cns-123.pdf

Central nervous system (CNS) BY: DR. ELHAM SULTAN Nervous system Anatomical subdivision of the brain  Functions:  Forebrain:  Cerebral cortex: thought, speech, perception & reasoning  Basal ganglia: voluntary movement  Limbic system: behavior, emo...

Central nervous system (CNS) BY: DR. ELHAM SULTAN Nervous system Anatomical subdivision of the brain  Functions:  Forebrain:  Cerebral cortex: thought, speech, perception & reasoning  Basal ganglia: voluntary movement  Limbic system: behavior, emotional reaction, learning & memory  Thalamus: sensory processing, pain sensation  Hypothalamus: body temperature regulation, emotions, sleeping, hunger, thirst & sexual response  Midbrain: vision & hearing  Hindbrain:  Cerebellum: movement, balance & posture  Pons: respiration & relays sensory information between the cerebrum down to the cerebellum & medulla oblongata  Medulla oblongata: heart rate & blood pressure regulation  Brain neurotransmitter (NTs)  Amino acids: 1. GABA: major inhibitory NTs in the CNS, act on GABA-A & GABA-B receptors, BDZs act by enhancing GABA action, Picrotoxin is the non-competitive antagonist of GABA-A receptor 2. Glycine: inhibitory NTs in the spinal cord, act on glycine receptors (opening Cl- channels, Strychnine is selective glycine receptor blocker 3. Aspartate & glutamates: both excitatory NTs in CNS, act on NMDA receptor  Acetylcholine: excitatory NTs in the basal ganglia (act on M1 receptor), blocked by atropine  Monoamines: 1. Dopamine : exert a slow inhibitory action on CNS 2. Norepineherine (NE): mainly on locus coeruleus & lateral tegmental field 3. Serotonin (5-HT): has both excitatory (5HT3) & inhibitory (5-HT1A) effects  Peptides: 1. Opioids: as Endorphins, Enkephaline & Dynorphins 2. Non-opioids: as Neurotensin, Neuropeptide & substance -P  Anxiolytic & hypnotic drugs  Anxiolytic: drug reduces anxiety  Hypnotic: drug induces sleep  Classification: I. Drugs affecting GABA action: BDZs, Barbiturates, Zolpidem II. 5-HT1A agonist (Buspirone) III. Other drugs : B-blocker, clonidine, antihistamine, antidepressants, alcohol  Benzodiazepines (BDZs) - DOC to treat anxiety & insomnia due to great margin of safety 1. long acting (t1/2 >24 hrs): Diazepam, Chlordiazepoxide, flurozepam 2. Intermediate acting (t1/2 = 5 -24 hrs): Alprazolam, Lorazepam, clonaazepam, oxazepam 3. Short acting (t1/2 < 5 hrs): Midazolam,, Triazolam  MOA:  Action: sedation, hypnosis, anesthesia, anticonvulsant, muscle relaxation, slight effect on CVS & respiration  PK: given orally & parenterally, all lipid soluble, bound to plasma proteins, pass brain, placenta & excreted in breast milk, redistribution to peripheral tissue occure to highly lipid soluble drugs as diazepam, metabolized by N-dealkylation & hydroxylation, their clearance decreased in old pts & pts with liver disease  Uses: anxiety & sleep disorder, panic disorder, epilepsy (petit male epilepsy use clonazepam, & diazepam in febrile seizure), muscle spasm & rigidity, preanesthetic medication & short surgical operations, alcohol withdrawal syndrome.  Adverse effects: drowsiness, confusion, ataxia, high doses cause tolerance ( due to ↓GABA-A receptor or ↑sensitivity of excitatory neurotransmitters as glutammat) & dependence, rebound insomnia after discontinuation, memory disturbance( in high doses )  BDZs anatgonist ( Flumazenil) GABA receptor antagonist, given IV b/c of its high hepatic first pass metabolism, has short DOA used by repeated injection, dose (0.2 mg IV one time over 30 sec, if no response after seconds repeated 0.5 mg every minute ( max total dose 3 mg).  Barbiturates 1. Ultra-short: thiopentone ( t1/2 = 3-8 hrs) 2. Short acting: Pentobarbitone ( t1/2 = 20-25 hrs), Secobarbitone ( t1/2 = 19-34 hrs) 3. Long acting: Phenobarbitone ( t1/2 = 24-140 hrs)  MOA: prolong GABA induced opening Cl- channel & enhance GABA inhibitory neurotransmition, also have inhibitory effect on the release of excitatory neurotransmition (glutamate), so more powerful than BDZs  PK: rapidly & completely absorbed from GIT, except thiopentone ( given IV), widely distributed including BBB, thiopentone is highly lipid soluble, so enter CNS rapidly, metabolized by oxidation in liver, phenobarbitone is microsomal enzyme inducer & can be enhance its excretion by alkalanization of urine  Action: similar to BDZs CNS: sedation at therapeutic dose, hypnosis, coma & death at large dose (inhibition of medullary center) CVS: minimal effect at therapeutic dose, hypotension at large doses due to depression in vasomotor center Respiration: respiratory depression at large dose, due to depression in respiratory center Liver: hepatic microsomal enzyme inducers  Uses: hypnotic to treat insomnia, anesthesia (Thiopental I.V), anticonvulsant (Phenobarbital used in grand-mal epilepsy), skeletal muscle relaxant, neonatal jauindce  BDZs preferred more than barbiturates b/c of: i. High TI ii. More selective on CNS iii. Mild physical dependence & tolerance iv. Little or No CVS & Respiratory depression v. Not significantly enzyme inducer, so less drug-drug interaction vi. Available specific antidote (Flumazenil)  Side effects:  Hangover, hypersensitivity reaction, CVS & respiratory depression, tolerance & dependence, I.V injection can cause apnea, laryngospasm, CVS collapse & hypotention  Contraindications: respiratory diseases, shock (hypotention), sleep apnea syndrome , liver & kidney disease, pregnancy, with other CNS depressants as alcohol  D-D interaction: 1. enzyme inducers, so ↑metabolism of oral anticoagulants, oral hypoglycemics, oral contraceptives, Vit D, dexamethasone 2. Poteniate CNS depressants (alcohol, analgesics & anaesthatics)  Zolpidem  Potentiate GABA by binding to a subset of the BDZs receptor family BZ1  Short acting hypnotic ( 2 hrs), antagonized by Flumazenil  Only specific hypnotic ( No anxiolytic, No anti convulsant)  Its advantages over BDZs: less hangover, less rebound insomnia on stopping the drug  Buspirone  Partial 5-HT1A agonist (sedation = antianxiety), has no muscle relaxant or antiepiletic effect, used to treat generalized anxiety disorder  Advantages: selective anxiolytic with minimal sedation resulting in no effect psychomotor skills ,no additive CNS depression with alcohol, not associated with abuse.  Disadvantages: delay onset of action (give response after 14 days), , no treat insomnia & panic disorder, may cause nervousness & excitement, cause tachycardia & hypertention with MAOIs or SSRIs ( dangerous serotonin syndrome)  Ethanol ( Ethyl alcohol)  CNS depressant producing sedation & hypnosis with increasing dose  Acts by potentiate GABA receptor & also inhibit glutamate excitatory on NMDA receptors  Metabolised to actaldehyde by alcohol dehydrogenase & then to acatate ( acetic acid ) by aldehyde dehydrogenas  Action: 1. CNS: at small dose (uncontrolled speech, laughing, euphoria), moderate dose (irregular gait, incoordination of movement, analgesic, hypnotic), large dose (RC & VMC depression, coma , death) 2. Chronic use is a risk factor of hypertension & stroke 3. stimulate gastric acid secretion, so not advisable for ulcer pts 4. Induction of hepatic ME, so chronic use may cause hepatitis & liver cirrhosis 5. Inhibit ADH secretion 6. Teratogenic effect (fetal alcohol syndrome = microcephaly, retard growth, short nose, malformation of eye & ear, cardiac abnormalities) 7. Tolerance & physical dependence  PK: rapidly absorbed from GIT, widely distributed, pass placenta, follow 1st order kinetic at small dos & zero order kinetics at high dose.  Use: skin antiseptic , as stringent used to harden skin to prevent bed sores, injection around nerves causes loss of transmission, treatment of methanol toxicity (competes with methanol for alcohol dehydrogenase enzyme, so the main product will be acetic acid instead of formic acid which not cause tissue damage & blindness (ethanol has more affinity for the enzyme than methanol)  Toxicity of ethanol: a. Acute toxicity : euphoria, blurred vision, hypothermia, vomiting, hypoglycemia, respiratory failure→ death b. Chronic toxcity (alcoholism): dependence, tolerance, addiction, liver cirrhosis, hallucination, decrease immunity  Management of acute ethanol toxicity: 1. Stomach wash with NaHCO3 2. O2 & artificial respiration 3. Glucose IV to treat hypoglycemia 4. Thiamine (I.V or I.M) 5. Correction of electrolytes  Management of withdrawal syndrome:  Signs & symptoms: agitation, anxiety, insomnia, hallucination, arryhmia & convulsion. These symptoms controlled by long acting sedative hypnotic as diazepam, clonidine & propranolol, I,V phenytoin to prevent convulsion.  Management of alcohol dependence:  Disulfiram ( block oxidation of acetaldehyde producing its accumulation ( flushing, throbbing, headache, nausea, vomiting, sweating, hypotention, confusion).  Other sedative & hypnotics  Ramelton  Selective agent at MT1 & MT2 subtype of melatonin receptors (promotion of sleep & maintaince the normal circadian rhythm)  Used to treat insomnia  Not produce dependence & withdrawal effects  Chloral hydrate  Its hypnotic effect due to its active metabolite trichloroethanol  Given as syrup for children, induce sleep in about 30 mins  Adverse effects: rashes, gastric discomfort, renal & hepatic failure  Antihistamine (1st generation as Doxylamine) Analgesic drugs  Opioids analgesic  Opiates: natural drugs derived from opium from plant Papever somniferum  opioids: synthetic drugs & the endogenous compounds that produce morphine-like effect  Endogenous opioid peptides are: Endorphins, Enkephalins & Dorphins → that bind to opioid receptors  Opioid drugs reduce the pain without loss of consciousness & induce tolerance & physical dependence  Also called narcotic drug Classification of opioid drugs Opioid receptors & their function Receptor type Functions Mue (µ1,2) Supraspinal analgesia, euphoria, respiratory depression, physical dependence, GIT motility Kappa (k1,2) Spinal analgesia, sedation, dysphoria, miosis Delta (δ 1, 2) Spina & supraspinal analgesia sigma Dysphoria, hallucination, stimulation of respiratory & CVS, mydriasis Epsilon Horectsmonal ef  MOA of opioid analgesics i. morphine stimulates specific opioid receptors in CNS stimulation of these receptors decrease the release of substance-P which responsible for pain transmission in the spinal cord ii. All opioid receptors are coupled to inhibitory G-protein that leads to K+ channels activation & Ca+2 channels inhibitory → leads to hyperpolarization of nerve cell iii. Inhibition of nerve cell leads to ↓ release of excitatory neurptransmitters  Strong agonists 1. Morphine (prototype) natural alkaloid Papever somniferum plant PK: absorbed slowly from GIT, so given usually parentrally, pass all tissues & coss BBB, Bioavialvility (25% reach blood if taken orally due to 1st pass metabolism), metabolised in liver by conjugation with glucuronic acid ( children & old pts can not metabolised it), 90% excreted by renal & 10% by other rotes DOA (4-6 hrs), & tolerance occures after 10-14 days  Pha. Action of morphine 1. CNS: Depressant effects Stimulant effects Sedation, analgesia, RC, Euphoria, excitation, CTZ cough center depression, (nausea & vomiting), miosis VMC, ACTH  Phrmacological action of morphine i. analgesia : relieve all types of pain ( especially sever pain) except itching (b/c morphine causes histamine release). The mechanism of releieving the pain by activation the receptors in:  Afferent pain conducting fibers (peripheral analgesia)  Spinal cord (spinal analgesia)  Thalamus, brain stem & cerebral cortex (supraspinal analgesia)  Limbic system : reduce emotional pain & induce euphoia ii. Sedation & euphoria iii. respiratory depression : inhibit RC directly in the brain, ↓the sensitivity of RC to CO2. contraindicated in pts with head injury b/c of cerebral V.D that result from PCO2 caused by respiratory depression may leading to ↑ ICP. Also, contraindicated in asthma & lung disease iv. On eye: acts on the Edinger-Westphal nucleus of oculomotor nerve & enhances parasympathetic stimulation to eye that results in miosis (pin point pupil). It ↓ IOP in normal & glucomatous eye v. CTZ: nause & vomiting iv. Cough center: cough suppression, not used b/c of addiction , weak agonists used as antitussive agents 2. GIT: ↓ secretion & delay gastric emptying rate of stomach, ↑ tone of the wall & sphincters but inhibit peristalsis of intestine (used in ttt of diarrhea). Also cause spasm of sphincter of biliary muscle leading to intrabilliary pressure &aggravates pain. Never give morphine alone in biliary or intestinal colic pain ( give it with atropine to antagonize the spasmogenic effect of morphine) 3. Urinary system : urinary retention (spasm of wall & sphincter), so not given for elderly pts with enlarged prostate 4. CVS: bradycardia, hypotention due to V.D & histamine release, so cntraindicated in shock pts 5. Skin: itching due to histamine release 6. Bronchi: BC , so not given in bronchial asthma 7. Uterus: prolongation of labor due to direct reduction of uterine muscle tone & indirect effect by blocking the oxytocin effect on uterus 8. Tolerance  Therapeutic uses: 1. Analgesic in sever pain 2. Anesthesia adjuvant in major surgery 3. Management of acute pulmonary odema: ↓ pain & anxiety, also causes vendilator due to histamine release, sopreloade & afterload, & inhibit RC so respiration return to normal rate & depth 4. Therapy of diarrhea or antitussive, but other prefered 5. Sever renal & intestinal colic pain with atropine  Adverse effects: 1. Respiratory depression 2. Vomiting 3. Hypotension, bradycardia 4. Allergy 5. Restlessness, hyperactivity, drowsiness 6. Urinary retention, constipation 7. Miosis 8. Tolerance & dependence  Contraindications:  Head trauma, bronchial asthma, hypotension, bradycardia, old pts with enlarged prostate, biliary colic, myxedema ( hypothyrodism) due to pts with myxedema have exaggerated response to morphine & also those pts suffering from bradycardia, liver failure, old people & children, undiagnosed abdominal pain  Toxicity of morphine : 1. Chronic ( addiction) toxicity : signs ( miosis, itching, behavioral changes, loss of appetite) 2. Sudden withdrawal syndrome ( after 12-24 hrs) : palpitation, headache, restlessness, tremor, sweating , diarrhea, nervousness  Treatment of withdrawal syndrome: 1. give methadone: has long t1/2, slowly released & slowly disappeared & reduce the dosegradually 2. Clonidine: suppress sympathetic outflow (sedation) 2. Acute toxicity: ( cauma, respiratory depression, hypotention), diagnosed by pin point pupil. Treated by: i. Ventilator ii. Opiod blocker (Nalaxone I.V iii. IV fluid to correct BP iv. GIT lavage  D-D interactions: 1. CNS depressants as sedative, hypnotics, alcohol 2. Antipsychotic & antidepressant potentiate the sedative effect of morphine 3. MAOIs with opiod produce sever respiratory depression Hydromorhone & Oxymorphone: (like morphine) 2. Methadone  Potent Mu agonist, also block NMDA receptors  Has equal potency to morphine as analgesic, but less euphoria  Orally active & has long DOA (24 hrs) b/c its plasma protein binding, not used parenteral  Used in ttt of chronic morphine addiction (main use) b/c it is less addictive & easily to gradual withdrawal ( less withdrawal symptoms) & as analgesic in sever pain  Can cause arrhythmia in toxic doses 3. Meperidine  Opioid agonist with anticholinergic effect  Uses: sever pain, biliary & renal colic alone ( have atropine like effect), preanesthetic medication, labor (less respiratory depression to fetus) b/c of short DOA & not delay the birth process, can used in asthmatic pts b/c not cause release of histamine  May cause convulsion due to its metabolites(converted to Nor-mepiridine that is neurotoxic & stimulate serotonin morphinereceptor, so may causingmeperidine serotonin syndrome) -Natural -Synthetic -Slow onset, Long DOA (6-8 hrs) - faster onset, Short DOA (2-4 hrs) -Very potent as analgesic -10% analgesia as codeine - Strong addictive -Weak, less addictive -Narcosis -excitation -Respiratory & VMC depression -No -Cough depression -No -CTZ stimulation -Less emetic -Miosis -Mydriasis -Spasmogenic -spasmolytic -Histamine release - NO 4. Fentanyl, alfentanile,sufentanil  more potent than morphine as analgesic (80 times), short DOA (15- 30min)  Due to its extensive 1st pass metabolism in GIT, not given orally. It is used as skin patches, parenteral, epidural  used in combination with droperidol to induce neuroleptanalgesia ( needed in intubation, changing burn dressing, the emetic effect of fentanyle is blocked by droperidol (D2 blocker).  Used I.V anesthetic in cardiovascular surgery  May cause truncal rigidity when given rapidly, so given by infusion  Safe for renal failure pts, b/c non-nephrotoxic & don’t depend on kidney for elimination 5. Heroin  Is an acetyle- morphine, very potent Not approved for clinical uses, b/c produce great degree of euphoria (abuse & highly addictive)  Moderate agonists  Codiene , dihydrocodiene  Is methyl morphine , so in liver convert to morphine(demethylation)  60% bioavailability, Less potent, less euphoria  Has antitussive activity  Used with aspirin & paracetamol as analgesic  Weak agonists  Dextromethorphan, noscapine, propoxyphene  Used in cough mixtures with no addictive effect  Diphenoxylate , loperamide  Opiod agonists act peripherally only ( not pass BBB)  Used with atropine in ttt of diarrhea (↓ motility & ↓ water reabsorption)  Mixed agonist-antagonist  Pentazocin, butorphane, nalbuphine  Act as K agonist & µ antagonist  Used in moderate & sever pain  Less respiratory depression & Not addictive  May cause dysphoria & nightmares, & withdrawal syndrome  Buprenorphine  Acts as partial agonist on µ receptor  Tramadol  Synthetic analog of codiene, weak µ agonist, inhibit uptake of NA (i.e ↑ NA not as morphine ), block 5-HT2 receptor. has analgesic activity, may cause seizure, respiratory depression, & addiction. Used for mild-moderate pain  Opioid antagonist  Nalaxone  Used IV , has Short DOA(2-4 hrs)  used in emergency & in a acute opioid toxicity to prevent respiratory depression, & management of apenic infant after birth when the mother received an opioid analgesic  Naltrexone  Used orally, long DOA (10hrs)  Beneficial effects in treating chronic alcoholism  Nausea is the main side effect  Used to treat morphine addiction after complete withdrawal Antiepileptic drugs (AEDs) By: Dr. Elham Sultan   Definition: A chronic neurolological disorder characterized by disturbances of electrical activity in the brain with associated motor, sensory &behavioral changes ( i.e seizure). The groups of unstable neurons that initiate the seizure called epileptic focus or seizure focus The site of origin of the abnormal neuronal firing determines the symptoms that are produced. E,g:  motor cortex involved →pt experience abnormal movement or generalized convulsion  Parietal or occipital lobe → include visual, auditory & olfactory hallucinations  Seizure may : a. Remain localized (focal or partial epilepsy) b. Spread (generalized epilepsy)  Etiology A. Primary (idiopathic) B. Secondary due to:  Change in physiological factors (extreme acidosis or alkalosis, hyponatremia, hypocalcemia, hypoglycemia) & fever  Changes in environmental factors (sleep deprivation, alcohol intake,& stress)  Local causes ( as trauma, meningitis, tumor)  Drugs as CNS stimulants, antipsychotic, sudden withdrawal of BNZs & barbiturates  Pathophysiology: i. Change in neurotransmitters (↑excitatory as glutamate or ↓ inhibitory as GABA) ii. ↑ Membrane permeability to ions (Ca+2, Na+)  Classification  Partial Seizure Start locally (60%) & divided to: 1. Simple partial (Jacksonian): at any age without loss of consciousness, epileptic focus in the motor cortex, convulsion in single group of muscle or limb, lasts for 2 min. 2. Complex partial (Psychomotor ): impairment of consciousness for 30sec-2min, epileptic focus in the temporal lobe, disturbances of cognitive, psychomotor (chewing, diarrhea, urination), & sensory hallucinations (smell or taste)  Generalized seizure Begin locally, rapidly spread affecting whole brain, may convulsive or non- convulsive, immediate loss of consciousness, (40%), divided to : 1. Tonic-clonic (grand-mal) seizure: most common, tonic rigidity of all extremities with clonic jerking, bite his tongue with salivation, lose control of bladder or bowel, lasts for 3-4 mins 2. Absence (petit mal) seizure : common in children (4-12 y), brief impairement of consciousness with no motor manifestations , rapid eye blinking or lips tremor, lasts 3-5 sec 3. Myoclonic seizure : jerking of a single or muscle group without loss of consciousness, rare & occur as a result of hypoxia, uremia, encephalitis or drug poisoning 4. Atonic seizure : sudden loss of muscle tone causing person to fall down 5. Status epilepticus: sever sustained seizure without period of recovery( fatal). Lasts for > 5mins 6. Febrile seizure: young children with illness accompanied with high fever, consist of generalized tonic-clonic convulsion with short duration  First aid for seizures  Do: 1. Remove harmful objects nearby 2. Cushion their head 3. Aid breathing by gentle placing in recovery position  Don’t: 1. Restrain the person movement 2. Put anything in the mouth or giving anything to eat & drink until fully recovery  Management: Therapy is symptomatic, but no prophylaxis or cure is available The goal of therapy is to ↑the seizure control &↓ drug side effects & ensure compliance Antiepileptic is indicated when there is 2 or more seizures occurred in short interval (6m-1 year) Drug choice depending on: a. Classification of seizure, frequency & severity b. Pt’s age & health state c. Data on efficacy, tolerability, safety & pharmacokinetics Starting treatment (start low, go slow)   Classification of antiepileptic drugs (AEDs): Classical Newer (before 1990) (after 1990) Phenytoin Vigabatrin Phenobarbital Lamotrigine Primidone Famotrigine Carbamazepine Felbamate Ethosuximide Gabapentin Valporic acid Tiagabine Benzodiaepines (BNZ) Topiramate AEDs act by: I. Block the initiation of the electrical discharge from the focal area II. Prevent the spread of abnormal electrical discharge to adjacent brain area AEDS prevent depolarization of neurons by: a. Modification of ion conductance (direct membrane stabilization) b. Inhibition of excitatory (glutameric)activity c. Stimulation of inhibitory (GABAergic) transmission  They do their action by ! 