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

2

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

3

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

4

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

5

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

6

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.

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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

16

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

17

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

18

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