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Lecture 3

Fall Week 3 - InflammationImmunity.pdf

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Janet O' Connell

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Fall Week 3 - Inflammation/Immunity September-20-10 10:43 PM Lilley Ch 11: Analgesic Drugs Overview • Meds that relieve pain without causing loss of consciousness(commonlyreferred to as painkillers) are considered analgesics. ○ Several classes of analgesic, determined by the chemical structures and mechanisms of action of drugs. ○ Focus of Ch 11 is the drugs used to relieve moderate to severe pain: opioid analgesics. Next commonanalgesic class are NSAIDs. Physiology and Psychology of Pain Definition and Classification of Pain • Acute Pain is sudden (minutes to hours); usually sharp, localized; physiological response (SNS: tachycardia, sweating, pallor, increased BP). Usually subsides when treated. • Persistent Pain (or chronic pain) is slow (days to months);long duration; dull, long-lasting aching. ○ Often more challenging to treat because changes happen in the nervous system (tolerance) which require increasing drug doses. • Pain can be further classified into its sources: ○ Acute NociceptivePain is classified as either somatic or visceral.  Somatic pain originates from skin, bone, muscle, connective tissue, or joints and is often described as localized and throbbing.  Visceral pain originates from internal organs and can be well-localized or referred. □ Referred pain occurs because visceral nerve fibres synapse at a level in the spinal cord close to nerve fibres that supply specific subcutaneous tissues in the body. ○ Sometimespain is described as superficial,which originates from the skin and mucous membranes. ○ Another type of pain is vascular pain, which possibly originates from some pathology of the vascular or perivascular tissues, thought to account for migraine headaches. • Pain management may be more appropriately selected when the source of the pain is known. • Neuropathic pain results from injury or damage to peripheral nerve fibres or to central neurological damage to the CNS, rather than stimulation of nerve receptors. ○ Phantom pain is a type of neuropathic pain that occurs in an area where a body part has been removed.It can also occur in attached limbs following trauma to the spinal cord. • Cancer pain can be acute, persistent or both. Stems from causes such as pressure on nerves, organs, or blockage to an organ; metastasis;pathological fractures; muscle spasms; and adverse effects to cancer treatment. • Psychogenic pain is pain that originates from psychological factors, not physical conditions or disorders. Theories of NociceptivePain Transmission and Relief • Gate theory uses the analogy of a gate to describe how impulses from damaged tissues are sensed in the brain. Four distinct processes,all of which occur at the same time, are required for nociceptive pain to occur and are widely believed to determine the perception of, and response to acute pain. 1. Transduction ○ Begins in the periphery (skin, subcutaneous tissue, somaticstructures) where primary afferent neurons (nociceptors) are scattered. These nerve endings are sensitive to noxious or tissue- damaging stimuli. ○ Such stimuli cause the release of numerous chemicals (PGs, bradykinin, serotonin, histamine, leukotrienes).These substances convertthe stimulus to an impulse (or action potential). Some current pain managementstrategies aim at blocking these substances (think NSAIDs!) ○ The action potential is created on the neuron cell surface. The inside of the neuron carries a negative charge and the outside carries a positive charge. negative charge and the outside carries a positive charge. ○ The substances released by the noxious stimulus causes the receptor membrane to become permeable to extracellular sodium (Na+) ions, causing a temporaryreversal of the charges (depolarization). Potassium,K+, leaves the cell, causing repolarisation. 2. Transmission ○ Involves the transmittal of the pain impulses along pain fibres, to activate pain receptorsin the spinal cord and brain. ○ Nociceptivenerve fibres enter spinal cord in the dorsal (posterior)horn of the spinal cord. From here, ascending nerve fibres carry the impulse to the brain stem and thalamic regions.  Gate theory: there are also "gates" in the dorsal horn, which control pain transmission. ○ There are two types of nociceptorpain fibres:  A-delta (A-δ) □ Sensitive to mechanical and thermal stimuli, transmit well-localized,sharp, cutting or stabbing pain. □ Also activate fight or flight response (SNS) □ Gate theory: Activation of A fibres closes the gates, inhibiting transmission of pain impulses to the brain.  