1. ↓ Axonal conduction by preventing Na+ influx through fast Na+ channels E.x: Carbamazepine, oxcarbamazepine, phenytoin, also at high doses barbiturates & valporate.lamotrigine , topiramate 2. ↓ Presynaptic Ca+2 influx through type T channels in thalamic neurons E.x: Ethosuximide, Valporic acid. Lamotrigine 3. Inhibitory tone through: i. Facilitation GABA mediated hyperpolarization (Barbs, BZs) ii. Inhibiting GABA metabolism (valporic acid & vigabatrin) iii. Or action on reuptake of GABA (Tiagabine) 4. Excitatory effects of glutamic acid: iv. Block AMPA receptors ( lamotrigine & topiramate) v. Block NMDA receptors (Felbamate & phenobarbital)  Mechanism of action of AEDs   Phenytoin Oldest AEDs Fosphenytoin (prodrug) used for parenteral use Slow oral absorption, High plasma protein binding, low TI (10-20mcg), so dosage should be small & the serum level should be monitored periodically to avoid toxicity or ineffectiveness MOA: stabilizes neuronal membranes by↓the flux of Na+ (block voltage gated Na+ channels) Use: grand male epilepsy (DOC), partial seizure (simple & complex), status epilepsy (I.V), cardiac arrhythmia & in digitalis toxicity. Not effective in absence seizure & may worsen it.  Side effects: 1. Neurologic: Daiplopia (double vision), ataxia, hallucination, cognitive impaired 2. Haematologic: Megaloblastic anemia (due to↑ folic aid metabolism & ↓intestinal absorption) 3. Gingival (Gum): gingival hyperplasia 4. Liver: heptotoxicity 5. Dermatological: rash, dermititis, pruritis & hirsutism 6. Metabolic: hyperglycemia & glycouria (due to inhibition of insulin release), osteomalacia (due to↑ vit D metabolism) 7. GIT disturbance 8. Teratogenicity: Fetal hydantoin syndrome (cleft lip & palate, congenital heart disease, slowing growth & mental deficiency) N.B: Carbamazepine is the alternative drug for phenytoin in females due to unwanted side effect  Drug interactions: a. Phenytoin is an enzyme inducer (↑ metabolism of anticoagulant, oral contraceptive, theophylline, methyledopa &levodopa) b. Chloramphenicol, cimitidine, warfarin & isoniazide inihibit phenytoin metabolism (i.e. ↑ its plasma concentration) c. Carbamazepine, phenobarbitaone & ethanol enhance phenytoin metabolism ( i.e.↓its level) d. Aspirin, sulfonamide & phenylbutazone can displace phenytoin from plasma protein→ toxicity  Carbamazepine (Tegretol)(CBZ) Similar to phenytoin Absorbed slowly, enters brain rapidly (lipid soluble), potent inducer of hepatic enzymes, t1/2 reduces over 2-3 weeks Oxcarbazepine: derivative of CBZ with less potent & less side effects MOA: block Na+ channels Uses: grand male epilepsy (alternative to phenytoin), partial seizure (DOC in simple & complex), has antidepressant & antipsychotic effects (so used in manic depressive pts). Not effective in absence or myclonic seizure Adverse effects: allergy, neurological (ataxia, diplopia), GIT disturbances, respiratory depression, hepatitis, anemia Drug interactions: It is enzyme inducer (↑metabolism of theophyline, warfarin & some hormones), complex drug interactions with other anticonvulsant agents, its metabolism inhibited by drugs as cimitidine, isoniazid & erythromycin  Phenobarbital Old antiepileptic, & safest one, but has sedative effects Well absorbed, easily penetrate to brain, enzyme inducer Considered a DOC in infant seizure MOA: altering Na+ conductance as phenytoin, enhance GABA receptor, block excitatory glutamate Uses: for simple partial (not effective in complex), grand male& febrile seizure. Not effective in absence seizure Adverse effect: sedation, cognitive impairment, behavior changes, osteomalaalcia, rash, can cause grand male epilepsy when withdrawn suddenly Drug interactions: enzyme inducer, so↑ metabolism of oral contraceptives & oral anticoagulants, and isoniazid & chloramphenicol ↓its metabolism  Primidone Metabolized to phenobarbital and phenylethylmalonamide Alternative in partial & tonic-clonic seizure Absorbed completely, low PP binding Should started slowly to avoid sedation & GI problems Used with CBZ & phenytoin Ineffective in absence seizure Its MOA may closer to phenytoin than Barbiturates Toxicity same as phenobarbital (sedation occurs rapidly & GIT complaints)  Valporic acid Is carboxylic acid with antiepileptic effect, its amides & esters are also active. Available as tablet & syrup for children food delay its absorption, high PP binding Metabolized by oxidation (80%) & by conjugation (20%) MOA: ↑ GABA level in brain by inhibiting GABA transaminase (breakdown GABA), facilitate glutamic acid decarboxylase, ↑ membrane K conductance, block Na channels Use: tonic-clonic, partial, absence (second choice due to its hepatotoxicity) seizure, DOC in myoclonic epilepsy, management of bipolar disorders & migraine prophylaxis Adverse effects: allergy, hair loss, GIT upset, ↑ appetite &wt, fatal hepatotoxicity, teratogenicity (Spina bifida) Drug interactions: enzyme inhibitor (inhibit metabolism of other AEDs) & can displace phenytoin from plasma protein  Ethosuximide DOC for absence (petit mal) seizure, not effective in other types High efficacy & safety Completely absorbed orally, not plasma protein or fat binding, metabolized by hydroxylation MOA: Block T-type Ca+2 channels especially in thalamic neurons (theses channels responsible for generating the rhythmic cortical discharge of an absence attack) Adverse effect: GIT distress, lethargy & fatigue, headache & dizziness, rare hypersensitivity reactions (steven-Jhonson syndrome)  Benzodiazepines (BDZs) Diazepam is DOC in status epileptic (faster action) Clonazepam (most potent) is effective in absence & myoclonic seizure, but tolerance develops Clorazepate is effective in partial seizure with other AEDs All BDZs have sedative ppt (causing drowsiness, ataxia, fatigue, behavioral changes), and may cause respiratory & cardiac depression when give I.V  Newer AEDs May used as mono therapy or as add-on in resistant case of epilepsy  Vigabatrin Irreversible inhibition of GABA transaminase enzyme Rapid absorbed Use: for partial seizure, infantile spasm Adverse effect: drowsiness, dizzness, wt gain, agitation, confusion, psychosis , so contraindicated if preexisting mental illness is present  Lamotrigine Inhibit glutamate & aspartate release, block Na channels Use: in partial, generalized grand-mal, absence seizure Side effect: rash & minor CNS effect  Gabapentin Analogue of GABA that does not act on GABA receptors, it may alter its metabolism, non- synaptic release and transport Use: as an adjunct in partial & grand-mal epilepsy Adverse effects: Dizziness, ataxia, headache, tremor  Felbamate Effective against partial seizure but has sever side effects ( so it has been relegated to a 3rd line drug used only for refractory cases) Adverse effects: aplastic anemia, sever hepatitis  Topiramate Block Na channels, potentiate GABA activity, block glutammte receptors Use: in grand-mal epilepsy Adverse effects: fatigue, dizzness, cognitive slowing, nervousness, confusion  Tiagabine 99% bioavilable, highly protein binding MOA: blocks GABA reuptake into presynaptic neurons by inhibition of GABA transporter-1 (more GABA available for receptor binding enhanced inhibitory activity) Use: partial seizure Adverse effects: skin rash, GIT discomfort, dizziness, difficulty concentration, nervousness, confusion, depression, psychosis Levetiracetam is marketed since 2000, used alone or with other medications for all types of seizures. MOA: its novel mechanism of action is modulation of synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain ( i.e preventing the rupture of vesicles that have excitatory neurotransmitteres) side effects: drowsiness, dizziness or loss of coordination. Treatment of special types  Febrile seizure (diazepam used rectally)  Infantile spasms (corticosteroids, vigabatrine & clonazepam)  Status epilepsy (started with fast acting medication as IV diazepam, followed by slower acting as IV phenytoin, muscle relaxants  Epilepsy in pregnancy  Seizure very harmful for pregnant women, phenytoin & valporate are contraindicated )  Monotherapy better than drug combining  Lamotrigine & folic acid supplement, Vit K supplement (b/c antiepileptic drugs inducer enzymes & cause ↓in vit K that lead to hemorrhage Choice of AEDs Seizure type Drug of choice Recently developed simple Partial CBZ→ phenytoin→ Gabapentin, Complex partial valporate lamotrigine Partial with secondarily CBZ→ phenytoin→ vigabatrin generalized Phenobarbital valporate Generalized tonic-clonic CBZ→ phenytoin→ Lamotrigine (grand-mal) Phenobarbital valporate topiramate Absence (petit-mal) Ethosuximide→ lamotrigine valporate→ clonazepam Myoclonic seizure Valporate→ lamotrigine ,vigabatrin clonazepam Status epileptic Diazepam (IV)→phenytoin (IV)→ Phenobarbital (IV)  Summary: Drug Main use Phenytoin All types except absence seizure CBZ All types except absence seizure Valporate most types especially myoclonic seizure& including absence seizure Ethosuximide absence seizure Phenobarbital All types except absence seizure BDZs All types, diazepam used IV in status epilepsy viagabatrin All types lamotrigine All types Topiramate All types except absence seizure Neurodegenerative diseases BY: DR. ELHAM SULTAN Definitions:  Degenerative diseases characterized by progressive & irreversible loss of structure or function of neurons, including death of neurons  Include: Parkinso’s, Alzheimer's & Huntington’s diseases Amyotrophic lateral sclerosis (ALS)  Parkinso’s & Huntington’s diseases due to loss of neurons from structures of basal ganglia resulting in movement abnormalities, while Alzheimer's due to loss of hipopocampal & cortical neurons resulting in impaired memory & cognitive abilities.  Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a specific disease which causes the death of neurons controlling voluntary muscles & gradually muscles weakness due to muscle decreasing in size.  Parkinsonism  Is a progressive neurological disorder of muscle movement as a clinical consisting of 4 features: 1. Bradykinesia ( slowness of movement) , & in extreme cases, a loss of physical movement (akinesia) 2. muscular r rigidity 3. Resting tremor (usually disappears during voluntary movement) 4. Impairment of postural balance leading to disturbance of gait & falling 5. Non-motor manifestations ( depression, dementia, disturbance of sleep) Etiology A. Idiopathic Parkinson's disease: unknown cause with symptoms (tremor, rigidity, slowness of movement) B. Secondary Parkinson's disease: the causes could be hypertension, diabetes, a stroke (cerebrovascular accident), cardiac disease with symptoms (difficulty speaking, making facial expression or swallowing, problems with memory or cognitive) C. Other causes: viral encephalitis, CO & manganese poisoning, drug induced (as antipsychotic drug, respirine, methyl dopa Pathophysiology:  Loss of dopaminergic system (due to damage of dopaminergic neurons)& so relative excess of ACh Dopamine receptors  Dopamine present in brain & medulla & having different functions.  In brain: a. ↓ Dopamine in basal ganglia →parkinsonism, b. ↑ dopamine in meso-limbic region → Psychosis c. ↓ dopamine in anterior pituitary → ↑ prolactine (endocrine disturbance)  In medulla:  ↑ dopamine CTZ → vomiting - 5 dopamine receptors: 1. D1-like family (include D1 & D5 2. D2-like family (include D2, D3, D4  Dopamine agonists: these are known as the 'ergot' types and they include bromocriptine, pergolide and cabergoline. And non-ergot in type. These are apomorphine, pramipexole, ropinirole and rotigotine.  Dopamine antagonists They include metoclopramide, clozapine and phenothiazines.  Treatment: Aim: to enhance dopaminergic pathway or inhibit cholinergic pathway in the brain.  Classification: A. Drugs↑ dopaminergic activity 1. Dopamine precursors : Levodopa with carbidopa 2. Dopamine receptor agonists i. Ergot derivatives ( bromocriptine, pergolide) ii. Non-ergot derivtives (Pramipexole, Ropinirole) 3. COMT inhibitors(tolcapone, entacapone)→ ↑ transport of DA to brain 4. MAO-B inhibitors (selegline, rasagiline) → ↓ metabolism of DA 5. Amantadine (↑ release of endogenous release) B. Drugs that ↓ Ach activity (Trihexphenidyl, benzotropine mesylate, diphenhydramine & benzhexol) Physical therapy is helpful in improving mobility L-Dopa (levo-dopa)  Dopamine can’t be given in the treatment of PD as it does not penetrate the BBB  The most effective drug used  It is the metabolic precursor of dopamine  MOA: in the brain, it is converted to DA by decarboxylation primiraly within the presynaptic terminals of dopaminergic neurons in the statium ( by action of L-aromatic amino acid decarboxylase). The DA produced is responsible for the therapeutic effectiveness of the drug.  N.B: more than 95 % of L-dopa is metabolized outside brain & less than 5% enters the brain  L-dopa is combined with peripheral decarboxylase inhibitor ( as Carbidopa or benesrazide) which not cross BBB→ this ↑ brain level of DA & ↓peripheral side effects  L-dopa (200-250 mg) + Carbidopa (25-50mg) = Sinemet®  L-dopa (50mg) + Benesrazide (25mg) = Madopar ®  Use : in PD ( does not stop the progression)  Adverse effects: A. Central effects: 1. long term use lead to “wearing off phenomenon”: each dose of L-dopa improves mobility after1-2 hrs, but rigidity & akinesia return at the end of the dosing interval. Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias ( excessive& abnormal involuntary movement), Pts may fluctuate btw being “off” having no beneficial effects from their medications, and being “on” but with dyskinesias, a situation called the “on/off phenomenon”. This can be corrected by giving drug holidays (3-21 days). 2. Mental effects: depression, agitation, anxiety, hallucination, euphoria 3. Dyskinesias: tremor B. Peripheral effects: GIT (anorexia, nausea, vomiting duo to DA stimulation in CTZ) , CVS (hypotension due to DA displaces NA from α1-receptor & cardiac arrhythmia). C. other effects: mydriasis, hot flush, gout precipitation, high blood urea& bilurubine, smell & taste abnormality  A abrupt withdrawal of levodopa may precipitate the neuroleptic malignant syndrome  Drug interactions: 1. Pyridoxine (Vit B6) enhance the extracerebral metabolism of levodopa & prevent its therapeutic effect unless a peripheral decaroxylase inhibitor is also taken. 2. Levodopa should not be given for pts taking MAOI or within 2 weeks of their discontinuance, b/c this can lead to hypertensive crises 3. Amino acids in proteins delay its absorption, so not given with food 4. Anti cholinergic delay gastric emptying & ↓its absorption 5. Antipsychotic drugs (Antagonism effect)  Contraindications: Psychotic pts, angle-closure glaucoma, cardiac diseases, peptic ulcer Catechol O methyl transferase inhibitors( COMT)  Tolcapone, Entacapone  MOA: inhibit COMT which responsible for the conversion of L-dopa in peripheral to methyldopa. Elevated levels of methyldopa decrease the response levodopa for an active carrier mechanism to transport across BBB (CNS), Also, they prolong the action of levodopa by decreasing its peripheral mechanism.  Use : as adjuncts in pts receiving levodopa to reduce fluctuations in response ( not used alone)  Sid effects: GIT (diarrhea, nausea, anorexia), dyskinesia, hypotension, sleep disorders , hallucination ( side effects of L-dopa), serious hepatic necrosis ( is associated with tolacapone, so currently replace with Entacapone)  Monoamine oxidase inhibitors (MAOI)  2 types of MAO: 1. MAO-A metabolizes norepinephrine & serotonin 2. MAO-B metabolizes dopamine  Selegiline and Rasagiline MOA: these drugs inhibit MAO-B (selective), so retards dopamine breakdown Use: it has a week action if given alone, so used as adjunct therapy in pt with fluctuation response to L-dopa & may prolong L-dopa effect & reduce wearing off phenomenon Selegiline is metabolized to amphetamine & methamphetamine which may induce sleep disturbance (insomnia) & hallucination, Drug interactions: it should not be taken by pts receiving meperidine, selective serotonin reuptake inhibitors & tricycle antidepressants b/c of the risk of acute toxic interactions. The adverse effect of L-dopa may be increased by selegiline Rasagiline is more potent & not metabolized to amphetamine like substances  Dopamine agonists: A. Ergot derivatives (Bromocriptine & Pergolide)  Bromocriptine MOA: potent D2 receptor & partial agonist on D1 receptor. It inhibits of prolactine hormone from pituitary gland. Use: 1. In PD (combined with L-dopa or treatment of on-off phenomenon or who are refractory to treatment). 2. Hyperprolactenemia (b/c suppress prolactin production by inhibiting D receptor in anterior pituitary gland), Galactorrhea 3. In acromegaly ( b/c suppress somatotropin “GH” release)  Pergolide  Activate D1 & D2 receptors  More potent than bromocriptine as anti parkinsonism drug  Adverse effects: 1. Central ( Dyskinesias “less than L-dopa” & mental disturbances ), 2. GIT (anorexia, nausea, vomiting) 3. CVS ( hypotension, cardiac arrythmia, peripheral vasospasm) 4. Pulmonary fibrosis Contraindications: Psychotic pts, angle-closure glaucoma, card a diseases, peptic ulcer, peripheral vascular diseases B. Non-ergot alkaloids (Pramipexole, Ropinirole)  Pramipexole  New drug (has affinity to D3 receptor), effective in mild & advanced PD, not cause peripheral spasm as ergot  Side effects: GIT (nausea, vomiting, constipation) insomnia, dizziness, hypotension  Ropinirole (D2 receptor agonist, similar to Pramipexole in action & side effects)  Optimization of L-dopa treatment  Inhibition of dopa-decarboxylase in peripheral tissues by Carbidopa & Benserazide  Inhibition of dopamine degredation in CNS by Rasagiline  Reduction of L-dopa breaks down in the peripheral tissues by Entacapone Levodopa+ Carbidopa+Entacapone= Stalevo® Amantadine  Is antiviral agent against influenza A2 with unclear mode of action in parkansinsm. It has muscarinic antagonistic activity. It causes release of endogenous dopamine from the intact neurons in the nigrostratal tract. It may influence synthesis or reuptake of dopamine.  Use: less potent than levodapa,& its effects disappear only after few weeks of treatment ( not used alone)  Adverse effects: CNS disorders (restlessness, insomnia, hallucination & convulsion), peripheral edema, headache, heart failure, hypotension, urinary retention, GIT disturbances  Contraindications: should be used with caution in pts with seizure or heart failure  ACh blocking agents (Antimuscarinic)  Benzotropine, Biperidene, trihexyphenidyl & Benzhexol  MOA: they decrease excitability actions on cholinergic neurons by blocking the muscarinic receptors.  Use: they improve the tremor & rigidity of parkinsonism, but have little effect t on bradyskinesia. Also, effective against drug-induced parkinsonism & in treatment of early stages of PD when the imbalance btw dopaminergic & cholinergic is not so large  Adverse effects: atropin-like effects (mouth dryness, blurred vision, constipation, urinary retention, nausea, vomiting, cardiac arrhythmia) CNS effects (confusion, agitation, drowsiness, mood changes hallucination)  Withdrawal should be gradually in order to prevent acute exacerbation of parkinsonism  Contraindications: prostatic hyperplasia, obstructive GIT disease, glaucoma  Antipsychotic induced parkinsonism Treatment: 1. Drug withdrawal if possible 2. Anticholinergic drug is give ( no L-dopa b/c in this case dopamine receptors are blocked & L-dopa may aggravate the mental disorder) N.B: antimuscarinic may worsen tradive dyskinesia cause by antipsychotics (b/c of supersensitivity of D receptors or its up regulation) so when antimuscarinic are used, dopamine is dominant & this effect is aggravated  Alzheimer’s Disease  Is a slowly progressive neurodegenerative disease of the brain that is characterized by impairment of memory & cognitive ability.  Symptoms: normally progress in these stages  Stage 1 (mild) : getting lost, repetitive questions & conversations, losing things or misplacing them  Stage 2(moderate): forget recent events & their personal history, more disoriented, confused memories, loss reading & writing skills  Stage 3(Severe): lost ability to feed themselves, language is reduced to simple words, death is associated with complications of immobility Pathophysiology  The cause for the AD is still unknown  Several competing hypothesis exist trying to explain the cause of this disease. 1. Cholinergic hypothesis  The oldest hypothesis on which the most currently available drug therapies are based.  