Drugs Acting on CNS Summary Notes - Prof Bansal PDF

Lipinski rule of 5: Hydrogen bonds: - Increases solubility in water ∴ must be broken for compound to permeate into and through lipid bilayer - ↑ number of H-bonds  ↓ partitioning from aq phase into lipid bilayer  for permeation by passive di usion Molecular weight: - ↑ molecular siz...

Lipinski rule of 5: Hydrogen bonds: - Increases solubility in water ∴ must be broken for compound to permeate into and through lipid bilayer - ↑ number of H-bonds  ↓ partitioning from aq phase into lipid bilayer  for permeation by passive di usion Molecular weight: - ↑ molecular size = larger cavity must be formed in water to solubilise the compound ∴ solubility ↓ - ↑ Mw = ↓ compound concentration at the surface of intestinal epithelium  ↓ absorption - ↑ molecular size  impedes passive di usion though tightly packed aliphatic side chains in bilayer membrane Octanol-water partition coe icient Log P (measure of compound lipophilicity): - ↑ Log P = ↓ aqueous solubility = ↓ absorption - Log P > 0 = drug is lipophilic - Log P < 0 = drug is hydrophilic Mechanism of action of opioids: 1. Pro-opioid protein synthesis in nucleus = peptide formation 2. Peptides are transported 3. Peptides broken down into endogenous opioids by peptidases 4. Bind to opioid receptor  coupled to G-protein (inhibitory) 5. Inhibit adenylate cyclase  ↓cAMP  lead to hyperpolarisation 6. Activation of Gi receptor  activates K channels  leads to hyperpolarisation Morphine nomenclature: Stereochemistry determines interactions with receptor Morphine: - 5-10 mg injections - Severe pain + first line treatment for moderate pain in cancer - Nausea + vomiting - Feeling of detachment + euphoria  useful in management of anxiety in palliative care Why is codeine less e ective than morphine? - Codeine = pro-drug - Codeine metabolised to morphine in vivo (liver)∴ Ine icient  5-fold ↓ in activity + variation in metabolic rates in individuals - Mild to moderate pain - Nausea + constipation  not suitable for long term Diacetylmorphine: - More rapid penetration of BBB - Converted into morphine in vivo - 2-fold ↑ in potency compared to morphine Hydrocodone: - More potent than codeine - Semi-synthetic  derived from codeine + thebaine - Orally active narcotic analgesic + antitussive Oxycodone: - Addictive opioid analgesic - Synthesised form thebaine - E ective orally - Post operative pain - Moderate to severe pain - First line for cancer pain How does the addition of polar / non-polar group of tertiary Nitrogen e ect the agonistic properties of morphine? - Addition of ethyl group = reduces activity - Phenylethyl = increases activity Morphine antagonists: - Naloxone - Naltrexone - Pure antagonist - Pure antagonist - Allyl group on nitrogen - Cyclopropyl group on - Ketone at C6 nitrogen - Hydroxyl at C14 - Ketone at C6 - C6 -C7 reduced - Hydroxyl at C14 - C6-C7 reduced Synthetic analogous: Common pharmacophore: - Longer duration of action than morphine - Sublingually = 6-8hrs Buprenorphine: - Less e ective than morphine  need high conce to achieve reasonable degree of analogues - ↑ risk of vomiting - Both agonist + antagonist - Can lead to withdrawal symptoms - High a inity to mu receptor  e ect partially reversible by naloxone - 4th line option for cancer pain Phenylpropylamine Methadone - Strong agonist - R (-) > S (+) - Long half life  long duration of action than morphine - Once a day  due to risk of accumulation - Less sedating + given to patient where morphine not e ective - Opioid dependence Tramadol: - Weaker opioid than morphine  ∴ step down analgesic from morphine - Min sedative + abuse potential - Agonist at opioid receptor + e ects noradrenaline pathway (NA)  Inhibit NA uptake - Oral + parenteral forms - 4-phenylpiperidine derivative of morphine Pethidine: - Weak mu receptor agonist  20% of morphine activity - Does not inhibit cough - Rapid onset of action + high first pass metabolism - Used in obstetrics  administered in small doses to mother  ∴ does not cause respiratory depression in newborn  Phenylpiperidines: Fentanyl sulfentinil - Very strong agonist - Very strong agonist (50x - Vey rapid onset of action morphine) - Very short duration of - Rapid onset of action + action short duration of action - Does not cause histamine release on IV injection - Dose 10-40microgram Metabolism:  N-dealkylation of alkyl amines Determines:  O-dealkylation of methoxyethers  Hydrolysis of esters - Onset of action  Conjugation of alcohols - Duration of action - Potency Bosy makes opioid more hydrophilic via NSAID + paracetamol: Prostaglandin Biosynthesis:  Biosynthesised from arachidonic acid  Arachidonic acid  found esterified on cell membrane phospholipid  