Review of Pharmacology PDF

CHAPTER 8 Central Nervous System Sedative Hypnotic rug D s Sedative is a drug that calms a person whereas hypnotics induce sleep. CNS depressant drugs can produce sedati...

CHAPTER 8 Central Nervous System Sedative Hypnotic rug D s Sedative is a drug that calms a person whereas hypnotics induce sleep. CNS depressant drugs can produce sedation, hypnosis, anaesthesia and coma depending on the dose. Major group of drugs useful for the treatment of insomnia include barbiturates, benzodiazepines and newer drugs. GABAC receptors are present GABAA-BZD-Cl– channel complex is an ion channel, which on opening increases in retina and are inotropic the conductance of chloride ions resulting in CNS depression. Several compounds mediating influx of chloride can modulate the effect of this channel. (like GABAA) whereas GABAB GABA increases the duration of channel opening by directly binding to GABAA receptors are G-protein coupled receptor site. receptors. Barbiturates bind to another site on this channel to exert GABA mimetic (direct activation of GABAA receptors) as well as GABA facilitatory (increase the binding of GABA to GABAA receptors) actions. Benzodiazepines bind to a different site (BZD receptor) and increase the binding of GABA to GABAA receptor (GABA facilitatory action). These drugs increase the frequency of Cl– channel opening. Bicuculline binds to GABAA receptor and acts as a competitive inhibitor of GABA and non competitive inhibitor of benzodiazepines. β-carboline acts as an inverse agonist at benzodiazepine site and thus produces convulsions due to stimulation of the brain. Flumazenil acts as a competitive antagonist at BZD site and therefore inhibits the action of benzodiazepines as well as b-carboline. 1. Barbiturates These are the derivatives of barbituric acid and act by increasing the Cl- conductance across GABAA-BZD-Cl– channel complex. These drugs have GABA mimetic as well as GABA facilitatory action to increase the duration of Cl– channel opening (no effect on frequency). Important indications of barbiturates in clinical practice are epilepsy (phenobarbitone) and anaesthesia (thiopentone as inducing agent). These are generally not used for other purposes because These have narrow therapeutic index due to steep dose response curve (with slight increase in dose, severe CNS depression leading to coma can occur). These are powerful enzyme inducing agents and are prone to several drug interactions. These have high abuse liability and may precipitate withdrawal symptoms. If poisoning occurs, no specific antidote is available. dverse effects and contraindications A Due to the long duration of action, hangover is common. Barbiturates can cause distortion of sleep architecture by decreasing the duration of REM and stage 3 and 4 sleep and increasing the duration of stage 2 sleep. Learning and memory impairment can occur. Idiosyncratic reaction resulting in excitement can occur in some patients. Barbiturates are absolutely con ­ These are absolutely contraindicated in acute intermittent porphyria (because traindicated in acute inter-mittent porphyria porphyrin synthesis is increased due to induction of d-ALA synthase; rate limiting enzyme in porphyrin synthesis, by barbiturates). https://kat.cr/user/Blink99/  Review of Pharmacology At high doses, acute poisoning may occur (manifests as coma, depressed respiration, hypotension, cardiovascular collapse and barbiturate blisters). It is treated by gastric nsafe drugs in porphyria: lavage, symptomatic treatment and with forced alkaline diuresis. Hemodialysis can U S- Sulfonamides also be done. E- Erythromycin V- Valproate 2. Benzodiazepines E- Ergot Alkaloids R- Rifampicin These drugs act by GABA facilitatory action. These also possess anxiolytic, anticonvulsant and E- Estrogens skeletal muscle relaxant properties. P - Phenobarbitone (and other Benzodiazepines used for various indications are: barbiturates like thiopentone) O O al contraceptives Hypnotic: Diazepam, flurazepam, nitrazepam, flunitrazepam, temazepam, triazolam, r R quazepam and midazolam P - Phenytoin Anti-convulsants: Diazepam, clonazepam, clobazam, lorazepam H Hydralazine Y Anti-anxiety: Diazepam, oxazepam, lorazepam, alprazolam, chlordiazepoxide R I Muscle Relaxant: Diazepam A - Alcohol Benzodiazepines are preferred over barbiturates as hypnotic drugs due to several reasons: BZDs have flat dose response curves (these have high therapeutic index and require high dose to produce coma). These cause less hangover and less distortion of sleep architecture. Duration of REM sleep is shortened but increase in the number of REM cycles compensate for that. Nitrazepam actually increases REM sleep. Central Nervous System These are less prone to drug interactions (because they do not induce microsomal enzymes). Short acting Benzodiazepines are Abuse liability is less. Triazolam BZD poisoning can be treated with specific antidote, flumazenil. Temazepam Oxazepam Diazepam can produce analgesia whereas barbiturates may even cause hyperalgesia.    