Pharmacology 2 - Lecture 2: Nervous System Drugs PDF

Pharmacology 2 -- Lecture 2 Chapter 8 pg165-177 **What do CNS Drugs Do?** - Alter the nerve impulse transmission between the spinal cord and brain - These are potent potentially lethal drugs, therefore it is imperative that we fully understand their effects - Uses: restraint, seda...

Pharmacology 2 -- Lecture 2 Chapter 8 pg165-177 **What do CNS Drugs Do?** - Alter the nerve impulse transmission between the spinal cord and brain - These are potent potentially lethal drugs, therefore it is imperative that we fully understand their effects - Uses: restraint, sedation, analgesia, anesthesia, CNS Reversal Agents CNS drugs can be either stimulatory or depressive Recall: - A drug with both a good affinity for the receptor and the ability to produce a maximum response (intrinsic activity) is called an agonist (attaches and produces a response) - A drug with a good affinity, but blocks response (little or no intrinsic activity), is called an agonist drug (attach but produces no response) More Terminology: - Mixed agonist antagonists -- bind & activate opioid receptors to a certain extend, but also have the ability to block or inhibit the effects of other opioids - Partial agonist/antagonist -- when 2 drugs bind with a receptor and cause intrinsic effect. The drug that causes the lesser effect is the partial agonist/antagonist - Partial Agonist -- one drug that exerts only a partial effect - Partial antagonist -- one drug, a weaker drug, replaces stronger drug at a receptor and produces the same type of effects but much reduced - Competitive Antagonist -- when the effects of one drug stop the effects of another drug when connected to the same receptors **Pain Pathway**  A diagram of a dog\'s nervous system Description automatically generated Transduction -- if tolerable threshold exceeded, signal is turned into sensory electric stimulus Transmission -- electric stimulus sent up peripheral nerves to spinal cord then CNS Modulation -- sympathetic reflexes stimulated to dampen pain response -- endogenous opioid endorphins Perception -- being aware/conscious of nociception Pain signals travel from nociceptors via peripheral nerves to the dorsal horn of the spinal cord and then the brain (thalamus, reticular formation, limbic system & cerebral cortex) Nociceptors are free sensory nerve endings that are activated by painful stimuli Peripheral nerve fibers then transmit the pain signal to the dorsal root of the spinal cord, which can activate reflexes via motor neurons The dorsal horn also modulates and directs the pain signal to the brain. The thalamus, which is found between the midbrain and the cortex within the brain, processes and relays pain signals to the cerebral cortex, which ultimately perceives pain **Analgesic Drugs** *[Opioids ]* act on all parts of pain pathway - Highly controlled -- abuse potential & extremely addictive - Narcotics -- narcosis/stuporous state - Pain management - MAC sparing (used in combination during anesthesia to reduce the amount of inhalants or other required drugs) - Originally used to treat diarrhea -- reduces ileus (constipation) - Cough suppressant [Classification:] Full Agonists -- maximal/full response Full Antagonist -- No response/prevents agonist attachment Partial Agonist or partial antagonist -- partial response Mixed -- meaning attach fully or partially to more than one opioid receptor [Opioid Receptors: ] Mu-U (pain) Kappa-K (sedation) Opioid receptors found throughout the pain pathway and in GI tract (pulls water out of intestines and slows GI movements) [MOA] Mu analgesia occurs primarily by decreasing the release of excitatory neurotransmitters (acetylcholine, dopamine, serotonin) and dampening excitation of the postsynaptic sites where neurotransmitters would normally act Mu receptors have sub receptors -- not all species react the same to opioids [Effects of Opioids] Respiratory Depression = decreased RR, tidal vol, hypercapnia, hypoventilation, hypoxia - Resp arrest, cardiac arrest (overdose) Analgesia Sedation Nausea, vomiting, hypersalivation (side effects) Decreased GI secretions & movement (ileus) Euphoria (pleasant effects) or dysphoria (hallucinations or bad effects) Pupillary miosis or mydriasis Parasympathetic stimulation: bradycardia Histamine release (hives, redness, morphine)  [Morphine (Trade Name)] "OG" Opioid, everything is compared to morphine Class -- Opioid MOA -- Mu agonist Positive Effects -- Analgesia - Excellent for visceral pain & superficial pain receptors - Some sedation -- better opioid for aggressive dogs - Low doses can cause euphoria Side Effects (disadvantages) -- Excess Salivation - Vomiting (most of all opioids - dysphoria, miosis or mydriasis - Most histamine release of all opioids - Most ileus of all opioids (constipation) [Hydromorphone (Trade Name: Dilaudid)] Class - Opiods [ ] MOA -- pure mu agonist (we love Mu) Advantages -- profound analgesia (moderate to severe pain) - Mild to moderate sedation - Reversable - Anesthetic sparing - Minimal direct CV effects Suitable in compromised/ill - Less nausea & histamine release than morphine but more than fentanyl or methadone Disadvantages -- CV & resp depression - Vomiting, nausea, hypersalivation - Dysphoria - Hyperthermia seen in cats - Ileus - Some histamine release - Abuse potential class II narcotic Tech Tips - Can be titrated to effect to minimize negative effects - Various concentrations - Never leave unattended (heavily controlled) - Potent analgesic - Causes resp depression (hypoventilation hypercapnia +/- hypoxia - Reversible - IM? -- Panting & emesis: may