825 exam 2

things to know about drugs

what are the amide local anesthetics

lidocaine

prilocaine

ropivacaine

mepivacaine

bupivacaine

articaine

what are the defining characteristics of amide local anesthetics

extensively, slowly, metabolized by the liver

more likely to have systemic toxicity

moderate to fast onset of action

• pka of these drugs is closer to physiological pH which allows for a faster onset

bupivacaine

LONG doa = 2-4 hours

risk of cardiotoxicity

should not be used in high volume ie nerve blocks

lidocaine

intermediate doa = 1-2 hours

high risk of transient neurological symptoms when used spinally

mepivicaine

intermediate doa = 1-2 hours

• less vasodilation than other inhaled

not for epidural use due to risk of fetal toxicity

ropivacaine

long doa = 4-8 hours

lower cardiotoxicity

articaine

very common in dentistry

intermediate doa = 1-2 hours esp when admin w/epi

what are the ester local anesthetics

cocaine

chloroprocaine

benzocaine

procaine

tetracaine

what are the defining characteristics of ester local anesthetics

metabolized by plasma cholinesterase

less likely systemic toxicity

PABA formation may cause allergic reaction

generally slow onset because drug pKa is generally greater than physiologic pH

cholorprocaine

short doa = < 1hr

rapidly hydrolyzed

low TNS risk

tetracaine

long doa = 1-6 hours

most commonly used as ophthalmic because onset is generally seconds

procaine

short acting doa

less often used because of high ADE risk

aka novocaine

benzocaine

topical

not for children under 2

• can induce methemoglobinemia which decreases the amount of oxygen in the bloodstream

what is the general mechanism of action for local anesthetics

block Na channels → reduces Na influx → blocks membrane depolarization → prevents action potential conduction = no sensory input to the brain

(block nerve impulse by inhibiting action potential and targeting ion channels)

why are most local anesthetics lipophilic

they are aromatic drugs

improves membrane clearance

what impact does pka have on local anesthetics

a higher pka = more ionized fracture in solution

so a lower pka allows for a quicker onset of action because the unionized form of the drug interacts with Na channels

which nerves are the most sensitive to local anesthesia

small, unmyelinated nerve fibers

what are the type of nerve fibers and their susceptibility to local anesthetics

type A

• large diameter and heavy myelination

• low sensitivity to anesthetics

type B

• medium diameter and light myelination

• ok sensitivity to anesthetics

type C

• small diameter and no myelination

• best sensitivity to anesthetics

why are local anesthetics often combined with vasoconstrictors

increases the time of drug at the site of action by negating the vasodilatory effect of local anesthetics

• decreases systemic toxicity

• increases duration of action

most common is epi

• contraindicated in tissues supplied by end arteries

phentolamine mesylate

used for reversal of local anesthetic

non-selective adrenergic antagonist

• vasodilator to ½ the reversal time of anesthesia

what are the three phases of general anesthesia

induction

• rapid via IV

maintenance

• maintain appropriate depth

• inhalation or IV

• must balance admin with vital response

• frequently combined with opioids

emergence/recovery

• return to consciousness

• drug is redistributed from site of action

• sometimes reversal agents are needed

what are the four stages of general anesthesia

analgesia

• loss of pain sensation

  • interference with sensory transmission in spinothalamic tract

excitement

• pts experience delirium, sometimes competitiveness

• BP and respiration are increased and irregular

• try to shorten or eliminate

surgical anesthesia

• CNS depression

  • gradual loss of muscle tone, reflexes, spontaneous movement

• monitor so pts done progress into medullary paralysis

medullary paralysis

• too much anesthesia

• begins with respiratory depression progresses to death

• very deep CNS depression

  • requires mechanical ventilation and circulation to prevent death

what are the patient factors to monitor for safety and selection for general anesthesia