Ach is needed to passes signals along from cell to cell. A. Neurochemical changes in the brain occur: loss of cholinergic neurons or loss of Ach B. Cholinergic nerves are mainly affected: ↑Ach esterase (responsible for Ach breakdown) ↓Ach transferase (responsible for formation of Ach) 2. Amyloid hypothesis Enzymes act on the APP(amyloid precursor protein) and cu it into fragments to form beta-amyloid fragment. Abnormal disposition of β amyloid proteins around the neurons→ block the normal transport of electrical messages btw the neurons. 3. Tau hypothesis Tau proteins: are proteins that stabilize microtubules& they are a bundunt in neurons of the CNS. Changes in this protein lead to formation of neurofibrillary tangles inside nerve cell → disintegration of microtubules in brain cells (cell death) → alzheimer’s disease  Management: No cure for AD. The goal is to slow the progression, manage symptoms, change home environment & support family members  Anti-Alzheimer’s drugs: I. Cholinesterase inhibitors ( Tacrine, Donepezil, Rivastigmine, Galantamine) Tacrine was the first to become available, but has been replaced b/c of its hepatotoxicity MOA: bind with cholinesterase enzyme & inactivate it→↑ Ach concentration in Synapse Adverse effects: GIT disturbances II. NMDA “N-methyl-D-aspartate” receptor antagonists ( Memantine) Glutammate is useful excitatory neurotransmitter of CNS, although an excessive amounts in the brain cause neuronal excitotoxicity can lead to cell death MOA: 5-HT3 receptor blocker, nicotine receptors antagonist, D2 receptor agonist Adverse effects: dizziness, confusion, insomnia, hallucination III. Supplements(A diet rich in Vit E may ↓the risk of developing AD) Huntington’s disease (HD) is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. It deteriorates a person's physical and mental abilities during their prime working years.It is characterized by progressive chorea & dementia that usually begin in adulthood. The development of chorea seems to be related to imbalance of dopamine, Ach, GABA & other neurotransmitter in the basal ganglia. Drugs used are: 1. Reserpine & tetrabenazine ( deplete central neurotransmitters) 2. Phenothiazine, butyrophenones (block dopamine receptors) Depression By: Dr. Elham Sultan  Introduction  Def: is a mental illness characterized by pathological changes in mood, loss of interest or pleasure, feelings of low-self worth, disturbed sleep or appetite, low energy & poor concentration. ( i.e emotional due to↓ NE & biological symptoms due to ↓serotonin)  It can be severe & sometimes fatal.  Types: 1. Reactive depression (60 %): as a response to real stimuli as illness (MI, Cancer), poverty, or due to used drugs as alcohol & reserpine 2. Major depression (25%): genetically determined biochemical order. Characterized by feeling of sadness, hopelessness, mental slowing, loss of concentration, decreased energy & suicidal behavior. 3. Bipolar depression (Manic depression or mania)(10-15%): the patient swings between episodes of mania & depression.  Pathogenesis:  Depression is associated with changes in the level of neurotransmitters in the brain that help nerve cells to communicate. E.x: decrease in Serotonin, norepinepherine (NE),& dopamine. While mania is caused by overproduction of theses transmitters.  The level can be influenced by physical illness, genetics, substance abuse, diet, hormonal changes, brain injures or social circumstances.  Antidepressants  Drugs enhance alertness & may result in an increased output of behavior  Potentiate directly or indirectly the action of dopamine, serotonin, & noradrenalin  The purpose of antidepressants is to increase the neurotransmitters in the synapse.  Are used for the relief of symptoms of moderate & severe depression  Are taken for at least 4-6 months  Can be used alone or in combination with other drugs  Types: 1. Tricyclic anti-depressants (TCAs) 2. Monoamine oxidase inhibitors (MAOIs) 3. Selective serotonin reuptake inhibitors (SSRIs) 4. Atypical anti-depressants (others)  Tricyclic anti-depressants (TCAs)  First generations, has been employed since the 1950s  Largest group of drug agents used for treatment of depression  Referred to “ tri-cycli” compounds-3rings  well absorbed from GIT & metabolized in liver ( either by hydroxylation & conjugation to form glucoronides, or demethylation)  High protein binding & high lipid solubility (Large Vd), pass BBB  Low TI→ high toxicity (toxic dose 10mg/kg), Long t1/2  Once daily dose at night is often preferred  MOA:  Inhibit the reuptake of NE & 5-HT at presynaptic nerve terminals thus lead to increased their concentration in the synaptic cleft. Also TCAs block α1, H1 & M receptors.  Takes up to 4 weeks for all TCAs to have an effect  Drugs Notes Amitriptyline Prophylaxis in migraine Nortriptyline Metabolite of Amitriptyline used in liver disease Imipramine In nocturnal enuresis (bed wetting in children) Desipramine Metabolite of Imipramine used in liver disease Clomipramine Mainly used to delay ejaculation (rarely used  Adverse effects: in depression) Doxepine 1. sedation Treatment →due to block of insomnia H1 receptor 2. Wt gain (increase appetite) → due to block serotonin receptor 3. Atropine like effect → duo to block muscarinic receptor ( treated by Physostigmine) 4. Sexual dysfunction (delay of ejaculation) 5. Postural hypotension, flushing, headache, reflex tachycardia, odema → due to block α1 receptor 6. Seizure →due to lower seizure threshold (treated by diazepam) 7. Cardiotoxicity (fatal arrhythmia) in over dose → due to quinidine like effct (block NA reuptake) (treated by phenytoin or lidocaine) Note: No specific antidote due to the tissue level of free TCAs up to 100  Therapeutic uses: 1. Sever major depression 2. Enuresis in children older than 6 years by causing contraction of the internal sphincter of the bladder 3. Phobic & Panic disorders 4. Neuropathic pain 5. Obsessive compulsive disorder 6. Eating disorders  Contraindications: Benign Prostatic hyperplasia, urinary retention, glaucoma (atropine like effects) and epilepsy  Drug interactions: 1. Warfarine or aspirin: displacement in plasma protein→↑ free drug → toxicity 2. LME inhibitors or inducers 3. Clonidine (risk of sever hypertension) 4. Quinidine (arrhythmia) 5. MAOIs (increase release of NA→ sever hypertension crisis 6. SSRIs (serotonin syndrome)  Monoamine oxidase inhibitors (MAOIs)  Started used to treat depression in 1950s  Not widely used today, although small number of patients appear to be better in MAOIs than TCAs or other drugs  Readily absorbed from GIT, widely distributed, have active metabolites, inactivated by acetylation  Effects persist even after theses drugs are no longer detectable in plasma  MOA: MAO is a mitochondrial enzyme found in nerve & other tissues. It breaks down NA, serotonin & dopamine. a. MAO-A→ metabolizes NA, 5HT & dopamine b. MAO-B → metabolizes dopamine  Classifications of MAOIs: a. Non-selective MAO inhibitors (irreversible) ( E.x: Phenelzine, Isocarboxazid, Tranylcypromine) b. Selective MAO-A inhibitors (reversible) (E.x: Moclobemide, Corgyline)  Clinical uses: depression& phobic disorders  Side effects: insomnia, fatigue, tremors, atropine like effects, postural hypotension, wt gain, hepatotoxicity (phenelzine), sexual dysfunction  Drug interactions: 1. MAOIs + sympathomimetics → hypertensive crisis 2. MAOIs + TCAs → hypertension, hyperthermia & convulsion (serotonin syndrome) 3. MAOIs +SSRIs → serotonin syndrome 4. MAOIs +Tyramine rich food (cheese reaction) →↑ release of NA → hypertensive crisis. Treated byα-blockers as Phenotolamine or Na- Nitroprusside or B blockers 5. MAOIs + morphine → respiratory depression, hyperthermia & convulion 6. MAOIs + L-dopa → hypertension  Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine, Paroxetine, Sertaline, Fluvoxamine  More modern group of drugs in use  1st drug Fluoxetine available in 1988  Safest antidepressant for use (first line of treatment due to fewer side effects).  Good absorption orally, metabolized in liver, long t1/2, excreted from kidney, & fewer from feces  MOA:  Inhibition of serotonin reuptake into the presynaptic cell, increasing the level of serotonin leading to great post synaptic neuronal activity  Not have significant effect on NA & dopamine, so this drug affect just on emotional symptoms  Takes 2-12 week to produce improvement in mood.  Uses:  Depression, obsessive compulsive disorder, panic disorder, generalized anxiety, premenstrual dysphoric disorder, Bulimia nervosa  Adverse effects: anxiety, insomnia, agitation, sexual dysfunction, wt gain  Drug interactions:  with MAOIs or TCAs induce serotonin syndrome  Atypical anti-depressants  Bupropion, Trazodone, Mianserin  Mixed group of agents that have actions at several different sites  MOA: block 5HT2-A receptor They ease depression by affecting chemical neurotransmitters (NA, 5-HT & Dopamine) used to communicate between brain cells Act as a weak dopamine inhibitor & NA reuptake inhibitor  Uses: 1. Major depression 2. Bupropion is effective in tobacco smocking quitting as it prevent dopamine reuptake  Side effects: Anxiety, restlessness, blurred vision, agitation, seizure at high dose  Other therapy  Psychotherapy: increase the speed of recovery from a period of depression  Treatment using medical devices Electro-convulsion therapy (ECT) Used for severe major depression which not responded to antidepressants Has quicker effects than antidepressant therapy Electric current is applied while the pt under general anesthesia  Mania (Bipolar depression)  Extreme Mood swings that include emotional highs (mania or hypomania) to overly low “depressed” feel sad or hopeless and lose interest or pleasure in most activities. →Bipolar (Manic episodes, hypomanic episodes, major depressive episodes)  episodes of bipolar-related mania can last between three and six months. With effective treatment, a manic episode usually improves within about three months  Mixed episodes are defined by symptoms of mania and depression that occur at the same time or in rapid sequence without recovery in between.  Manic episodes ( exist for 1 week) involves grandiosity, irritability, high energy, racing thoughts and speech, and overactivity or agitation.  Hypomanic episodes ( milder of mania): exist for 4 days or longer  major depressive episodes ( 2 weeks or longer): felling of sadness, loss of interest  Causes: genetic factors, neurotransmitters factors ( as elevated of NE), hormonal imbalance, environmental factors as high stress,  Types of Bipolar Disorder 1. Bipolar I disorder involves periods of severe mood episodes from mania to depression. 2. Bipolar II disorder is a milder form of mood elevation, involving milder episodes of hypomania that alternate with periods of severe depression. 