PHARMACOKINETICS AND THE CYP SYSTEM

ABSORPTION - Process by which drug enters the circulation

Dependent upon:
Dissolution of drug
Lipid solubility
Gastric emptying
Stomach acidity
Presence of food in stomach
First-pass effect
Anxiety
GASTRIC EMPTYING TIMES
Clear liquids~ 90 minutes
10 ml/min
Fat delays emptying time~ 4 hrs
Anxiety - doubles emptying time
FIRST-PASS EFFECT
Drug absorbed through small intestine enters the liver via the portal circulation where it is partially metabolized
before entering the general circulation
Results in decreased bioavailability of drug
SUBLINGUAL ADMINISTRATION
Dr. David Greenblatt
Demonstrated a two-fold increase in plasma conc with stacked dose of 0.25 mg triazolam every 30 mins
Sublingual administration of triazolam increases bioavailability by 28%
DISTRIBUTION - Process by which drug enters target tissues
Dependent upon:
Lean body mass vs. fat content
Concentration of plasma proteins
Tissue blood flow
Presence of other drugs
DISTRIBUTION
Alpha-phase
Sedative activity begins and ends
Uptake into tissues
Redistribution
Beta-phase
Drug inactivation by metabolism and excretion
BIOTRANSFORMATION
Drug metabolism
Convert drugs into less active or inactive forms
Influenced by:
Liver blood flow
Liver disease
Activity of CYP enzymes
Activation or inhibition by other drugs
EXCRETION - Removal of drug from the body
Urinary excretion of water-soluble metabolite
Affected by: Kidney function and disease

HALF-LIFE - Time required to reduce blood level of drug by one-half

Affected by:
Age
Disease
Alterations in liver blood flow
CYP
DRUG RESPONSE VARIATIONS
Age ; Children vs Elderly
Genetics ; CYP enzymes
Disease states
Anxiety level: Physiological antagonism
Drug interactions:
Potentiation by CNS depressants
Antagonism by CNS stimulants
Normal biologic variation**
Pharmacokinetic factors
NORMAL BIOLOGIC VARIATION
Bell-shaped curve:
70% respond appropriately
15% hyper-respond (sensitive)
15% hypo-respond (resistant)
UNTOWARD DRUG REACTION : Any noxious or unintended reaction to a drug that is administered in standard
doses by the proper route for the purpose of prophylaxis, diagnosis, or treatment
Toxicity
Adverse effect
Idiosyncrasy
Interaction
Allergy
INCIDENCE OF UNTOWARD REACTIONS
15%-17%
Patients and health care professionals commonly associate untoward drug reactions as allergic in nature
Many patients have been mislabeled as allergic when, in fact, they are not
Differentiating drug allergies from other untoward responses is difficult
TOXICITY: Adverse effect that is a direct extension of a drugs pharmacology
Oversedation
Unconsciousness
Cardiorespiratory depression
ADVERSE EFFECT: Unwanted side-effect of a drug
Nausea and vomiting
Dizziness
Disorientation
Hypotension
IDIOSYNCRASY :Unusual or unpredictable response to a drug
Hyperalgesia
Dysphoria

DRUG INTERACTIONS
PHARMACOKINETIC INTERACTION
One drug inhibits or stimulates the absorption, distribution, biotransformation or excretion of another drug
PHARMACODYNAMIC INTERACTION
An interaction that results from a common physiologic action, without alteration of pharmacokinetics
SUMMATION
An interaction between two drugs in which the effect is approximated by simple addition of the effects taken
separately
POTENTIATION
An interaction between two drugs in which the total effect of both is much greater than would be predicted by
simple addition of the two
ANTAGONISM
An interaction in which one drug reduces the effect of another
(may be competitive at receptor sites or non-competitive)
DRUG ALLERGY: An immunologically mediated reaction that exhibits specificity and recurrence on re-exposure to
the offending drug.
THE CYTOCHROME P-450 SYSTEM
CYP1, CYP 2, CYP 3, CYP 4
CYP 1A2 12%
2E1 6%
CYP 2C9 20%
CYP 2D6 4%
CYP 3A4 28% accounts for 60% of clinically prescribed drugs
BNZS ARE INACTIVATED BY CYP 3A4 OXIDATION
Drugs that inhibit CYP 3A4 will intensify and prolong the effects of benzodiazepines
May have more intense effects and slower clearance in older patients or medically compromised patients
Drugs that induce or activate CYP 3A4 will reduce the effectiveness and duration of action of benzodiazepines
CYP 3A4 INHIBITORS
Azole antibiotics
Ketoconazole
Fluconazole
Itraconazole
Protease inhibitors
Ritinovir
Nelfinavir
Aprenovir
Calcium channel blockers
Diltiazem
Verapamil
Macrolide antibiotics
Erythromycin
Clarithromycin
SSRIs
Fluoxetine
Fluvoxamine
Miscellaneous
Grapefruit juice
Cimetidine
Omeprazole
Propranolol
Oral contraceptives

CYP 3A4 INDUCERS : Drugs which reduce benzodiazepine effectiveness

Rifamycin: Treatment of tuberculosis
Carbamazepine: Treatment of seizures and pain syndromes
Phenytoin: Treatment of seizures
Theophylline: Treatment of asthma
Miscellaneous
Alcohol
Smoking