Pharmacology Finals - Lesson 1: Management of Inflammation - PDF

PHARMACOLOGY - FINALS Lesson 1: Management of Inflammation National University – College of Dentistry Transcribed by: Morales, Kyla Grace B. Professor: Dr. Paul Benzo I. Sia INFLAMMATION o Increase in heat...

PHARMACOLOGY - FINALS Lesson 1: Management of Inflammation National University – College of Dentistry Transcribed by: Morales, Kyla Grace B. Professor: Dr. Paul Benzo I. Sia INFLAMMATION o Increase in heat generation, decrease in heat loss Protective response to an injurious stimulus ▪ Body contains heat can be evoked by noxious agents, NSAIDs suppress this response by infections, and physical injuries inhibiting COX-2-dependent PGE2 inflammation may be exaggerated and synthesis sustained without apparent benefit and even with severe adverse consequences What happens during an Injury? o e.g., hypersensitivity (allergies), autoimmune diseases, chronic inflammation o body attacking normal tissues because it sees it as foreign The inflammatory response is characterized mechanistically by: transient local vasodilation and increased capillary permeability; o the cells fighting off injury are in the blood stream. o Blood vessel will dilate at the site of injury so that more WBC will go infiltration of leukocytes and phagocytic cells; and 1. Stimulus – open wound resolution with or without tissue 2. Disturbance of cell membrane degeneration and fibrosis 3. Phospholipid will break down into Arachidonic Acid by phospholipase PGE2 & PGI2 To stop this ↑, use corticosteroids or phospholipase Prostaglandin E2 & Prostaglandin I2 inhibitors to manage inflammation primary prostanoid that mediate inflammation 1. Arachidonic Acid can produce o increase local blood flow, vascular Cyclooxygenase (Cox) and Lipoxygenase permeability, and leukocyte (Lox) infiltration Cyclooxygenase can be stop by NSAIDs to stop o To fight the infection inflammation FEVER hypothalamus regulates the set point at NSAIDs which body temperature is maintained elevation results from tissue damage, Non-steroidal anti-inflammatory drugs inflammation, graft rejection, or malignancy for management of inflammation, fever, o the body is trying to kill the infection pain, hyperuricemia, gout with higher temperatures act by inhibiting cyclooxygenases (COX) o cox-1- expressed throughout the body Metabolism and excretion Gastric acid regulation, and gastric Hepatic biotransformation and renal mucous secretions excretion Maintenance of renal blood flow NSAIDs are not recommended for Promotes platelet aggregation advanced kidney or liver disease cox-2- induced at sites of inflammation Therapeutic Effects of NSAIDs role in blood pressure regulation Antipyretic endogenous inhibitors of hemostasis Anti-fever Pharmacokinetics of NSAIDs can reduce fever in most situations Absorption no effect on the circadian variation in ter response to exercise or increased ambient rapidly absorbed following oral ingestion temperature peak plasma concentrations are reached Analgesic within 2-3 h Food intake may delay absorption and low-to-moderate intensity systemic availability maximal efficacy is generally less than the Antacids, commonly prescribed to patients on opioids NSAID therapy, variably delay absorption o opioids can be used for intense pain Distribution NSAIDs lack the unwanted adverse effects of opiates in the CNS Most NSAIDs are extensively bound (95%- o Respiratory depression 99%) to plasma proteins, usually albumin o Potential dependence on opiods o any changes in the plasma protein can be coadministered with opioids concentration can have toxic effect o opiods can be abused, NSAIDs can on the body reduce that ▪ because of the drugs flowing not effective against pain arising from hollow inside the body viscera except menstrual pain Most NSAIDs are distributed widely o menstrual pain can be addressed by throughout the body and readily penetrate NSAIDs