Exam 3 Flashcards
What are prostaglandins created from?
Arachidonic acid is further metabolized to:
- Prostaglandins (PG, TX)
What is the pathway that converts phospholipids to arachidonic acid?
Explain the biosynthesis of prostaglandins from arachidonic acid
What is the COX enzyme responsible for?
responsible for the formation of prostanoids, including thromboxane and prostaglandins
What are the tissue differences between COX-1 and COX-2 inhibitors?
COX-1 –> constitutive in move all tissues
COX-2 –> induced in many tissues by stimulators
What are the functional differences between COX-1 and COX-2 inhibitors?
COX-1 –> platelet aggregation, GI protection, renal blood flow, autoregulation, initiation of parturition
COX-2 –> Inflammation, fever, pain, parturition, renal homeostasis
What are the inhibitor differences between COX-1 and COX-2 inhibitors?
COX-1 –> classical NSAIDs
COX-2 –> classical NSAIDs, COX-2 selective NSAIDS
What are COX-1 and COX-2 inhibitors?
There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining. NSAIDs block the COX enzymes and reduce the production of prostaglandins.
How do NSAIDs produce their anti-inflammatory effects?
Anti-inflammatory – modify inflammation reaction
— Primary drug action = COX inhibition –> inhibits prostaglandin production by COX
How do NSAIDs produce their analgesic effects?
Analgesic – reduction of pain
— Mainly against pain produced by inflammation or tissue damage
— Drug action = decrease the production of prostaglandins that sensitize nociceptors to inflammatory mediators
— Combines with opioids
How do NSAIDs produce their antipyretic effects?
Antipyretic – lowering fever
— Body temperature regulated by the hypothalamus
— Drug action = inhibition of prostaglandin production in the hypothalamus
How do non-selective COX-inhibiting NSAID work?
H-binding with an arginine residue at position 120 (non-selective binding site)
Blocks movement of arachidonic acid to active site
Reversible
How does inhibition by a COX-2 selective NSAID work?
Wider channel in COX-2
- Position 53 residue:
- COX-1 = i-leucine
- COX-2 = valine
- Less bulky valine produces side-pocket binding site
- COX-2 NSAIDS
o Bind to side-pocket binding site
o Have rigid side chain that block entry of arachidonic acid
How do NSAIDS affect the GI tract?
Most common: estimated 34%-46% of patients on non-specific NSAIDs will develop gastric damage (may be asymptomatic)
Prostaglandin production by COX-1 protects the gastric mucosa
- Decreases gastric acid production
- Increases protective mucous secretion
What are the GI effects of NSAIDs?
Effects:
* Dyspepsia (painful digestion)
* Diarrhea or constipation
* Nausea, vomiting
* Gastric ulceration (may bleed)
What are common skin side effects that NSAIDs cause?
Second most common
-Mild rash
-Urticaria (hives, eruption of wheals with itching)
-Photosensitivity
-Rare fatal complications
What are the common renal side effects of NSAIDS?
Acute, reversible renal insufficiency in susceptible patients –> Due to inhibition of synthesis of renal prostaglandins (PGs) involved in maintaining renal blood flow and Inhibition of PG synthesis reduces renal blood flow
What is analgesic nephropathy, and what is it caused by?
chronic nephritis and renal papillary necrosis
- Chronic NSAID use or NSAID abuse
- Associated with phenacetin, now withdrawn
How do NSAIDs cause cardiovascular effects?
Appears to be increased risk of cardiovascular “events”
NSAIDs can lead to an elevation in blood pressure, especially in patients treated with drugs inhibiting RAAS. The risk of blood pressure elevation shows a large variability between individual NSAIDs. Patients with congestive heart failure are at risk of the disease decompensation while taking NSAID
How do COX-2 selective NSAIDs minimize adverse GI effects?
- Use of COX-2 inhibitors
- Or prostaglandin analog misoprostol administration p.o.
