Download Pharmacology of Enteral Agents

Pharmacology of
Enteral Agents
Oral Sedation…
Advantages
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Acceptance
Administration
Low cost
Decreased incidence of
adverse reactions
Decreased severity of
adverse reactions
No needles
Various dosage forms
Decreased severity of allergic
reactions
Disadvantages
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Patient compliance
Delayed onset
Erratic absorption
Inability to titrate
Inability to readily alter level
of sedation
Prolonged duration
Not for severe anxiety levels
Adverse drug-drug
interactions
Special training and permit
Terminology…
Absorption—the process by which a drug
enters the circulation
– Factors affecting absorption
Drug form (tablet, capsule, elixir)
Gastric emptying
Acidity
Presence of food and types of food
GI motility
Most drugs are absorbed in the small
intestine
Alterations in Drug Absorption
P-glycoprotein carrier system
– Found in the plasma membranes in the intestine,
proximal tubules of the kidney, brain, liver,
testes
– Acts as a pump for drugs and toxins being
transported away from tissues, out of the tissues
Part of the “first pass effect”
– “Gate-keeper” for cytochrome P450 system
P-glycoprotein (P-gp)
Extracellular
Membrane
Intracellular
CYP3A4
Terminology…
First Pass Effect--initial extensive
metabolism in the liver as the drug travels
from the small intestine via the hepatic
portal system through the liver
– Results in reduction of plasma concentration
– Important for benzodiazepines with low
bioavailability
Triazloam
Midazolam
FIRST PASS METABOLISM
Terminology…
Distribution—process by which the drug in the
plasma enters target tissues, depot tissues,
metabolic and excretory sites
Factors affecting distribution
– Lean-body mass vs. fat content
– Concentration of plasma proteins
Malnutrition
Age
Pregnancy
– Competition for protein binding sites from other drugs
Bioavailability (%)…
ROUTE
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IV
IM
SUBCUTANEOUS
ORAL
RECTAL
INHALATION
TRANSDERMAL
BIOAVAILABILITY
100
75 to </=100
75 to </=100
5 to <100
30 to <100
5 to < 100
80 to </=100
Terminology…
Biotransformation—metabolic pathways in
the body, primarily the liver, convert
absorbed drugs into different chemical
configurations, usually with the end result of
making the drug less active and more readily
excretable (polar and water soluble)
– Phase I—utilizing Cytochrome P450
– Phase II—conjugation
Phases of Metabolism
Phase I
– Oxidation, hydrolysis, or reduction increasing the
drugs water solubility
Phase II
– Attachment of an additional molecule creating an
inactive and more water soluble compound
Glutathione, conjugation, glucuronidation, sulfation,
acetylation, methylation
Metabolism
Phase I
Hepatocyte
Billiary
capillary
R
Phase II
O - Glucuronide
Cytochrome P450…
Genetically determined super family of enzymes
found in the liver and gut to detoxify endogenous
and exogenous substances
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Blood flow the liver
Activity and concentration of enzymes
Liver disease
Basis for the pharmacokinetic drug interactions most
frequently encountered in dentistry. (CYP 3A4 isoenzyme
inhibition)
Terminology…
Excretion– process by which a drug in the
circulation is removed from the body (urine,
bile, feces)
– Renal function and disease
– Water solubility and chemistry of a drug or
metabolite
*Peripheral compartment
Enhanced Bioavailability of Triazolam following
Sublingual Versus Oral Administration.
Scavone JM et al,
J. Clinical Pharm 1986;26:208-210
AUC greater for sublingual than orally
– 28.9 vs 22.6 ng-hr/ml
Sublingual peak plasma concentration greater
– 4.7 vs 3.9 ng/ml
No difference in elimination half-life and the
time of peak concentration
Enhanced Bioavailability of Triazolam following
Sublingual Versus Oral Administration.
– First-pass extraction
bypassed
Clinical effects may
likewise be enhanced by
sublingual
administration.