Lorazepam    Estazolam harmacokinetics P     All BZDs are almost completely absorbed except clorazepate (converted to nordiazepam by STOLE gastric juice which is absorbed). Most of the BZDs are metabolized in the liver to produce active products (thus long duration of action). Active metabolites may result in cumulative effects. After metabolism these are conjugated and are excreted via kidney. Estazolam, lorazepam, oxazepam, temazepam and triazolam are directly conjugated without metabolism to active products. These drugs are thus short acting and do not accumulate on repeated administration. Further these drugs can be safely administered in liver failure and in elderly because these are conjugated directly without undergoing metabolism in the liver. Compounds with shorter half life are favored in patients with sleep onset insomnia whereas longer acting BZDs are favored in patients with day time anxiety. dverse effects A Benzodiazepines are much safer than barbiturates (less chances of respiratory depression and coma) and also have less abuse potential. However, these drugs can also impair learning and memory. Flunitrazepam is a tasteless BZD and is implicated as a date rape drug due to its propensity to cause dose dependent amnesic effects. Paranoia and other psychiatric distrubances can occur with triazolam. Midazolam can cause ataxia and blackouts in elderly. Benzodiazepine ends with pine Flurazepam results in paradoxical stimulation and increase in nightmares in some persons. which in hindi means drink. The antagonist will stop the Benzodiazepine ntagoni t enjoyment (in hindi maze). Thus, A s the name is Flu MAZE NIL [Maze Flumazenil is the substance that acts as a competitive antagonist at BZD receptor. It blocks the of drinking have become nil] depressant action of benzodiazepines, zolpidem and zaleplon as well as the convulsant action of inverse agonists (like β carboline). 314 https://kat.cr/user/Blink99/  Central Nervous System It is administered i.v. for the treatment of BZD poisoning (specific antidote) and can also be used to reverse BZD anaesthesia. Its duration of action is approximately 30-40 minutes and half life is 1 hour. 3. ewer Hypnotic rugs N D. opiclone A Z It stimulates GABAA receptors by binding to a site different than benzodiazepines. It prolongs stage 3 and 4 sleep and does not affect REM sleep. Chances of rebound insomnia and hangover are less than benzodiazepines and barbiturates. It is used for the treatment of N insomnia. It is also indicated in the patients taking benzodiazepines regularly for induction Suv X ANT of sleep. It helps in weaning off hypnotic medications in such patients. The active enantiomer, ore eszopiclone is also available now. Orexin Antagonist B. olpidem Z It binds selectively to w1 subtype of benzodiazepine receptors and increases GABA mediated neuronal inhibition. It possesses pronounced hypnotic and amnesic effects but lacks anti- anxiety, muscle relaxant and anticonvulsant actions. It has little effect on sleep architecture and does not produce hangover and rebound insomnia. Abuse potential of zolpidem is very low. It is also indicated for the short term treatment of insomnia.. aleplon C Z General Central Nervous It also acts by selectively binding to w1 subtype of benzodiazepine receptors. It decreases sleep latency without affecting total sleep time or sleep architecture (therefore useful in persons having difficulty to fall asleep). Other properties are similar to zolpidem. Pharmacology. Suvorexant D It is an orexin receptor antagonist. Orexin acts as a central promotor of wakefulness. Therefore, its antagonist (suvorexant) has been approved for insomnia. System 4. ther Hypnotics O Chloral hydrate (active metabolite is trichloroethanol), glutethimide and meprobamate (a metabolite of carisoprodol, a skeletal muscle relaxant) have CNS depressant properties but are rarely used in clinical practice. Trazodone is an antidepressant that can be used for insomnia at low doses. Priapism is a rare side effect of this agent. Ramelteon is agonist of MT1 MELATONIN is a hormone of pineal gland that synchronizes the circadian rhythm. It and MT2 receptors of melatonin increases the sleep during night but has no effect on latency or duration of sleep. It is used in suprachiasmatic nucleus. It to reduce symptoms of jet lag. It can also synchronize the sleep wakefulness cycle in shift is approved for long term use workers and is also used in elderly hypnotic dependent insomniacs. Lowering of seizure in treatment of sleep onset insomnia. threshold and psychiatric changes are the possible adverse effects. Ramelteon is agonist of MT1 and MT2 receptors of melatonin in suprachiasmatic nucleus. It is approved for long term use in treatment of sleep onset insomnia. It do not possess addictive property but causes hyperprolactinemia, dizziness, somnolence and fatigue as adverse effects.It is metabolized by microsomal enzymes (CYP1A2) and should not be given N with enzyme inducers (e.g. rifampicin) or inhibitors (e.g. ciprofloxacin) Tasimelteon is melatonin receptor agonist (like ramelteon) Mnemonic: R A M E L T E O N indicated for treatment of non- 24 hour sleep-wake disorder in Receptor Agonist Melatonin totally blind. 315 https://kat.cr/user/Blink99/  Review of Pharmacology arkin oni m P s s It is a neurodegenerative disease characterized by rigidity, bradykinesia, dyskinesia, tremor, mask like facies and unstable gait. Idiopathic Parkinsonism is known as Parkinson’s disease. In basal ganglia, the output neurons are controlled by dopamine and acetylcholine. Due to their opposite action, a balance is required between these two neurotransmitters for proper functioning of basal ganglia. Major pathology in Parkinsonism is decrease in nigrostriatal dopaminergic neurons, (with appearance of Lewy bodies) consequently cholinergic activity becomes dominant. Thus, two major strategies for the treatment of Parkinsonism are to increase brain dopaminergic activity or to decrease central cholinergic activity. rugs ncreasing Brain opaminergic ctivity D I D A Brain dopaminergic activity can be increased by precursors of dopamine, inhibitors of dopamine metabolism, dopamine receptor agonists and drugs increasing presynaptic release of dopamine. Central Nervous System. opamine recur or A D P s s Dopamine itself cannot cross blood brain barrier (BBB) but