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 is the most important cardiac glycoside?
Digoxin most important
What is Digoxin used for?
Digoxin is used to treat heart failure and abnormal heart rhythms (arrhythmias). It helps the heart work better and it helps control your heart rate.
What are the indications for being prescribed Digoxin?
Digoxin is indicated in the following conditions: 1) For the treatment of mild to moderate heart failure in adult patients. 2) To increase myocardial contraction in children diagnosed with heart failure. 3) To maintain control ventricular rate in adult patients diagnosed with chronic atrial fibrillation.
What are the adverse effects of Digoxin?
Nausea / vomiting
Diarrhea
Confusion
What are the uses/ indications of Glyceryl trinitrate?
It is used to treat angina (chest pain). It can help stop chest pain if an angina attack has already started. It can also help to prevent them from starting. GTN ointment can also be used to treat tears in the skin around your bottom (anal fissures)
What are the uses of organic nitrates (in general)?
Organic nitrates are efficacious drugs for treatment of angina pectoris attacks, acute coronary syndromes, pulmonary edema, and hypertensive crisis. They work by releasing nitric oxide (NO) or a NO-related compound (eg, nitrosothiols)
What are the indications of organic nitrates (in general)?
Current indications include treatment and prevention of angina attacks and management of acute coronary syndromes
What are the side effects of organic nitrates (in general)?
Side effects of nitroglycerin include headache, dizziness, weakness, flushing, syncope, tachycardia, palpitations and postural hypotension. Dermal forms can cause local rash and irritation
What are the side effects of glyceryl nitrate?
The most common side effects are headaches, feeling dizzy, weak, tired or sick (nausea), and flushing. Usually you will use GTN for a long time, possibly for the rest of your life.
What are the uses of Isosorbide mononitrate?
Isosorbide mononitrate is used to prevent angina (chest pain) caused by coronary artery disease (heart disease). It does not work fast enough to relieve the pain of an angina attack that has already started.
What are the indications of Isosorbide mononitrate?
Isosorbide mononitrate is indicated for the prevention and management of angina pectoris due to coronary artery disease. The onset of action of oral isosorbide mononitrate is not sufficiently rapid to be useful in aborting an acute anginal episode.
What are the side effects of Isosorbide mononitrate?
- Abnormal heart sound.
- absence of or decrease in body movement.
- arm, back, or jaw pain.
- black, tarry stools.
- bladder pain.
- bleeding after defecation.
- blood in the urine or stools.
- body aches or pain.
What are Inodilators?
agents that have both vasodilatory and positive inotropic properties
What class of medication is Pimobendan?
Inodilators
What is the clinical application of Pimobendan?
- Clinical management of canine heart failures
- Nontaurine responsive dilated cardiomyopathy in cats
What are the uses of Pimobenden?
Pimobendan (brand name: Vetmedin®) is a heart medication used to treat dogs with congestive heart failure (CHF), usually caused by either dilated cardiomyopathy or valvular insufficiency. Its use in cats to treat heart failure is ‘off label’ or ‘extra label’.
What are the indications of Pimobendan?
Vetmedin (pimobendan) is indicated for the management of the signs of mild, moderate, or severe (modified NYHA Class IIa, IIIb, or IVc) congestive heart failure in dogs due to atrioventricular valvular insufficiency (AVVI) or dilated cardiomyopathy (DCM).
What are the side effects of Pimobendan?
The most common side effects include gastrointestinal effects such as decreased appetite, and diarrhea. Other possible side effects include lethargy and difficulty breathing This short-acting medication should stop working within 24 hours, although effects can be longer in pets with liver or kidney disease.
What is the functional unit of a kidney?
The functional unit of the kidney is the nephron. Each kidney consists of millions of nephron which plays a significant role in the filtration and purification of blood. The nephron is divided into two portions, namely, the glomerulus and the renal tubule and helps in the removal of excess waste from the body.
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.
What does the glomerulus do, and what are the transporters involved in the movement of wanted and ions in this segment?
glomerular filtration produces protein-free filtrate
- Fluid driven from capillaries into capsule by hydrostatic force
- Low MW chemicals go with the flow
- High MW chemicals stay in blood (proteins)
What does the proximal convoluted tubule do, and what are the transporters involved in the movement of wanted and ions in this segment?
- Resorption of: Na+, Cl-, HCO3-, glucose and amino acids
- Passive water resorption along with ions
- Active excretion of organic acids and bases (transporters)
- Na+/H+ exchanger (anti-port)
Moves Na+ out
H2CO3 is H+ source - Na+ pump (active process)
- K+ ion channels
What does the loop of henle do, and what are the transporters involved in the movement of wanted and ions in this segment?
