Lecture 8: Pharmacokinetics II Drug disposition Flashcards
ADME processes of pharmacokinetics
-> Absorption from the site of administration
-routes of administration.
-> Distribution within the body
- special drug delivery systems
-> Metabolism
- Involves enzymatic conversion of one chemical entity to another within body (L9)
-> Excretion
- consists of elimination from the body of drug, or drug metabolites (L9)
Absorption vs. Administration
Absorption: the passage of a drug from its site of administration into the plasma.
-Important for all routes BUT intravenous injection.
-Inhalation of a bronchodilator aerosol doesn’t require absorption as defined above for the drug to act.
-Drug must enter the plasma before reaching its site of action in most cases.
Common routes of drug administration
- Oral
- Sublingual
- Rectal
- Application to other epithelial surfaces (skin, cornea, vagina, and nasal mucosa)
- Inhalation
- Injection (subcutaneous, intramuscular, intravenous, intrathecal, intravitreal)
Oral (enteral) administration
-Most small molecules taken by mouth and swallowed.
- Little absorption occurs until the small intestine.
-SA are poorly absorbed
Pros: simple, cheap, convenient, painless
Cons: exposed to harsh GI environment, first-pass metabolism, slow delivery
Sublingual Administration
- Absorption directly from oral cavity.
-Anti-anxiety drugs
Pros: Rapid response
Cons: drug have bad taste
Rectal administration
- Similar to sublingual
- local effect or systemic effects.
Pros: Good for vomiting
Cons: not reliable, inconvenient
Cutaneous administration
-local effect.
-Absorbed very poorly through unbroken skin.
-Transdermal contraceptive patch (delivers hormones)
- Hormone replacement therapy (estrogen)
Nasal spray administration
-Drug that binds to blood vessels
-Absorption through mucosa (high blood supply)
-Sniffing drugs can perforate or destroy the nasal septa.
Eye drops administration
-locally into the eye
- absorption through the epithelium of the conjunctival sac
-can be done w/o systemic side effects.
-Bronchospasm in asthma patients (people w/ asthma it would exaggerated it)
Administration by inhalation
-systemic administration of anesthetics.
-the lung route of both administration & elimination.
transdermal administration
PROS: simple & convenient, slow absorbed (longer effects)
CONS: Drugs have to be lipophilic
Subcutaneous administration
PROS: slow onset
CONS: Done in small volumes
Intramuscular administration (vaccine)
PROS: immediate onset
CONS: painful
Intravenous administration (IV)
PROS: Rapid, controlled easily
CONS: Overdose if long use
Intrathecal injection
-> regional anaesthesia (labour, child delivery)
-> Implantable pumps
Pros: cross BBB
Cons: high infection risk
Factors affecting gastrointestinal absorption
- gut content (fed versus fasted) -> influence of feeding
- gut motility -> a drug taken after a meal is slowly absorbed.
- splanchnic blood flow
- particle size and formulation -> Capsules designed to remain intact for hours after ingestion in order to delay absorption.
-> some drugs designed to not be absorbed. - physicochemical factors (ex. drug interactions) -> chemical drug interactions that affect drug absorption.
- genetic polymorphinsms in transporters
- drug-drug competition for transporter
Bioavailability
Used to indicate the fraction of an orally administered dose that reaches the systemic circulation as intact drug.
Bioavailability= Quantity of drug reaching systemic circulation/ Quantity of drug administered
Distribution of drugs in the body:
Different Body compartments
- Total body water: Small water-soluble molecules (ethanol)
- Extracellular water: Larger water-soluble molecules (mannitol)
- Blood plasma: highly plasma protein-bound molecules, very large molecules, highly charged molecules (heparin)
- Fat: Highly lipid-soluble molecules (diazepam)
- Bone and teeth: certain ions (fluoride, strontium)
Distribution of drugs in the body:
Body fluid compartments
- 50 to 70%, less in women than in men.
1. Extracellular fluid comprises:
-the blood plasma (4.5%)
-interstitial fluid (16%)
-lymph (1.2%)
2. Intracellular fluid (30-40%)
-sum of all fluids of cell in body.
3.Transcellular fluid (2.5%)
-cerebrospinal, intraocular, peritoneal, pleura; and synovial fluids , and digestive secretions.
Volume of distribution of a drug (Vd):
Dependence on solubility of various drug
Vd -> the volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma
Vd= Dose/[Drug]plasma
- Higher for lipid soluble.
Volume of distribution of a drug (Vd):
Define “Loading dose”
If a drug takes a long time to reach therapeutic levels, then higher dose (loading dose) may be given initially before dropping down to a lower maintenance dose. (to get to correct concentration of drug)
Principles of evidence-based medicine
To compare the contraceptive effectiveness, cycle control, adherence (compliance), and safety of the skin patch or the vaginal ring vs. combination oral contraceptives (COCs)?
Characterise the blood-brain barrier
- endothelial cells joined by tight junctions and pericytes.
-brain is consequently inaccessible to many drugs.
-Inflammation can disrupt the integrity of the BBB allowing normal impermeant substances to enter the brain.
-Most antibiotics wont get into brain unless the BBB is disturbed.
Examples of special drug delivery:
-prodrugs
-antibody-drug conjugates
-packing in liposomes
-coated implantable devices