its precursor levo-dopa can cross BBB. Levo-dopa is metabolized by dopa decarboxylase (contains pyridoxine as co-factor) to dopamine. This conversion occurs both in periphery as well as in the brain. Peripheral conversion is undesirable due to two reasons: It forms dopamine peripherally that cannot cross BBB, therefore only about 1-3% of l-dopa can reach its target site (brain). Peripherally formed dopamine will result in adverse effects like postural hypotension. Therefore levo-dopa is always given in combination with peripheral dopa decarboxylase inhibitors like carbidopa or benserazide. This combination has beneficial effects on all symptoms of Parkinsonism, although tremors respond less well than rigidity or bradykinesia. dverse ffects A E Peripherally formed dopamine can lead to postural hypotension and arrhythmias. Nausea and vomiting occurs commonly due to CTZ stimulation by dopamine Addition of carbi-dopa to (Domperidone but not metoclopramide can be used for the treatment of this vomiting). On I-dopa therapy long term use “wearing off” effect and on-off phenomenon can result. ‘On’ means Increase entry of L-dopa in brain. patient is having no symptoms of Parkinsonism (but abnormal movements are ­ Decrease adverse effects due present) and ‘off’ means patient has full blown symptoms of Parkinsonism (like to peripherally formed dopa- no treatment is given). This effect is due to short half life (1-2hrs) of l-dopa and mine is reduced by carbidopa. Long acting dopamine agonists show little tendency to cause on-off phenomenon. 316 https://kat.cr/user/Blink99/  Central Nervous System Abnormal choreiform movements (dyskinesia) of limbs, trunk and tongue Carbi-dopa decrease all adverse can occur with prolonged high dose treatment. Carbidopa does not prevent or effects of l-dopa therapy except decrease this adverse effect. This adverse effect responds to amantadine and Abnormal movements possibly levetiracetam. Behavioural Changes L-dopa especially in elderly can result in hallucinations, vivid dreams, sleep disturbances and even psychosis (thus C/I in psychosis). These behavioural disturbances are not prevented by carbidopa. Clozapine and quetiapine can be used to treat levodopa induced psychosis. It may even cause mydriasis (C/I in angle closure glaucoma). Vitamin complexes containing pyridoxine decrease the effectiveness of levo- dopa (pyridoxine is a cofactor of dopa decarboxylase and increases the formation of dopamine in the periphery. This results in decrease in l-dopa’s central penetration). Abrupt withdrawal of levodopa may precipitate neurolept malignant syndrome. Levo-dopa should be given carefully in patients with active peptic ulcer (increased risk of bleeding) and malignant melanoma (levo-dopa is a precursor of melanin). Adverse Effect of L-dopa Adverse Effect Mechanism Remarks 1. Nausea, Vomiting CTZ stimulation Reduced by carbi-dopa 2. Postural hypotension D1 stimulation Reduced by carbi-dopa 3. Arrhythmias b1 stimulation Reduced by carbi-dopa General Central Nervous 4. Hypertension a1 stimulation Reduced by carbi-dopa More likely when combined with MAO inhibitors 5. Mydriasis a1 stimulation Contraindicated in acute angle closure glaucoma Pharmacology 6. Dyskinesia ↑ Activity of DA in Brain Not reduced by carbi-dopa 7. Psychotic symptoms ↑ Activity of DA in Brain Not reduced by carbi-dopa System B. rug n i iting eta oli m of opamine D s I h b M b s D Dopamine is metabolized by MAO and COMT (catechol-o-methyl transferase). (i) nhibitors COMT I This enzyme metabolizes dopamine as well as l-dopa to form 3-O-methyldopa. Tolcapone and entacapone (act by inhibiting this enzyme) help in Parkinsonism because: Metabolism of l-dopa is inhibited, so more is able to cross BBB. These can be given in combination with l-dopa + carbidopa (inhibition of dopa decarboxylase diverts the metabolism of l-dopa to methylation by COMT) 3-O-methyl dopa formed by metabolism of l-dopa competes with it for entry in the brain. Tolcapone and entacapone decrease this interaction. By inhibiting dopamine metabolism in brain (tolcapone only), its duration of Tolcapone inhibits COMT in action is increased. periphery as well as brain whereas entacapone acts only Tolcapone inhibits COMT in periphery as well as brain whereas entacapone acts only in the periphery. in the periphery. Major beneficial effect of these drugs in Parkinsonism is due to peripheral inhibition of COMT. Tolcapone is more potent and longer acting than entacapone but is not preferred because of hepatotoxic effects. Toxic to Liver (ii) -B nhibitors MAO I Selegiline and rasagiline are irreversible and selective inhibitors of MAO-B. These drugs ToLcapone can be given in combination with levo-dopa + carbidopa to decrease the dose of levo-dopa 317 https://kat.cr/user/Blink99/  Review of Pharmacology (and thus decreased abnormal movements). At normal doses these inhibit only MAO-B and thus have no interaction with cheese or tricyclic antidepressants. However, at high doses, they also inhibit MAO-A and can lead to hypertensive crisis (cheese reaction) with tyramine containing foods and serotonin syndrome with TCAs. Rasagiline is more potent than selegiline. These drugs are thought to reduce the disease progression.. opamine goni t C D A s s Ergot alkaloids are short acting These drugs directly activate D2 receptors and can be used as monotherapy in Parkinsonism. and can cause digital vasos- Ergot derived dopamine agonists include bromocriptine and pergolide. These drugs are opasm (leading to gan-grene) short acting and can cause digital vasosopasm (leading to gangrene) and erythromelalgia. and pleural, peritoneal and car- These drugs can also result in pleural, peritoneal and