arthritic joints, ▪ NSAIDs stops pain by o yielding synovial fluid concentrations inhibiting prostaglandins in the range of half the plasma ▪ Menstrual pain comes from concentration the release of prostaglandins NSAIDs are treatment for inflammation, so it in the endometrium is in the joint lacks efficacy in neuropathic pain o Ibuprofen, naproxen Anti inflammatory sufficient concentrations in the CNS to have a central analgesic effect rheumatoid arthritis and osteoarthritis o stops the pain at the CNS, not just antipyretic and analgesic PNS Note: Acetaminophen Analgesia- stop pain Antipyretic and analgesic 2 mechanisms Tylenol, paracetamol largely devoid of anti-inflammatory Stop the pain the brain or spine; or activity Stop the pain at the PNS NSAIDs stops the pain from the CNS Closing of patent ductus arteriosus Cardiovascular birth defect Aspirin is non selective NSAIDs. When in the womb, the ductus arteriosus is It affects (stops) platelet aggregation, open to allow fetal circulation. Once born, it COX-2 inhibitors depress formation of PG12 should close. But in some case, it doesn’t. but do not inhibit the COX-1-catalyzed The hole is open is because of the formation of platelet TxA prostaglandins. o It only affects COX-2, has no effect o Inhibiting prostaglandins can close. on COX-1, so e.g. indomethacin, Ibuprofen o increased risk of MI and CVA Cardioprotection aspirin prolongs bleeding time Aspirin reduces the risk of serious vascular events in high-risk patients o MI and CVA by 20%-25%; subsequent thrombotic strokes roughly 10%-15% Aspirin stops platelet from aggregating so there wouldn’t be blood cloth COX-2 causes no GI problems, and you will cardioprotection is lost when combining low- have platelet aggregation dose aspirin with NSAIDS Renal Events o There is drug-drug interaction. hypertension (5%); more on cox-2 ▪ NSAIDs and Aspirin are o problem on cardiovascular and competing with receptors renal. More on renal o cox2 selective drugs don’t have anti o To lessen hypertension, lower platelet activity, so it can be used sodium intake NSAIDs impair the prostaglandin induced Adverse Effect of NSAIDs inhibition of reabsorption of chlorine and the action of the antidiuretic hormone Gastrointestinal o Result to retention of salt and water Inhibition of cox-1 in gastric epithelial cells = higher BP Abdominal pain dysplasia nausea vomiting, and rarely, ulcers or bleeding Reye's syndrome (asked in the boards) Cox-1 responsible for gastric secretion, for acid acute onset of encephalopathy, liver production. dysfunction, and fatty infiltration of the liver Using NSAIDs non-selective drugs (Cox-1) and other viscera can affect gastric epithelial cells aspirin and other salicylates are o Less mucous secretion contraindicated in children and young adults o More acid secretion less than 20 years of age with viral illness- Causing gastrointestinal defects associated fever don’t use aspirin on children 20yrsold below may use acetaminophen and ibuprofen NSAIDs Classifications Acethaminophen Non-selective COX inhibitor Paracetamol selective Cox-1 inhibitors active metabolite of phenacetin selective Cox-2 inhibitors non-selective cox inhibitor o do not affect platelet function at their not an NSAID usual doses o doesn’t have anti-inflammatory effect o may increase incidence of edema raises the threshold to painful stimuli and hypertension well tolerated but can be hepatotoxic o improved GI safety o DAMAGES THE LIVER conventional oral dose of acetaminophen is 325-650 mg every 4-6 h; total daily doses should not exceed 4g (2g/d for chronic ASPIRIN AND OTHER SALICYLATES alcoholics). o Because the liver is already injured aspirin aka ASA (acety|salicylic acid) Single doses for children 2-11 years old irreversible inhibitors of cox activity depend on age and weight (-10-15mg/kg); duration of aspirin's effects is related to the no more than five doses should be turnover rate of