Synthetic prostaglandins such as misoprostol given orally “replace” the prostaglandins whose production is inhibited by NSAIDs and have been shown to protect the lining of the stomach from NSAID-induced ulcers.
G. Explain why COX-2-selective NSAIDs may increase the risk of cardiovascular events (thrombosis)
- COX-produced PGs maintain balance between clotting and thrombolysis
- Non-selective COX-inhibiting NSAIDs do not upset that balance
COX-2 selective inhibitors favor clotting action
COX-1 PGs promote platelet aggregation
COX-2 PGs promote thrombolysis, which is diminished
Decrease PGI2 by vascular endothelium with little inhibition of prothrombotic thromboxane A2, which increases vasoconstriction and platelet aggregation
What happens when COX-2 > COX-1 inhibition?
- Stroke
- Myocardial infarction
Explain how low-dose aspirin provides its cardiovascular protective effect.
Aspirin interferes with the blood’s clotting action. When a person bleeds, clotting cells, called platelets, collect at the site of the wound. The platelets help form a plug that seals the opening in the blood vessel, stopping the bleeding.
But this clotting can also occur within the vessels that carry blood to the heart. If blood vessels are already narrowed from a buildup of fatty deposits in the arteries (atherosclerosis), a fatty deposit in the vessel lining can tear, exposing the blood to the inner wall of the artery, which then clots.
The clot prevents blood flow to the heart and causes a heart attack. Aspirin therapy reduces the clotting action of platelets — possibly preventing a heart attack.
What are morphine-like drugs used for?
Analgesia – Highly effective in most kinds of acute, as well as end of life (cancer), but less effective in neuropathic pain and other chronic pain states.
- Neuropathic pain: severe, debilitating, chronic pain
- Diabetic neuropathy
- Post-herpetic neuralgia
- Phantom limb pain
What is Codeine (3-methoxymorphine) used for?-
- More reliably absorbed p.o. than morphine, but less analgesic effect (<20%); used for mild pain.
- Causes little or no euphoria & is rarely addictive.
- Antitussive activity = cough remedy.
What is Etorphine used for?
- Potency 1000X that of morphine.
- In conjunction with sedative, used to immobilize wild animals, since effective dose small enough to administer by dart.
What is Methadone used for?
- Used to treat morphine and heroine addition
What is Tramadol used for?
- Post-operative or chronic pain; cough
What are NSAIDS used for in term of analgesic use?
- Used for mild, inflammatory pain
What are the major adverse effects of opioid analgesics?
- Respiratory depression
- Depression of cough reflex = antitussive
- Nausea and vomiting
- Miosis –> constriction of pupil
- GI effects = constipation
Describe the mechanism of action for Movantik in relation to relieving opioid-induced constipation.
- Opioid antagonist indicated for the treatment of opioid-induced constipation
- Peripherally acting μ receptor antagonist
- CNS penetration is negligible
- Doesn’t significantly reduce analgesia nor precipitate withdrawal.
MOVANTIK blocks opioids from attaching to something called “mu-receptors” in bowels—directly targeting the area impacted by opioid-induced constipation. This design helps provide relief efficiently and enable bowel movements.
μ-receptor
Analgesia ++/+++
Respiratory depr. +++
Miosis ++
Reduced GI motility ++
Euphoria +++
Dysphoria -
Sedation ++
Catatonia -
Phys. dependence +++
δ-receptor
Analgesia ++
Respiratory depr. ++
Miosis -
Reduced GI motility ++
Euphoria -
Dysphoria -
Sedation -
Catatonia -
Phys. dependence -
κ-receptor
Analgesia +/++
Respiratory depr. -
Miosis +
Reduced GI motility +
Euphoria -
Dysphoria +++
Sedation ++
Catatonia -
Phys. dependence -
NOP receptor
Analgesia Anti-opioid (supraspinal) ++ spinal
Respiratory depr. -
Miosis -
Reduced GI motility -
Euphoria -
Dysphoria -
Sedation -
Catatonia ++
Phys. dependence -
What is the mechanism of action of opioid receptors?