cardiac fibrosis. Ergot alkaloids require diac fibrosis. slow upward titration of dose. Long term use of pergolide is associated with cardiac valvular defects. Newer non-ergot dopamine agonists; pramipexole and ropinirole do not have these limitations (these are long acting and do not cause gangrene). All four drugs can cause confusion and hallucinations. In developed countries, these are now the first choice drugs Pramipexole and ropinirole for Parkinsonism (preferred over levo-dopa). Ropinirole has also been approved for restless are long acting and do not cause leg syndrome. Pramipexole is excreted mainly by kidney whereas ropinirole is metabolized gangrene. These are now the by liver. Rare but important adverse effect of these drugs is excessive day time sleepiness. first choice drugs for Parkin- Recently, dopamine agonists have been associated with impulse-control disorders including sonism. pathological gambling, hypersexuality, etc. Rotigotine is a dopamine agonist that can be administered through a transdermal patch but was discontinued due to crystal formation on the patches. Apomorphine can be given subcutaneously for temporary relief of off-periods. However, it cause troublesome nausea. Pramipexole and Ropinirole are used for treatment of restless Central Nervous System leg syndrome. rug ncrea ing opamine evel at Synap e D D s I s D L s Amantadine is an antiviral drug that is also useful in Parkinsonism. It increases synaptic dopamine level by increasing presynaptic release and decreasing its reuptake. It also possesses anticholinergic and antiglutaminergic (NMDA blocking) activity. Adverse effects of this drug include nausea, insomnia, ankle edema and livedo reticularis. It ameliorates dyskinesia associated with chronic levo-dopa therapy. Subcutaneous apomorphine rugs nhibiting Brain holinergic ransmission D I C T (D4 agonist) has been approved as a rescue therapy of ‘off’ Central anticholinergic drugs like trihexiphenidyl (benzhexol), procyclidine, benztropine, episodes when oral dopamine orphenadrine and biperiden are the drugs of choice for drug induced Parkinsonism. Drugs agonists or COMT inhibitors fail that act by blocking D2 receptors in the brain (like antipsychotics, metoclopramide etc.) can to control these episodes. cause Parkinsonism. In this condition, increasing dopamine level is not effective because the receptors on which it has to act (D2) are already occupied, therefore anticholinergics are preferred. First generation antihistaminics with high antimuscarinic activity like promethazine Rotigotine is a dopamine ago- and diphenhydramine can also be used for this indication. nist that can be adminis-tered through a transdermal patch Adverse effects of antimuscarinic drugs include urinary retention, blurred vision, dry but was discontinued due to mouth and constipation. crystal formation on the patches. t er eurodegenerative i ea e O h N D s s s lzheimer’s isease ( ) A D AD It is a form of senile dementia that is due to the deposition of amyloid plaques in Central anticholinergic drugs the hippocampus (Presence of neurofibrillary tangles). There is loss of cholinergic like trihexiphenidyl (benzhexol), neurons in the brain. Anticholinesterases that can cross the blood brain barrier are procyclidine, benztropine, the mainstay of treatment of this disease. orphenadrine and biperiden are Tacrine was used previously but its use has declined due to its hepatotoxic potential the drugs of choice for drug and the need of frequent (four times a day) dosing. induced Parkinsonism. Donepezil, rivastigmine and galantamine are newer cholinesterase inhibitors 318 https://kat.cr/user/Blink99/  Central Nervous System useful in AD that are less toxic than tacrine. Donepezil can be administered once daily, offering an advantage over other anticholinesterases. Rivastigmine is approved for Acetyl-l-carnitine (structural analogue of ACh) has antioxidant property apart from treatment of dementia due to increasing cholinergic transmission. It shows promise in decreasing symptoms and Alzheimer’s disease as well as slowing the progression of AD. due to Parkinsonism. Memantine is an NMDA antagonist approved by FDA for the treatment of advanced AD. Huntington’s horea C It is due to loss of GABAergic neurons in the striatum that lead to dopaminergic overactivity (opposite to Parkinsonism). Thus D2 blockers like chlorpromazine, haloperidol as well as olanzapine are useful in the treatment of this disease. Tetrabenazine (dopamine depleter) has been recently approved for this indication. Reserpine also act by depleting central monoamines. myotrophic ateral Sclerosis ( S) A L AL This disease is due to degeneration of neurons in spinal cord, medulla or cortex. Spasticity is the major presenting feature. Riluzole is an NMDA antagonist that is useful in ALS. Most Mitoxantrone has broadest indication in multiple sclerosis useful agent for symptomatic treatment of spasticity in ALS is baclofen. (RR , SPMS and worsening ms RRMS) but not used as first-line ultiple Sclerosis ( S) drug because of cardiotoxicity M M It is an autoimmune disease resulting in demyelination of neurons. Frequency of relapses can be decreased by beta-interferon or glatiramer (resembles myelin basic protein) in relapsing General Central Nervous remitting MS. Spasticity can be decreased by baclofen or tizanidine. Recently, a monoclonal antibody, natalizumab is being tried for multiple sclerosis. It has important adverse effect to cause progressive multifocal leuko-encephalopathy. Fingolimod is a sphingosine 1-phosphate Pharmacology receptor modulator recently approved for the treatment of patients with relapsing forms of multiple sclerosis. Dalfampridine is