4
3
PLASMA TRIAZOLAM CONCENTRATION (ng/ml)
The bioavailability of
sublingual triazolam
increased by an average
of 28% vs oral
administration
Scavone JM et al,
J. Clinical Pharm 1986;26:208-210
0.5 mg oral
2
0.5 mg sublingual
1
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.4
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2
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6
8
10
12
14
16
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HOURS AFTER DOSE
Triazolam Pharmacokinetics After Intravenous,
Oral and Sublingual Administration
16
14
12
Triazolam Route Of Administration
6
TRIAZOLAM (ng/ml)
Fraction absorbed
relative to IV was 20%
greater SL vs Oral
Bioavailability 44%
(oral) 53% (sublingual)
SL avoid first-pass
metabolism producing
earlier and higher peak
concentrations
Kroboth, PD et al
J Clin Psychopharm 15: Aug 95 259-262
4
2
0
0
2
4
6
TIME (hr)
8
10
12
Terminology…
Half-life—time required to reduce the amount of
drug in the circulation by one-half
– Age
– Disease
– Blood flow to liver
Idiosyncrasy—unusual/unpredictable response to a
drug
– Hyperalgesia
– dysphoria
Terminology…
Toxicity—Adverse effect that is a direct
extension of a drug’s therapeutic actions
(loss of consciousness)
Therapeutic Index—ratio of the toxic dose
of a drug to its therapeutic dose: the higher
the ratio, the greater the relative safety of
the drug
Patient Considerations…
Factors determining variability in patient
response:
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Age (very young and old)
Genetics (CYP)
Disease states
ETOH consumption
Normal biological variations
Pharmacokinetic factors
Special Considerations…
Pediatric patients
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Weight and dosage calculations
Enhanced vagal responses
Ability to swallow solid dose forms
Taste variations
Increased likelihood of aspiration
Special Considerations…
Geriatric patients
– Phiz changes: decreased functional reserve cerebral, renal
and hepatic blood flow
– Chronic diseases
– Multiple medications
– Decreased intestinal absorption
– Decreased receptor populations
– Decreased lean body mass
– Decreased plasma protein binding
– Decreased initial doses of sedatives
Medically Compromised Patients
Drug interactions
Altered response to drugs
Need for adjunctive medications
Stress-reduction protocol
Factors in Drug Selection and
Dosage…
Age
Weight
Medical status
Level of anxiety
Pharmacologic Principles for Oral
Sedative Drugs…
All produce CNS depression
– Drowsiness, dizziness
– Drug interactions—CNS depressants
Warnings
– Drowsiness—don’t drive, legal decision, etc
– May be habit forming
– Accompanied by a responsible adult
Food interactions
– Presence of food delays gastric emptying and delays
onset/reduces effectiveness of agents
Principles Continued
Re-administration of Oral Agents
– NOT recommended secondary to accumulation
When more than one agent is used the dosage
of both agents must be reduced
Variable effects of oral sedation
Dosage of sedatives should be reduced in
children, elderly, and the medically
compromised patients
FDA Pregnancy Categories…
A—studies fail to demonstrate a risk to the
fetus in the first trimester, no evidence of
risk in later trimesters. The possibility of
fetal harm appears remote
B—either animal studies have not shown a
risk, but there are no controlled studies in
pregnant women, or animal studies have shown
a fetal risk that was not confirmed in
controlled studies in women
FDA Pregnancy Categories…
C—animal studies have shown a risk but no
