Analgesics PDF

Analgesics Classification of Analgesics - Narcotic analgesics (opioids) - Non-narcotic analgesics (antipyretics) Types of Opioids - Endogenous - Endorphines, enkephalins, dynorphins - Plant alkaloids - Morphine, codeine, thebaine - Semisynthetic - Di...

Analgesics Classification of Analgesics - Narcotic analgesics (opioids) - Non-narcotic analgesics (antipyretics) Types of Opioids - Endogenous - Endorphines, enkephalins, dynorphins - Plant alkaloids - Morphine, codeine, thebaine - Semisynthetic - Diamorphine (heroin), oxycodone, hydromorphone, buprenorphine - Synthetic - Pethidine, methadone, fentanyl, tramadol, pentazocine Pharmacology - Opioids bind to specific receptors in CNS and other tissues - Opioid receptors - G-protein coupled receptors - Types - Delta (s1 and s2) - Kappa (k1,k2,k3) - Mu (m1,m2,m3) - Nociception (NOP) Pharmacological Actions of Opioids - Desirable - Analgesia - Sedation - Antitussive - cough suppressant - Sometimes desirable - Constipation - not usually used (would be used to treat diahrrea) - Hypotension - Undesirable - Nausea/vomiting - Respiratory depression - Mental clouding - Confusion → coma - Tolerance - Addiction - Physical dependence Therapeutic Indications of Opioids - Pain (analgesic effect) - for severe pain - Anxiety - sedative - Cough (codeine) - Diarrhea (opium only)  - Opioids dependence (buprenorphine and methadone) Opioids as Analgesics - Strongest known analgesics - Act on mainly on mu and kappa receptors - Variable dose with no upper limit - Type of pain: SEVERE - Acute: eg. post op - Chronic - Specially in terminal conditions eg. cancer (palliative care) - Dependence is not the main concern - Most annoying adverse effect is SEVERE constipation - Gradual stoppage of drug - To avoid withdrawal manifestation Opioids Action as Pain Killers - Mainly mu and kappa receptors - Local Effects - Decreases presynaptic release of chemical transmitters that are mobilized by pain impulse - Blockade of postsynaptic effect of these transmitters - Block the response of the neurotransmitters on the postsynaptic neuron - Central Effects - Activation of descending inhibitory pathways to block pain input - Boosts the inhibitory pathways to prevent feelings of pain - Decreased emotional reaction to pain by acting on limbic system of the brain - Modify emotions to interpret the pain less severely Tolerance, Addiction, Dependence - Tolerance - After repeated use, body adapts to opioids → decreased drug potency → higher dose is needed to obtain same analgesic effect - Cross Tolerance - Tolerance to an opioid → tolerance to other opioids - Addiction - Psychological attachment to certain effects of opioids → compulsive repeated use - Physical dependence - Development of opioid withdrawal syndrome after: - Cessation of drug administration - Administration of an opioid antagonist Opioid Withdrawal Syndrome - CNS stimulation - Tachypnea - Tachycardia and hypertension - Severe flu like illness - sneezing - Yawning, lacrimation, diaphoresis - Nausea, vomiting, diahrrea - Abdominal cramping, leg cramping  - Tremors and muscle twitching - Gooseflesh - Dilated pupils Opioid Antagonists - Antagonists - naloxone - Mixed agonists/antagonists - pentazocine Naloxone - Competitive opioid receptor antagonist - Has no analgesic effect - Causes withdrawal symptoms - Therapeutic use - Treatment of opioid drug overdose (antidote) - Diagnosis and treatment of opioid dependence - Should always be available when opioids are used - Administration: IV or nasal spray Pentazocine - Has agonist (activates kappa receptors) - Also has weak antagonists action - Blocks mu receptors → more associated with addiction blocking → withdrawal - If used with opioid agonists → can induce withdrawal symptoms - Activates k but blocks m Drug Therapy of Dependence - Buprenorphine or methadone - Partial agonist at mu receptors - Same opioid effect → prevent