3. Cyclothymic disorder describes brief periods of hypomanic symptoms alternating with brief periods of depressive symptoms that are not as extensive or as long-lasting as seen in full hypomanic episodes or full depressive episodes. 4. "Mixed features" refers to the occurrence of simultaneous symptoms of opposite mood polarities during manic, hypomanic or depressive episodes. It's marked by high energy, sleeplessness, and racing thoughts. At the same time, the person may experience hopeless, despairing, irritable, and suicidal feelings. 5. Rapid-cycling is a term that describes having four or more mood episodes within a 12-month period. Episodes must last for some minimum number of days in order to be considered distinct episodes.  Treatment: a. Psychotherapy ( help to ↓relapse rates, improve life quality, improve symptoms) b. Pharmacological therapy  Lithium carbonate (drug of choice)  May used in combination with low dose of anxiolytic as Lorazepam & antipsychotic as Haloperidol to stabilize the behavior of the patient. OR Lithium carbonate is used during mania stage, while SSRIs is used during depression stage  Effective in 80-9-% of pts with antimanic effects occur within 2 weeks  P.K: absorption ( peak plasma level in 30mins-2 hrs), low TI, no protein binding, urinary excreted  Dose: 600-900 mg/day  MOA: the exact mechanism is unknown 1. Li+ interfere with resynthesis (recycling)of phosphatidylinositol biphosphate (PIP2) leading to depletion in neuronal membrane→↓ Inositol triphosphate (IP3) →↓ Ca+2 influx  Pre- Li+ workup: CBC, electrolytes, renal function tests, urin analysis, ECG, pregnant test.  Adverse effects: low therapeutic index, so not prescribed with other drugs a. Tremor (most common). Treated propranolol or by↓ dose b. CNS: confusion & convulsion c. GIT: anorexia, nausea, vomiting & diarrhea d. Kidney: polyuria , polydipsia ( nephrogenic diabetes insipidus), inhibition of ADH→ excessive thirst. Treated by↓ dose + thiazidr (block Li+ uptake by tubules) e. Thyroid: hypothyrodism ( Lithium compete with iodine) f. CVS: arrhythmia& hypotension g. Teratogenicity: in early pregnancy  Management & of Treatment Li+ toxicity 1. monitor serum Li+ level 2. Thyroid function test 3. Serum creatinine level Treatment of Li+ toxicity by dialysis  Drug interactions: 1. ACEIs or Thiazide (diuretic): due to depletion of Na+→↑reabsorption of Li+ due to compitition of Na & Li →↑serum Li level 2. NSAIDs: the excretion of Li+ is reduced in pt taking NSAIDs, b/c NSAIDs block PGs in kidney, ↓clearance of Li+ leading to↑ its plasma concentration 3. Aminophylin/theophylin: ↑Li+ excretion→ ↓ Li+concentration Antipsychotic drugs (neuroleptics) By: Dr.Elham Sultan  Introduction  Antipsychotic drugs (also called neuroleptic or major tranquilizers) are used primarily to treat schizophrenia (a biologic illness), but they are also effective in other psychotic states, including manic states with psychotic symptoms such as hallucination & delusions (false beliefs)  These drugs are not curative & don’t eliminate the chronic though disorder, but they often decrease the intensity of symptoms & permit the person with schizophrenia to function in a supportive environment.  Schizophrenia:  is a mental disorder characterized by combination of hallucination, delusions & disordered thinking & behavior (+ ve symptoms), and social isolation (-ve symptoms)  Causes & pathophysiology ( not completely understood)  Genetic, psychological & environmental factors, or difference in brain structure  Dopamine hypothesis: ↑dopaminergic activity in the mesolimbic  Treatment  Antipsychotic drugs are the first line for schizophrenia  Classification: A. 1st generation antipsychotic (Typical Neuroleptics) Antipsychotic effects due to blocking D2 receptors & have extrapyramidal side effects (tremor, dystonia, dyskinesia) i. Low potency ( as Chlorpromazine, Thioridazine) ii. High potency (as Fluphenazine, Haloperidol, Perphenazine) B. 2nd generation antipsychotic (Atypical neuroleptics) Effects due to block of both dopamine & serotonin receptors, have fewer extra pyramidal side effects & little or no effect on M,H or α receptor. Current antipsychotic therapy commonly comprises 2 nd generation agents to minimize risk of extra pyramidal side effects associated wit 1st generation (Aripiprazole, Clozapine, Olanzapine, sulpiride, Risperidone)  Pharmacological action:  CNS: Antipsychotic action (due to block D2 receptor in mesolimbic system), Antiemetic action (due to block D2 receptor in CTZ), Hypothermic action (by depression the heat regulating center in hypothalamus), large doses cause parkinsonism (due to block D2 receptor in basal ganglia)  CVS: hypotension (due toα- blocking effect, direct V.D, inhibition of vasomotor center), Tachycardia (due to atropine like effects & reflex from hypotension)  Endocrine: ↑ prolactine level (due to block D2 receptor in pituitary gland)  Clinical Uses: 1. Schizophrenia or mania 2. Antiemetic in small dose (not used in pregnancy) 3. Pre-aneasthetic medicationerse effects:  Adverse effects: 1. Extrapyramidal side effects (1 st generation) 2. Neuroleptic malignant syndrome ( hyperthermia, muscle rigidity, hypertension, sweating , convulsion), if happen drug must be stopped 3. Autonomic disturbance: Anti-muscarinic effect (atropine like), α- 1adrenoceptor block (postural hypotension) 4. H1 receptor block (sedation) 5. Endocrine effects (amenorrhea & galactorrhea in female, gynecomastia & impotence in male) 6. Weight gain with 2nd generation ( due to block serotonin receptor in brain making the patient hungry) 7. Arrhythmia ( due to block Dopamine peripherally) 8. Cholestatic Jaundice ( Chlorpromazine is most likely causing these side effects) 9. Agranulocytosis (W.B.C) ( commonly with Clozapine, so preserved as the last option )  Contraindications: hypersensitivity, glaucoma, Parkinson's disease, CVS disease  Drug interaction: a. Enhance sedative effects ( alcohol, barbiturates & BDZs) b. Block α-receptor, so can reverse the hypertensive effect of adrenaline CNS stimulants By: Dr. Elham Sultan  Introduction  CNS stimulants are drugs with few clinical uses & important of drug abuse  Factors that limit the therapeutic usefulness include 1. Physiological “physical” dependence 2. Psychological dependence “ addiction” 3. Tolerance to the euphoric & anorectic effects  Classified according to their action into: A. Psychomotor stimulants B. Brain stem stimulants (analeptics) C. Spinal cord stimulants D. Psychomimetic drugs (hallucinogens)  A. Psychomotor (cerebral) stimulants 1. Methylxanthines  Natural alkaloids of plant origin e.g tea leaves, coffee bean, cola seeds, coca & chocolate  They include: Caffeine, Theophylline , Theobromine  MOA: i. inhibit phosphodiesterase enzyme type-4(PDE4) → accumulation of cAMP responsible for V.D in SM ii. Block adenosine receptor →bronchodilatation  Pharmacological action: 1. CNS: caffeine is more selective & potent on CNS, stimulation of cerebral cortex→↑mental activity of alertness, stimulation of medulla→ stimulate RC, VMC, CIC, stimulation of spinal cord in large doses 2. CVS: +ve inotropic & chronotropic effect on heart 3. Kidney: diuretic effect due to inhibition of Na+ reabsorption 4. SM: spasmolytic effect on bronchi, GIT & urinary bladder 5. Secretion: ↑release of catecholamine & gastric HCL  Therapeutic uses: 1. Bronchial asthma e.g. Theophylline 2. Simple headache e.g caffeine +aspirin 3. Migraine headache e.g caffeine +ergotamine  Adverse effects: 1. CNS: insomnia, restlessness, tremors & convulsion 2. CVS: ↑HR(direct acting on heart), hypotension (central acting → inhibition of CIC) 3. GIT: ulceration  Drug interaction of theophylline (has low TI) Drugs ↑metabolism of theophylline (enzyme inducers) as phenytoin & barbiturates → ↓therapeutic effect Drugs ↓ metabolism of theophylline (enzyme ihibitors) as ketoconazole & erythtromycin → ↑toxicity 2. Nicotine Is active ingredient in tobacco Not currently used therapeutically MOA: a. in low dose → stimulate ganglia b. In high dose → block ganglia  Pharmacological action: a. CNS: nicotine is high lipid soluble →cross BBB, during smocking of low dose of nicotine produce some degree of euphoria, while high doses cause inhibition of RC & VMC. Nicotine is also an appetite suppressant b. Peripheral effect: stimulation of sympathetic ganglia & adrenal medulla → ↑heart rate & BP  Varenicline: acting as agonist of the nicotinic receptor, & partially stimulates the receptor without producing a full effect like nicotine. So, used to quite smocking 3. Cocaine  It is widely available & highly addictive drug  Obtained from leaves of coca plants  MOA: i. inhibit reuptake of monoamines (NE, serotonin & dopamine) ii. Block Na+ channels (local anesthesia)  Pharmacological action: a. CNS: powerful stimulation of the cortex & brain stem, ↑mental awareness & produce a feeling of euphoria, can produce hallucination & delusions, high doses cause tremor, convulsion & inhibit RC & VMC b. Peripheral effects: adrenergic stimulation tachycardia, VC & mydriasis  Side effects: Agitation, convulsion, hypertension, sweating, dependence. Toxic effect: fatal cardiac arrhythmia & respiratory failure 4. Amphetamine  MOA: 1. ↑ release of NE & dopamine & prevent reuptake 2. Powerful CNS stimulant  Uses: 1. Treatment of nacrolepsy (hypersomnia) & obesity 2. Attention deficiency hyperactivity disorder (ADHD)  Side effects: dependence & tolerance  Methylphenidate : as amphetamine but less side effects  B. Brain stem stimulants (analeptics)  Stimulate RC & VMC in medulla  produce convulsion in high doses  Use: in respiratory failure e.g, Doxapram (wide margin of safety) & Amiphenazole  Cardiozole & Picrotoxin (narrow TI) cause convulsion & have no clinical uses. C. Spinal Cord stimulants Strychnine Acts by blocking receptors inhibitory glycine Cause tonic convulsion, & death occur after 2-5 convulsions from spasm of diaphragm & respiratory muscle (modularly paralysis) This can treated by : specific antidote (mephenesin IV, stomach wash, using other anticonvulsants)  D. Psychomimetic drugs (hallucinogens) 1. LSD (Lysergic acid diethylamide)  Synthetic from ergotamine  MOA: stimulate 5-HT1, 5-HT2 receptors in CNS  Pharmacological action: mydriassis, hallucination, mood changes, depression & suicide  Side effects: tolerance 2. Tetrahydrocannabinol (Cannabis or Hashish) Stimulate cannabinoid receptors (CB1 & CB2) → ↓ release of NTs  MOA: Both CB1&CB2 cannabinoid receptors are couples to inhibitory G-proteins →inhibits the activity of adenylyl cyclase. The CB1 receptors are highly expressed through peripheral & central nervous system.  