large, structurally abnormal, immature red blood cells (megaloblasts)
  12. NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms
  13. producing good effects; beneficial
  14. Orthostatic hypotension — also called postural hypotension — is a form of low blood pressure that happens when you stand up from sitting or lying down.
  15. Pyridoxine is a cofactor of dopa decarboxylase enzyme
  16. make more noticeable or prominent