controlled studies in women, or there are no studies
in women or animals. Drugs should be given only if
the potential benefits justify the potential risks to
the fetus
D—there is positive evidence of fetal risk. If the
drug is needed in a life-threatening situation or for
a serious disease for which safer drugs cannot be
used or are ineffective
X—the drug is contraindicated in women who are or
may become pregnant
Standard Dose
The standard dose of a drug is based on
trials in healthy volunteers and patients with
average ability to absorb, distribute,
metabolize and eliminate the drug
The standard dose will not be suitable for
every patient
Benzodiazepines…
Mechanism of action
– GABA receptor agonist (facilitator)
Metabolism/excretion; Liver/urine
Advantages
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Sedation
Wide therapeutic index
Antianxiety effects
Useful for producing sleep the night before
Reversal agent (flumazenil)
Diazepam (Valium)
Usual dosage; 1o prior to appt
– Adults; 2-10 mg
– Children; 0.15-0.3 mg/kg
Onset; 1 hr, peak concentration in 2 hrs
Duration; 1-3 hours
Contraindications
– Allergy, narrow angle glaucoma
Precautions
– Drug interactions at CYP3A4 and CYP2C19
Availability
– 2,5,and 10 mg tablets; syrup 10mg/5cc
Active metabolites—yes
Pregnancy category D
Lorazepam (Ativan)
Usual dosage 1 hour prior to appt
– Adult 2-4 mg
– Child; 0.05 mg/kg not to exceed adult dose
Onset; 1 hour
Duration; 2-4 hours
Containdications
– Allergy, narrow angle glaucoma
Precautions
– Excessive sedation
– Not to be used in patients with primary depressive disorder or
psychosis
Active metabolites—No
Pregnancy category--D
Oxazepam (SERAX)
Usual dosage one hour prior to appt
– Adult;10-30 mg
– No child dose
Onset; 1 hour
Duration; 2-4 hours, peak at 3 hours
Contraindications—allergy
Precautions—same as other sedative agents
Availability
– 10,15,30 mg capsules and 15 mg tablets
Active metabolites—No
Pregnancy category—D
Triazolam (HALCION)
Usual dosage one hour prior to appt
– Adult; 0.25 mg
– Not recommended for children
Onset; 1 hour, peak plasma level 2 hours
Duration; 1-3 hours
Contraindications—pregnancy
Precautions—can produce anterograde amnesia. Excessive
sedation in elderly
Availability
– O.125 and 0.25 mg tablets
Active metabolites—No
Pregnancy category—X
Alprazolam (XANAX)
Usual dosage one hour prior to appt
– Adult; 0.25-1 mg
– Not recommended for children
Onset; 1 hour, peak in 1-2 hours
Duration; 1-3 hours
Contraindications—allergy and narrow angle glaucoma
Precautions
– Drug interactions at CYP 3A4
Availability
– 0.25, 0.5 and 1 mg tablets
Active metabolites—No
Pregnancy category--D
Midazolam (VERSED)
Usual dosage 15-30 min prior to appt
– Not recommended for adult
– Child; 0.25-0.5 mg/kg not to exceed 20 mg
Onset; 15-30 minutes
Duration; 30 min to 1 hour
Contraindications
– Allergy
– Narrow angle glaucoma
Precautions
– Drug interactions at CYP3A4
Availability; syrup 2 mg/cc
Active metabolites—No
Pregnancy category—D
Zolpidem (AMBIEN)
Usual dosage 1 hour prior to appt
– Adult; 10 mg
– Not recommended for children
Onset; 1 hour peak effect in 1.6 hours
Duration; 2-3 hours
Contraindications; allergy
Precautions; same as other oral sedatives
Availability; 5 and 10 mg tablets
Active metabolites—No
Pregnancy category—B
Antihistamines…
Sedation is a common action of some H-1
receptor antagonists
Additional beneficial effects; anticholinergic
actions and some reduction in salivation
– Hyproxyzine
– Diphenhydramine
Hydroxyzine
(ATARAX, VISTARIL)
Usual dosage 1 hour prior to appt