the COXs in different target administered in 24h. tissues toxicity may be managed with n- Inhibition of platelet COX-1-dependent TxA2 acetylcysteine formation is cumulative with repeated doses o for runny nose. of aspirin (at least as low as 30 mg/d) and o 100% effect against hepotocixity if takes 8-12 days (the platelet turnover time) taken within 8 hours to recover fully once therapy has been o Stops metabolites from forming stopped o aspirin inhibits platelet aggregation Drug metabolizes ↓ so there is prolonged bleeding Toxic metabolites form analgesic-antipyretic dose of aspirin for ↓ Liver damage adults is 325-1000 mg orally every 4-6 h. maximum recommended daily dose of Diclofenac aspirin for adults and children 12 years or older is 4g potency is substantially greater than that of Low-dose aspirin (5100 mg daily) lowers other NSAIDS. cardiovascular risk and is recommended for Although it was not developed to be a COX- the prevention of myocardial infarction and 2 selective drug, the selectivity of diclofenac stroke in patients at elevated risk for COX-2 resembles that of celecoxib use of salicylates is contraindicated in 50% reaches circulation patients with chronic liver disease accumulates in synovial fluid Patients with severe hepatic damage, o after oral administration – making it hypoprothrombinemia, vitamin K deficiency, stay longer than in the plasma or hemophilia should avoid aspirin for management of rheumatoid arthritis, If possible, aspirin therapy should be osteoarthritis, ankylosing spondylitis, pain, stopped at least 1 week before surgery primary dysmenorrhea, and acute migraine ototoxic Indomethacin o toxic to auditory system non-selective cox-inhibitor closure of patent ductus arteriosus Others Propionic acid derivatives ENOLICN ACIDS nonselective COX inhibitors with the effects Oxicams and side effects common to other NSAIDS Piroxicam approved for use in the symptomatic o nonselective COX inhibitor with the treatment of rheumatoid arthritis, juvenile longest t1/2 arthritis, and osteoarthritis o approved for treatment of Ibuprofen and naproxen have been shown rheumatoid arthritis andosteoarthritis to interfere with the antiplatelet effects of o usual daily dose is 20 mg aspirin Meloxicam o Do not mix naproxen/ibuprofen and o shows modest COX-2 selectivity aspirin. comparable to celecoxib and was approved as a COX-2-selective Ibuprofen NSAID in some countries An injectable formulation of ibuprofen is o 7.5 mg/d of meloxicam approved to close patent ductus arteriosus COXIBS in premature infants 200 mg or less are available without a Cox-e selective inhibitors prescription Most are restricted in their use or withdrawn usual dose for mild-to-moderate paín is 400 from the market in view of their adverse mg every 4-6 h as needed cardiovascular risk profile Ibuprofen is better tolerated than aspirin and Celecoxib currently is the only COX-2 indomethacin and has been used in patients inhibitor licensed for use in the U.S. with a history of Gl intolerance to other o e.g. celecoxib, rofecoxib, valdecoxib NSAIDs and its prodrug parecoxib, o Mefenamic Acid causes GI etoricoxib, and lumiracoxib disturbance. Some older NSAID compounds-diclofenac, Ibuprofen can be used occasionally by etodolac, meloxicam, and nimesulide-exhibit pregnant women; however, the concerns selectivity for COX-2 that is close to that of apply regarding third-trimester effects, celecoxib including delay of parturition. elimination t1/2 is about 11 h Excretion into breast milk is thought to be management of acute pain for the treatment minimal of ostecartritis heumatoid arthritis, juvenile 200-800 mg 3-6 times/d with food rheumatoid arthritis, ankylosing spondylitis, (maximum 3,2 g/d); and primary dysmenorrhea Children: 4-10 mg/kg/dose, 3-4 times/d recommended dose for treating osteoarthritis is 200 mg/d as a single dose Naproxen or divided as two doses Due to cardiovascular