an oral K+ channel blocker indicated to improve walking in patients with multiple sclerosis. Modafinil is approved for improving fatigue in multiple System sclerosis. DRUGS USED FOR MULTIPLE SCLEROSIS Drug Mechanism Route Frequency Adverse Effects 1. Interferon-b 1a Downregulates i.m. Once a Flu-like symptoms expression of week Altered LFT MHC molecules on Injection site reaction Glatiramer consists of 4 amino Interferon antigen presenting S.C Thrice a on s.c. route acids b 1b cells week Formation of Glutamate ↓ Pro-inflammatory neutralizing antibodies Lysine and ↑ regulatory Alanine cytokines Tyrosine ↓ T-cell G iramer proliferation lat ↓ Entry of inflammatory cells in CNS 2. Glatiramer ↑ Suppressor S.C. Thrice a Injection site reactions T-Cells week Flushing, Chest Displace MBP by tightness, dyspnea, binding to MHC palpitations, anxiety molecules Lipoatrophy Drug of choice for acute ↓ Pro-inflammatory attacks in MS is steroids and whereas interferon-b is D for oc ↑ regulatory preventing the relapse in RRMS cytokines Contd... 319 https://kat.cr/user/Blink99/  Review of Pharmacology Contd... 3. Natalizumab Prevents i.v. Once a Progressive multifocal (Monoclonal lymphocytes infusion month leucoencephalopathy if antibody against from binding to used for >2years 4 subunit of endothelial cells, α 4b1 thus inhibits α integrin on transfer across lymphocytes) BBB and entry in CNS 4. Fingolimod Traps lymphocytes Oral Once a day Altered LFT in spleen and First degree heart lymph nodes by block preventing their Bradycardia egress Thus, entry in CNS decreases 5. Mitoxantrone Topoisomerase II i.v. Once in 3 Cardiotoxicity (Anthracycline inhibition months Acute leukemia anticancer drug) 6. Dimethyl Promotes anti- Oral Twice a day Progressive multifocal fumarate inflammatory leucoencephalopathy (approved in and inhibit UK, not in USA) pro-inflammatory cytokines Central Nervous System 7. Teriflunomide Dihydroorotate Oral Once a day Hepatotoxicity (Active dehydrogenase metabolite of inhibitor leflunomide) 8. Cladribine Inhibit DNA Oral Used for 2 Immunosuppression (Purine analog synthesis and weeks every Secondary neoplasms anticancer drug) repair year Herpes zoster 9. Dalfampridine K+ Channel Oral Once a day Seizures (4-Aminopy- blocker to improve ridine) weakness in MS 320 https://kat.cr/user/Blink99/  Central Nervous System Wilson’s isease D Penicillamine and trientine can It is characterized by hepatolenticular degeneration due to excessive accumulation of copper. worsen neurological symptoms d-Penicillamine can be used as a copper chelating agent but it can cause lupus like syndrome, in Wilson disease, therefore are optic neuritis and blood dyscrasias. Trientine is another copper chelating agent with much not recommended for initial neu- less toxicity. Zinc sulphate and potassium sulfide decrease intestinal absorption of copper and induce rological therapy hepatic metallothinein synthesis, that sequester additional toxic copper. Zinc sulphate can be used for maintenance therapy and is much safer than other drugs. Wilson disease Drug of choice 1. Hepatitis or cirrhosis without decompensation Zinc 2. Mild to moderate hepatic decompensation Trientine + zinc 3. Neurological or psychiatric symptoms Tetrathiomolybdate + zinc 4. For maintenance, children, pregnancy ntiepileptic rug Zinc R G A D s V Epilepsy is the condition characterized by recurrent episodes of seizures. Seizures may be generalized, partial or unclassified. Generalized seizures include tonic clonic (grand mal), d absence (petit mal), myoclonic, tonic, atonic and clonic seizures. Partial seizures may be simple partial (jacksonian) or complex partial (psychomotor or temporal lobe epilepsy). ti e Febrile seizures and infantile spasms are unclassified forms of seizures. Lennox Gestaut syndrome is a form of epilepsy with impaired cognitive function. Adenosine is an endogenous antiepileptic substance. General Central Nervous echanism of ction n M A Drugs useful for epilepsy act by various mechanisms like: U Pharmacology (a) Inhibition of Use Dependent Na+ Channels: - Phenytoin, carbamazepine, valproate, topiramate lamotrigine and lacosamide act by inhibiting the sodium channels when these are open. These drugs also prolong 9 the inactivated stage of these channels (Na+ channels are refractory to stimulation till System these reach the closed/resting phase from inactivated phase). ri 9 h ta 321 https://kat.cr/user/Blink99/  Review of Pharmacology (b) Increase in Inhibitory Neurotransmission: GABA is a major inhibitory neurotransmitter in the brain. Barbiturates (phenobarbitone, primidone) and benzodiazepines (diazepam, clonazepam, clobazam) activate GABAA receptors by binding to GABA-BZD-Cl– channel complex. Ganaxolone (a neurosteroid) also acts by activating this channel but the binding site is different. Drugs can also act by increasing the release (Gabapentin), decreasing the metabolism (Vigabatrin) or inhibiting the reuptake in neurons (Tiagabine). (c) Decrease in Excitatory Neurotransmission: Glutamate and aspartate are major excitatory amino acids in the brain. Glutamate can act by stimulating metabotropic (GPCRs) or ionotropic receptors (kainate, NMDA and AMPA). Felbamate acts by inhibiting NMDA receptors. Topiramate act by inhibiting kainate receptors. (d) Inhibition of Ca2+ Channels: T-type Ca2+ channels are important in absence seizures. Drugs inhibiting these channels (ethosuximide, valproate, lamotrigine) are useful in petit mal epilepsy. Mechanism of Action of Anti pileptic rugs e d DRUG ↑ G B activity ↓ Glutamate Prolong lock Other a a B Activity inactivated T- a2+ c Na+ Channels channels 1. Phenytoin  2. Carbamazepine  Central Nervous System 3. Valproate  (a)   