– Adult; 50-100 mg
– Child; 1.1-2.2 mg/kg
Onset; 30min, peak effect 2 hours
Duration; 3-4 hours
Contraindications; allergy
Precautions; same as other oral sedatives
Availability
– Atarax; 10, 25, 50, 100 mg tabs; syrup 10mg/5cc
– Vistaril; 25,50,100 mg capsules;oral susp 25mg/5cc
Active metabolites—No
Pregnancy category—D
Diphenhydramine (BENADRYL)
Usual dosage 1 hour prior to appt
– Adult; 50-100 mg
– Child; 1.5 mg/kg not to exceed adult dose
Onset; 1 hour
Duration; 4-6 hours
Contraindications; allergy
Precautions; anticholinergic actions;
– Worsen asthma, glaucoma GI/urinary obstruction
Availability; 25, 50 mg tabs; elixir 12.5/5cc
Active metabolites—No
Pregnancy category—B
Phenothiazines…
Traditionally used in the treatment of some
major psychiatric diseases
Some members of this group possess
significant sedative activity
Other therapeutic actions
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Anticholinergic
Antidopaminergic
Anti-adrenergic
antiemetic
Promethazine (PHENERGAN)
Usual dosage 1 hour prior to appt
– Adult; 25-50 mg
– Child; 2.2 mg/kg as a sole agent
1.1 mg/kg in combination with other drugs
Onset; 1 hour peak effect 2 hours
Duration; 3-4 hours (may persist 12 hrs)
Precautions
– Use with caution in pts with Sz disorders
– Tardive dyskinesias
Availability; 12.5, 25, 50 mg tabs;
– Syrup 6.25 and 25 mg/5cc
– Suppositories 12.5, 25, 50 mg
Active metabolites—No
Pregnancy category—C
New FDA warning: (2006) this drug is no longer indicated in children under 2
years of age…and should be used with great caution in any child (all preps of the
drug)
Drug Interaction Involving
Sedative Agents
Pharmacokinetic interactions
– One drug inhibits or stimulates the absorption,
distribution, metabolism or excretion of another drug
Increased activity of some Benzos by erythromycin which inhibits
CYP3A4 isoenzyme
Pharmacodynamic interactions
– Interaction of 2 drugs as a result of a common physiologic
effect
Increased CNS depression with co-administration of opioid and
Benzodiazepine
Drug Interaction Involving
Sedative Agents
Summation; interaction between 2 drugs in which
the effect of both drugs is approximated by the
simple additive effect of each drug given separately
– 1+1=2
Potentiation; interaction in which total effect of
both drugs given together is greater than predicted
by the sum of each drug given separately
– 1+1>2
Drug Interaction Involving
Sedative Agents
Antagonism; the reduction in the effect of
one drug by another
– Competitive
– Non-competitive
– Physiologic
Clinically Significant Drug
Interactions of Sedatives
Inhibitors of benzodiazepine oxidation
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Azole antifungal drugs (NIZORAL) 2
Cimetidine (TAGAMET) 3
Disulfiram (ANTABUSE) 3
Diltiazem (CARDIZEM) 2
Fluvoxamine (LUVOX) 3
Indinavir (CRIXIVAN) 2
Macrolide antibiotics (ERYC) 2
Nefazodone (SERXONE) 3
Omeprazole (PRILOSEC) 3
Oral contraceptives 3
Protease inhibitors (NORVIR) 2
Oxidatively Metabolized
Benzodiazepines
Alprazolam (XANAX)
Chlordiazepoxide (LIBRIUM)
Cdlonazepam (KLONOPIN)
Cloraxepate (TRANXENE)
Diazepam (VALIUM)
Estazloam (PROSOM)
Flurazepam (DALMANE)
Halazepam (PAXIPAM)
Quazepam (DORAL)
Trazolam (HALCION)
Drugs Which Reduce Effect of
Benzodiazepines
Primarily triazolam and midazolam
– Stimulate metabolism
Rifamycins (RIFAMPIN) 2-3
Carbamazepine (TEGRETOL) 3
Theophylline (THEO-DUR) 2
Extensive Impairment of Triazolam and Alprazolam Clearance
by Short-Term Low-Dose Ritonavir: The Clinical Dilemma of
Concurrent Inhibition and Induction
J Clinical Psychopharm 19: Aug 99, 293-296
