Principles/Drug biotransformation Flashcards
Pharmocodynamics
The study of drug effects and their mechanism of action
The study of what drugs do to you
Pharmacokinetics
Quantitative descriptions of the time course of drug and drug metabolite concentrations in the plasma, tissues, or urine.
Drug fate or what you do to the drug
Drug action
Molecular mechanism of action
May or may not be known. Is not observable.
Drug effect
Desired therapeutic effect
Undesired side effect
Effect is usually known and is observable
Enteral
Route of administration via the gastrointestinal tract
- Oral
- Sublingual
- Rectal
Parenteral
Route of administration via injection, but also includes other non-oral routes
- SQ, IM, IV, inhalation, intranasal, intraarticular
Sublingual Administration
Under the tongue
- Warm, moist, high blood flow
- Rapid absorption, no first pass effect
- Unpleasant taste
EX: nitroglycerin
Barriers to oral Administration
(per os, PO)
- Drug must first dissolve and be in solution: variations –> drug already dissolved in water, dry power, soft tablet, hard tablet, capsule, capsule with slow dissolving capsule
- Absorption from stomach less than from small intestine
- Large surface area of small intestine
- 2 barriers for drug to cross: epithelial cells and capillary wall
Absorption pattern of oral administration
- Highly variable among pts
- Gastric and intestinal pH
- Gastric emptying time
- Presence of absence of food
- Co-administration of other drugs
Advantages and disadvantages of oral administration
Advantages
- The most used route of administration
- Convenient
- Safe, drug recall is possible (emesis or lavage)
- Inexpensive
Disadvantages
- Slow absorption
- Highly variable b/w pt
- Highly variable at different times in same pt
- Some drugs inactivated by acid, enzymes, or bacteria
- First pass metabolism by liver
- Requires conscious, cooperative pt
- G.I. irritation can occur
Advantages and disadvantages of intravenous injection (IV)
Advantages
- No barriers to absorption
- Rapid onset and subsequent control of drug concentration is possible
- Large fluid volumes are possible
Disadvantages
- Unsuitable for non-aqueous solutions, drug must be soluble
- High cost compared to oral
- Difficult to administer- must have trained personnel
- Inconvenient- in-patient only
- Irreversible- no recall
- Infections, embolism possible
Subcutaneous injections
- Lower blood flow in SQ region leads to slower drug absorption
- Slower absorption allows for sustained action
- Allows injections of drugs poorly soluble in water
- Drawbacks- discomfort, inconvenience, potential for injury
EX: insulin-diabetics
epinephrine- anaphylaxis
Intramuscular injection
- Fairly rapid absorption of water soluble drugs
- Time course of absorption dictated by water solubility of drug and blood flow to the site
- Allows injection of depot preparations –> benzathine PCN G
- Painful, inconvenient
- Possible hematoma
Factors affecting rate and extent of absorption
- Rate of drug dissolution
- Concentration gradient
- Blood flow
- Size of the absorbing surface
- Lipid Solubility
- pH, drug charge, polarity
- Condition of the absorbing surface
Distribution
Site of administration –> plasma –> interstitial space –> intracellular space
Redistribution
Intracellular space –> interstitial space –> plasma
Volume of distribution
Hypothetical volume of fluid in which the drug is distributed
Major factors influencing passive diffusion of drugs
- Concentration gradient
- Blood flow: higher blood flow maintains steeper concentration gradients and faster rates of drug movement
- Size
- Charge (pH of environment)
- Polarity
- Lipid/water solubility: water partition coefficient- the ratio of solubility in oil vs water
ionization
Must drugs are weak acids or bases. They exist in solution in both an uncharged (unionized) form and in a charged (ionized) form.
The concentration of charged and uncharged forms of a drug are determined by the pKa of the drug and the solution pH
Quarternary salts
Drugs that become permanently charged. Do not cross membranes very well, are poorly absorbed and is rapidly eliminated in urine
- Neostigmine
- Physostigmine
Clinical significance of a protein bound drug
- Displaced drug is highly protein bound
- Has a limited volume of distribution
- Is slowly eliminated
- Has a low therapeutic index
Xenobiotics
Foreign compounds
-Diet, environment, drugs
Drug biotransformation
The enzymatically-driven process whereby a substance is changed from one chemical to another
- Reactions can be anabolic or catabolic
General strategy: change substances into more polar, sometimes larger, derivatives. Polar and water soluble products are more readily excreted by the kidneys
Consequences
- Inactivation
- Active to active
- Activation
First pass effect
The process by which oral drugs undergo extensive metabolism after absorption prior to entering circulation. They are absorbed from the small intestine and transported to the liver via the portal system.
- Greatly limits the bioavailability of some drugs
- Some drugs may be metabolically inactivated or activated in the stomach and GI tract
Drugs administered parenterally do not undergo first-pass biotransformation.
Phase I reactions
Result in the biological inactivation of the drug
- Consist of enzymes that convert the parent drug to a more polar metabolite by introducing or unmasking a functional group
- Enzymes located in lipophilic ER membranes of the liver
- Oxidations, reductions, and hydrolysis reactions
- Catabolic
Phase II reactions
Produce a metabolite with improved water solubility and increased molecular weight (enhances elimination)
- Consist of enzymes that form a conjugate of the substrate
- Anabolic
Cytochrome P450 enzymes
Superfamily of enzymes that carry out phase I reactions
- Contain a molecule of heme that is noncovalently bound to the polypeptide chain
- Have the capacity to metabolize many diverse chemicals- multiple forms of P450s exist and a single one that metabolize many structurally distinct chemicals
Succinylcholine
- Depolarizing skeletal muscle relaxant
- Individuals with genetic defects in pseudocholinesterase can metabolize succinylcholine at 50% the rate as normal individuals
Slow acetylator phenotype for N-acetyltransferase enzyme
- An autosomal recessive trait that causes a decrease of N-acetyltransferase in the human liver
- Isoniazid, hydralazine, and caffeine
- Occurs in 50% of the US population, 83% of French population, and less common in Asian populations
- Risk of hepatotoxicity (hepatitis) in pts taking isoniazid
Competitive inhibition (reversible)
Direct binding to the heme iron and reducing metabolism of substrates
Suicide inhibitors (irreversible)
Covalent interaction of a metabolically generated reactive intermediate that reacts with the P450 apoprotein or heme moiety
Grapefruit juice effect
Consumption of grapefruit juice with drugs taken orally can irreversibly inhibit intestinal CYP3A4
Prodrug
An inactive drug that undergoes biotransformation to become an active drug
Main drug metabolizing enzymes for phase I
- Cytochrome P450s
- Flavin-containing monooxygenases (FMO)
- Epoxide hydrolases (mEH, sEH)
Enzyme induction
Leads to increased substrate metabolism and a decreased pharmacologic action of the inducer and/or the coadministered drug.
Some P450 substrates can induce P450 activity by increasing the rate of synthesis or reducing the rate of degradation.
Well characterized inducers
- Phenobabital
- Chronic ethanol
- Aromatic hydrocarbons- tobacco smoke, PCBs, dioxin
- Clofibrate (VLDL lowering drug)