4. Lamotrigine  (b)  5. Ethosuximide  6. Gabapentin  (c) 7. Topiramate  (d)  (e)  Activates K+ Channel 8. Tiagabine  (f) 9. Phenobarbitone  (g) 10. Primidone  (g) 11. Benzodiazepines  (g) 12. Felbamate  (h) 13. Levetiracetam Block SV2A 14. Zonisamide   15. Lacosamide  CRMP-2 inhibitor 16. Rufinamide  17. Retigabine K+ (Ezogabine) channel opener a - Increase GABA by activating Glutamic acid decarboxylase and inhibiting GABA transaminase b - Inhibits release of glutamate c - Inhibits release of GABA d - Increases postsynaptic GABA activity e - Blocks AMPA receptors of glutamate f - Inhibits reuptake of GABA by inhibiting GAT-1 g - Act on GABA-BZD-Cl– channel complex h - Blocks NMDA receptors of glutamate 322 https://kat.cr/user/Blink99/  Central Nervous System mportant rugs I D 1. Bar iturate b s Phenobarbitone and primidone act as anticonvulsant drugs due to GABA mimetic as well as GABA facilitatory properties. These drugs increase the duration of opening of chloride channels. These drugs are useful in generalized tonic clonic seizures (GTCS) and partial seizures. These drugs are highly sedating but tolerance develops to this effect. Barbiturates are contraindicated in acute intermittent porphyria. These drugs can cause paradoxical excitation in some patients. Phenobarbitone is drug of choice for GTCS in infants but can cause hyperkinesia in older children. 2. Benzodiazepine s Diazepam, clonazepam, lorazepam and clobazam are benzodiazepines that act by GABA facilitatory activity. These drugs increase the frequency of Cl– channel opening. Diazepam, lorazepam and clonazepam are useful for the management of acute seizures. These can also be used i.v. for status epilepticus (Lorazepam is DOC). Diazepam given by per rectal R G Benzodiazepines (preferably lo- razepam) is drug of choice for ­ route is DOC for febrile seizures. Benzodiazepines also have prominent sedative effects like status epilepticus barbiturates. Tolerance develops to the antiepileptic effect so these are not indicated for long term use. 3. enytoin dV Ph ti e It is a non sedating oral antiepileptic drug. Fosphenytoin is a water soluble prodrug of Adverse effect of phenytoin: phenytoin that can be administered parenterally (i.v. or i.m.) for acute attack of seizures H – Hirsutism (status epilepticus). These drugs act by blocking the use dependent Na+ channels. Phenytoin Hypertrophy of gums is useful in GTCS and partial seizures. General Central Nervous O – Osteomalacia digitalis induced arrhythmia. Recently it has been found to enhance wound healing. U n It can also be used as an anti-arrhythmic drug (class Ib) for the treatment of T – Teratogenicity M A Megaloblastic anemia – Ataxia and nystagmus – Pharmacology L – Lymphadenopathy - This drug follows saturation kinetics (kinetics changes from first order to zero I Inhibits insulin release – order within therapeutic concentrations). (hyperglycemia) Phenytoin from different manufacturers (different brands) have different K – Vitamin K deficiency 9 System bioavailability and therefore brand change can lead to toxicity or suboptimal A – Arrhythmias levels. ri 9 At toxic plasma levels oral dose of phenytoin can result in cerebellar symptoms (ataxia, vertigo, nystagmus, diplopia). Fetal Hydantoin syndrome: Fosphenytoin should be given by slow i.v. infusion because fast administration of P – Hypoplatic Phalanges h high doses can lead to arrhythmias, cardiovascular collapse and coma. Prolonged use of phenytoin can result in gingival hyperplasia (gum hypertrophy). C – Cleft Lip and palate M – Microcephaly ta It results due to over-expression of platelet-derived growth factor (PDGF). It may regress after discontinuation of phenytoin. Other adverse effects on long-term use include hirsutism, coarsening of facial features, megaloblastic anemia (treated N with folic acid), vitamin D deficiency (rickets and osteomalacia), vitamin K Eslicarbazepine is a Na+ chan- deficiency, hyperglycemia (due to inhibition of insulin release), hypersensitivity nel blocker (like carbamazepine) and teratogenicity (fetal hydantoin syndrome; hypoplastic phalanges, cleft lip, indicated for adjunctive treatment cleft palate and microcephaly). of focal seizures. Osteomalacia may not always be ameliorated by administration of vitamin D because some vitamin K dependent proteins also play a role in Ca2+ metabolism in bone. Lymphadenopathy (pseudolymphoma) and malignant lymphoma (associated with reduced IgA) and inhibition of ADH release (in SIADH patients) has also been reported. Phenytoin should be stopped gradually because sudden discontinuation may result in precipitation of seizures. It is also a potent enzyme inducer and can increase the metabolism of various drugs. 323 https://kat.cr/user/Blink99/  Review of Pharmacology 4. ar amazepine and xcar azepine C b O b Carbamazepine is drug of choice These drugs act by blocking the use dependent sodium channels. Oxcarbazepine has similar for partial seizures and trigemi- efficacy but less toxicity than carbamazepine (CBZ). These are the drugs of choice for partial nal neuralgia. seizures and can also be used in GTCS. Carbamazepine is DOC for trigeminal neuralgia and can also be used for glossopharyngeal and post herpetic neuralgia. Another use of carbamazepine is in the treatment of bipolar disorder (manic depressive psychosis) and as an antidiuretic in DI. It is a potent enzyme inducer and can induce its own metabolism (thus requiring more dose if used for long term). Major adverse effects of these drugs include dizziness, Phenytoin and carbamazepine can worsen generalized sei headache, ataxia, vertigo and diplopia. It can also cause leukopenia, aplastic anemia and hepatotoxicity. Congenital malformations are induced in children delivered to females taking ­ zures including absence, myo ­ ­ clonic, tonic and atonic seizures. this drug during pregnancy. 