be contraindicated - Can last between 2-6hrs - IV = less emesis. Can be given SC, IM, IV [Fentanyl (Trade Names: Duragesic, Fentadon)] Class: Opioid MOA- Mu agonist Advantages -- Profound analgesia - Very limited vomiting - Little histamine release Disadvantages -- short duration (30mins-2hrs) - Higher doses can cause dysphoria - Miosis or mydriasis occurs, challenges with administration due to short duration Administration -- IV, CRI, Transdermal (patch) Controlled & most potent of the commonly used small anima opioids Patches: Transdermal patch, based on surface area of the animal - Shave, clean surface, warm patch in armpit and warm skin on animal before application - Never cut the patch - Cover patch is ideal - 12-24hrs for patch to be fully effective - Place on animal day before surgery or use injectable for balanced analgesia - Exact location as identified in the packaging to ensure absorption at rate specified by manufacturer - Caution should be used, consider: what if patch falls of (kids, other animals) Dog/cat still seems painful? Dog eats patch? [Meperidine (Demerol)] - Less common opioid - 1/5 analgesic properties of morphine - Weaker mu agonist - More cardiac depressant effects compared to opioids - Shorter acting - Oral or injectable [Butorphanol (Torbugesic -- Trade Name)] MOA -- Partial mu agonist & kappa agonist (mixed partial agonist/antagonist) - Can be weak Mu agonist to mu antagonist plus strong Kappa agonist Mixed Opioids -- work on more than one receptor. Full & partially bind, antagonist & agonist actions Advantages -- Mild-Moderate Analgesia - Mild to moderate sedation (stimulates kappa receptors causing sedation) - Partially reversable (naloxone will reverse only Mu effects) - Antitussive effects - Good in GI compromised - Can administer to partially reverse a pure Mu already administered (only MU effects) - Can suppress cough - Can also be used to reverse some of the resp side effects of full mu agonists (less resp depressant effects) Disadvantages -- weaker analgesic if stronger needed - Analgesia plateau at high doses - Blocks MU receptors and therefore a pure Mu drug should not work well - Abuse potential class IV - Not as potent as morphine, short duration of analgesic (30-60 mins dog, 90 in cat) - Recommended to be used alone as source of analgesia Tech Tips - Great in compromised patients with mild or no pain Great in dyspnea (less resp depressive effects) - More sedative in the dog than cat (Kappa agonist -- up to 2 hrs for both) - Mild analgesic effects (Mu agonist -- 45min duration only) [Buprenorphine (Trade Name "Vetergesic")] MOA -- Partial mu agonist, kappa antagonist Advantages -- mild -- moderate strong analgesia (partial mu agonist), less analgesia than a mu agonist - Reversable or partially (Naloxone) - Anesthetic sparing - Good in GI compromised - Higher doses may increase duration, & 72hrs from available Disadvantages -- analgesia plateau at high doses - Slow onset (30 min regardless or route) - Abuse potential class III - Long duration (can be an advantage too) - Can not be given with pure mu Tech Tips -- good for moderate to severe pain - Dose dependent, works for mild pain too - Partial agonist actively bind & partially activate Mu receptors - Longer duration (6-8hrs) - Longer/delayed onset - Rapid absorption across MM [Methadone (Trade names: Comfortan, Methadyne)] MOA -- Mu agonist &binds to NMDA receptors Advantages -- profound analgesia & assist with windup pain control/prevention - Less hypersensitivity or reaction to other sensory stimuli - Short onset of action -- crossed BBB readily - No histamine release - No vomiting Disadvantages -- similar to other opioids - Dysphoria - Nasea - Bradycardia - Respiratory depression - Ileus [Tramadol (Trade Names: Tralieve)] MOA -- Various: reduces pain perception - Causes Mu agonist effects, prevent reuptake to serotonin and norepinephrine. Block receptors that normally respond to acetylcholine & may stimulates alpha 2 receptors to produce sedation and analgesia Advantages -- some analgesic effect - Better analgesic metabolism in the cat than in the dog Disadvantages -- little to no pain control (full extend of analgesic effort, uses not entirely known - Dog -- less effect/not well metabolized - Not to be given with behavioral modification drugs classified as serotonin reuptake inhibitors -- serotonin syndrome **Caution with ALL Opioids** - Mu agonist depresses resp system = hypoventilation -- hypoxia Leads to resp arrest then cardiac arrest - Drug diversion -- theft, use, tampering, altering logs etc. (Illegal) - Careful oversight required for prevention, diligent tracking, logging, wasting etc **Opioid Antagonist (Reversal)** Naloxone (Narcan) - Work by competing for spaces on the mu & some kappa receptors - Reverses resp depression, sedation and analgesic effects Best used in cases of overdose or prolonged compromised recovery Bolus dosages have a wide range, start low & work up OR Titration of Naloxone - To reduce sedation while preserving as much analgesia as possible. Draw up 0.04mg/kg Naloxone and dilute it to 10mL in saline (1mL for vert small patients). Administer 10% of the contents of the syringe at a time at intervals of 2-5mins until the patient becomes more alert - On average dogs, cats and rabbits respond well to approximately 20-40% of the total Naloxone dose without exhibiting overt signs of pain - In recover CPR bolus dosages are used If the patient needs the analgesia but the other side effects need to be reversed, try Butorphanol (partial mu agonist and kappa agonist) first choice OR Buprenorphine (kappa antagonist, mu agonist)