Pharmacokinetics Flashcards
Absorption defn
Process by which a drug proceeds from the site of administration to the site of measurement
Two categories of drug admission?
- Intravascular (IV) – We do not have to worry about absorption here.
- Extravascular – GI or Non-GI
GI
oral
All routes of extravascular drug administration
- Oral (GI)
- Sublingual & Rectal (Non GI)
- Transdermal (Non GI)
- Subcutaneous (Non GI)
- Inhalation (Non GI)
- Intradermal (Non GI)
- Intramuscular (Non GI)
Sublingual and Rectal administration info
Avoid 1st pass metabolism, do not drain to the hepatic portal system
Transdermal administration info
Only suitable for some lipophilic drugs
Inhalation administration info
- Enter the pulmonary circulation
- Localise effect to lungs while avoiding systemic side-effects
Intravenous administration info
- Deliver a drug directly into the blood stream
- 100% of dose circulated before being broken down
What does the rate and extent of absorption depend on?
- The environment where the drug is absorbed
- Chemical characteristics of the drug
- Route of administration
Chemical characteristics affecting absorption
Whether they were absorbed by:
- Passive diffusion
- Facilitated diffusion
- Active transport
- Endocytosis
Passive diffusion (most common) defn
Drug moves from a region of high concentration to one of lower concentration.
Passive diffusion drug movement of polar and lipophilic drugs
- Water-soluble drugs penetrate cell membrane through aqueous channels/pores
- Lipid-soluble drugs move across membranes due to their solubility in membrane lipid bilayers
Facilitated diffusion defn
Specialised transmembrane carrier proteins undergo conformational changes to facilitate passage of large molecules from an area of high concentration to an area of low concentration. Requires energy.
Active transport defn
Specific transmembrane carrier proteins move drugs from region of low concentration to one of higher concentration. Requires energy.
Endocytosis
Engulfment of an exceptionally large drug by cell membrane & transport into cell by endo/exocytosis of drug-filled vesicle.
Environment body factors that drug absorption depend on (6)
- pH
- Surface area for absorption (↑ in intestine due to folds)
- Vascularity (↑ in intestine due to increased blood flow)
- Food (variable effect for drugs)
- Gastric emptying
- Disease – alter the exposure of tissues
7.Secreted substances
Bioavailability (F) defn
The relative amount of administered drug that reaches the general circulation & the rate at which this occurs
How is bioavailability determined?
by comparing plasma levels of a drug, after a particular route of administration, after a certain time.
What is bioavailability affected by?
- Route of admission
- Properties of drug eg. particle size, solubility
- Absorption factors eg. luminal pH, gastric emptying
- Metabolism (1st pass)
- Pharmacogenetics – inherited genetic differences in drug metabolic pathways
- AUC – extent of drug absorption
First pass mechanism
- When a drug is absorbed from the GI tract, it enters the portal circulation before entering the systemic circulation.
- If the drug is rapidly metabolised in the liver/gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased.
Disadvantage for drugs with high 1st pass metabolism: (2)
- Large does prescribed
- Unpredictability in response due to marked individual respins
Disadvantage for drugs with high 1st pass metabolism: (2)
- Large does prescribed
- Unpredictability in response due to marked individual respins
How is the first pass mechanism avoided ?
Drugs administered IV enter directly into systemic circulation & have direct access to rest of body.
Double peak after single dose (eg. Morphine)
- Morphine goes into circulation via intestinal wall → liver
- At liver, morphine metabolised into → morphine glucuronide
- Morphine glucuronide goes into gall bladder → bile duct → secreted into intestinal wall again
- At intestinal wall, gut flora cleaves morphine glucuronide → morphine & glucuronide
First pass mechanism general disadvantage
Limits the efficacy of many oral medications and causes low bioavailability even if drug is well absorbed
Explain pH as an environmental factor
Most drugs are either weak acids/weak bases. A drug passes through membranes more readily if it is electrically neutral (protonated acids & deprotonated bases). Hence, WA are absorbed in an acidic environment (they are unionised & therefore absorbed in their protonated form), while WB are absorbed in a basic environment (they are ionised & absorbed in their unprotonated form).
Give an example of disease as an environmental factor
In celiac disease, you lose SA in gut and can’t absorb properly
Give an example / explain vascularity as an environmental factor.