withdrawal manifestations - Much less dependence - Reduce the opioid and increase the buprenorphine, tapering the opioid - Naloxone - Opioid antagonistic effect - Blocks drug seeking behaviour - Helps stop the craving of the opioid Acute Opioid Toxicity - Manifestations - Mild/early - Pinpoint pupils - Hypoventilation - Hypotension and bradycardia - Flaccid muscles - Severe/ late - Severe respiratory depression → respiratory arrest - Severe cardiovascular depression - Seizures - Coma  - CPR - 3H - Coma - Pinpoint pupils - Respiratory depression - Hypotension - Hypothermia - Hyporeflexia - Treatment - Naloxone - Reverses toxic manifestations - IV or nasal spray - Shorter half life → repeated dose - General supportive measures Antipyretics Cyclooxygenase (COX) Enzyme - Used in fevers, pain - 3 Isoenzymes - COX-1: widely distributed - in many cells - COX-2: limited distribution - in area of inflammation and macrophages - COX-3: mainly in brain - function is not confirmed Types of Antipyretics - Non-steroidal anti-inflammatory drugs (NSAIDs) - Acetylsalicylic acid (ASA, aspirin) - Other NSAIDs: ibuprofen, naproxen, diclofenac - Acetaminophen - Tylenol - paracetamol  - Selective COX-2 inhibitors - Celevoxib Acetylsalicylic Acid - Mechanism of action - Irreversible inhibition of COX 1 and COX 2 → decreasing production of prostaglandins (chemical in body that causes pain, swelling and fever) and thromboxanes - Blocking COX 1 gives adverse effects, blocking COX 2 gives the therapeutic effects - Pharmacological actions - Analgesics - Antipyretics - Anti-platelet - Anti-inflammatory at high doses - Other NSAIDs cause REVERSIBLE inhibition of COX enzyme - Therapeutic Indications - Pain - Mild to moderate (less effective than opioids) - Mechanism through inhibition of prostaglandin synthesis - Peripheral action: prevents sensitization of pain transmitting nerve fibers to chemical mediators released by tissue injury (basically it stops some of the signals being sent to the brain because less chemicals are coming to the site because it makes it less sensitive) - Central action: inhibits actions of transmitters involved in pain pathways - Helps with different types of pain including headaches and migraine - No tolerance, addiction, or dependence - Fever - Mechanism through inhibition of prostaglandin synthesis - Reset temperature center in hypothalamus - No effect on normal body temperature - Thromboembolic disease - Through antiplatelet effect - Treatment or prophylaxis - Inflammation - Rheumatic fever - Rheumatoid arthritis - Gout (high doses) - Adverse effects - Bleeding - GI upset - Bronchial asthma - Tinnitus - Acid base imbalance - Metabolic acidosis - Respiratory alkalosis - Chronic nephritis  - Hypersensitivity - Reye’s syndrome - Brain and liver damage - Occurs in children or adolescents who have viral infections and take aspirin - Contraindications - Bleeding tendencies - Peptic ulcer - Bronchial asthma - Allergy to aspirin - Chronic renal disease - Children or adolescents with fever and viral infection - Pharmacokinetics - Absorption in the stomach more than the small intestine - Metabolized in the liver - Excreted in the kidney Acute Aspirin Toxicity - Manifestations - Vomiting - Tinnitus - Hypoglycemia, hypokalemia - Hyperthermia, hyperventilation - Metabolic acidosis, respiratory alkalosis - Confusion, seizures, cooma - Pulmonary edema, hypotension, CV collapse - Treatment - No specific antidote - Supportive measures - Stabilize ABC - Fluids/electrolytes - Restore pH - Glucose - Alkalinization of urine - Charcoal ingestion - Gastric lavage - Dialysis Commonly Used Other NSAIDs - Ibuprofen - Naproxen - Indomethacin - Ketorolac - Diclofenac - Apparently increases the risk of HA and strokes Acetaminophen - Mechanism of action - Not fully understood  - Inhibits COX enzymes like NSAIDs - More COX 2 selective - May block COX 3? - No anti-inflammatory or