Inhibit adenylate cyclase, so lower intracellular [cAMP].
What are the types of opiod receptors?
4 types: μ, δ, κ, NOP (aka ORL1)
How do opioid receptors reduce neuronal excitability?
- Promote opening of potassium channels.
- Inhibit opening of voltage-gated calcium channels.
Opiod receptor effects on nociceptive pathway?
- Central effects account for analgesia.
- Opioid receptors are widely distributed in the brain and spinal cord
How do opiod receptors acts on a spinal level and peripheral level?
- Spinal level: morphine inhibits transmission of nociceptive impulses through dorsal horn and suppresses nociceptive spinal reflexes.
- Nociceptive afferent terminals in periphery, especially with inflammation
How do opiod receptors acts on a spinal level and peripheral level?
- Spinal level: morphine inhibits transmission of nociceptive impulses through dorsal horn and suppresses nociceptive spinal reflexes.
- Nociceptive afferent terminals in periphery, especially with inflammation
What is the significance of analgesia in terms of opioid use?
Highly effective in most kinds of acute, as well as end of life (cancer), but less effective in neuropathic pain and other chronic pain states.
What is the significance of sedation in terms of opioid use?
used to treat varying conditions; a few common examples include anxiety, tension, seizures, panic disorders and sleep disorders.
What is the significance of euphoria in terms of opioid use?
Powerful sense of contentment & well-being. Agitation & anxiety associated with pain reduced.
What is the significance of respiratory depression in terms of opioid use?
happens when the lungs fail to exchange carbon dioxide and oxygen efficiently. This dysfunction leads to a buildup of carbon dioxide in the body, which can result in health complications. A common symptom of respiratory depression is taking breaths that are slower and shallower than normal.
What is the significance of antitussive effects in terms of opioid use?
Cough remedy. Narcotic antitussives such as codeine reveal the antitussive effect primarily via the μ-opioid receptor in the central nervous system (CNS). The κ-opioid receptor also seems to contribute partly to the production of the antitussive effect of the drugs.
What is the significance of antitussive effects in terms of opioid use?
Cough remedy. Narcotic antitussives such as codeine reveal the antitussive effect primarily via the μ-opioid receptor in the central nervous system (CNS). The κ-opioid receptor also seems to contribute partly to the production of the antitussive effect of the drugs.
Cough remedy. Narcotic antitussives such as codeine reveal the antitussive effect primarily via the μ-opioid receptor in the central nervous system (CNS). The κ-opioid receptor also seems to contribute partly to the production of the antitussive effect of the drugs.
Cough remedy. Narcotic antitussives such as codeine reveal the antitussive effect primarily via the μ-opioid receptor in the central nervous system (CNS). The κ-opioid receptor also seems to contribute partly to the production of the antitussive effect of the drugs.
What is the significance of nausea/vomitting effects in terms of opioid use?
Cannot be dissociated from analgesic effect.
Usually diminishes and disappears with repeated use. Nausea and vomiting have a negative impact on treatment efficacy and successful patient management because they limit the effective analgesic dosage that can be achieved and are frequently reported as the reason for discontinuation of opioid pain medication or missed doses.
What is the significance of urinary effects in terms of opioid use?
Opioids also are known to cause urinary retention in patients outside of the postoperative period, occurring with the use of oral or sublingual medications in the outpatient setting
What is the significance of GI effects in terms of opioid use?
Constipation. Increases tone and decreases motility of smooth muscle. May be severe. Can delay absorption of other drugs administered p.o.
Constricts gall bladder & biliary sphincter –> contraindicated in patients suffering from gall stones –> increased pain.
