Course #
142Pharmacology of Injectable Meds
1
Pharmacologyof
Injectable Medications
Tammy P. Than, MS, OD, FAAO
Resources
Drugs@FDA http://www.accessdata.fda.gov/scripts/cder/drugsatfd
a/index.cfm?fuseaction=Search.Search_Drug_Name Get to know your drugs!
Epocrates
LOCAL ANESTHETICS Local Anesthetics
block nerve conduction decrease action potential amplitude slow conduction velocity lengthen refractive period increase firing threshold nerve becomes inexcitable
Local Anesthesia
reversible no damage patient remains conscious
benefit?
Local Anesthesia
topical minor manipulation
injectable more extensive procedures local infiltration nerve block retrobulbar or peribulbar
anesthesia akinesia
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Chemical Classification
synthetic (except cocaine) weak bases amphipathic all contain:
aromatic portion important for potency
amide portion intermediate alkyl chain amide or ester link
used for classification
Classification of Local Anesthetics Duration of Action
proportional to contact time chemical structure concentration amount delivered rate of removal by diffusion and circulation
Fate of Local Anesthetics
Esters hydrolyzed in plasma by pseudocholinesterases metabolite is PABA (para-aminobenzoic acid)
Amides metabolized by liver so… caution in certain patients
Akten
3.5% lidocaine Gel Indication: ocular anesthesia during
ophthalmologic procedure Onset 20-60 seconds 5-30 minute duration Useful if allergic to ester anesthetics PF / single use
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INJECTABLE ANESTHETICS
Additives
Epinephrine 1:50,000 – 1:200,000 increases duration of action decreases bleeding decreases systemic side effects not for fingers and toes not with cocaine not with topicals
Epinephrine
Vasoconstriction onset is 7-15 minutes So… wait about 10 minutes although anesthesia
onset was rapid Acidic injections are more painful
Xylocaine with epi is made more acidic to prevent degradation of epinephrine
Epinephrine Side Effects
anxiety tremor dyspnea restlessness palpitations tachycardia hypertension headache aggravate underlying cardiac disease
Additives
hyaluronidase enzyme breaks down hyaluronic acid enhances spread through tissue for retrobulbar or peribulbar injections
Classification of Local Anesthetics
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Local Injectable AnestheticsAnesthetic Concentration
(%)
Onset of Action (min)
Duration of Action (hr)
Procaine (Novocain) 1,2, and 10 7-8 ½ - ¾
Lidocaine(Xylocaine)
0.5, 1, 1.5, 2, and 4
4-6 2/3-1
(1-2 with epi)
Mepivacaine (Carbocaine)
1, 1.5, and 2 3-5 2-3
Bupivacaine
(Marcaine, Sensorcaine)
0.25, 0.5, and 0.75
5-10 4-12
Etidocaine
(Duranest)
1 and 1.5 3-5 5-10
Procaine (Novocain)
ester risk of allergic reactions not used much
Lidocaine (Xylocaine)
most widely used injectable anesthetic Amide FDA Pregnancy Category B multiuse vials of 0.5%, 1%, and 2%
with or without 1:100,000 epinephrine
With epi Sodium metabisulfite
Lidocaine (Xylocaine)
skin surgery – 1% nerve blocks – 2% maximum safe doses of 1%
30 cc without epi - 50 cc with epi
4% - topical only
Bupivacaine (Marcaine)
onset of action 5-10 minutes DOA 4-12 hours partial paralysis of EOMs for 1-2 days retrobulbar injections
anesthesia akinesia
no need for epinephrine often combined with lidocaine
Side Effects of Local Anesthetics
can have local and systemic reactions more common with injectables
98% of systemic reactions due to overdose maximum dosages
tetracaine 0.5%: 7 drops OU 5 mL of 2% is lethal
proparacaine 0.5%: 14 drops OU
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Ocular Toxic Effects
stinging and burning epithelial keratitis (often delayed onset) severe toxicity
necrotizing keratitis with filaments corneal edema / Descemet’s folds lacrimation ocular pain
management:
Systemic Absorption of Local Anesthetics
too large a dose unusually rapid absorption unusually slow drug detoxification slow elimination
Systemic Toxic Effects tingling circumoral numbness cardiovascular
early: HTN, tachycardia late: hypotension, weak heart beat
CNS early: stimulatory, convulsions, tinnitus, metallic
taste late: depression; loss of consciousness
Systemic Toxic Effects
management early diagnosis supportive
O2
local anesthetics rapidly eliminated
Allergic Reactions
Ocular conjunctival injection conjunctival chemosis eyelid edema lacrimation itching
Courtesy JD Bartlett
Allergic Reactions
more common with ester linkages metabolize to PABA
avoid agents of same group amide agents rarely implicated
preservatives may be cause
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Allergic to ALL Anesthetics?