- Controls concentration of urine –> regulates osmotic balance of body
Permeable to water, passive reabsorption
i. Very low water permeability
ii. Na+ reabsorption
iii. Na+/K+/2Cl- symporter
iv. Na+ pump active transport
- Filtrate becomes hypotonic wrt plasma, due to sodium reabsorption w/o water reabsorption
What does the distal tubule do, and what are the transporters involved in the movement of wanted and ions in this segment?
- NaCl reabsorption without water reabsorption –> dilution of urine
- Na+ reabsorption driven by active Na+ pump
- Ca2+ excretion is regulated here
What do the collecting tubules and ducts do, and what are the transporters involved in the movement of wanted and ions in this segment?
Movement of ions and water are under independent hormonal control
- Aldosterone enhances Na+ absorption and K+ excretion
- ADH affects water absorption
EtOH inhibits ADH secretion –> and has a diuretic effect
What are osmotic diuretics?
diuresis due to solutes in the urine that are not absorbed by tubules and cause water to be retained therein by osmotic pressure
What is the mechanism of action of mannitol?
Mannitol hinders tubular reabsorption of water and enhances excretion of sodium and chloride by elevating the osmolarity of the glomerular filtrate.
What is the relative efficacy of mannitol?
Mannitol, an osmotic diuretic is commonly employed and the immediate efficacy is likely to result from a plasma-expanding effect and improved blood rheology due to reduction in haematocrit. However repeated administration of mannitol can result in renal dysfunction caused by hyperosmolality and dehydration.
What is the classification of Mannitol?
Osmotic diuretic
What are the unwanted effects of Mannitol?
Transient increase in ECF –> left ventricular failure
Hyponatremia
Headache, nausea, vomiting
What is the most effective type of diuretic class?
Loop diuretics are the most potent diuretics as they increase the elimination of sodium and chloride by primarily preventing the reabsorption of sodium and chloride. The high efficacy of loop diuretics is due to the unique site of action involving the loop of Henle (a portion of the renal tubule) in the kidneys.
What is the function of Carbonic anhydrase inhibitors?
increase bicarbonate excretion
What is the pharmacological classification of acetazolamide?
Carbonic anhydrase inhibitor
What is the function of acetazolamide?
- Increase excretion of bicarbonate, Na+, K+, and water
- Produce alkaline urine and metabolic acidosis due to bicarbonate loss
o Still used to treat some forms of glaucoma
–> Reduce aqueous humour formation
What is the mechanism of action of acetazolamide / carbonic anhydrase inhibitors?
Carbonic anhydrase in the lumen of the proximal tubule of the kidney converts carbonic acid to water and carbon dioxide. Water and carbonic dioxide enter the intracellular space via diffusion
What is the relative efficacy of acetazolamide / carbonic anhydrase inhibitors?
Diuretic effect is not particularly useful
The diuretic efficacy of carbonic anhydrase inhibitors is relatively low, and it becomes further diminished with over several days of treatment due to the development of metabolic acidosis, with an associated reduction in bicarbonate in the glomerular filtrate.
What are the generic names of loop diuretics?
Furosemide/Lasix
What is the function of loop diuretics / furosemide/Lasix
Inhibit Na+/K+/2 Cl- symport transporter
Combines with chloride binding site
Increase delivery of Na+ to distal nephron
Cause loss of H+ & subsequent metabolic alkalosis, and loss of K+
Increase Ca 2+ and Mg 2+ excretion
Decrease uric acid excretion
What is the mechanism of action of loop diuretics?
Loop diuretics reduce sodium chloride reabsorption in the thick ascending limb of the loop of Henle. This is achieved by inhibiting the Na-K-2Cl carrier in the luminal membrane in this segment, thereby minimizing the entry of luminal sodium and chloride into the cell
What is the relative efficacy of loop diuretics?
Loop diuretics are the most potent diuretics as they increase the elimination of sodium and chloride by primarily preventing the reabsorption of sodium and chloride. The high efficacy of loop diuretics is due to the unique site of action involving the loop of Henle (a portion of the renal tubule) in the kidneys.
What is the function of Thiazide-like diuretics?
Inhibit Na+/Cl- symport transporter
What is the mechanism of action of Thiazide-like diuretics?
Thiazide and thiazide-like diuretics act on the nephron mainly at the proximal part of the distal tubule. Sodium excretion and urine volume are increased by interference with transfer across cell membranes. The result is a reduction in blood volume.
What is the relative efficacy of Thiazide-like diuretics?