conce is very low  Biosynthesis of eicosanoids  depends on release from cellular stores by acyl hydrolysis OR phospholipase 1. Glycerophospholipid’s ester bond is broken down by phospholipase 2. Arachidonic acid is formed 3. This is converted into prostaglandin How are prostaglandin G2 and prostaglandin H2 formed? Enzyme = Cyclooxygenase  catalyses 2 reactions NOTE: Arachidonic acid is converted Number of reactions = 2 into prostaglandin 1. Cyclooxygenase + 2 molecules of oxygen (O2) + Arachidonic acid  Prostaglandin G2 2. Peroxidase + Prostaglandin G2  Prostaglandin H2 Mechanism of action of NSAIDS: - Inhibit prostaglandin synthesis  - NSAIDS  competitively inhibit cyclooxygenase ∴ enzyme cannot catalyse synthesis of cyclic endoperoxide from arachidonic acid to form prostaglandin COX-1 vs COX-2 Physiological stimulus  COX-1  produces TXA2, PG2, PGE2 COX-1 found in: o Intestine o Platelets o Stomach o Kidneys Inflammatory stimulus COX-2  produces PGI2, PGE2 COX-2 found in: o Macrophages o Leukocytes o Fibroblasts o Endothelial cells COX-2 specific inhibition  reduces pain, fever, inflammation  without causing GI and renal injury COX-1 COX-2  Substrate = Arachidonic  Substrate = Arachidonic acid acid OR dihomo-y-linolenate  Isoleucine (IIe) at position  Valine (Val) at position 434 and 434 and 523 in active site 523 in active site  Long + narrow binding site  Wider shapes fit in binding site Salicylates  Potent anti-inflammatory activity  Mild analgesic + antipyretic  COX-1 selective  GIT irritation occurs Inactive  once inside the body becomes active  Paracetamol + aspirin Aspirin (acetylsalicylic acid): - Covalently + irreversibly modifies COX-1 & COX-2  by Acetylating Serine 530 in active sire - Acetylation of COX-1  creates steric block  prevents binding of arachidonic acid at cyclooxygenase active site - Acetylation of COX-2  retains cyclooxygenase activity  reaction produces novel product 15-R-HETE Profens:  Phenyl propanoic acid  strong acids  pka = 3-5  Alpha -methyl  ↑ cyclooxygenase inhibitory activity  S (+) = more potent cyclooxygenase inhibitor  All profens = racemates  EXCEPT Naproxen  R – Naproxen  liver toxicity  Inactive R (-)  converted into active S (+) isomer in vivo  only S- isomer present in plasma  profens: o Anti-inflammatory, analgesic, antipyretic (reduce fever) o Slightly COX-1 selective o Naproxen  more COX-2 selective o Rheumatoid and osteoarthritis o Less GIT e ect than salicylates Arylacetic Acids: Indomethacin Sulindac - COX-1 selective - Pro-drug  sulphoxide - Primary anti-inflammatory, reduced to sulphide some analgesic + antipyretic (more active) in body activity - Primary anti- - RA + OA inflammatory - CNS toxicity = headaches + - COX-1 selective delusions + psychosis - RA + OA Anthranilates:  Steric e ect in structures  Primary anti-inflammatory, some analgesic + antipyretic activity  Diclofenac RA, OA, post op pain COX-2 Inhibitors: - Pka 6.3  less acidic than -COOH NSAIDS - More COX-2 selective - RA + OA - Slow absorption + half life 20-50hrs + 1 a day dose COX-2 selective inhibitors:  Anti-inflammatory, analgesic + antipyretic  Low ulceration potential  COXIBS  can cause infertility + ↑ cardiovascular risk  Celecoxib  RA + OA   Etoricoxib  2nd gen  more selective COX-2  OA + RA  Refecoxib  withdrawn Paracetamol:  No carboxylic acid functionality + little to no inhibition against cyclooxygenase  Acts as a scavenger of hydroperoxide radicals  No anti-inflammatory activity  Analgesic + antipyretic  Overdose = liver damage  binding of toxic metabolite to liver  Prevention of toxicity  IV administration of sulfhydryl donors e.g. N-acetylcysteine Anaesthetics: Anaesthesia = loss of sensation with OR without loss of consciousness of whole body or parts of it  GOAL to depress CNS Local anaesthesia  a ects only part of the body (local nerves) General anaesthesia  full body  depresses CNS + consciousness o Medically induced coma  Loss of protective reflexes o Can be administration of 1 or more general anaesthesia agents Inhaled Anaesthesia:  Gas OR nebulised liquid  Minimum alveolar conce = fraction of compound in lungs needed for lack of response to pain  Halogenated ∴ volatile  liquid at room temp Intravenous anaesthetics:  Suspension or solution  Administered with adjuvants for pain + blood pressure o Adjuvants = medication not indicated for pain but provides pain control  Used for induction Propofol:  Parenteral  IV  Enhances GABAergic neurotransmitter in CNS  GABA-A receptor complex  Distinct form Benzodiazepine binding site  Poorly soluble  Octanol : water partitioning coe icient 7000:1  Oil in water emulsion (o/w)  pKa = 11 emulsion at pH 7-8.5   2-2.5mg/kg  hypnosis in 30-60 sec  Fast metabolism + Fast