C Fibres □ Sensitive to mechanical, thermal and chemical stimuli, transmit dull, poorly localized, aching pain. □ Gate theory: Opening of the gate is affected by stimulation of C fibres, transmitting pain impulses to brain and perception of pain. 3. Perception ○ Less an actual physiological event than a subjective phenomenon ○ The level of stimulus needed to produce a painful response is called the pain threshold. It is similar for most people. ○ Pain tolerance is the psychological element of pain, the amount of pain a person can endure without it interfering with daily life. Can vary from patient to patient because it is subjective. 4. Modulation: to make alterations in something to make it less strong, forceful, or severe. ○ Neural activitythat controls pain transmission to neurons in both the PNS and CNS. ○ Descending nerve fibres (from brain stem to spinal cord) release endogenous (made within the organ/tissue) neurotransmitterscalled enkephalins and endorphins.  These substances bind with opioid receptorsand inhibit the transmission of pain impulses by closing the gates, producing analgesia by blocking the release of neurotransmitters.  Responsible for the phenomenon of "runner's high."  Behave like exogenous (from outside the body) opioids.  Usually break down too quickly to be useful as analgesics. Psychologyof Pain and Pain Management • Pain is a subjective and individual experience; it can be defined as whatever the patient says it is, wherever they say it is, whenever the person says it does. Treatment of Pain in Special Situations • Patients in special situations such as AIDS, cancer and sickle cell anemia may experienceperiods of acute pain. • WHO recommendedthe three-step analgesic ladder, which is often applied as the pain managementstandard for the use of nonopioids and opioid drugs. ○ Step 1: use of nonopioids (with or without adjuvant medications)once the pain has been identified and addressed. If pain persists or increases, treatment movesto step 2. ○ Step 2: use of opioids with or without nonopioids and with or without adjuvants. Should pain persist or increase, treatment movesto step 3. ○ Step 3: use of opioids indicated for moderateto severe pain, administered with or without nonopioids or adjuvant medications. Opioid Drugs Opioid Drugs Mechanism of Action and Drug Effects • Opioids can be classified as agonists, partial agonists or antagonists (nonanalgesic). ○ Agonists bind to an opioid pain receptor in the brain and causes an analgesic response resulting in the reduction of pain sensation. ○ A partial agonist a.k.a mixed agonist a.k.a agonist-antagonist binds to a pain receptor but causes a weaker neurological response than that of a full agonist. ○ An antagonist binds to a pain receptor but does not reduce pain signals. It also functions as a competitiveantagonist because it competeswith and reverses the effects of agonist and partial-agonist drugs at the receptor site. • Five types of opioids receptors have been identified to date: μ, K, б, δ, and ε. The μ, K, and δ receptors are the most responsive to drug activityand are where the opioids bind to relieve pain. • Opioids also act outside the CNS, and many of their unwanted effects stem from these actions. Indications • The degree to which pain is relieved or unwanted adverse effects occur depends on the specific drug, the receptor to which it binds, and its chemical structure. • Opioids also suppress the medullary cough centre, which results in cough suppression. • Constipation from decreased GI motility can be used to treat diarrhea. • Often drugs from other chemical categoriesare added to the opioid regimen as adjuvant analgesic drugs (or adjuvants). These assist the primary drugs in relieving pain. Such drugs can include NSAIDs, antidepressants, and corticosteroids. ○ This allows for smaller doses of opioids, which accomplishestwo important functions:  Diminishes some of the adverse effects seen with higher dosages of opioids (e.g. respiratory depression, constipation and urinary retention);  Approaches the pain stimulus by another mechanismof drug action and has a beneficial synergistic (combined effort) effect in reducing the pain. Contraindications • Known drug allergy and severe asthma; • Extremecaution should be used in cases of respiratory insufficiency, especially when resuscitative equipment is not available; • Conditions involving elevated intracranial pressure (e.g. head injury); • Morbid obesity or sleep apnea; • Myasthenia gravis (disease causing extremeweakness of muscles); • Paralytic ileus (bowel paralysis); • Pregnancy. Adverse Effects • Strong abuse potential. • Patients who have never taken opioids are said to be opioid-naive and are not accustomedto the powerful effects of the drug. Such patients require lower drug doses. • A person taking opioids to deliberately achieve an altered mental status will become psychologically dependant (a.k.a addicted). • In contrast, physical dependence is
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