anti-platelet action - Pharmacokinetics - Absorption in GIT, not in stomach - Metabolized by liver - Excreted by kidney - Adverse effects - Usually safe if taken in proper dose - Safe during pregnancy - Main adverse effects - Liver damage - Renal damage Acetaminophen Acute Toxicity - Commonly due to suicide - Acute liver damage - may be fatal - Treatment - Antidote: N-acetylcysteine (NAC) - Supportive measures - Charcoal ingestion - Gastric lavage N-Acetylcysteine (NAC) - Antidote of acetaminophen - Source of glutathione → decrease levels of NAPQI → decrease liver damage - Most effective within 8 hours of exposure - Oral or IV COX-2 Inhibitors - Selective inhibitors of COX-2 isozyme - Less COX-1 induced side effects - Asthma, gastric irritation, bleeding - More risk of thrombosis and cardiovascular morbidity and mortality Over The Counter Drugs OTC Drugs - Definition - Medications available without a prescription at drugstores or supermarkets - General characteristics - Safe when used at recommended doses - Limited toxicity with self-limiting symptoms - Effective but less potent than prescription Safe Use of OTC Drugs - Mild illness - Familiar with symptoms and the drug - Read the label carefully and follow directions - Keep a list of current medications - Consult with physicians or pharmacist if - Unfamiliar with the drug or symptoms - Symptoms get worse - Develop adverse effects - Pregnant or breastfeeding - Don’t - Combine medications with the same active ingredients - Use for more than 2 weeks How to Select OTC Drugs - Select the drug that has - Proven efficacy - Simplest formulation - List all ingredients with concentration - Proper dose - Appropriate administration form - Known level of toxicity Commonly Used OTC Drugs - Analgesics/antipyretics - Cold preparations - Anti-ulcer drugs Analgesics/Antipyretics - Acetaminophen - NSAIDs - ASA - aspirin - Ibuprofen - Naproxen Cold Preparations - Antihistamines - Decongestants - Antitussives - Expectorants Antihistamines - Symptomatic treatment - Alleviate symptoms if there is an allergic componenet - Mechanism - Block histamine (H1) receptors - Competitive inhibition - By blocking the binding of histamine to the receptor you reduce the symptoms of inflammation, redness, swelling - Adverse effects - Anticholinergic symptoms - Drowsiness (more with older drugs) - Preparations - Alone - Combined with other medications - Administrations - Oral - Topical - Injections - Examples - Older drugs - Chlorphenamine - Diphenhydramine (benadryl) - More recent - Loratadine (claritin) - Cetirizine (zyrtec) Decongestants - Mechanism - Alpha 1 agonist - Vasoconstriction of blood vessels of nasal mucosa - NOT RECOMMENDED FOR CHILDREN UNDER 6 - Adverse effects - May increase blood pressure in hypertensive patients - May lead to rebound congestion after stopped - Examples - Pseudoephedrine (oral) - Phenylephrine (local) Antitussives - Mechanism - Suppress the cough center in the medulla - Indications  - Dry (non productive cough) - Examples - Dextromethorphan (Benylin) - Codeine - Adverse effects - Risk of dependence Exportants - Mechanism - Increase volume and reduce viscosity of bronchial secretions - Allow cilia to expel loosened secretions - Indications - Productive cough - Adverse effects - Renal stones - Examples - Guaifenesin OTC Anti-Ulcer Drugs - Antacids - H2 blockers - Proton pump inhibitors Drug Interactions with OTC Drugs - Antihistamines + CNS depressants - Increase CNS depression - Decongestants +MAOI - Malignant hypertension and IHD - ASA + anticoagulants - Increase risk of bleeding - Aluminum antacids/ mineral oil laxative - Decrease absorption of some drugs Anti-Peptic Diseases Physiological Control of Gastric Acid Secretion - Parietal cells are stimulated to secrete H+ by: - Gastrin hormone - Acetylcholine - Histamine - HCl is secreted by the H/K ATPase proton pump into the gastric lumen - Gastrin hormone - Secreted by G cells in response to - Intraluminal dietary peptides - Ach through vagal stimulation - Passes from the blood vessels into the submucosal tissue of the fundic glands - Binds to G/CCK-B-R on parietal cells and ECL cells - Vagus nerve stimulates the release of Ach → binds to M3-R on parietal and ECL cells - Gastrin and Ach stimulate ECL cells to release histamine - Acid secretion must eventually be turned off - Increased H+ concentration + passing of proteins and fats into the duodenum → stimulates antral D cells to release somatostatin which inhibits further gastrin release Acid-Peptic Diseases - Gastroesophageal reflux disease - Peptic ulcer - Stress related mucosal injury - Zollinger-Ellison syndrome Common Causes of Peptic Ulcer - Infection - Helicobacter pylori - Drug induced - NSAIDs - Steroids - Antineoplastics - Alcohol Pharmacotherapy of Peptic Ulcer - Drugs that reduce intragastric acidity - Antacids - Muscarinic receptor antagonists (anticholinergics) - Histamine-2 receptor antagonists (H2 blockers) - Proton pump inhibitors - Drugs that promote mucosal defense - Sucralfate - Prostaglandin analogs - Bismuth compounds Antacids - Have been around for centuries - Widely used - OTC - Weak bases - Na, Ca, Al, Mg - Mechanism of actions - Neutralize the gastric acid - Systemic/Non-systemic (here is what systemic does → non systemic does the opposite) - CO2 release and gastric distension - Absorption into the body - Systemic effects - metabolic alkalosis - Fluid retention/constipation - Less safe Muscarinic Receptor Antagonists - Compared to other medications - Less effective - More adverse effects - Limited use H2 Blockers - Introduced in 1970 - Pharmacokinetics - Half life: 1-4 hours - Metabolized by the liver - Excreted through the kidney - Mechanism of action - Selectively block H2 receptors on the parietal cells - Decrease gastric acidity - Adverse effects - Diarrhea, headache, fatigue, myalgias, and constipation - SAFE: but may increase substances that may lead to carcinogenic effect - Drug interactions - Cimetidine decreases hepatic microsomal enzymes → decreases metabolism of other drugs → increases drug levels and toxic response - Administration - Oral - IV - Drug names - Ending with TIDINE Proton Pump Inhibitors - Most potent acid suppressors - Were introduced in the late 80s - All contain benzimidazole ring - Pharmacokinetics - Absorption - Through the intestine  - Delayed by food intake - Half life: 0.5-2 hours - Mechanism of action - Irreversible - Decreases H/K ATPase proton pump → prevents acid secretion into the gastric lumen → decreases gastric acidity - Adverse effects - Diarrhea - Headache - Abdominal pain - Low gastric acidity → - Interfere with vitamin B12 absorption - Bacterial colonization - Administration - Oral - Once a day before meal - Availability - Rx - OTC (some) - Drug names - Ends with PRAZOLE Sucralfate - Composition: sucrose +Al(OH)3 - Acts locally in the stomach - Reacts with gastric HCl → viscous paste like coat → protects the gastric mucosa - Minimal absorption → no systemic adverse effects - Administration - Oral - Limited use Prostaglandin Analogs - Misoprostol - PGE analog - Mechanism of action - Increase mucus secretion and HCO3 → protects gastric mucosa → decreases NSAID induced ulcers and decreases HCl secretion - Pharmacokinetics - Rapidly absorbed and metabolized - Short half life: less than 0.5 hours - Administration - Oral Bismuth Compounds - 2 Compounds - Bismuth subsalicylate - Bismuth subcitrate potassium - Frequently used in combinations  - With PPI and antibiotics - With kaopectate - Very safe Peptic Ulcer and H.Pylori - Helicobacter pylori - Gram negative bacilli - Responsible for >90% of peptic ulcer disease - Treatment - Quadruple therapy - PPI + tetracycline + metronidazole + bismuth - Triple therapy - PPI + clarithromycin + amoxicillin - 10-14 days for eradication of the bacteria