Effects: loss of sense of time, antiemetic effect, stimulate appetite, euphoria, red conjunctiva, High HR  Side effects: tolerance 3. Phencyclidine Is an analogue of ketamine, cause dissociative anesthesia & analgesia  MOA: inhibit reuptake of dopamine,NE & serotonin, has anticholinergic activity  Effects: numbness of extremities, staggered gait, slurred speech & muscle rigiditynn Drug Abuse By: Dr. Elham Sultan  Drug abuse  Drug abuse: Using the drug for non-medical purpose  Drug misuse: using the wrong indication of the drug  Dependence: is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use.  Classification of drugs abuse: 1. CNS depressants a. sedative-hypnotics: Barbiturates, BDZs, alcohol b. Narcotics: morphine, heroin, codeine, pethidine 2. CNS stimulants: caffeine, cocaine, amphetamine 3. Hallucinogens :LSD 4. Marijuana (Cannabis) 5. Inhalants a. Industrial solvents (toluene) b. Aerosol propellants (flurocarbones) 6. Organic nitrite (amyle nitrite) General Anesthesia BY: DR. ELHAM SULTAN  Introduction  Def: General anesthetics (GA) are drugs which causes reversible loss of all sensation & consciousness  The cardinal features of GA a. Loss of all sensation, especially pain b. Sleep (consciousness) & amnesia c. Immobility & muscle relaxation d. Abolition of somatic & autonomic reflexes  MOA:  Main sites of action are cortex, Thalamus & Hippocampus  Can also act at peripheral sensory nerves, spinal cord & brain stem  Molecular mechanism  potentiate Chloried Channel GABA-A receptor complex  Activation of ligand gated K channel that linked to several neurotransmitters (Ach, Dopamine, NA,5-HT)  Neuronal Nicotinic receptor  Antagonizing NMDA receptor  Ideal anesthetic:  For patient: pleasant, no nausea & vomiting, induction & recovery should be fast with no other effects  For surgeon: adequate analgesia, immobility & muscle relaxation, noninflammable & nonexplosive  For anesthetic drug: easy, wide margin of safety, potent, induce anesthesia rapidly & smoothly , rapid recovery, cheap, stable & easily stored, no react with tubing  Phases of Anesthesia 1. Pre-anesthesia: patient preparation (stabilize, sedate, start analgesia) 2. Induction: putting the patient to sleep 3. Maintenance: keeping the patient asleep (without awareness) 4. Recovery: waking the patient up  Balanced anesthesia  Regimen for balanced anesthesia 1. Pre-anesthetic medication (anxiolytics, analgesics, anti-muscaininc) 2. Induction (Thiopental, BDZ) 3. Maintenanace (Halothan, isoflurane or nitrous oxid) 4. Recovery (AChE inh, analgesics)  Stages of anesthesia  Stage I-Analgesia start with inhalation up to loss of consciousness, can hear, see & dream like state, reflexes & respiration normal, minor operations can be carried out).  Stage II-Excitement Delirium & combative behavior, rise & irregular in BP & respiration, chance of laryngospasm, pupils dilated, no procedure is carried out in this stage)  Stage III-surgical anesthesia Surgery may proceed during this stage. This stage started by regular respiration to cessation of spontaneous breathing, divided to 4 planes  Plane 1- regular respiration, irregular eye movement, loss of eyelid reflex  Plane 2- depression f chest respiration, fixed eye ball, Sk.M relaxation  Plane 3-more depression f chest respiration, mydriasis, loss of eyelight reflex & more Sk.m relaxation  Plane4- stop chest breathing, more dilated eye, more sk.m relaxation  Stage IV-Medullary Paralysis Cessation of breathing to failure of circulation, dilated pupil, low Bp, death, need to mechanichsl & pharmacological support. Treatment by using ventilation & doxapram IV infusion general anesthesia equipment  Preanaesthetic medications To relieve pt anxiety & produce amnesia (as BZDs) To prevent & control nausea & vomiting ( as Metaoclopramide) Supplement analgesic (as Morphine, Meperidine) Decrease secretions ( as Atropine)& vagal stimulation Decrease acidity & volume of gastric juice (H2 blocker) Induce muscle relaxation ( as Succinylcholine)  Selection of preanaesthetic drug Pt’s mental makeup Anesthetic agent to be used Type of surgery Presence of preoperative problems  Classifications A. Inhalational anesthetics i. Gases (Nitrous oxide, Cyclopropane) ii. Volatile Liquid( Ether, Halothane, Enfurane, isoflurane, Desflurane, Sevoflurane) B. I.V anesthetics i. Barbiturates ( Sodium thiopentone, Methhexitone) ii. Non-Barbiturates ( BNZ as diazepam & Midazolam, opioids as morphine & fentanyl, Ketamine, Etomidate)  Inhalational Anesthetics  Used to maintain anesthesia after I.V anesthetic administration  Depth of anesthesia depends on potency of the agent (Minimum alveolar concentration -MAC) & partial pressure (PP) attained in the brain  Induction & recovery depends on rate of changes of PP in the brain  MAC ( defined as the minimum alveolar concentration of inhalational anesthetic at one atmospheric pressure which produces immobility in 50% of patients when exposed to skin incision. E.g, one MAC of N2O=100. halothane=0.75, ether=2, enflurane=1.5. Halothane is 2 times more potent than enflurane. Individuals may require 0.5-1.5 MAC Pharmacokinetics:  Absorption: highly lipophilic, so rapidly absorbed from the lung into the blood & are transferred from the blood to the brain & other organs. Lung → → → → Blood → → → → Brain  Factors affecting inhaled anesthesia 1. PP of anesthetic in the inspired gas (Higher the inspired gas tension→ more anesthetic will be transferred to the blood) 2. Pulmonary ventilation ( delivery of GA to alveoli depends on ventilation , hyperventilation-more delivery per minute, hypoventilation-opposite effect) 3. Alveolar Exchange ( The GAs freely across alveoli, but if alveolar ventilation and perfusion are mismatched the attainment of equilibrium between alveoli & blood delayed, so induction & recovery both are slowed) 4. Solubility in blood ( determined by blood-Gas partition coefficient ) ( i.e., lower the blood –gas coefficient→ faster the induction & recovery as Nitrous oxide, while higher the blood –gas coefficient → slower the induction & recovery as Halothane 5. Solubility in tissue (most GAs are equally soluble in tissue as in blood, lipid soluble more rapidly enter & slowly leave adipose tissue  Elimination:  Anesthesia is terminated by redistribution of the drug from the brain to the blood & elimination of the drug by the lungs. They are enter & persist in adipose tissue for long periods-high lipid solubility & low blood flow. They are not metabolized except Halothane  Ether Colorless, highly volatile liquid with a pungent odor Produce irritating vapors, inflammable & explosive 85-90% eliminated through the lung Can cross the placenta  Advantages: 1. can be used without complicated apparatus 2. potent anesthetic & good analgesic 3. muscle relaxation, respiratory stimulation & bronchodilatation 4. wide safety of margin, 5. Does not sensitized the heart to adrenaline 6. Can be used in delivery 7. less hepatic or nephrotoxicity Disadvantages: 1. Inflammable & explosive 2. slow induction & slow recovery-nausea & vomiting 3. cardiac arrest, respiratory irritation 4. convulsion in children 5. cross tolerance-ethyl alcohol Precautions: not used in hot environment & with electro cautery  Halothane Fluorinated volatile liquid with sweet odor, non-irritant, non-inflammable & supplied in amber colored bottle, low cost used in developing countries. Commonly used in children due to its pleasant odor & not hepatotoxic Potent anesthetic, 2-4% for induction & 0.5-1% for maintenance & weak analgesic ( so usually used with N2O which potent analgesic)& weak hypnotic) 60-80% eliminated unchanged, 20% retained in the body for 24 hrs & metabolized  Advantages: 1. Quick & pleasant induction & recovery 2. Non-inflammable, electro cautery safe, non-irritant( no effect on secretion, bronchospasm, nausea &vomiting) 3. Not have pungent odour, Potent bronchodilator, so prefered in asthmatics & pts with airway proplems 4. Suitable for hypertensive pts  Disadvantages: 1. Costly, special apparatus required 2. Poor analgesic & poor muscle relaxant 3. Sensitize heart to Catecholamines- arrhythmia 4. causes hypotension by ↓CO (direct effect on heart muscle), bradycardia 5. Hepatic failure (rarely) due to immune response to trifluroacetylated proteins on hepatocytes after its metabolism 6. CNS: ↑ICP  Halothane on uterus Relaxation of uterine S.M Useful for manipulation of position of fetus in perinatal period (internal & external version of the fetus) Not useful as analgesic or anesthetic during labor b/c causes prolongation of labor & increase blood loss  Adverse effects: Hepatic failure (1:10000) Malignant Hyperthermia: a syndrome characterized by severe muscle contraction & heat due to massive Ca+2 released & occur in genetically susceptible pts with abnormal Ca channel at sacroplasmic reticulum SR Treatment: stop the agent, rapid cooling, 100% O2, I.V Dantrolene (to block Ca release from SR & ↓sk.m contraction)  Precautions: Proper history regarding exposure  Enflurane  Volatile liquid, non-inflammable  Advantages: 1. Significant muscle relaxation, so small dose required in abdominal surgery 2. Enhance the effect of non-depolarizing muscle relaxant (curare) 3. Does not sensitize myocardium to CAs 4. No hepatotoxicity  Disadvantages and adverse effects: 1. Produce seizures in high doses 2. Respiratory depression is more 3. Causes hypotension with depression of myocardial contractility 4. Same effects on uterus with postpartum bleeding  Isoflurane  Isomer of Enflurane & have similar properties but slightly more potent used in US  Advantages: 1. Rapid induction of anesthesia (10 mins) & rapid recovery 2. Good muscle relaxation, Bronchodilator 3. No hepatotoxic, no epileptic attack, less myocrdium depression, no sensitization to CAs ( no arrythmia) 4. No nausea & vomiting 5. Relax uterine muscles, potentiate NMB agents  Disadvantages: 1. Special apparatus needed 2. Causes respiratory depression & irritant to airways due to its pungent odour causing cough & laryngospasm 3. Hypotension due to it’s a vasodilator 4. Cause tachycardia at high concentrations b/c its direct effect on B1 receptor 5. Costly  Desflurane  Expensive, Pungent odour, so used for maintaince  Rapid onset & recovery due to low lipid solubility  Less toxic  Only causing BC, so not suitable for asthmatic pts  Sevoflurane:  Low pungent odour, so used in induction & maintaine  Rapid onset & recovery  Produce toxic metabolites (hepatotoxic)  Nitrous Oxide Laughing gas, Non inflammable, non-explosive, colorless & odorless gas Weak & low efficacy anesthetic Produce light anesthesia, so not used alone ( only as adjuvant with I.V anesthetics to give rapid induction)  Advantages: 1. quick & pleasant induction & recovery 2. Potent analgesic 3. No nausea & vomiting, not