cardiovascular

• hypotension

  • anesthetics can interrupt CV function and cause vasodilation

respiratory

• respiratory depression can be dangerous in asthmatics

  • may also cause bronchodilation tho

liver and kidneys

• drug clearance and distribution

nervous system

• epilepsy and any neuromuscular disease

pregnancy

• first trimester is especially important

what are given as pre-anesthetics

antiemetics

benzodiazepines

opioids

• can reduce the need for other drugs

what are the hallmarks of inhaled anesthetics

typically used for maintenance

steep dose response curve = small therapeutic window

• dose dependant CNS depression

decrease cerebrovascular resistance

• increased brain perfusion

cause bronchodilation

dependant on blood solubility

• anesthesia is faster when not soluble in blood

what are the two categories of inhaled anesthetics

volatile

• liquid at room temp

• high boiling point and low vapor pressure

• isoflurane, sevoflurane, desflurane

gaseous

• gaseous at room temp

• low boiling point and high vapor pressure

• nitrous oxide

what is the MAC

minimum alveolar anesthetic concentration

measure of potency

higher MAC is lower potency

clonidine can lower MAC

• so can age, hypothermia, sepsis, pregnancy

what is malignant hyperthermia

increase in skeletal muscle oxidative metabolism triggered by inhaled anesthetics

to treat give dantrolene and withdraw anesthetics

• blocks calcium channel release

what is the relationship between partial pressure and general anesthesia

a higher partial pressure means a higher rate of anesthetic out of the lung

anesthesia is terminated by redistribution of drug from brain to blood and eliminated through the lungs

what is the mechanism of action for general anesthetics that effect GABA receptors

an increase in GABA sensitivity → increases Cl- influx → hyperpolarization of neurons → decrease in neuronal excitability and CNS activity = decreases response to sensory input

what are the general anesthetics that potentiate GABA mediated activation of GABA receptors

inhaled

• sevoflurane

• isoflurane

• desflurane

IV

• propofol

• etomidate

• benzodiazepines

what is the solubility comparison of the inhaled general anesthetics

iso > sevo > des

sevoflurane

good for pediatrics because low airway irritation

low blood solubility

• rapid onset

• rapid recovery

some hepatic risk

isoflurane

higher blood solubility than other fluranes

high airway irritant (not for induction)

does not undergo a lot of metabolism of the liver and kidney = low toxicity risk

desflurane

low blood solubility

low toxicity

may stimulate respiratory reflexes

what is the common ADE among inhaled general anesthtics

all exhibit dose dependant hypotension

this can be treated with a direct acting vasodilator

propofol

first choice med

inherent antiemetic properties

may cause

• CNS depression with risk of excitatory elements

  • hypotension because of reduced peripheral resistance

etomidate

just induction, no analgesia

short acting

no effect on heart or circulation

hypnotic

benzodiazepines

midazolam is the benzo of choice

• flumazenil admin to accelerate recovery

induces interograde amnesia

what is the role of opioids in general anesthesia

analgesia

agonist of the mu opioid receptor

fentanyl common because it induces analgesia faster than morphine

can cause hypotension, respiratory depression, muscle rigidity, and post op N/V

what is the general mechanism of action for NMDA related general anesthetics

antagonism of the NMDA receptor which prevents excitatory NT glutamine binding

nitrous oxide

inhaled, potent analgesic

NMDA receptor antagonist

poorly soluble in blood → quicker in quicker out

safe

• low respiratory depression

• safe in liver

• not much impact on CV events

ketamine

intravenous NMDA receptor antagonist

causes dissociative state

stimulates CNS outflow

• increased BP/CO

• not not use in history of stroke or uncontrolled hypertension

potent bronchodilator so good for shock and asthmatics

intrathecal injection

subarachnoid

space between the arachnoid membrane and the pia mater

contains cerebrospinal fluid

lumbar puncture/spinal tap

injection between the L3 and L4

penetrates the dura and arachnoid members and enters the thecal space (penetrates cerebrospinal fluid)

epidural injection

next to the dura mater and does not penetrate the dura

no contact with cerebrospinal fluid

capsaicin

selectively stimulates nociceptive neurons

selective for TRPV1 channels → desensitization = analgesia

for treatment of mild pain

what are the conventional DMARDs

methotrexate

hydroxychloroquine

leflunomide

minocycline

azathioprine

sulfasalazine

penicillamine

what is the role of DMARDs in rheumatoid arthritis

significantly slows disease course

induces remission

reduces inflammation

prevent further joint/tissue damage

can DMARDs be used with NSAIDS and/or steroids

yes!