5. alproic cid V A It is a broad spectrum antiepileptic drug effective in all types of seizures. It acts by several mechanisms including blockade of use dependent Na+ channels, increased activity of GABA Valproate is drug of choice for GTCS (by increasing synthesis due to stimulation of glutamic acid decarboxylase and decreasing Myoclonic Seizures metabolism by inhibiting GABA transaminase), inhibition of T type Ca2+ channels and Atonic Seizures decrease in release of glutamate in the brain. It is the DOC in GTCS, myoclonic, atonic, Absence Seizures atypical absence, clonic and tonic seizures. It is also effective in Lennox Gestaut syndrome, Clonic Seizures absence seizures, infantile spasms and partial seizures. Tonic Seizures It should be gradually stopped to avoid withdrawl seizures. Other uses of this drug include bipolar disorder, prophylaxis of migraine and as an alternative to carbamazepine in trigeminal neuralgia. Recently it has also been used in tardive dyskinesia. It is also the drug of choice for bipolar disorder in patient having rapid cycles (4 or more cycles per Central Nervous System year). Valproic acid is a potent microsomal enzyme inhibitor. Adverse effect of this drug includes weight gain, alopecia, tremors, carnitine deficiency and irreversible hepatic necrosis (more in children < 2 yrs old). It is DOC for absence seizures (petit mal epilepsy). However, it should be avoided in children 4m Eq/L in acute overdose or > 1.5 mEq/L in chronic overdose. 333 https://kat.cr/user/Blink99/  Review of Pharmacology nti nxiety rug A A D s Reduction in the GABAergic activity or increase in serotonergic activity may result in anxiety. It is due to mild CNS stimulation. Drugs commonly used for anxiety are CNS depressants (like benzodiazepines) or those decreasing serotonin level (like buspirone). Benzodiazepine s Chlordiazepoxide is used for chronic anxiety states whereas oxazepam, lorazepam, alprazolam DOC for acute management of generalized anxiety is benzo- and diazepam are indicated for short lasting anxiety states. Oxazepam and lorazepam are safe in diazepines elderly and in patients with liver disease. Benzodiazepines are most commonly used anxiolytic drugs; SSRI are first line medications however sedation, cognitive impairment and abuse liability are potential limitations in their for sustained treatment of gen- use. eralized anxiety disorders. zapirone A s Buspirone, gepirone and ipsapirone act as partial agonists of presynaptic 5-HT1A receptors and decrease the release of serotonin. These drugs do not cause sedation or cognitive impairment and are devoid of abuse potential, muscle relaxant and anticonvulsant activity. Therapeutic effect of these drugs takes up to 2 weeks and therefore these are ineffective in acute anxiety states like panic attacks. These are indicated for mild to moderate generalized anxiety states. Beta locker b s Propanolol is indicated for performance anxiety where it decreases the sympathetic manifestations of anxiety. Central Nervous System t er rug O h D s Hydroxyzine is H1 antihistaminic having anti-anxiety activity but profound sedation limits its usefulness. SSRIs like fluoxetine are agents of choice for panic disorder whereas benzodiazepines are drug of choice for panic attacks and generalized anxiety disorder. lco ol A h s t yl lco ol ( t anol) E h A h E h Lorazepam is DOC for acute treatment of panic attacks It is a CNS depressant drug that can result in psychological as well as physical dependence. whereas for sustained treat- It is an imperfect food because it lacks essential constituents and it cannot be stored. It follows ment, SSRIs are preferred. zero order kinetics and plasma concentration >300 mg/dl may result in death. Acute ingestion of large quantities may result in fall in blood pressure whereas chronic alcohol consumption may contribute to hypertension and dilated cardiomyopathy. Moderate consumption of alcohol (18-20 g daily, roughly equivalent to 50-100 ml of whiskey) decreases the risk of coronary artery disease by increasing HDL and decreasing LDL cholesterol. Ethanol is metabolized to acetaldehyde (by alcohol dehydrogenase) and finally to acetic acid (by aldehyde dehydrogenase). Disulfiram (antabuse) and several drugs (chlorpropamide, cefoperazone, moxalactam, cefamandole, metronidazole, griseofulvin etc.) cause inhibition of aldehyde dehydrogenase resulting in accumulation of acetaldehyde. Acetaldehyde may lead to severe distressing symptoms known as disulfiram like reaction. Disulfiram like reaction is Chronic alcohol consumption induces microsomal enzymes. More generation of caused by : toxic metabolite (NAPQI) of acetaminophen is responsible for increased risk of Chlorpropamide hepatotoxicity in alcoholics. Cefoperazone Alcohol increases the chances of hypoglycemia in diabetic patients taking insulin Moxalactam and other oral hypoglycemic agents. Cefamandole Metronidazole reatment of lcohol ependence Griseofulvin T A D Alcohol can produce physical and psychological dependence. In the treatment of alcohol 334 https://kat.cr/user/Blink99/  Central Nervous System dependence, major aim is to prevent withdrawal symptoms first and to avoid relapse of addiction thereafter. Naltrexone is an opioid anta- gonist that can be used to Benzodiazepines (chlordiazepoxide and diazepam) are given to prevent reduce alcohol craving. withdrawal. These are long acting CNS depressants and can be withdrawn gradually. Naltrexone is an opioid antagonist that can be used to reduce alcohol craving. Acamprosate is an NMDA