hazard, physicians Fenamates are advised to use the lowers possible dose for the shortest possible duration pharmacological properties of the confers a risk of myocardial infarction and fenamates are those of typical NSAIDS, and stroke, and this appears to relate to dose therapeutically, they have no advantages and the underlying risk of cardiovascular over others in the class disease drugs are not recommended for use in Chronic use of celecoxib may decrease children or pregnant women bone mineral density, particularly in older o e.g. meenamic acid, male patient meclofenamate, flufenamic acid PHARMACOLOGY - FINALS Lesson 2: CNS Drugs National University – College of Dentistry Transcribed by: Morales, Kyla Grace B. Professor: Dr. Paul Benzo I. Sia CNS Disorders Dopamine due to imbalance in neurotransmitters Responsible for behavior o chemical signaling mechanism of Others the brain Norepinephrine Mechanism of Neurotransmitters Epinephrine Acetylcholine *Serotonin, Dopamine, and NE are all catecholamine* Psychiatric Diseases Anxiety - ↑ catecholamine Depression - ↓ NE, ↓serotonin Mania- ↑ NE, ↑ serotonin Schizophrenia- ↑ dopamine Parkinson’s- ↑ Acetylcholine, ↓ Dopamine 1. Signal is transfer from one neuron to another ↑ catecholamines = ↑ firing of neurons = Anxiety 2. Impulse travel through the axons ↓ catecholamines = ↓ firing of neurons = Depression 3. Signal will be stored in the vesicle 4. Vesicle releases neurotransmitters in Bipolar Disorders synapse (gap between neurons) 5. The neurotransmitters will move to the neighboring neuron Depression Mania 6. neurotransmitters bind to receptors Shifting between mania and depression CNS Neurotransmitters Psychosis Glutamate Giving impaired reality o Hallucinations – false perception Major excitatory neuron o Delusions - altered reality GABA (Gamma-aminobutyric acid) o Confusion – impaired memory Major inhibitory neuron Serotonin (5-HT) Responsible for mood, wakefulness, sleep Schizophrenia Mania Most common psychiatric disease Excessive enthusiasm manifested by psychosis Excessive confidence Dopamine Theory - ↑ dopamine Irritability Treatment: inhibit dopamine Delusion Illusion of grandeur Positive symptoms +sx o Feeling self-importance, power Hallucinations Anti-depressant Drugs Delusion MAO Inhibitor (Monoamine oxidase) Negative symptoms -sx Stops the deamination of amines Absent o In the synaptic cleft o Apathy (detachment) Stops amines from getting destroyed o Asociality = ↑ dopamine, serotonin and NE o Anhedonia (lack of interest) o Inattentiveness TCA (Tricyclic Antidepressants) Antipsychotic Drugs for schizophrenia blocking of reuptake transporters (SERT and NET) = increase amount of Typical serotonin in synaptic cleft Atypical Can’t be used with MAO inhibitors Typical Atypical SSRI (Selective Serotonin Reuptake Receptor Blocks Blocks Blockade dopamine Dopamine & Inhibitors) Serotonin First line treatment + sx Effective ✔ Effective ✔ Used for premenstrual dysphoric - sx Effective More effective syndrome ✔ ✔✔ inhibiting reuptake of serotonin = Extra increase amount of serotonin in pyramidal more less synaptic cleft symptoms Can’t be used with MAO inhibitors Serotonin-Norepinephrine Reuptake Depression Inhibitors (SNRI) Emotional symptoms First line treatment o Apathy blocks the reuptake of both serotonin o Indecisiveness and norepinephrine/noradrenaline = o Pessimism increase levels of this chemicals o Low self esteem Can’t be used with MAO inhibitors o hopelessness o loss of motivation MAOIs ↑ dopamine, ↑ 5HT, ↑ NE Biological symptoms TCA ↑ 5HT, ↑ NE o sleep disturbance SSRIs ↑ 5HT o Loss of appetite SNRIs ↑ 5HT, ↑NE o Loss of libido Adverse effects of Antidepressants Benzodiazepines Nausea “zolams”, “zepams” Anorexia Hypnotic Insomnia Muscle relaxant Loss of Libido Anticonvulsants Failure of Orgasm Used for pre-op surgery Intake of MAOIS with SSRIs, TCAs, and SNRIs Adverse effect of Benzodiazepines can cause