PE2

What happens when platelets bind to collagen?

release chemical mediators, change in surface receptor expression, become more sticky

What two things cause further platelet activation and trigger vasoconstriction?

ADP and thromboxane

cross linked fibrin is broken down by which enzyme to dissolve a stable clot?

plasmin

What is the only thing necessary for a clot to form?

platelets

erythrocytes and other cells trapped in fibrin but not necessary

What is an embolus?

clot moving through body

What is an embolism?

when embolus gets lodged in vessel

What are reasons to take an anti thrombotic drug?

for clot prevention when vascular endothelial cells are disrupted or when other risk factors are present

What are anti platelet drugs?

decrease platelet activation/plug formation

ex. clopidogrel, aspirin

What is an ADP receptor antagonist drug?

anti platelet

clopidogrel

What is a TXA2 synthesis inhibitor?

anti platelet drug

aspirin

What is an anticoagulant?

decreases clotting factor activity

What is an anticoagulant that decreases synthesis of clotting factors?

warfarin

What is an anticoagulant that inhibits factor Xa?

rivaroxaban

What is an anticoagulant that inhibits thrombin?

dabigatran

What is an anticoagulant that inhibits action of multiple factors?

heparin

How does aspirin work?

inhibits cyclooxygenase-1 (COX-1) which is required in the pathway to synthesize TXA2 from arachidonic acid

GI symptoms

how does clopidogrel work?

irreversibly blocks P2Y12 (ADP) receptor expressed by platelets

synergistic effects when taken with aspirin

bruising, bleeding most common side effects

How does warfarin work?

vitamin K-dependent carboxylase produces active clotting factors

vit K is a cofactor that gets oxidized in this reaction and must be reduced in order to be used again

step performed by vitamin K reductase, which is blocked by warfarin

What is prothrombin time and what is it used for?

common lab test to measure ability of blood to clot

tissue factor added to sample, timed until clot forms

expressed as INR (international normalized ratio), which is a ratio of a patient's clotting time to normal reference value

What does a high INR mean?

decreased ability to clot

how to reverse warfarin therapy?

vitamin K (~24 hr effect)

Kcentra or fresh frozen plasma (rapid)

direct oral anticoagulants are also known as

non-vitamin K antagonist oral anticoagulants

what are direct oral anticoagulant examples?

rivaroxaban and dabigatran

advantages of direct oral anticoagulants?

monitoring of coagulation and dose titration generally not needed

rapid onset/offset of action

few drug/diet interactions

disadvantages of direct oral anticoagulants?

less clinical experience

higher cost

antidotes relatively new and may not be widely available

how does heparin work?

polysaccharide that binds and activates antithrombin

antithrombin inhibits thrombin and other clotting factors

immediate effect, useful for acute clotting risk

what is a topical option for when excessive bleeding occurs?

tranexamic acid mouth rinse

inhibits plasmin

What is analgesia?

relief from pain despite presence of painful stimulus

What are analgesics?

drugs that decrease pain without major impairment of other senses

What are anesthetics?

block all sensation

What is the basic pain pathway?

nociceptors in skin and other tissues detect painful stimuli

enters spinal cord, synapse at dorsal horn

signal carried up to brain through ascending pathway

What is the body's natural pain control system?

descending pathways

inhibit transmission of pain in spinal cord

What is a chemical stimuli?

some directly activate nociceptors while others (prostaglandins) sensitize the neuron, making it easier to reach threshold (peripheral sensitization)

receptors for thermal stimuli?

TRPV1, TRPV2 receptors

receptors for mechanical stimuli?

mechxnosensitive ion channels

What is allodynia?

something that is normally painful becomes painful

ex. showering after sunburn

prostaglandins make more painful

What is hyperalgesia?

a normally painful stimulus is more painful than usual

ex. pricked with a pain

What are TRP channels?

ion channels that open in response to temp and certain other chemicals

major NTs that work in transmission of pain signals from primary neuron to secondary neuron in spinal cord?

glutamate (acts on AMPA and NMDA receptors, directly depolarize postsynaptic neuron)

substance P (peptide, allows channel to open more readily)

how does the brain modulate pain?

A beta fibers (light touch) activate inhibitory interneurons that decrease transmission of ascending pain signals

descending pathways from medulla cause release of endogenous opioids (enkephalins)

2 major mechanisms for pain control?