Is it the preservative? Can get PF Xylocaine
Injectable saline Injectable antihistamine
Topical Anesthesia – General Considerations
best for mucous membranes cryoanesthesia
ice refrigerant spray
ethyl chloride or dichlorotetrafluoroethane
temporary hardening of skin
Topical Anesthesia – General Considerations
topical lidocaine preparations EMLA (eutectic mixture of local anesthetic)
2.5% lidocaine and 2.5% prilocaine apply under occlusion 3 hours preop
2 and 5% cream Lidoderm patch
10x14 cm Iontophoresis
Topical Anesthesia Applications
Prior to subconjunctival / sub-Tenon’s injections Prior to putting on chalazion clamp Prior to minor manipulation of the conjunctiva
LOCAL INJECTABLE ANESTHESIA
Injectable Anesthesia
Papilloma excision Cyst removal Management of chalazion Etc.
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Injectable Steroids
Systemic Steroids
Steroids are internalized into cell entering nucleus
Effects take several hours to days Block entire AA cascade Decrease inflammatory cells Decrease fibroblasts Decrease collagen deposition
Glucocorticoids
Catabolic hormones Important Roles
glucose metabolism - lipid metabolism cardiovascular - CNS fluid balance - Blood Immune system - growth
Too much – Cushing’s Too little – Addison’s
Which Steroid? Routes of Administration in Eye Care
Topical Ophthalmic Dermatologic
Periocular Injection Subconjunctival Sub-Tenon’s retrobulbar
Intramuscular Injection Oral Intravitreal
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Injectable Steroids Triamcinolone Acetonide
Suspension Not for IV!
Kenalog
10 mg/mL IND: intralesional; intra-articular
40 mg/mL IND: intramuscular; intra-articular
Triesence
40 mg/mL Preservative free
Uses of Triamcinolone
Intralesional Chalazion 0.1 – 0.3 cc
Side Effects from Triamcinolone
Infection Depigmentation Rare occlusive event
Use proper technique
Uses of Triamcinolone
Subconjunctival (Sub-Tenon’s?) Refractory Uveitis
Side Effects from Triamcinolone
Increased intraocular pressure
Should not use if: Infectious etiology Unknown etiology
Uses of Triamcinolone
Intramuscular “allergic states”
Local atrophy likely to occur unless deep IM injection
40-80 mg Injected deeply into the gluteal muscle! For adults – minimum needle length of 1.5” is
recommended
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Injectable Steroids
Methylprednisolone 40 or 80 mg/mL
Side Effects of Steroids
Adrenal suppression Mental changes Increased blood glucose Ulcers HTN Fluid imbalance
Side Effects of Steroids
Osteoporosis Cushingoid look Myopathies Inhibit growth in kids
Premature closure of epiphyseal plates
Acne
Antibiotics for SubconjunctivalInjections
The Basics: Anti-Infective Agents
Bacteriostatic stops growth and replication
Bactericidal kills bacteria
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A little review…
Gram Positive Staphylococci * Corynebacterium Streptococci * Clostridia
Gram Negative Haemophilus * Neisseria Pseudomonas * Serratia Proteus Moraxella Enteric Bacteria
Antibiotic Agents
inhibit cell wall synthesis disrupt cell membranes alter protein synthesis affect intermediary metabolism inhibit DNA synthesis
Cell Wall Synthesis Inhibitors
MA: membrane exposed lysis death bactericidal low toxicity includes:
beta-lactams (PCNs, cephalosporins) Vancomycin Bacitracin
Vancomycin MA: inhibits cell wall synthesis at a site
earlier than -lactams Gram(+) including MRSA Poor oral absorption – usually IV Ophthalmic Indications
Empiric treatment of endophthalmitis Intravitreal and topical Along with Amikacin
MRSA ocular infections Alternate choice for Gram (+)
Vancomycin SE
Topical irritating (pH 3.5-4.5)
Systemic (with systemic use)OtotoxicRenal toxic
Drugs that Disrupt Cell Membranes
Polymyxin B Gramicidin
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Polymyxin B MA: Interacts with phospholipids of cell
membranes Affects osmotic integrity of cell
bactericidal
Good Gram (-) Not used orally
Neurotoxic, nephrotoxic
Altering Protein Synthesis
Bacterial Ribosomes different than Humans Smaller Different subunits
Drugs work on either: 30S subunit 50S subunit
Large number of drugs
Altering Protein Synthesis 30S Subunit
tetracyclines Aminoglycosides
Neomycin, Gentamicin, Tobramycin, Amikacin
50S Subunit macrolides
Erythromycin, Azithromycin, Clarithromycin chloramphenicol clindamycin
Mechanism of Action