can decrease steroid dose

methotrexate

folic acid antagonist

• inhibits dihydrofolate reductase → inhibits purine biotide synthesis

safe with other DMARDs

avoid chemotherapeutic properties with a low dose (1x/week)

• monitor CBC, liver enzymes

chronic use may cause cytopenias, cirrhosis, acute pneumonia

• leucovorin reduced

do not use in pregnancy, liver disease, high alcohol intake

leflunomide

inhibits dihydroorotate dehydrogenase → interferes with autoimmune lymphocyte proliferation

often combined with methotrexate

not for use in liver disease

hydroxycholoroquinine

unknown moa - generally antimalarial

combined with methotrexate

do not expect quick relief onset is 6 weeks-6 months

may cause ocular toxicity/damage, CNS disturbances, skin discoloration or irritation

minocycline

tetracycline antibiotic

early treatment

sulfasalazine

unknown moa

• inhibition of inflammatory cytokine production and release

1-3 month onset

combo with methotrexate or hydroxychloroquine

may cause male infertility

azathioprine

prodrug for mercaptopurine

• cytotoxic to rapidly proliferating cells → inhibitor of proliferation or B and T lymphocytes → intrinsic anti-inflammatory

increases infection risk

carcinogenic

penacillamine

depresses T cell activity

can be used for lead poisoning, wilsons dieasese

HIGHLY PROTEIN BOUND = long T½ (4-6 days)

discontinue treatment with no benefit in 12 months

kidney and bone marrow damage

cyclosporine and tacrolimus

inhibit calcineurin and IL-1/IL-2 receptor production

• cyclosporine binds cyclophilin

• tacrolimus binds FK binding protein

Metabolized by CYP3A4

high incidence of bladder cancer

what are the categories of biologic DMARDs

recombinant DNA

T-cell modulating

B-cell modulatin

Anti-IL-6

IL inhibitors

TNF-α inhibitors

what are common features of all biologic DMARDs

stop synovial cell proliferation and collagenase synthesis aka cartilage degradation so causes an increased infection risk as a class feature

do not administer with live vaccines

-MAB = monoclonal antibody

-CEPT = recombinant fusion protein

what are the TNF-α inhibitors used in rheumatoid arthritis

adalimumab

certolizumab

etanercept

golimumab

infliximab

what is the mechanism of TNF-α inhibitors in rheumatoid arthritis

bind TNF-α to decrease immune response through blocking the cytokine cascade which stops the inflammatory response

adalimumab

recombinant monoclonal antibody

binds directly to TNF-α

can be combined with methotrexate

also indicated in crohn’s or psoriatic arthritis

increases risk of agranulocytosis

certolizumab Pegol

monovalent Fab fragment of humanized anti-TNF-α antibody (lacks Fc region)

combined with PEG to increase the T ½ of antibody in blood

infliximab

chimeric monoclonal antibody

always combined with methotrexate

golimumab

TNF-α inhibitor

can combine with csDMARDs

increase in hepatic enzymes

also indicated in psoriatic arthritis, UC, ankylosing spondylitis

etanercept

recombinant fully human receptor fusion protein

also indicated in psoriatic arthritis, ankylosing spondylitis

what is the mechanism of action for interleukin 1 inhibitors

inhibits IL-1 which is a pleiotropic cytokine that plays a major role in synovitis mech leading to joint destruction

anakinra

interleukin 1 inhibitor

recombinant IL-1RA

used more frequently for cryopyrim associated periodic syndrome

what are the interleukin 1 inhibitors

anakinra

canakinumab

tocilizumab

sarilumab

canakinumab

human IgGk monoclonal antibody

indicated for systemic juvenile idiopathic arthritis

tocilizumab

human MAB for the interleukin 1 receptor

sarilumab

human MAB for the interleukin 1 receptor

abatacept

T cell modulator

• competes with CD28 for binding on the CD80/86 protein which prevents t cell activation

soluble recombinant fusion protein

can be combined with csDMARDS

decreased incidence of CV disease compared to TNF-α inhibitors (no combo)

rituximab

chimeric mouse/human monoclonal antibody

directed against b cell CD20 antigen which results in b cell depletion

for patients with an inadequate response to TNF-α inhibitors

admin methylprednisolone 30 min prior

tofacitinib

baricitinib

upadacitinib

oral JAK (janus kinase) inhibitor

• inhibits intracellular enzymes that modulate immune response (inflammatory mediator)