1. activate opioid receptors
2. decrease production of inflammatory mediators that sensitize pain fibers (NSAIDS)

What are opioids?

compounds that activate the body's endogenous opioid receptors to produce analgesia

include morphine and codeine, derived from poppy plant

name the opioid receptors and what they do?

mu: responsible for most, if not all, analgesic effects

kappa: dysphoria and hallucination at high doses

delta: not well understood, may have role in analgesia

endogenous peptide ligands: endorphins, enkephalins, dynorphins

all GPCR coupled to Gi

cellular effects of opioid receptors?

inhibit adenylyl cyclase (decreased cAMP)
open K+ channels and close Ca channels

physiological effects of opioid receptors?

inhibition of NT release at pro-nociceptive synapses
release of inhibition on descending pathways

actions of opioids at brain, spinal cord, peripheral nociceptors, and brainstem?

brain: decreased emotional suffering associated with pain, sedation, euphoria especially when large dose is given quickly

spinal cord: decreased activity of ascending pathways

peripheral nociceptors: decreased activation

brainstem: increased activity of descending inhibitory pathways

adverse effects of opioids?

respiratory depression most serious (main cause of overdose, decrease sensitivity of brainstem to increased CO2, effects are additive with alcohol)

abuse/addiction

pruritis

nausea, vomiting, constipation

natural and semisynthetic opioids? (phenanthrene)

morphine (prototype drug)

hydromorphone (10x potency, better water solubility)

oxycodone (lower efficacy, good oral bioavailability)

codeine (low efficacy, prodrug susceptible to CYP2D6 pharmacogenetics)

synthetic opioid drugs?

fentanyl (fast acting, potent, short duration of action)

methadone (treat addiction and pain, long duration of action)

What is loperamide?

antidiarrheal

effect at normal dose is restricted to GI tract

activation of mu receptors in GI tract reduces contraction and decreases secretions

potential for abuse

what is tramadol?

inhibits serotonin and norepinephrine reuptake
very weak mu agonist

CYP2D6 converts it into mu agonist 300x more potent

adverse effects: dependence potential, lowers seizure threshold

What are symptoms of narcotic (opioid) toxidrome?

CPR-3H

Coma, pinpoint pupils, respiratory depression, hypotension, hypothermia, hyporeflexia

What is naloxone?

treats overdose

opioid antagonist

will cause precipitated withdrawal in people that are physically dependent

What is buprenorphine?

partial mu agonist with high potency

helps to wean pts off opioids by preventing severe withdrawal symptoms

can precipitate withdrawal if full agonist in pt's system

combined with naloxone to deter IV and intranasal abuse

symptoms of opioid withdrawal?

anxiety, sweating, muscle aches, nausea

T/F physical dependence means addiction

false

What is addiction? how to treat?

lack of impulse control over taking a drug, seeking it despite negative consequences

wean off drug using methadone (long acting agonist) and buprenorphine (partial agonist)

dost enough to withdrawal but not enough to cause intoxication

dentists write about __% of opioid prescriptions in US

6-7

before opioids, you should try __ for pain relief

NSAIDS

What does COX convert arachidonic acid to?

prostaglandins (increase pain/inflammation plus variety of other effects)

prostacyclin (platelet inhibitor and vasodilator)

thromboxane A2 (increases platelet aggregation)

What is COX1?

generally considered constitutive (around all the time), performs "housekeeping" functions

What is COX2?

some constitutive, induced after tissue injury

What do prostaglandins do?

reduce activation threshold for nociceptors (peripheral sensitization)

increase blood flow, vascular permeability and leukocyte recruitment in injured area

in CNS, work as pain-increasing neuromodulators (central sensitization) and pyrogens

how does aspirin work?

acetylsalicylic acid, modified from a component of willow tree bark

inhibits COX1/2 by irreversible acetylation

therapeutic uses of aspirin?

analgesic: effective for mild-moderate nociceptive pain, lower ability to relieve pain compared to opioids but lacks the unwanted effects

antipyretic: fevers due to prostaglandins, promote return to normal

antithrombotic: low-dose aspirin is an effective anti-platelet agent, irreversible

What are examples of nonselective NSAIDS?

ibuprofen, naproxen, ketorolac

side effects of NSAIDS?