Aminoglycosides MA: Inhibit bacterial protein synthesis by
binding to 30s subunit of ribosome bactericidal Some Gram (+) including staph but mostly
Gram (–) Not for anaerobic infections
O2 dependent to transport drug into bacteria
Not for streptococci, MRSA Synergistic with β-lactams
Aminoglycosides
Poor oral absorption used parenterally for systemic use
Inactivated by PCN or cephalosporin Separate solutions
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Macrolides
MA: Inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit
Erythromycin Clarithromycin Azithromycin
Subconjunctival Injections of Antibiotics
Painful ± xylocaine injection first? No antibiotics formulated for this
Use IV or IM
Antibiotic DoseGentamicin 20 mg
Tobramycin 20 mg
Cefazolin 100 mg
Penicillin G 500,000 units
Bacitracin* 10,000 units
Erythromycin 50 mg
Vancomycin 25 mg
Polymyxin B 10 mg
Smear Morphology Topical* SubconjunctivalNo organism Cefazolin (50 mg/ml)
and gentamicin (13.6 mg/ml) or tobramycin(13.6 mg/ml)
Cefazolin (100 mg) and gentamicin (20 mg) or tobramycin (20 mg)
Gram-positive cocci Cefazolin (50 mg/ml) or bacitracin (10,000 units/ml)
Cefazolin (100 mg) or methicillin (100 mg)
Gram-positive rods Gentamicin (13.6 mg/ml) or tobramycin (13.6 mg/ml)
Gentamicin (20 mg) or tobramycin (20 mg)
Gram-negative cocci Penicillin G (100,000 units/ml) or bacitracin (10,000 units/ml)
Penicillin G (500,000 units/ml)
Gram-negative rods Tobramycin (13.6 mg/ml) and ticarcillin (6.7 mg/ml)
Tobramycin (20 mg) and ticarcillin (20 mg)
Ophthalmic Dyes
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Fluorescein
yellow acid dye MW = 376 g/mol usually sodium salt is used light -> absorbs -> emits longer
IVFA (intravenous fluorescein angiography)
circulating fluorescein is absorbed by blood plasma proteins and also binds to RBC
exciting = 465 nm; emitted = 525 nm view retinal blood vessels in high contrast choroidal fluorescence appears early and usually
precedes the arterial phase fluorescein will leak from choroidal vessels no leakage from normal retinal vasculature
FA Applications
macular lesions diabetic retinopathy neovascularization etc.
Oral FA
used when venipuncture is difficult useful for children evaluate fundus lesions evaluate disorders that demonstrate leakage Adults: 1-2 g of powder or 3 vials of 10% Children: 1mL of 10%/20 mL juice/5kg bw fluorescein appears in 15-30 minutes Not used very often
FA – Side Effects
10% incidence Nausea Vomiting Allergic reactions
be prepared!
skin discoloration excreted unchanged – warn patient!
Indocyanine Green (ICG)
water soluble dye peak absorption = 805 nm peak emission = 835 nm RPE and choroid absorb less light in 800 nm
range compared to 500 nm for FA near IR photography – better with media
opacities and subretinal fluid
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ICG
completely PPB no leakage through fenestrated capillaries in
choroid
better visualization of choroid clinical uses:
viability of rabbit corneal endothelium retinal and choroidal angiography
choroidal neovascular membranes occult CNV
ICG
Cardio-Green® Side Effects:
well tolerated rapidly metabolized by liver no discoloration of skin
Promethazine Trade Name = Phenergan Phenothiazine derivative
Antihistamine Sedative Antimotion-sickness Antiemetic Anticholinergic
Promethazine 25 or 50 mg/mL
Duration of action: 4-6 hours FDA Pregnancy Category: C
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Indications Adjunct in anaphylaxis Prevention and control of N/V
IVFA AAC
25 mg is adult dose Max dose is 50 mg
Available in preloaded syringe IM
Subcutaneous can be irritating
BLACK BOX WARNING
Resp. Depressioncontraindicated in pts <2 yo due to cases of resp. depression, some fatal, at a wide-range of weight-based doses; in pts >2 yo use w/ caution at lowest effective dose, avoid combo use w/ other resp. depressant effect drugs
Severe Tissue Injury, Gangrenepromethazine injection can cause severe chemical irritation and tissue damage including burning, pain, thrombophlebitis, tissue necrosis and gangrene regardless of administration route; may result from perivascular extravasations, unintentional intra-arterial injection, and intraneuronal or perineuronal inflitration; some cases require surgical intervention
Side Effects CNS
Sedation
Do not combine with other CNS depressants EtOH, opioids, etc.
