Chapter 19 Pharmacology for the Interventional Pain Physician Flashcards
Iodinated contrast agents provide greater attenuation
of x-ray radiation, relative to
tissue and bone, reducing
the amount of radiation reaching the detector (fluoroscopic intensifier) This allows contrast to be easily visualized on x-ray images
Iodinated contrast media (ICM)
in image-guided procedures is utilized to
define the anticipated spread and location of the injectate. This improves safety by avoiding injection of drugs into unintended locations such as intravascular or intrathecal
spaces
ICM are based on variations of
the 2, 4, 6 tri-iodinated benzene ring
ICM are classified on the basis of
their chemical structure, osmolality, iodine content, and ionization
The iodine content is responsible for
x-ray attenuation and the concentration in mg iodine/ml is used to express the strength of the
attenuation of a particular agent
Clinically used ICM agents
have how much iodine
between 180 to 400 mg/ml of iodine.
The chemical composition of contrast media is in four different forms:
ionic monomers,
ionic dimers,
nonionic monomers
nonionic dimers
Ionization of ICM is produced
by
substitutions on the benzene ring at the 1, 3, and 5 positions to produce water solubility and physiologic pH
Solubility of the nonionic contrast media is due to
substitution with hydrophilic side chains such as
hydroxyl or amide groups
The concentration of iodine necessary to obtain
radiographic attenuation dictates
the number of particles in solution (osmolality) needed for a particular agent to be effective
Contrast osmotoxic reactions
pain on injection, hemolysis,
endothelial damage (capillary leak and edema), vasodilation
(flushing, warmth, hypotension, and cardiovascular
collapse), hypervolemia, and direct cardiodepressive effects
Ionic ICM are strictly contraindicated for all applications involving the
central nervous system (CNS) and may cause severe or fatal neurotoxic reactions following
intrathecal administration
ICM agents of choice for interventional pain procedures
Non-ionic ICM are the agents of choice due to their lower osmolality and toxicity
Commercially Available Ionic Monomeric X-ray Contrast Media
Meglumine iothalamate (Conray) Meglumine ioxithalamate (Telebrix) Sodium amidotrizoate (Urografin, Hypaque)
Commercially Available Nonionic Monomers X-ray Contrast Media
Iohexol (Omnipaque) Iopentol( Imagopaque) Ioxitol ( Ixilan) Iomeprol (Iomeron) Ioversol (Optiray) Iopromide (Ultravist) Iobitridol (Xenetix) Iopamidol (Iopamiro)
Commercially Available Ionic Dimer X-ray Contrast Media
Ioxaglate (Hexabrix)
Commercially Available Non- Ionic Dimer X-ray Contrast Media
Iotrolan (Isovist)
Iodixanol (Visipaque)
ICM Distribution
ICM are hydrophilic and demonstrate low protein binding. After intravascular injection there is rapid
distribution into the extracellular space and the fall in plasma concentration is rapid.
ICM Metabolism
Elimination is by glomerular filtration without reabsorption and there is virtually no metabolism.
ICM Elimination in patient with and without renal impairment.
In patients with normal renal function the elimination half-life is approximately 2 hr, and with renal impairment excretion can last for weeks.
Severe reactions of ICM
anaphylactic or anaphylactoid symptoms of severe bronchospasm, laryngeal edema, angioedema, pulmonary edema, hypotension, convulsions, cardiac dysrhythmias, or arrest
Adverse reactions to ICM can be classified as
idiosyncratic or immediate and delayed.
The immediate reactions of ICM
are generally the most severe and consist in this setting of
anaphylactoid type reactions of varying severity. These reactions are generally independent of dose and unpredictable, and usually occur within 1 hr of administration. There is increased risk in patients with a prior reaction to ICM, and with underlying disease including asthmatics,history of atopy, and advanced heart disease
Treatment of immediate reactions of ICM
If suspected these reactions need to be treated with antihistamines,
epinephrine, corticosteroids, and full cardiopulmonary
resuscitation as needed
Delayed reactions of ICM
Delayed reactions are composed of chemotoxic reactions and cutaneous manifestations of delayed hypersensitivity. The chemotoxic reactions
include contrast mediated nephrotoxicity, decreased cardiac
contractility, and neurotoxicity, all of which are dose
dependent and should be rare in this setting with use of
nonionized agents.
The delayed allergy-like skin reactions of ICM
are twice as frequent for nonionic dimers as for nonionic monomers
How to prevent adverse reactions of ICM?