onset of action + Fast recovery Fospropofol:  Phosphate ester pro-drug  metabolic conversion o In fospropofol phosphate ester bond is hydrolysed in vivo  phosphate + aldehyde + propofol released  Avoids emulsion formation  6.5mg/kg  Onset delayed 4-10 min Ketamine:  Potent + fast acting  Short duration of action  10-25min  Recovery accompanied by  visual + auditory + confusional illusions  disturbing dreams + hallucinations for 24hrs after administration  Does NOT act on GABA-A receptor  Non-competitive antagonist of glutamate receptor  NMDA receptor  Also binds to mu + kappa opioid preceptor  analgesic e ects  Abuse potential Etomidate:  Carboxylated imidazole  general anaesthesia o Positive modulation of GABA receptor  R – enantiomer = more potent  Not water soluble o 2mg/ml in 35% propylene glycol o Lipid soluble  ∴ penetrates BBB + CNS  Metabolised by liver esterase  75% drug eliminated in urine as inactive hydrolysed carboxylic acid COCA TROPANE ALKALOIDS: - Relieve fatigue + cope with low oxygen levels - Ecgonine esters are active  hydrolyses by body enzymes destroys activity  Strong stimulant  E ect on CNS: o Loss of contact with reality o Happiness OR agitation   Physical symptoms: o Fast heart rate o Sweating o Large pupils o High doses  high b.p. + high temp  Medical uses: o Numbing o ↓ bleeding during nasal surgery Cocaine + cocaine derivatives:  Benzoylecgonine  primary metabolite of cocaine o Formed by metabolism catalysed by carboxylesterase o Excreted in urine Benzoyl esters of amino alcohols  benzoyl tropine  strong LOCAL anaesthetic properties  NO cocaine addiction Procaine: - pKa = 8.9 - Low lipid solubility - Ester group is unstable - Included in penicillin G formulation  to ↓ pain of intramuscular injections - Metabolised by cholinesterase in liver - Used in dentistry - Lidocaine more e ective Mechanism of action of anaesthetics (e.g. Lidocaine): 1. Normally = Influx of Na+ ions through voltage-gated Na channels  causes axon depolarization ∴ propagation of nerve impulse 2. With LOCAL anaesthetics (LA) = unionised LA di use across cell membranes as they are lipophilic 3. LA becomes ionised due to lower intracellular pH  ∴ is no longer lipophilic 4. Ionised LA blocks the Na channel  ∴ prevents propagation of action potentials a. There is a local anaesthetic binding pocket  LA binds there b. Repulsive forces between LA (+ charged) and Na+ ions Diazepam: Diazepam (benzodiazepines)  can cross BBB  Agonists for GABA receptor  Muscle relaxant (half-life 24-48hrs)  Metabolised to Nordiazepam o Clearance 2-5 days  ∴ conce builds up - Oxazepam (metabolite of diazepam) Rapidly glucuronidation in liver Eliminated in kidneys - Chlordiazepoxide o New tranquiliser o Anti-anxiety   Flunitrazepam (Rohpol)  Hypnotic – causes amnesia  No hangover a ect = more gradual and prolonged onset of sedation  Half life 8hrs  Midazolam (most used anaesthesia) o Amine gets protonated in water  ONLY SOLUBLE benzodiazepine o Short acting HCl o Half-life 1-3 hrs o Amnesia for 10 min  continuous IV sedation for patient in intensive care GABA either: 1. Acts on post-synaptic receptor GABA synthesis: 2. Is taken up by glial cells and is converted back to glutamine If GABA-T is inhibited: 1. Conce of GABA in synaptic cleft increases y-aminobutyric acid (GABA) GABA biosynthesis and catabolism: Glutamine  Glutamate y-aminobutyric acid  Succinic semi aldehyde PLP Co-factor = pyridoxylphosphate GAD = Glutamic acid decarboxylase GABA-T = GABA- Aminotransferase Vigabatrin 1  Irreversibly binds to GABA-aminotransferase  Prevents GABA catabolism  as enzyme cannot convert GABA into succinic acid or GHB  ∴ leads to ↑ conce of GABA in synaptic cleft Partial epilepsy who do not respond to other drugs Lyrica (Pregabalin / Gabapentin):  Anticonvulsant activity (3-alkyl GABA) not related to GAD activation  Gabapentin  selectively binds to alpha2 delta subunit of voltage gated Ca channel o Inhibits release of substance P and glutamate from excitatory amino acid terminals o Lowering excitatory neurotransmitter is the same as raising inhibitory neurotransmitter  90% bioavailability  3-isobutyl GABA and 3-alkyl GABA = substrates to S transporter o Actively transported into brain o Substrate is L-Leucine  structurally similar to Lyrica  ∴ Lyrica transported into brain by the S transporter instead  Postherpetic neuralgia (shingles)  Neuropathic pain from diabetes = 300mg   Gabapentin  Anti-epileptic (anticonvulsant)  slows down impulse in the brain that cause seizures  A ects chemicals in brain that send pain signals Lyrica indication: 1. Pain caused by fibromyalgia 2. Nerve pain in diabetes (diabetic neuropathy) 3. Herpes zoster (post-herpetic neuralgia) 4. Spinal cord injury