irritating to airways 4. Not toxic to liver, kidney & brain  Disadvantages: 1. Costly 2. Supplementation required 3. No muscle relaxation 4. Diffusion hypoxia (should used with O2 , 30% N2O:70% O2)  Uses: Weak anesthetic, so used as an adjuvant with other agents Obstetrics (without loss of consciousness) & terminal illness- 50%+O2 Maintenance anesthesia- 30-60% Good analgesic, so used in postoperative pain, change burn dressing, dental procedure  Precautions: Should used with 30% O2 Should avoided in pts with collection of air in pleural, pericardial or peritoneal space On prolonged use- bone marrow depression, Megaloblastic anaemia (↓vit B12 & folate) due to inhibition of methionine synthase (B12- dependent enzyme)  Intravenous anesthetics I. Barbiturates:  Sod. Thiopentone Ultra short acting (5-10mins) due to redistribution from the brain to other tissues (muscle & adipose tissue) , most commonly used in induction of anesthesia (20sec) Dose (3-5 mg/kg), repeated as required, T1/2 (9hrs), highly lipid soluble & cross BBB, slowly metabolized & accumulate in body fat, so may cause prolonged effect if given repeatedly & may cause hangover following recovery MOA: facilitate GABA action at GABA receptor resulting in Cl channel opening & hyperpolarization  Advantages: 1. Rapid induction & recovery 2. No CNS excitement 3. Patient directly goes into surgical anesthesia  Disadvantages: 1. No analgesic 2. No muscle relaxation 3. Ultra short-short procedure only 4. Potent cardiac & respiratory depressant, so replaced with Propofol  Uses: 1. Adjuvant to general anesthetics for major operations 2. Endoscopies with short acting muscle relaxant 3. Short surgical procedure 4. Status epileptics  Adverse effects (narrow safety of margin): apnea, hypotension, respiratory depression, pain, necrosis & gangrene if accidently injected into artery, porphyria, shivering, delirium during recovery  Contraindication: Porhyria, shocked patients, asthmatic patients  II-Non-barbiturates anesthetics  Etomidate: Wide safety margin, Used for pts with poor cardiac function as coronary artery disease b/c has no effect on BP & HR May cause pain at site of injection( lidocaine used to↓ pain). May cause myclonic movement (used with diazepam) Onset 30-60 sec, Duration of action 5-10 mins Metabolized in liver, excreted through kidney & bile  Advantages: 1. rapid induction & recovery 2. Not sensitize myocardium to Adrenaline 3. No nausea & vomiting 4. Non-explosive & non-irritant 5. Short operations(alone)  Disadvantages: 1. Involuntary movement during induction 2. On prolonged use, suppression of adrenal cortex & electrolyte imbalance 3. Not used in status epileptics  Propofol Similar to thiopental in its MOA, widely used Rapid induction & rapid recovery ( onset 30-40 sec, duration of action5-10 mins) Extensive metabolized by conjugation with glucuronic acid Antiemetic effect Not used after 8 hours from opening b/c of bacteria growth  Advantages: 1. Inducing agent, maintenance agent 2. Antiemetic & anticonvulsant action 3. Safe in pregnancy, can cross placenta 4. Suitable for OPD anesthesia  Disadvantages: 1. Hypotension , Bradycardia 2. Dose dependent respiratory depression 3. Pain during injection, local anesthetic combined  Ketamine Dissociative anesthesia ( the pt dissociated from surrounding with amnesia & analgesia without loss of consciousness) (light sleep) Commonly used as IV,I M, oral, rectal can also be given Act on NMDA receptors (blocking) Induction & maintenance Large VD & rapid clearance Metabolized in liver, excreted through kidney  Advantages & uses: 1. No vomiting, no hypotension 2. Bronchodilator-Asthmatics 3. Children- IM, rectal 4. change of burns dressing 5. Little impairment of pharyngeal & laryngeal reflex  Disadvantages: 1. No muscle relaxation 2. ↑BP (only G.anesthetics), ↑ cerebral blood flow, ↑ O2 consumption 3. Hallucination, disorientation 4. Involuntary movement  Contraindications: a. Contraindicated in pregnancy (oxytocic action) b. History of mental illness c. Hypertension, glaucoma, head injury  Benzodiapenes (diazepam, lorazepam, Midazolam) Used for induction , maintenance & supplementation of anesthesia Produce sedation, amnesia,& unconsciousness in 5 mins No respirator or CVS depression Preferred for endoscopy, cardiac catheterization  Opioid Analgesic  Morphine & Fentanyl Opoid analgesic, given at the start of painful procedures Commonly used in cardiosurgery b/c have less effect on myocardial activity Fentanyl with BZDs, diagnostic & minor procedure Local Anesthesia  Introduction local anesthetics (LAs) produce loss of sensation to pain in a specific area of the body without loss of consciousness  Epidural anesthesia involves the injection of medication into the “epidural space.” Because the medication needs to cross the membrane (dura mater) surrounding the spinal cord before reaching the targeted nerves, it usually takes approximately 10-15 minutes for pain relief to occur.  Spinal anesthesia involves the injection of medication into the fluid (CSF) that bathes the spinal cord. the duration of pain relief is finite (about 1-2 hours).  Classifications: All LAs are weak bases. Chemical structure of them have an amine group on one end connect to an aromatic ring on the other, and an amine group on the right side. The amine end is hydrophilic, & the aromatic end is lipophilic. According to the nature of connecting group that links both groups together: A. Esters (cocaine, procaine, benzocaine, tetracaine). They are metabolized by Pseudocholinesterase, so they have short duration of action B. Amides (lidocaine, bupivacaine,prilocaine etidocaine, mepivacaine). They are metabolized by liver microsomal enzymes, so have long DOA  Mechanism of action: LAs block Na+ channel to prevent the rapid influx of Na+ ion essential for the transmission of the nerve impulses across the nerve cell membrane (i.e inhibition of generation & propagation of action potential) Mechanism of action of LAs.  Structures of amides & esters  The amine end is hydrophilic anesthetic molecule dissolve in water in which it delivered from the dentist’s syringe into the pt’s tissue. It is responsible for the solution to remain on either side of the nerve membrane  The aromatic end is lipophilic. Because nerve cell is made of lipid bilayer it is responsible for anesthetic molecule to penetrate through the nerve membrane.  Tables for difference bet ester & amides of LAs page 176 & routes of administration pg 177  Desirable properties of LAs 1. Not be irritating to tissue 2. Not cause any permanent alteration of nerve structure 3. Systemic toxicity should be low 4. Time of onset of anesthesia should be short 5. Should be effective 6. Duration of action should be long enough to permit the completion of procedure 7. Should have the potency sufficient to complete anesthesia 8. Free from allergic reactions 9. Stable in solution & sterile  Factors affect LAs activity 1. lipid solubility  ↑Lipid solubility→ faster nerve penetration, block Na channels & speed up the onset of action  LAs have 2 forms, ionized & non-ionized. The non-ionized form can cross the nerve membrane & block the Na channels. So, the more no n-ionized presented, the faster the onset action 2. PH influence  Usually at range 7.6-8.9  ↓in PH shifts equilibrium toward the ionized form, delaying the onset of action  Lower PH (as in inflammatory tissues), solution more acidic, gives slower onset of action. For this reason, local anesthetics added with NaHCO3 3. Vasodilatation  Vasoconstrictor is a substance used to keep the anesthetic solution in place at a longer period & prolongs the action o the drug. It is also delays the absorption. Therefore lower vasodilator activity of LAs leads to a slower absorption & longer duration of action. E.x : Epinephrine decrease vasodilator( not used in pts with cardiac diseases & replaced b Felypressin)  N.B: Vasovonstrictor drugs contraindicated in anesthesia of fingers & toes supplied by end arteries b/c may lead to gangrene  I- Amides  Lidocaine The most widely used (effective by all routes, available as injection, topical solution, jelly & ointment) Intermediate DOA, absorbed rapidly parentrally , not used orally b/c of its extensive first pass metabolism. It is used as antiarrhythmic drug. Use: topically to relieve itching, burning pain, injected as a dental anesthetic or local anesthetic for minor surgery, epidural anaesthesia, ophthalmology, antitussive  Bupivacaine Potent agent with long DOA Preferred for epidural anesthesia Has cardiotoxic effect (ventricular arrhythmia & myocardial depression)  Prilocaine Similar to lidocaine in action, but less toxic, used in dermal anesthesia Should not be used in pts with cardiac or respiratory disease or those with idiopathic or congenital metheamoglobinemia b/c toluidine metabolites may produce methmoglobin that can be reserved by administration of methylen blue  II- Esters  Cocaine Controlled substance (abuse, psychological dependence) Short DOA, so used only for topical anesthesia of mucus membrane Blocks the uptake of catecholamines into nerve terminals & may induce severe V.C ( so, should not be used with adrenaline) Adverse effects: euphoria, CNS stimulation, tachycardia, restlessness, tremor, seizure & arrhythmia Should used in caution with hypertension, CVS disease, thyrotoxicosis & with drugs that potentiate catecholamine's activity Was used in ophthalmology, but has the disadvantages of producing mydriasis  Benzocaine Poorly soluble in water, too slowly absorbed & has low toxic effects Not ionized & cannot bind to its receptor in Na channels, but dissolve in the lipid causing expansion of lipid membrane & alteration of its permeability Uses: 1. for wounds, & ulcerated surfaces as dusting powder 2. also as lozenges for somatitis (oral ulcers) & sore throat, & as suppositories for rectal anesthesia  Procaine Low potency, short DOA, slow onset, so not prefered Metabolized to PABA which inhibits the action of sulfonamides May cause allergy  Tetracaine Long acting, potent, metabolized slowely, has high systemic toxicity. Used widely in spinal anesthesia & ophthalmology  Side effect of LAs 1. CNS: headness, dizziness, restlessness, visual disturbances. At high doses cause toni-clonic convulsion, respiratory depression, coma & death. Cocaine is a powerful stimulant. Treated by I.V diazepam to control convulsion. 2. CVS: bradycardia, hypotension. Bupivacaine is more cardiotoxic that lead to arrhythmia. Treated by I.V fluid & vasopressor agents (as phenylephrine) 3. Allergic reactions: associated with ester type including rash, edema, anaphylaxis. 4. Blood: prilocaine causes methamoglobenimia that treated by reducing agents (ascorbic acid or methylene blue) QUESTIONS