The first step is to understand the risk factors, including a previous reaction to ICM, and take a history to elucidate the type of reaction the patient experienced. The history should also include the type of agent and whether it was an ionic or nonionic agent
Treatment protocols for anaphylactic and anaphylactoid reactions,
antihistamine and corticosteroid prophylaxis against anaphylactic and anaphylactoid reactions,
including oxygen, intravenous fluids, antihistamines (H1 and H2blockers), adrenergic drugs (epinephrine), and corticosteroid
Ionic ICM vs. non-ioninc agents adverse reactions
Ionic ICM have 4 times the incidence of these reactions
compared to nonionic agents
Gadolinium containing
contrast agents
the use of gadolinium containing contrast agents beneficial as an alternative in
high-risk patients. However, there is an upper limit to safe
dosage of gadolinium (0.3 mmol/kg body weight)
Adverse Effects of Gadolinium containing contrast agents
caution and reduced dosage have to be taken in patients
with moderate to severe renal dysfunction due to its association with development of nephrogenic systemic fibrosis
Local anesthetics Mechanism of Action
LAs prevent generation and conduction of the nerve impulse by blocking voltage gated Na+ channels within
the cell membrane. This reduces or prevents the transient increase in Na1+ permeability needed for depolarization and propagation of a nerve impulse.
Akyl substitutions on a LA increase
the lipid solubility
The potency of LAs have been shown to be directly related
to
lipophilicity and is often expressed as the octanol:water partition coefficient
Local anesthetics Acid or Base?
All LAs are weak acids as quaternary amines and are positively charged. As tertiary amines they are weak bases
and uncharged
Local anesthetics be in what form to access their site of action on the Na+ channel?
They must be in their lipophilic base form
to access their site of action on the Na+ channel
pKa of the Local anesthetics
The pKa of the LA and pH at the site of injection (usually physiologic pH of 7.4 but can be locally altered, such as in areas
of infection) influence the amount of LA in base form and the speed of block onset. In general, the lower the pKa of the LA the faster its the onset.
The addition of bicarbonate to a
solution does what to local anesthetics?
The addition of bicarbonate to a
solution to increase the pH and speed of onset can be done to epinephrine-containing LAs that are adjusted to an acidic pH for stability
factors influencing the speed of onset include
the concentration and amount of LA used and the anatomic location of injection or application
Fibers response to local anesthetics
small unmyelinated C-fibers, autonomic fibers,
and small myelinated Ad delta fibers (pain and temperature)
are more sensitive than larger myelinated
Ag, Ab, and Aa fibers (motor, proprioception, touch, and
pressure.
Ropivacaine vs. Bupivacaine
More recently, ropivacaine, is stated
to be more motor sparing than bupivacaine and less cardiotoxicity at equipotent doses
multiple factors
that determine duration of action
Increased lipid solubility
increases its duration of action. the rate of metabolism can be a factor (e.g., amino-ester LAs). the speed of
uptake and/or elimination from the site of deposition, which is also dependent on tissue perfusion, influences the
duration of action. addition of vasoconstrictors to
decrease perfusion and uptake and thus prolong block
Perfusion of course is dependent on anatomic location
parauterine > intercostal >epidural > peripheral nerve >intrathecal
TABLE 19–2
Infiltration Anesthesia
most common adverse reactions of local anesthetic
The most common adverse reactions are autonomic responses or anticipatory reactions to medical procedures.
These include tachycardia, sweating, hypotension, and
syncope. They are characteristically short-lived with resolution
in minutes requiring no treatment or can be treated with muscarinic blockers or ephedrine
common reaction is the response to vasoconstrictor
additives, usually epinephrine
Symptomatically
this produces tachycardia, hypertension, and anxiety or feelings
of doom. If injected peri- or intra-arterial it can produce distal ischemia from arterial spasm
systemic toxicity of local anesthetics results first in the CNS and then has cardiovascular effects
CNS symptoms
consist of metallic taste, perioral numbness, dizziness, muscle twitching, and ultimately generalized seizures.
Toxic cardiovascular effects include arrhythmias, cardiac
depression, vasodilation, hypotension, and cardiac arrest/
collapse
Trearment of bupivacaine-induced cardiac toxicity
The use of 20% intralipid has been shown to be effective for resuscitation from bupivacaine-induced cardiac toxicity
Allergic reactions to LAs due to
The vast majority
of these are due to PABA from amino-ester LAs. Amino-amide LAs are exceedingly rare causes of allergic reactions
Paraben preservatives
Paraben preservatives are structurally very
similar to PABA and can show allergic cross-reactivity to
amino-ester LAs
The commonest allergic reactions of LA are
delayed (24 hrs to a week) minor cutaneous rashes. These
are generally self-limited and treated with antihistamines
and topical corticosteroids
allergic cross-reactivity to bisulfite preservatives in patients with
known food allergies and paraben preservatives in
patients with sulfa antibiotic allergY
A high level or complete
spinal block will result in
respiratory compromise by diaphragmatic and accessory muscle paralysis and in total
sympathectomy
Treatment of High Spinal
Immediate resuscitation can be required,
including respiratory and cardiovascular support
Adverse Effects of Local Anesthetics
Intrathecal
administration of some LAs (lidocaine, chloroprocaine)
and additives (metabisulfite) are suspected of causing toxic effects ranging from transient neurologic symptoms (TNS)
to adhesive arachnoiditis and permanent neurologic injury.