Explain the primary indications for the use of opioid antagonists
Movantik (Naloxegol)
- Opioid antagonist indicated for the treatment of opioid-induced constipation
- Peripherally acting μ receptor antagonist
- CNS penetration is negligible
- Doesn’t significantly reduce analgesia nor precipitate withdrawal (acts peripherally)
Opioid antagonist = naloxone (Narcan)
- Used to treat respiratory depression from opioid toxicosis
What does the Autonomic control of the heart do?
Influence rate and rhythm, myocardial contraction and
myocardial metabolism and blood flow
What are the functions of Sympathetic effects? (β1 adrenoceptors)
- Increases cAMP formation, which increases Ca2+ currents
- Increase force of contraction (positive inotropic effect)
- Increase heart rate (positive chronotropic effect)
- Increased automaticity
- Reduced cardiac efficiency
-Increased oxygen consumption - Cardiac hypertrophy
- Stimulation of α and β receptors, not hemodynamic changes
What are the cardiac parasympathetic effects (M2 AChR)?
Rate & Rhythm
- Inhibit cAMP formation, open K+ channels, hyperpolarization
- Slow heart rate
- Reduced automaticity
- Inhibition of AV conduction
Name the three clinical objectives for the use of cardiac medications.
Rate and rhythm of the heartbeat - to treat cardiac dsyrythmias
Myocardial contractions - to treat cardiac failure
Metabolism of bloodflow - to treat cardiac insufficency
C. Describe the route of blood flow through the heart, including valves
Name the components of impulse propagation of the heart.
- Sinoatrial (SA) node
- Internodal pathways
- Atrioventricular (AV) node
- Bundle of His
- Purkinje fibers
What is the impulse propagation of the heart?
Chamber contractions are coordinated to effectively pump blood
Coordination due to specialized conduction system
What does the SA node do in impulse propagation of the heart?
Normal cardiac pacemaker
Initiates and establishes normal sinus rhythm
What do Intrnodal pathways do in impulse propagation of the heart?
pick up action potential and pass it to
Atrioventricular node
What does the AV node do in impulse propagation of the heart?
passes action potential on to Bundle of His
What does the Bundle of His do in impulse propagation of the heart?
passes action potential to Purkinje fibers
What do the purkinje fibers do in impulse propagation of the heart?
passes action potential on to Ventricles cardiomyocytes
What is the order of impulse propagation?
SA node –> atria –> intranodal pathways –> AV node –> Bundle of His –> Purkinje fibers –> ventricles
Describe phase 0 of the myocardial action potential.
rapid depolarization
- Begins when potential reaches ~ -60 mV (critical firing threshold).
- Rapid influx of sodium ions through voltage-dependent sodium channels sufficient to initiate action potential (all-or-nothing regenerative depolarization).
- Channels close after a few milliseconds and remain closed through Phase 2.
Describe phase 1 of the myocardial action potential.
Occurs as sodium influx ceases.
Describe phase 2 of the myocardial action potential.
Plateau
- Results from slow influx of calcium ions through calcium channels.
- Voltage-sensitive activation and inactivation similar to sodium channels.
- Release of intra-cellular calcium from sarcoplasmic reticulum.
- Muscle contracts.
- Potassium channels remain closed.
Describe phase 3 of the myocardial action potential.
repolarization
- Calcium channel inactivates.
- Potassium channels open, outflow is slow.
Describe phase 4 of myocardial action potential.
pacemaker potential
- Gradual depolarization during diastole
- Slowly inactivating potassium permeability;
- Gradual increase in sodium permeability.
- Usually most rapid in SA node = heart’s pacemaker
What are the components of a nephron?
Each nephron is composed of a renal corpuscle (glomerulus within Bowman’s capsule), a proximal tubule (convoluted and straight components), an intermediate tubule (loop of Henle), a distal convoluted tubule, a connecting tubule, and cortical, outer medullary, and inner medullary collecting ducts.
Diagram / describe the Renin-Angiotensin system
What are the angiotensin receptor-mediated effects of the Renin-Angiotensin system.?