antagonist that can be used for maintenance therapy Drugs decreasing alcohol of alcohol abstinence. craving Disulfiram can be used in psychologically dependent persons who are motivated None – Naltrexone Of – Ondansetron to quit alcohol. It is contraindicated in physically dependent individuals. The – Topiramate Disulfiram produces severe distressing symptoms (like flushing, headache, Above – Acamprosate vomiting, visual disturbances and mental confusion) after intake of alcohol. These symptoms are due to accumulation of acetaldehyde. Due to these symptoms, individual’s resolution to quit alcohol is strengthened. Topiramate and ondansetron can also decrease alcohol craving. et yl lco ol ( et anol) M h A h M h It is metabolized to formaldehyde (by alcohol dehydrogenase) and finally to formic acid (by aldehyde dehydrogenase). Accumulation of formic acid may result in lactic acidosis (high anion gap metabolic acidosis), blindness and death. Specific toxicity of formic acid is retinal damage leading to blindness. Methanol poisoning can be treated by supportive measures, gastric lavage and sodium bicarbonate (to treat acidosis). Ethanol is useful because General Central Nervous it competitively inhibits the conversion of methanol to formic acid. Fomepizole can also be used in methanol poisoning because it is a specific inhibitor of alcohol dehydrogenase. Folic acid or folinic acid can also be used because folate dependent systems are responsible for conversion of formic acid to CO2. Pharmacology t ylene lycol E h G It is used as a solvent and as an anti-freeze in industry. It is metabolized to glycolaldehyde System and glycolic acid. At toxic levels, it can cause renal tubular acidosis with excretion of oxalate crystals in the urine. Fomepizole is the drug of choice for the treatment of ethylene glycol poisoning. pioid O s These are the substances obtained from the crude extract of Papaver somniferum (poppy plant). Morphine is the prototype opioid and acts by agonistic activity on µ, k and d receptors. ction mediated y opioid receptor A s b s µ k d Sedation Dysphoria (Psychomimetic effects) Spinal Analgesia Analgesia Constipation Modulation of hormone and Constipation Analgesia NT release Respiratory depression truncal Rigidity eUphoria Miosis Certain endogenous peptides (endorphins, dynorphins and enkephalins) act on these opioid receptors to produce analgesic effects. Recently a new endogenous peptide, nociceptin is isolated that acts on nociceptin/orphanin FQ (N/OFQ) or orphanin like receptors (ORL1) 335 https://kat.cr/user/Blink99/  Review of Pharmacology Endogenous peptide Major action on receptors Endorphin µ Dynorphin k Enkephalin δ Nociceptin N/OFQ armacokinetic Ph s Sufentanil is the most potent whereas meperidine (pethidine) and propoxyphene are the least potent opioids. Pethidine can result in sei-zures Morphine is metabolized mainly to morphine-3-glucuronide (M3G) that has if used for prolonged periods, neuroexcitatory properties. Approximately 10% of morphine is metabolized to in patients with renal failure or active product M6G. Renal failure can lead to accumulation of these metabolites those taking MAO inhibitors (due to accumulation of norpethidine). and can result in seizures (due to M3G) or prolonged opioid action (due to M6G). Pethidine is metabolized mainly to meperidinic acid by MAO and very little is demethylated to norpethidine. Latter has seizure inducing and cumulative properties. Pethidine can result in seizures if used for prolonged periods, in patients with renal failure or those taking MAO inhibitors (due to accumulation of norpethidine). Central Nervous System ction of pure opioid A s s Pure agonists include morphine, methadone, pethidine, levorphanol, codeine, hydrocodone, oxycodone and propoxyphene. Actions of these drugs are: 1. S ctions CN A Morphine produces spinal and supraspinal analgesia by acting on µ, κ and δ receptors. Fentanyl is responsible for post operative muscle rigidity µ receptor opioids have dependence producing actions due to euphoric action. κ whereas succinylcholine causes receptors mediate psychomimetic effects (dysphoria). Tolerance develops to all actions of opioids except 3C (Constipation, convulsions and constriction of pupil) ­ post operative muscle pain and fasciculations. Opioids produce marked sedation but chances of sedation are less with pethidine and fentanyl. Opioids can produce respiratory depression and cough suppression. Miosis can occur with morphine use and pin point pupil is a valuable sign in diagnosis of opioid poisoning. Highly lipid soluble drugs like fentanyl, alfentanyl and sufentanil can result in truncal rigidity on rapid i.v. infusion. By stimulating CTZ, opioids can result in nausea and vomiting. 2. eripheral ffects P E Opioids have no direct effect on heart except pethidine and pentazocine (that 336 https://kat.cr/user/Blink99/  Central Nervous System increase heart rate). Blood pressure may decrease due to depression of vasomotor system and release of histamine. Constipation can result due to decreased motility and increased tone of GIT. Alvimopan is a peripheral opioid antagonist developed for paralytic ileus. Opioids increase intrabiliary pressure by constricting biliary smooth muscle. (C/I in biliary colic). These may aggravate bronchoconstriction in asthmatics by releasing histamine. (C/I in asthmatics). Spinal or epidural administration of opioids may result in intense pruritus over lips and torso (due to histamine release). ction of ixed goni t -antagoni t A s M A s s s s Buprenorphine is partial agonist at receptor with k and d antagonistic property. It m is useful as an analgesic and as an alternative to methadone for the management of