Naturally occurring corticosteroids are classified into three
functional groups
mineralocorticoids, glucocorticoids,
and adrenal androgens.
corticosteroid
most commonly used for interventional pain procedures.
Glucocorticoids
mechanisms of action for corticosteroids
antiinflammatory effects, direct neural membrane stabilization, as well as modulation of peripheral nociceptor neurons and spinal cord dorsal horn cells
The anti-inflammatory effects of glucocorticoids are attributable to
their inhibition of inflammatory mediator production at both the local tissue and systemic immune response level
With any type of tissue trauma there is a release of inflammatory mediators including
arachidonic acid and its
metabolites (prostaglandins, leukotrienes), various cytokines (IL-1, IL-6, TNF-a), and other acute phase reactants
mechanisms of action for injected corticosteroids
inhibit the production of local inflammatory mediators, reduced spontaneous ectopic discharge rates seen following nerve injury, including in neuromas.. Reversible inhibition
of nociceptive C-fiber transmission, but not A-B fiber transmission
glucocorticoid receptor sites within the dorsal horn
glucocorticoid receptor sites have been located on noradrenergic and 5-hydroxytryptamine neurons within the dorsal horn substantia gelatinosa—known pathways of pain transmission. This suggests that corticosteroids may modulate nociceptive input from peripheral
nociceptors by a direct action on the spinal cord.
the anti-inflammatory efficacy and duration of activity are greater with
less soluble corticosteroid
preparations
major determinant
of corticosteroid selection
based upon
its duration of action (biological half-life) and antiinflammatory
potency, but steroid particulate size relative to a red blood cell and aggregation is emerging as a major determinant
of corticosteroid selection
An inadvertent injection of a steroid particulate into the artery of Adamkiewicz during thoracic or lumbar transforaminal epiduralsteroid injection could result in
spinal cord ischemia leading to profound lower extremity motor deficits, even paraplegia
complication of cervical level transforaminal
steroid injection
is infarction of the spinal cord or brain
following injection of a particulate corticosteroid into a
radicular artery or vertebral artery
Following systemic absorption, the vast majority of
corticosteroid is reversibly bound to two plasma proteins:
.
corticosteroid-binding globulin and albumin
the unbound and bound fraction of corticosteroid
the unbound fraction of corticosteroid is responsible for its cellular-mediated anti-inflammatory effects. The protein-bound corticosteroid undergoes sequential oxidative-reduction reactions yielding inactive compounds. This is followed by hepatic-mediated
conjugation (sulfate or glucuronide), resulting in watersoluble
metabolites that are renally excreted
adverse reactions following corticosteroid injection.
Sterile meningitis
and arachnoiditis have been reported following intrathecal injection of methylprednisolone.Brief euphoric or manic reactions have been reported following high-dose conticosteroid
therapy. analphylactoid reactions have been reported following intravenous, intramuscular,
and soft-tissue conrticosteroid injections
Any type of anaphylactic reaction should be treated promptly and aggressively with
supportive therapies (i.e., airway, breathing, circulation, supplemental oxygen), including advanced cardiac life support guidelines when indicated
Potential Adverse Systemic Reactions Associated
with Corticosteroids
Fluid retention, Elevated blood pressure, Hyperglycemia, Generalized erythema/facial flushing
Menstrual irregularities, Gastritis/peptic ulcer disease, Hypothalamic-pituitary-adrenal axis suppression, Cushing’s syndrome
Bone demineralization
Steroid myopathy
Allergic reaction
aqueous-based or alcohol-based skin preparation solutions.
Aqueous-based
iodophors, such as povidone-iodine, can be safely used on
mucous membrane surfaces. Alcohol-based solutions offer a
quicker onset and often more sustained antimicrobial activity.
The ideal preoperative skin antiseptic agent should
significantly reduce microbial counts on intact skin; be broad spectrum; be fast acting; have a persistent effect lasting for hours; and
be nonirritating to the skin