Early exposure of low-dose ritonavir will
produce important impairment of alprazolam
as well as triazolam clearance, similar to
ketoconazole
The hazard of an interaction will persist until
the dosage and/or duration of exposure to
ritonavir produces sufficient CYP3A induction
to offset the inhibitory effects of ritonavir
Extensive Impairment of Triazolam and Alprazolam Clearance
by Short-Term Low-Dose Ritonavir: TheClinical Dilemma of
Concurrent Inhibition and Induction
J Clinical Psychopharm 19: Aug 99, 293-296
3
30
2
WITH RITONAVIR
t1/2 = 22.7 hr
CL = 32 ml/min
PLASMA ALPRAZOLAM (ng/ml)
PLASMA TRIAZOLAM (ng/ml)
20
WITH RITONAVIR
t1/2 = 50 hr
CL = 15 ml/min
1
0.7
CONTROL
t1/2 = 3.7 hr
CL = 317 ml/min
0.4
0.2
10
7
4
CONTROL
t1/2 = 3.7 hr
CL = 317 ml/min
2
1
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HOURS AFTER DOSE
24
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24
28
32
HOURS AFTER DOSE
Drug Interactions Involving
Phenothiazines…
Beta-blockers 2
– Increased effect of both drugs
Cisapride (PROPULSID) 1
– Increased cardiac toxicity of cisapride
Dofetilide (TIKOSYN) 1
– Increased cardiac toxicity of dofetilide
Ethanol 2
– Increases CNS depression
Quinolones 1
– Increased cardiac toxicity of quinolones
Paroxetine (PAXIL) 2
– Increased phenothiazine effects via CYP 2D6 inhibition
Oral Erythromycin and the Risk of Sudden
Death from Cardiac Causes
Ray et al. NEJM September 9, 2004 1089-1096
1,249,943 person-years of follow-up
– 1476 confirmed sudden death from cardiac causes.
– CYP3A inhibitors studied: nitroimidazole antifungal
agents, diltiazem, verapamil, and troleandomycin
Each doubles the AUC for a CYP3A substrate
Evaluated the association of oral erythromycin and
the risk of sudden death of cardiac cause
– By itself
– In conjunction with CYP3A inhibitors
– The control was amoxicillin
Oral Erythromycin and the Risk of Sudden
Death from Cardiac Causes
Ray et al. NEJM September 9, 2004 1089-1096
The risk of sudden death from cardiac causes among
patients currently using erythromycin was twice as high as
that among those who had not used the antibiotic.
No significant increase in risk in former users of
erythromycin or those currently using amoxicillin
The use of erythromycin and concurrent use of CYP3A
inhibitors: 5 times as high to suffer sudden death of cardiac
origin
No increased risk in patients using amoxicillin and CYP3A
inhibitors
Why Do Some Cases Not Go Well?
Not “sleepy” enough
Too “sleepy”
Behavior difficulties
Why Do Some Cases Not Go Well?
There is not a single enteral agent intended to be
used for an office based sedation
– Off label use of drugs with a primary indication: short
term treatment for insomnia
triazolam (Halcion)
Off label indications: None Found
– Management of anxiety disorders, premedication, skeletal
muscle disorders, alcohol withdrawals
Diazepam (Valium)
Off label indications: None clinically relevant
Why Do Some Cases Not Go Well?
Since there are no drugs specifically
intended for enteral sedation in a dental
office one should expect variability
Quality of sedation is based on the drugs
pharmacokinetic and pharmacodynamics
properties
– Pharmacodynamic tolerance
Triazolam (Halcion)
Indicated for the treatment of insomnia
Plasma half-life: 1.5-5.5 hours
Peak plasma level in approximately 2 hours
– Peak levels of 1-6 ng/ml
– Peak levels dependent upon initial dose and
pharmacokinetics.
Why Such Variability?
Pharmacokinetics
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Absorption
Distribution
Metabolism
Excretion