Lipid soluble drugs often enter tissue at rate determined by blood flow.
Give an example / explain vascularity as an environmental factor.
Lipid soluble drugs often enter tissue at rate determined by blood flow.
Drug distribution defn
Process of reversible transfer of drug to & from the site of measurement
Factors affecting drug distribution include
- Molecular size of drug (affects Vd)
- Lipophilicity (affects Vd)
- Transport proteins
- Organ perfusion
- Body composition
- Plasma binding
Lipophilicity in drug distribution - lipo vs hydrophilic movement
- Lipophilic drugs readily move across most biologic membranes
- Hydrophilic drugs must pass through slit junctions
Plasma binding as a factor effecting drug distribution
Reversible binding to plasma proteins sequesters drugs in a non-diffusible form & slows their transfer out of the vascular compartment for action & excretion. Therefore a drug’s affinity for plasma proteins influences its availability & clearance.
Vd
Apparent Volume of Distribution
Vd defn
Vd is a pharmacokinetic parameter representing an individual drug’s propensity to either remain in the plasma or redistribute to other tissue compartments. Drug moves into other fluid compartments if volume > total volume of blood.
Factors influencing Vd (3)
- Molecular weight
- Lipophilicity
- Plasma proteins binding abilites
Vd calculation
Why does Vd have an important influence on the half-life of a drug?
Because drug elimination depends on the amount of drug delivered to the liver/kidney per unit.
If the drug has a large Vd where is most of the drug?
Most of the drug is in the extraplasmic space and is unavailable to the excretory organs.
Any factor that increases Vd can…
Increase the half-life and extend the duration of action of the drug.
Drug metabolism (drug biotransformation) defn
Process of a conversion of one chemical species to another chemical species.
Why is drug metabolism important (paragraph - general)
If drugs remained in the body indefinitely, accumulation would lead to toxicity. Instead, drugs are broken down into inactive metabolites. The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes & are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are first metabolised in the liver into more polar (hydrophilic) substances via 2 general sets of reactions.
Diagram for Phase I and II of drug metabolism
What is the first step in drug metabolism ? (Phase I)
Catabolic breakdown via either
- Oxidation
- Reduction
- Hydrolysis
by cytochrome P450
What are the most important isoforms of CYP450 in humans?
- CYP3A4
- CYP1A2
- CYP2C9
- CYP2C6
- CYP2C19
What happens if two drugs compete for the same isoform of cytochrome P450
Their breakdown can be impaired
Active metabolites effect
Have more potent effect than parent compound
Toxic metabolites
Responsible for the organ damage associated with some drugs
Why does Phase II occur?
If the metabolite from Phase I metabolism are still too lipophilic to be excreted by kidneys.
What occurs in Phase II reactions
Endogenous substrate are attached to xenobiotics to make them more water-soluble and less likely to accumulate in tissues. Conjugated products can then be secreted into the blood or bile for elimination.
What occurs with highly reactive metabolites produced from phase I reactions ?
Phase 2 involves the anabolic conjugation of these metabolites with another functional group in order to inactivate them.
What occurs with highly reactive metabolites produced from phase I reactions ?
Phase 2 involves the anabolic conjugation of these metabolites with another functional group in order to inactivate them.
Drug excretion defn
The irreversible loss of a drug from the site of measurement.
Systemic clearance defn
The hypothetical volume of blood from which the drug is totally and irreversibly removed per unit time.
Elimination half-life of a drug defn
The time taken for half the total amount to be eliminated.
Excretion main processes
- Renal excretion
- Biliary excretion
What occurs in renal excretion?
Water-soluble metabolites are filtered through the kidneys and excreted in the urine.
What occurs in renal excretion?
Water-soluble metabolites are filtered through the kidneys and excreted in the urine.
What is the rate of excretion (renal excretion para) measure as?
Renal clearance = (urine concentration / plasma concentration) x rate of urination.
Explain biliary excretion
Large molecules with polar or non-polar groups can be excreted into the intestines alongside bile.
1. Some metabolites are then excreted with faecal matter
2. Some are reabsorbed & returned to the liver via enterohepatic circulation.
- If the metabolite still retains some pharmacological activity, recirculation can lead to secondary spikes in physiological activity.