Less potent that loop diuretics
What is the function of potassium-sparing diuretics?
Aldosterone antagonists
Diuretic effect is minimal because sodium reabsorption is largely complete by the collecting tubule
What are the benefits of potassium-sparing diuretcs?
i. Anti-hypertensive effect
ii. Prolong survival in selected pts with heart failure
iii. Potassium-sparing –> prevents hypokalemia
What is the mechanism of action of potassium-sparing diuretics?
Potassium-sparing diuretics act to prevent sodium reabsorption in the collecting tubule by inhibiting aldosterone receptors This prevents excessive excretion of K+ in urine and decreased retention of water, preventing hypokalemia
What is the relative efficacy of potassium-sparing diuretics?
Weak diuretics, but effective anti-hypertensive agent and for treatment of heart failure
What are the effects of the Renin-Angiotensin system?
o Stimulates aldosterone secretion
o Controls sodium excretion & fluid volume
o Affects vascular tone
What are the chemical components of the Renin-Angiotensin system.?
- Renin
- Angiotensinogen
- Angiotensin I
- Angiotensin-converting enzyme (ACE)
- Angiotensin II
What is Renin?
proteolytic enzyme – catalyzes conversion of angiotensinogen to angiotensin I
What is Renin secreted by?
granular cells of juxtaglomerular apparatus
What is the release of Renin stimulated by?
o Renal sympathetic nerve activity
o Fall in renal perfusion pressure
o Fall in Na+ content of tubule fluid
o Prostaglandins
What is the function of renin / what is it involved in?
Involved in blood pressure regulation
What is Angiotensinogen? What is it synthesized by?
Serum protein precursor of angiotensin I
- Synthesized by liver
What is Angiotensin I?
Precursor to angiotensin II
What is Angiotensin II? What is it’s renal effect?
Potent vasoconstrictor by increasing NE release in sympathetic nervous system
Renal effect – salt retention
What does Angiotensin-converting enzyme (ACE) do?
Converts angiotensin I to angiotensin II
Diagram / describe the Renin-Angiotensin system
What are the angiotensin receptor-mediated effects of the Renin-Angiotensin system.?
Diuresis
increased excretion of urine
Diuretic
Agent that promotes urine secretion
Osmotic diuretic
diuresis due to solutes in the urine that are not absorbed by tubules and cause water to be retained therein by osmotic pressure
Anti-diuretic
something that suppresses excretion of urine
What is psychosis?
a mental disorder marked by derangement of personality and loss of contact with reality:
o Delusions
o Hallucinations
o Illusions
What is the general functions of antipsychotics / neuroleptics?
- Block CNS DA receptors (particularly D2)
Produces ataraxia – state of relative indifference to external stimuli - Metabolized by cP450
Possible drug-drug interactions
What is Acepromazine (ACE) used for?
Used to manage behavior problems by sedation and reducing general attention to environmental stimuli
When is the use of ACE indicated?
Use as adjunct for anesthesia
IM administration
Decreases apprehension
Reduces general anesthetic doses
What are anxiolytics?
Drugs used to relieve anxiety
What are some generic names of Benzodiazepines?
Diazepam (Valium®)
Clorazepate (Tranxene®, Novo-Clopate ®)
Alprazolam (Niavam®, Xanax®)
Oxazepam ( Alepam®, Medopam®, and several others)
Temazepam (Restoril ®)
What are Benzodiazepines used for?
Generally used for generalized anxiety or panic disorders
Also used as an adjunct for anesthesia and to treat seizures
What is the mechanism of action for benzodiazepines?
Act at BZD receptors in CNS enhancing GABAA-mediated chloride conductance inhibits neurotransmission
Behavioral effect attributable to GABA potentiated pathways acting to regulate release of monoamine NTs in CNS
What are the side effects of benzos?
Sedation
Ataxia (risk of falling)
Muscle relaxation
Increased appetite (hyperphagia)
Paradoxical excitation (idiosyncratic response; particularly dogs on alprazolam)
Memory deficits
Tolerance may develop to sedation, ataxia, muscle relaxation over time
Memory deficits, difficulty learning new behaviors
Little, if any CV or respiratory effects
Disinhibit behavior (humans & animals): use with caution in aggressive pts; CI for fearful & aggressive dogs
Hostility
Aggressiveness
Rage reactions
Irritability
Behavior dyscontrol
What is the antidote for overdosing on benzos?
Antidote: flumazenil (Romazicon®) = BZD antagonist
How should you dicontinue use of benzos?
Withdraw pt gradually from BZDs (taper 25% of dose per week for 4 weeks)
Avoids discontinuation syndrome
What are the signs of discontinuation sydrome?