• activation of JAK/STAT signaling pathway induces genes involved in immune response, inflammation, cell growth, and differentiation

  • STAT = signal transducer and activator of transcription

CYP3A4 metabolism

risk of anemia and renal and hepatic risk

recombinant protein definition

generated from cloned DNA which is mostly identical to the endogenous compund

recombinant fusion protein

highly bioengineered proteins created from the fusion of 2 or more genes encoding recombinant proteins to create a new gene

etanercept and alefacept

MABs

identical products of original gene that encodes the anti-body

recognize a single epitope

polyclonal = collection of antibodies from different B cells = multiple epitopes

role of NSAIDs in rheumatoid arthritis

used for treatment of symptoms but not first line

what is the role of glucocorticoids in rheumatoid arthritis

rapidly decrease inflammatory symptoms

do not impact disease progression

prednisone or prednisolone may be used as an oral low dose combo with DMARDs

triamcinolone or methylprednisolone can be given IA for targeted joint relief

colchicine

tubulin binding/inhibition of cytoskeletal proteins

• depolarization decreases granulocytes and leukocytes

• tubulin binding blocks cell division

for treatment of gouty attacks and the prevention of future attacks

CYP3A4 metabolism

• must dose adjust

allopurinol

xanthine oxidase inhibitor = inhibits uric acid synthesis

long t ½ = once daily dosing

combo therapy

dose adjust with

• 6mp

• theophylline

• azathioprine

febuxostat

xanthine oxidase inhibitor = inhibits uric acid synthesis

once daily dosing

dose adjust with

• 6mp

• theophylline

  • azathioprine

indomethacin in gout

one of the most potent NSAIDs, non-selective COX inhibitor

naproxen in gout

non-selective cox inhibitor

long half life

intra articular steroids in gout

triamcinolone

methylprednisolone

may increase blood sugar and change mood

probenecid

inhibits urate anion exchange in proximal tubule which promotes uric acid clearance and increases the urinary excretion of uric acid and decreases urate levels

for prevention

inhibits the excretion of methotrexate, naproxen, ketoprofen, indomethacin

blocks tubular secretion of penicillin and and such can be used to increase the levels of beta lactam antibiotics

pegloticase

recombinant protein that is the urate oxidase enzyme which converts uric acid to allantoin

long half life (1-2 weeks)

PEGylated which increases blood solubility and decreases immunogenicity and increases half life

what are the triggers for gout

low dose aspirin (decrease UA secretion)

diuretics (increase UA levels)

beta blockers (increase UA levels)

cyclosporine (decrease renal tubule clearance)

what is the mechanism of action of NSAIDs

analgesia through inhibition of COX1 and/or COX2

inhibiting these enzymes stops the breakdown of arachidonic acid

high levels of AA inhibits the synthesis of prostaglandins thus stopping inflammatory and pain response

what are the non-selective NSAIDs

indomethacin, piroxicam, diclofenac, ibuprofen, naproxen

what is the COX-1 selective NSAID

ketorlac

what are the COX-2 selective enzymes

etodolac, meloxicam, celecoxib, (carprofen in dogs)

100 fold more selective for COX-2

• rofecoxib, valdecoxib, etoricoxib, lumiracoxib

aspirin

irreversibly acetylates and inactivates COX

in low doses it also inhibits platelet aggregation via cox-1 mediated TXA2

contraindicated in

• children

• hemophiliacs

• pregnancy

• gout

  • increases uric acid secretion

  • contraindicated with probenecid

acetaminophen

not an NSAID but does have cox inhibitory properties

• does not have anti inflammatory properties

no peripheral side effects like NSAIDs

• no gi bleeding

• no black box warning

hepatotoxic do not used with alcohol or >4 g daily

what is the black box warning associated with traditional NSAIDs

renal failure

• especially in elderly patients with reduced renal function

  • especially with concomitant use of ACEi and diuretics

indomethacin

non-selective cox inhibitor

most potent

increase GI effects

piroxicam

non-selective COX inhibitor

very long t ½

increased GI effects

etodolac

cox-2 selective inhibitor