Serotonin Syndrome CNS depression Resulting in excess serotonin o Systems power down o Tremors anterograde amnesia o Cardiovascular damage o Inability to form new memories ▪ Death o Hyperthermia Epilepsy Intake of MAOIs with Tyramine can cause Chronic seizure disorder Hypertensive Crisis Seizure = action itself May result in MI and CVA o “storm” at neuronal activity o No spasms; just stops moving ▪ Does not affect voluntary Drugs for Bipolar Disorders muscle Drugs need to balance the spectrum Convulsion o Violent contraction of voluntary Lithium muscle First line treatment o With muscle spasm o Lithium carbonate Kinds of seizure o Lithium Citrate Focal – localized Mechanism of action is unknown o Simple - no alteration, no loss of Narrow therapeutic index consciousness o Small changes in dosage can o Complex-Loss of consciousness have lethal effect o Prone to toxicity General – both brain hemisphere o Petit mal (absence) - blank out Carbamazepine o Myoclonic – facial, limb, trunk Second line of defense muscle o Grand mal (Tonic clonic) – sustained tonic muscle extension Anti-Anxiety Drugs (Anxiolytics) ▪ Stiffening then contraction Barbiturates Anti-epileptic Drugs “Barbitals” (Phenobarbitals, Stops spread of excitation in the CNS Pentobarbitals) Stops neural transmission Adverse effect of Barbiturates o Inhibit Na+ channels o Promote GABA activity Respiratory depression (ADR) o Modulate Calcium activity Carbamazepine For focal simple Parkinsonism For focal complex Tremors for general Grand mal (Tonic Clonic) ↓ Dopamine, ↑ Acetylcholine slowing the recovery of voltage-gated o Acetylcholine = motor = tremor sodium channels = limiting repetitive Resting Tremors – while doing nothing neuron firing that causes seizures. Pill rolling Tremors –rolling pills Lamotrigine Action tremors - while doing activity for general Petit mal (absence seizure) for general Grand mal (Tonic Clonic) Inhibits voltage-gated sodium Anti-tremor Drugs channels = reducing glutamate release. Reverse the imbalance Valproic acid Levodopa General Myoclonic seizure Most effective treatment for Parkinson’s Inhibits GABA transaminase = Increases dopamine ↑ GABA levels Precursor of dopamine also blocks sodium and calcium Always taken with carbidopa channels. o stops levodopa to transform Phenytoin into dopamine peripherally, so it increases the bioavailability for generalized grand mal seizure of levodopa centrally Inhibits voltage-gated sodium ▪ Levodopa is transformed channels = limiting repetitive action into dopamine anywhere potential firing ▪ Parkinson’s is a CNS Causes gingival hyperplasia disease o Enlarged gingiva Diazepam for status epilepticus o prolonged grand mal seizure blocks Na+ channels  PHARMACOLOGY - FINALS Lesson 3.1: Hypnotics and Sedatives National University – College of Dentistry Transcribed by: Morales, Kyla Grace B. Professor: Dr. Paul Benzo I. Sia two types of drugs that affect the central Barbiturates nervous system (CNS): depress the activity of all excitable tissues Sedative drugs – Hypnotic doses of barbiturates increase o moderates excitement the total sleep time and alter the stages of o calming effect sleep in a dose-dependent manner Hypnotic drugs – Adverse Effects o induce drowsiness o help the patient fall asleep Respiratory depression vertigo, nausea, vomiting, or diarrhea or Sedatives sometimes may be manifested as overt excitement Benzodiazepines combine with other CNS depressants to “zepams” z-drugs cause severe depression used for calming and sedative effects. Insomnia Enhances the action of GABA neuron common sleep disorder Management of Benzodiazepines Hypnotic - or soporific drugs, commonly Flumazenil known as sleeping pills. Benzodiazepine receptor antagonist Categories of Insomnia For IV administration Transient Insomnia inhibiting benzodiazepine binding at the o < 3 days, environmental stresses GABA-A receptor = reversing the o Hypnotics should be at lowest