GI irritation/bleeding due to: direct irritation, loss of protective effect of COX1 (usually stimulates mucus production), anti-platelet effects (less TXA2 leading to more bleeding)

reduction in renal blood flow (impairs kidneys ability to increase GFR)

Reye's syndrome

Why is aspirin contraindicated in children?

Reye's syndrome

What are COX-2 inhibitors?

initially "blockbuster drug"

advantage of reduced COX1 inhibition is 50-60% reduction in GI bleeding

analgesic and anti-inflammatory effects similar to nonselective NSAIDS

BUT risk of stroke and MI increased

The only cox2 inhibitor on the market?

celecoxib

NSAID CV risk may be due to

renal effects, reduced prostacyclins

What is acetaminophen?

not true NSAID - lacks anti-inflammatory activity

works as analgesic and antipyretic

only weak inhibitor of COX 1/2, activity further reduced by high peroxide concentration found in areas of inflammation

active metabolite activates TRPV1 and cannabinoid CB1 receptors

dosage and toxicity of acetaminophen?

3 g/day

7-10 g/day toxic

initial flu-like symptoms

liver failure - jaundice, decreased blood clotting, death possible

antidote for acetaminophen toxicity?

N-acetylcysteine

replenishes glutathione

When to use NSAIDS vs acetaminophen?

NSAIDS: pain associated with swelling/inflammation (but bleeding risk)

What is neuropathic pain?

pain arises from nerve damage or dysfunction

nerve compression, diabetic neuropathy, neurotoxic effects of cancer chemo, MS, stroke, postherpetic neuralgia

difficult to treat - NSAIDS minimally effective

drugs used to treat neuropathic pain?

antidepressants

tricyclics (amitriptyline)

SNRI (venlafaxine)

anti-seizure drugs (gabapentin, carbamazepine)

NMDA antagonist (ketamine)

What does amitriptyline do?

tricyclics

increase serotonin and NE levels, also blocks Na channels

What does venlafaxine do?

SNRI

inhibit NT release by activating alpha-2 receptors

How does gabapentin work?

anti-seizure drug

inhibit voltage gated Ca channels

How does carbamazepine work?

anti-seizure drug

blocks Na channels

What is ketamine?

NMDA antagonist

What are topical anesthetics?

applied to skin or mucosa

penetrates 2-3 mm

What is infiltration anesthesia?

injection into subcutaneous tissue to numb a local region

works primarily on nerve endings in affected area

What is a field block or nerve blocK?

used to provide larger area of anesthesia

injection proximal to site of concern

anything in that nerve distal to where you injected

What is epidural anesthesia?

used for labor and some surgical procedures

allows for catheter placement and repeat infusions

most significant effects on nerve roots near infusion site

What is spinal anesthesia?

used for lower limb and pelvic surgery

injected into subarachnoid space caudal to L2

dependent on dose, can achieve full anesthesia of all distal structures

All local anesthetics are

weak bases

become ionized as pH decreases (so can't cross membranes)

functional consequence of local anesthetics being weak bases?

infected/inflamed tissues (which are more acidic) require higher dose of drug

two chemical classes of local anesthetics?

esters - less commonly used, more easily broken down, generally short duration, higher risk of allergy

amides: medium to long acting, includes drugs such as lidocaine

molecular structure of local anesthetics?

aromatic residue - provides lipid solubility

intermediate chain - separates aromatic and amino groups, gives chemical class (amide or ester), determines allergenicity and metabolism

amino terminus - provides water solubility and participates in acid-base reactions

onset, duration and degree of anesthesia influenced by

lipid solubility (moderate best)

degree of ionization (pKa)

nerve bundle diameter (smaller = quicker to anesthetize)

order of nerve function loss??

sympathetic - pain - cold - warm - touch - motor

how do local anesthetics work?

block voltage gated Na channels that carry action potentials down axon

LA preferentially binds what kind of channels?

open and inactive

what is a tonic block?

channel opens infrequently, drug diffuses away between action potentials

what is a phasic block?

channel opens frequently, number of channels bound to drug increases with each action potential

what is the critical length hypothesis?

in order to be effective, the field of action of a LA must include at least 3 nodes of an axon

examples of amide LA

lidocaine, artisane, bupivacaine, mepivacaine

examples of ester LA

benzocaine, tetracaine + oxymetazoline