Drug Movement in the Body Flashcards
Fate of drugs in the body?
Absorption - process by which a drug enters the body from its site of administration (the lumen of GI tract is considered to be outside of the body)
Distribution - process by which a drug leaves the circulation and enters the tissues perfused by blood; once within a tissue, further, blood-independent distribution may occur by diffusion/carrier-mediated transport
Metabolism - process by which tissue enzymes (principally in the liver - hepatic metabolism catalyse the chemical conversion of a drug to a MORE POLAR FORM that is more readily excreted from the body)
Excretion - processes that remove the drug from the body (principally the kidneys - renal excretion)
What is elimination?
Metabolism and excretion
Overview of drug disposition?
Where does most absorption occur?
In the small intestine, as there is a greater absorptive surface area
However, some substances, e.g: ethanol, are absorbed from the stomach
Physiochemical factors controlling drug absorption?
- Solubility
- Chemical stability
- Lipid to water partition coefficient
- Degree of ionisation
Why is solubility important in drug disposition?
Drug must dissolve (dissolution) in order to be absorbed
Why is chemical stability important in drug disposition?
Some drugs are destroyed by acid in the stomach, or enzymes in the gastrointestinal tract
Why is lipid to water partition coefficient important in drug disposition?
Absorption of a drug commonly occurs by simple diffusion across membranes (importantly, some agents are transported); for a given drug conc. gradient across a membrane, the rate of diffusion increases with the lipid solubility of the drug.
Drug MUST have a degree of lipid solubility (amphipathic)
Why is degree of ionisation important in drug disposition?
Many drugs exist as weak acids or weak bases, existing in both ionised and unionised forms (dynamic equilibrium between the 2 forms)
ONLY UNIONISED FORMS READILY DIFFUSE ACROSS THE LIPID BILAYER
What is an acid?
Donates protons (reaction driven to right by increasing pH)
What is a base?
Accepts protons (reaction driven to left by decreasing pH)
What does degree of ionisation depend upon?
pKa of the drug and local pH
pKa = pH at which 50% of drug is ionised and 50% is unionised
How to calculate proportions of ionised and unionised drugs?
Henderson-Hasselbalch equation
Acid: pKa - pH = log (HA/A-)
Base: pKa - pH = log (BH+/B)
Absorption of acids and bases?
Absorption of weak acids is facilitated by pH of stomach lumen; bases are not readily absorbed until they reach the small intestine
Majority of absorption (even weak acids) occurs in small intestine (large SA) Weak acids and weak bases are well absorbed, strong acids (pKa 10) are poorly absorbed
What happens to acids and bases in different environments?
Acidic drugs become less ionised in an acid environment; basic drugs become less ionised in a basic environment
Good pH for drug absorption?
pH 4.5 - 90% of drugs absorbed
Factors affecting GI absorption?
GI motility - the rate of stomach emptying and movement through the intestines; modified by some drugs and presence of food
pH at absorption site (varies along GI tract)
Blood flow to stomach and intestines (increased by food)
Way in which the tablet, capsule etc is manufactured; can be customised to release drugs at different rates and sites, e.g. intestine vs stomach
Physicochemical interactions, e.g. the rate of absorption of some drugs is modified by calcium rich-rich foods
Presence of transporters in the membranes of epithelial cells of the GI tract which can facilitate drug absorption
What is oral availability?
Fraction of drug that reaches the systemic circulation after oral ingestion, i.e. amount in systemic circulation / amount administered
What is systemic availability?
Fraction that reaches the systemic circulation after absorption, i.e. amount in systemic circulation / amount absorbed
Drugs administered i.v. have 100% systemic availability
Disadvantages of orally administered drugs?
Once absorbed, can be inactivated by enzymes in the gut wall and liver (FIRST-PASS or pre-systemic METABOLISM) before reaching the systemic circulation and body tissues in general
What are common routes of drug administration?
Oral
Inhalational
Buccal/sublingual
Transdermal/subcutaneous
Intravenous
Rectal
Intramuscular
Advantages and disadvantages of drugs administered orally?
Advantages - convenient, non-sterile route; good absorption for most drugs
Disadvantages - inactivation of some drugs by acid/enzymes; variable absorption; first pass metabolism; G.I. irritation
Advantages and disadvantages of drugs administered sublingually?
Advantages - by-passes portal system and avoids first pass; avoids gastric acid
Disadvantages - infrequent route, few sublingual preparations available
Advantages and disadvantages of drugs administered rectally?
Advantages - as for sublingual; used for noctural administration of some drugs
Disadvantages - infrequent route; variable absorption; aesthetically unacceptable (in UK)
Advantages and disadvantages of drugs administered intravenously?
Advantages - rapid onset (emergency) route, continuous infusion; complete availability; route for drugs that cause local tissue damage
Disadvantages - sterile preparation required; risk of sepsis or embolism; high drug levels at the heart
Advantages and disadvantages of drugs administered intramuscularly?
Advantages - rapid onset of lipid soluble drugs, depot injection for slow prolonged release possible
Disadvantages -painful; tissue damage with some drugs; absorption variable
Advantages and disadvantages of drugs administered by inhalation?
Advantages - lungs ideally suited due to huge surface area; good for volatile agents (anaesthetic gases), aerosols etc. Ideal for local effect
Disadvantages - few disadvantages
Advantages and disadvantages of drugs administered by topical?
Advantages - ideal for local effect
Disadvantages - few disadvantages
Forms of a drug in relation to distribution to body fluid compartment?
Drugs within the systemic circulation can be distributed to one + body fluid compartments
Exist in BOUND or FREE forms within each compartment; only free drug can move between compartments:
- Ionised and unionised drugs that are not bound to protein (e.g. albumin, α1-acid glycoprotein) can move freely by diffusion
- Only unionised drugs move readily by diffusion
What is the volume of distribution?
Vd - apparent volume in which a drug is dissolves, as drugs are not evenly distributed in the body
Calculating Vd?
Vd = dose / plasma concentration
What do different Vd values mean?
Vd of 15L indicates distribution throughout total body water (or concentration in certain tissues), e.g. highly lipid soluble drugs (ethanol)
Difference between enteral and parenteral?
Enteral - via the GI tract, inc. oral, sublingual, rectal
Parenteral - not via the GI tract, inc. iv, intramuscular, inhalational, topical