dose sedative and respiratory depressant Short term insomnia effects of benzodiazepines o 3days -3 weeks Hypnotics o Personal stressors (grief, illness) o Hypnotics for 7-10 nights Melatonin Congeners Long term insomnia Ramelteon o > 3 weeks o Identifiable stressor synthetic tricyclic analogue of melatonin Insomnia Accompanying Other medical illnesses treatment of insomnia, specifically difficulties of sleep onset Insomnia from COPD agonist at MT1 and MT2 melatonin o may be resolved with proper treatment receptors = mimicking the natural hormone of the underlying sickness melatonin's effects Insomnia from chronic pain o effective pain management may eliminate Tasimelteon the need for hypnotics by treating treatment of non-24-h sleep- wake both the pain and the insomnia syndrome in totally blind patients experiencing circadian rhythm disorder Insomnia Accompanying Psychiatric Illnesses selective melatonin receptor agonist at Insomnia from depression the MT1 and MT2 receptors, helping to o SSRIs (that has insomnia as a side entrain and regulate circadian rhythms effect) can alleviate sleep disturbance because it treats the primary illness  PHARMACOLOGY - FINALS Lesson 3.2: Opioids and Narcotics National University – College of Dentistry Transcribed by: Morales, Kyla Grace B. Professor: Dr. Paul Benzo I. Sia Narcotics If administered for cough with phlegm, codeine prevents phlegm from coming out compounds having addictive potential o N-acetylcysteine is preferred Opioids ▪ Acts peripherally inhibit the transmission of pain signals Dextromethorphan “HBr” addictive = withdrawal should not be abrupt Robitussin – Acts centrally Acts at mu (μ) receptors, centrally ↑ threshold for coughing Principle of all Opioids o reducing the sensitivity of the cough reflex, making it less likely for a opioids reduce the excitability of neurons by person to cough in response to causing hyperpolarization of postsynaptic irritants or stimuli. neurons, making it harder for them to fire Acts on cough center in the brain action potentials and send signals. (specifically the medulla) to suppress the o dampens the transmission of pain cough reflex signals in the nervous system Heroin Full Agonist Opiods Loperamide Morphine Morphine Overdose Antidiarrhea Imodium, Diatabs Poison Triad Slows down GI motility: circular & o Comma longitudinal o Pinpoint pupils Used for non-infectious diarrhea o Respiratory depression If infectious, diarrhea is for the excretion of ▪ Opioids depresses the the infectious agent medulla - ↓respiratory control o loperamide administration would trap Morphone the infectious agent Fentanyl Tramadol For high grade pain Analgesia Partial Agonist Opioids For low grade pain binding to the mu-opioid receptors in the Function as brain, which helps to alleviate pain o Analgesia causes nausea o Antitussive o Antidiarrhea Antagonist Opioids Codeine Opioid overdose causes respiratory depression antitrussive o Depresses medulla for non-infectious cough (no phlegm) o Lowers control for respiration binding to opioid receptors in the brain, Naloxene which helps to reduce pain perception and Nalorphine suppress cough reflexes. Naltrexone Stages/ Effects of Abrupt Opioid Withdrawal Stage I o Up to 8 hours o Anxiety o Drug craving Stage II o 8-24 hours o Anxiety o Diarrhea o Insomnia o Tremors Stage III o Up to 3 days o Hypertension ▪ High blood pressure o Arrhythmia ▪ Irregular heartbeat o Fever Drug Scheduling Depends on the abuse rate or dependency potential of the drugs Schedule I o not prescribed; only for researches o ↑ abuse rate o ↑ psychological/physical dependence o Heroin Schedule II o Prescribed by S2 licensed ▪ Except tramadol Causes nausea Schedule III o moderate potential for abuse o moderate or low physical or high psychological dependence o Codeine (with Acetaminophen) Schedule IV o accepted medical uses. o Benzodiazepines Schedule V o Has the least potential for abuse