Systemic Hyperosmotics Effects
increase serum osmolarity fluid shifts from eye to vascular space results in reduced IOP
No oral agents anymore Mannitol (15-25%)
IV 0.25-2 g / kg one time; delivered over 30-60 minutes CI
Dehydration CV and renal disease
Indications: AAC
Botox Botulinum Toxin A
Botox™ Blepharospasm Strabismus
inject into muscle avoiding spread of toxin
Cervical Dystonia ETC…
Botox™ Cosmetic Glabellar Lines
Added Labeling…
migraines discovered by accident during treatment for facial
wrinkles not only ACh inhibition but also blocks
parasympathetic nervous system for acute and prophylactic treatment
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Botulinum Toxin A muscle-relaxing agent
Acetylcholine release inhibitor and neuromuscular blocking agent
A serotype is most studied A, B, C1, D, E, F, G all have different properties and actions
Other Off-labeled Uses
hemifacial paresis lid entropion corneal ulcer secondary to exposure nystagmus myokymia rhytids
Botox Cosmetic Approved April 2002 Allergan Inject once / 3 months Average cost is $400 / treatment
Botox
Holographic film on vial label Confirm!
Single-use 50 U, 100 U, and 200 U / vial Reconstitute with sterile PF 0.9% NaCl Injection Mix Use within 24 hrs (refrigerate) Add 4 mL to 50 U Vial to yield 1.25 U / 0.1 mL
Botox
Precautions Neuromuscular disorders Compromised respiratory function Corneal disease
Reduced blinking Presence of inflammation at injection site
FDA Pregnancy Category C
Black Box Warning
Distant Spread of Toxin Effecteffects of all botulinum toxin products may spread beyond tx area to produce sx consistent w/ botulinum toxin; swallowing and breathing difficulties, incl. fatal, have been reported; sxoccur hours to weeks after injection; risk greatest in children treated for spasticity but can occur in adults, especially if underlying risk factors
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Drugs Used in Emergency Medicine
Type I Hypersensitivity Reaction
Causes:
systemic: angioedema urticaria bronchospasm hypotension
be prepared!
Anaphylaxis: Be Prepared…
immediate hypersensitivity reaction may begin with hives airway obstructions hypotension 20-30 minutes after exposure
Epinephrine Direct acting adrenergic agonist Effects
Vasculature Cardiovascular Respiratory Hyperglycemia Lipolysis
Anaphylaxis Epinephrine
IM or subcutaneous Epipen
1:1000 0.3 mL
(Also an Epipen Jr.) IV
1:10,000 3-5 mL
no absolute CI in life-threatening situation
Adjunct Medications
IV colloidal fluids
Steroids Antihistamines
Benadryl 50 mg/mL 25-50 mg IM
Pressor agents Supplemental oxygen
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It Could Happen To You…
vasovagal response sweating lightheadedness pale
not a reaction to the drug recline patient No ammonia
Hypoglycemia
Check blood glucose Sample protocol… Mild Hypoglycemia (BG 60-70 mg/dl): Give 15
carb grams a. Glucose oral gel 40% 15 gramsb. Glucose 3 tablets orallyc. Juice 4 ounces orally d. Regular soda 3/4 cup (6 ounces)
Hypoglycemia Moderate Hypoglycemia (BG 45-59): Give 20 carb grams
a. Glucose oral gel 40% 20 gramsb. Glucose 4 tablets orallyc. Juice 6 ounces orallyd. Dextrose 50% 25 ml IV
Severe Hypoglycemia (BG <45): Give 30 carb grams a. Glucose oral gel 40% 30 grams orallyb. Glucose 6 tablets orallyc. Juice 8 ounces orallyd. Dextrose 50% 25 ml IV
Hypoglycemia Unconscious with severe Hypoglycemia (BG<45)
a. Dextrose 50% 25 ml IV or b. Glucagon 1 mg SQ or IM (0.5 mg for child) c. Vomiting and aspiration risk d. Roll patient onto their side when used Protocol: Glucose monitoring
a. Monitor Blood Glucose every 15 minutes until >100 mg/dl
b. Re-dose glucose replacement per above every 15 min prn