Nervousness
Tremors
Seizures
What are the uses of benzos for dogs?
Fears and phobias
Generalized anxiety
Combined with TCA
To decrease latency and reduce panic-like thunderstorm phobia & separation anxiety
What are the uses of benzos in cats?
Urine spraying (efficacy 55% with relapse upon cessation)
Travel
Generalized anxiety (changes in home environment)
What are the generic names of Azapirones?
Buspirone, Buspar®
What is the function of Azapirones?
Agonist for 5HT1A pre-synaptic receptors
Decreases 5HT synthesis
Inhibits neuronal firing
it is a serotonin receptor agonist, which means that it increases action at serotonin receptors in your brain. This, in turn, helps to alleviate anxiety.
What are the 3 groupings of antidepressants?
- Tricyclic antidepressants (TCAs)
- Selective serotonin reuptake inhibitors (SSRIs)
- Monamine oxidase inhibitors
What are the geenric names of TCAs?
Amitriptyline (Elavil)
Imipramine (Tofranil)
Doxepin (Sineqan)
Clomipramine (Clomicalm)
What is the function of TCAs?
Inhibit reuptake of NE and 5HT
Also:
Antagonistic activity for α1 receptor
Antihistaminic effects
Anticholinergic effects (anti-Ach effect)
What are the uses of TCAs in humans?
- Moderation of excessive arousal
- Reduction of anxiety
What are the uses of TCAs in dogs?
mild aggression, canine compulsive disorders, anxiety states
What are the uses of TCAs in cats?
aggression, inappropriate urination/spraying, excessive grooming, anxiety states, excessive vocalization
What are the uses of TCAs in horses?
limited use; enhance behavioral calming; reduce anxiety in breeding males
What are the advers effects of TCAs?
- Mild sedation
- Mild GI effects (usually vomiting)
- Antihistamine effects
- Anticholinergic effects
- Dry mouth (increased water consumption)
- Constipation
- Urinary retention
- Contraindications: glaucoma or keratoconjunctivitis sicca
What should be done before prescribing TCAs?
- Conduct cardiac assessment before administration
- Anticholinergic effects –> ht rate elevation (vagal block)
- Elevate ht rate due to reflex response to α1 antagonism
- α1 –mediated agonistic effects: vasoconstriction
What is the function of SSRIs?
- More specific than TCAs
- Makes 5HT more available in synapse
- No effect on NE
As the name suggests, SSRIs exert action by inhibiting the reuptake of serotonin, thereby increasing serotonin activity. Unlike other classes of antidepressants, SSRIs have little effect on other neurotransmitters, such as dopamine or norepinephrine.
What are the uses of SSRIs in humans?
OCD, eating disorders, impulsivity, aggression, pain syndromes, premenstrual dysphoria
What are the uses of SSRIs in dogs?
separation anxiety, compulsive behaviors, dominance-type or impulsive aggression
What are the uses of SSRIs in cats?
urine spraying, aggression, compulsive behavior (psychogenic alopecia, fabric chewing)
What are the uses of SSRIs in horses?
anxiety, compulsive behavior
What are the general adverse effects of SSRI’s?
- Vary by agent
- GI effect
- Nervous system: sedation or agitation, irritability, insomnia
What are the adverse effects of SSRIs in dogs?
most commonly lethargy/depression/calming; anorexia/decreased appetite
What are the adverse effects of SSRIs in cats?
GI effects; closely monitor food and water consumption, fecal and urinary elimination, body wt
- Minimize by starting at lower dose and titrate up as necessary
What is the function of Monamine Oxidase Inhibitors?
An enzyme called monoamine oxidase is involved in removing the neurotransmitters norepinephrine, serotonin and dopamine from the brain. MAOIs prevent this from happening, which makes more of these brain chemicals available to effect changes in both cells and circuits that have been impacted by depression.
What is Monoamine oxidase?
intracellular enzyme that catabolizes monoamine NTs (NE, 5HT, DA)
What are MOIs used for?
Approved by FDA for treatment of canine cognitive dysfunction
Extralabel for geriatric cats with cognitive dysfunction
What does MAO-B inhibition of MOIs do?
increases DA in CNS restoring NT balance and improving cognition
Do MOIs have anti-anxiety effect for dogs?
Has not produced beneficial effects on anxiety of depression in dogs
Do MOIs have anti-anxiety effect for dogs?
Has not produced beneficial effects on anxiety of depression in dogs
Do MOIs have anti-anxiety effect for dogs?
Has not produced beneficial effects on anxiety of depression in dogs
