Pharmacokinetics Flashcards
Distinguish between pharmacokinetics and pharmacodynamics.
Pharmacodynamics = What the drug does to the body Pharmacokinetics = What the body does to the drug
Identify the steps in the time course of drug distribution.
LIBERATION = the release of the drug from it’s dosage form
ABSORPTION = the movement of drug from the site of administration to the blood circulation
DISTRIBUTION = process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues)
METABOLISM = chemical conversion or transformation of drugs into compounds which are easier to eliminate
EXCRETION = elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes.
List the major routes of drug administration, plus their benefits and drawbacks.
ORAL
Pros: Convenient
Cons: First-pass effect (reduced systemic availability of the drug as a result of significant metabolism), many variables and barriers.
SUBLINGUAL
Pros: No first-pass effect
Cons: Inconvenient, small dose limit, taste
INHALATION (gets drugs to lungs)
Pros: Fast, rapid delivery to blood
Cons: Requires special properites of drug (e.g. atomised, vapourised)
TOPICAL
Pros: Convenient, localised
Cons: Only local
TRANSDERMAL
Pros: Prolonged release
Cons: Skin very effective barrier
INTRAMUSCULAR
Pros: Rapid for aqueous, slow for oil
personnel
Cons: Painful, requires trained
INTRAVENEOUS
Pros: Direct, total dose (no first-pass effect), rapid, if short half life of elimination of a drug then possible to continuously infuse it instead (otherwise would only have an effect for v short time)
Cons: Requires professional, infection
risk, rapid response
Which route of administration is most commonly used ?
Oral
Define bioavailability. What is the relative bioavailability of oral vs IV ?
Fraction of unchanged drug that reaches the systemic circulation
IV injection gives 100% bioavailability
Oral intake much lower bioavailability due to being vulnerable to enzymes, acidic environments, liver metabolism before reaching systemic circulation.
How may we calculate percent bioavailability of an oral drug ?
% Bioavailability oral drug = (Area under curve for oral drug / Area under curve for intravenous drug) x 100
in graph showing bioavailabilities of IV and oral injections.
Identify the ways through which small molecules cross cell membranes. How is this concept of crossing cell membranes relevant to pharmacology ?
1) Diffusing directly through the lipid
- Lipid solubility highly important (need to be lipophilic and ideally unionised)
2) Diffusing through aqueous pores
- More likely important for diffusion of gases
3) Transmembrane carrier protein
- e.g. solute carriers
4) Pinocytosis
- Mostly macromolecules, not drugs
This is relevant because it applies to oral drugs getting into plasma but also
drugs already in plasma trying to get to target tissues.
Relate the general chemical properties of a drug to its subsequent absorption and distribution throughout the body.
- Hydrophilic vs Lipophilic
- Hydrophilic drugs are soluble in aqueous, polar media such as blood plasma, cytosol and interstitial fluid (hence require transmembrane proteins to enter cells)
- Lipophilic drugs are soluble in fats and non-polar solutions such as interior of the lipid bilayer and fat (hence can diffuse easily) - Ionisation state
-Affects drug absorption
-Many drugs are weak acids or bases (e.g. local anaesthetics weak bases)
-Ionised:unionised ratio depends on pH
-Ionised drugs have low lipid solubility
-Depending on whether weak acid or weak base, more preferentailly or less preferentially absorbed in different parts of GI (since different pH in different compartments of GI, meaning they may be ionised in some and
unionised in others)
Which kinds of drugs barriers to absorption affect ?
Those that are not injected directly to the systemic circulation (e.g. oral drugs)
Identify the factors that affect distribution.
- Degree of drug ionisation
- Lipid solubility
- pH of compartments
- Cardiac output and blood flow (Influences how much exposure specific tissues have. e.g. small amounts of drugs distributing to fat tissue at slow rate because low blood supply there. On the other hand drug distribution to kidney much faster)
- Capillary permeability (Eg brain tight permeability)
- Plasma protein binding (Lipophilic drug in plasma tightly bound to proteins)
Explain the compartment model.
-Oral drugs start out circulating in a reservoir in the GI system. They then undergo absorption to get to a single, well-stirred compartment (PLASMA + potentially EXTRACELLULAR FLUID, depending on whether drug travels there or just stays in plasma, like warfarin). As soon as drug is in this compartment, it is susceptible to excretion and metabolism.
-This first compartment can be explained as one volume (Vd)
-IV drugs are given directly in this second, well-stirred compartment (and hence vulnerable to excretion and metabolism).
-Some drugs have a second compartment (peripheral compartment)
E.g. biphosphonates in bone (high affinity to calcium). Only way for them to get out again is for them to get back into compartment where they are susceptible to excretion and metabolism
Describe the main characteristics of biphosphonate, in the context of pharmadynamics.
- Phosphonate groups have a high affinity for calcium
- Quickly distributed to the skeleton
- Oral alendronate – Daily/weekly
- IV zoledronate – Yearly (binds more substantially)
Discuss the effects of protein binding upon the distribution and availability of drugs within the body.
- A drug must be free to distribute widely or bind to its receptor (otherwise may not have its effect)
- BUT many drugs bind to plasma proteins (such Albumin, α-1 acid glycoprotein, Lipoproteins, Globulins) so fraction of unbound drug can be as low as 1%
- Competition for binding sites on plasma proteins can cause big increases in free drug concentrations
-For instance, 98% of warfarin bound to albumin. BUT, Aspirin has high affinity for albumin so in presence of aspirin, some warfarin is dislodged due to competition and the amount of unbound warfarin undergoes relatively large increases
Explain the general concept of pharmacokinetic compartments.
-Body water is distributed in to four main compartments (intracellular water, interstitial water, transcellular water, and plasma water)
-Specialist compartments also exist (e.g. fat, bone)
-These compartments may differ in pH,
-The degree of distribution between these compartments depends on tissue- and drug- dependent factors (including perfusion)
-Side-effects of some drugs can be minimised by limiting their distribution via the route of administration
-Only unbound (free) drug molecules can cross from one compartment to the other
(binding occurs within compartments)
Relate the general chemical properties of a Pilocarpine and Bethanechol to their subsequent absorption and distribution throughout the body.
Both non-selective muscarinic agonists
BETHANECHOL
- Quaternary ammonium
- Poorly absorbed and distributed
- If given orally, action will limit itself to where it can get (which is limited given how poorly absorbed it is, so mainly used just for bladder and gastrointestinal hypotonia)
PILOCARPINE
- Tertiary amine
- Better absorbed and distributed because slightly less charged
- As a result, more systemic effects if given orally (including for glaucoma to decrease IOP, for xerostomia following head/neck radiotherapy, and to constrict pupils = miosis)
