What is clinical pharmacokinetics?
The study of the rate of movement of drugs within systems.
What does clinical pharmacokinetics allow?
Individualisation of drug therapy
Ensures patient benefit
Minimises risk of adverse effect
What is pharmacokinetics defined by?
What is absorption?
In order to have an effect, a drug must be absorbed into the bloodstream and be distributed to a site of action.
Name some common routes of absorption.
Oral Subcutaneous Intramuscular Inhalation / nasal Other GI - sublingual / rectal Transdermal
Are intravenous drugs absorbed
No- they directly enter systemic venous circulation.
What do the terms Tmax, Cmax and AUC apply to?
What is Tmax?
.Time to peak concentration
What is Cmax?
What is AUC?
The area under the curve.
How is the Tmax affected by an increased rate of absorption?
Does increasing the dose affect the Tmax?
Does increasing the dose affect the Cmax?
What does the AUC represent?
The area under the curve represents the amount of drug which reaches the systemic circulation when a medicine is absorbed.
What is the therapeutic range?
The range at which a drug has a therapeutic benefit.
What happens below the therapeutic range?
No pharmacological activity.
What happens above the therapeutic range?
What does AUC allow us to estimate?
The AUC allows us to estimate the amount of the drug which is circulating and ready for action.
What kind of bioavailability does an intravenous drug have?
What factors affect bioavailability within oral absorption?
Formulation Availability of drug to pass physiological barriers GI effects First pass metabolism Route of administration
What happens during passive diffusion?
Drug passively diffuses down a concentration gradient.
Is there an active role of the membrane in passive diffusion?
Do drugs ionise in water?
Most drugs do not completely ionise in water.
What type of acid/base are most drugs?
Why do most drugs not fully ionise in water?
Most drugs are weak acids/bases therefore do not fully dissociate in water.
What does drug ionisation depend on?
pH of surrounding environment.
Does the ionised or unionised form of the drug cross the membrane?
When does the unionised form of a drug cross across the membrane until?
Crosses membrane until an equilibrium is established.
What is the relationship between the local pH and the degree of ionisation described by?
How does lipid solubility affect drug absorption?
To pass through a lipid layer, a drug must be lipid-soluble.
What is the ability of a drug to pass the lipid bilayer expressed as?
Lipid-water partition coefficient.
How fast will a drug with high lipid solubility pass?
What does filtration usually occur through?
Channels in the cell membrane.
What is filtration the usual method for?
Water soluble molecules with a low weight.
What is the main method drugs use to cross the capillary wall?
Bulk flow through intercellular pores.
What is active transport?
Transport of molecules which goes against a concentration gradient and therefore requires energy.
What must drugs resemble in order to undergo active transport?
Must resemble naturally occurring compounds.
What is the drug reversibly bound to during active transport?
Reversible carrier system.
What gastrointestinal factors can affect drug absorption?
What is first pass metabolism?
First pass metabolism is the metabolism of a drug prior to reaching systemic circulation.
What drugs bypass first pass metabolism?
Subcutaneous / intramuscular Sublingual / buccal Rectal Inhalation / nasal Transdermal
What is drug distribution?
Once a drug has been absorbed, it must be made available for biological action and distribution to the tissues. It must leave the bloodstream and enter the intravascular spaces.
What part of the drug is active when binding to plasma proteins?
Only the unbound drug is active.
Is the binding of drugs to plasma proteins permanent?
No- it is reversible.
What is the volume of distribution?
The volume of plasma that would be necessary to account for the total amount of drug in a patient’s body, if that drug were present throughout the body at the same concentration as found in the plasma.
How does the Vd (volume of distribution) relate to the drugs ability to diffuse into and through membranes.
Greater Vd = greater ability to permeate membrane.
What is clearance?
Clearance is the theoretical volume from which a drug is completely removed in a certain time.
What is the half-life?
The half life is defined as the time taken for the drug concentration in the blood to decline to half of the current value.
What is the half-life dependent on?
Volume of distribution and clearance.
What can prolongation of a drugs half-life increase?
What is chronic administration?
Long-term administration of drug, usually intravenously.
What is drug elimination?
Removal of drug and its metabolites from the body.
What 2 parts is drug elimination made up of?
Where does drug metabolism occur?
Where does drug excretion occur?
Kidneys and biliary system.
What are the 3 principal mechanisms used in kidney drug excretion?
Passive tubular reabsorption
Active tubular secretion
What is renal function important in causing?
What is glomerular filtration?
All unbound drugs will be filtered at the glomerulus as long as their molecular size, shape and charge are not excessively large.
What aspects of the unbound drug does glomerular filtration pay most attention to?
Size / shape / charge.
What is passive tubular reabsorption?
Passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation. Passive diffusion occurs in the distal tubule and the collecting duct. Only unionised drugs such as weak acids can be reabsorbed.
How do concentrated drugs move back through distal tubule/collecting duct and into circulation?
Can ionised drugs be reabsorbed?
Where does passive diffusion back into circulation occur?
Distal tubule and collecting duct.
What is active tubular secretion?
Some drugs are actively secreted into the proximal tubule- acids and bases. This is the most important system for eliminating protein bound cationic and anionic drugs.
Where are drugs actively secreted into in active tubular secretion?
What does active tubular secretion primarily affect?
Acids and bases.
What is the re-absorption of drugs from bile into the circulation called?
Enterohepatic circulation- occurs until the drug is metabolised by liver or excreted by the kidneys.
What can lead to drug conjugation?
Metabolism in liver.
Are conjugated drugs reabsorbed in the intestine?
What is drug metabolism?
Biochemical modification of pharmaceutical substances by living organisms, usually through specialised enzymatic activity.
What does drug metabolism often involve?
Specialised enzymatic activity.
How does drug metabolism limit the life of a drug in the body?
Turns them into water-soluble/polar compounds so that they can be excreted.
What is the purpose of drug metabolism?
To increase water solubility and aid excretion.
To deactivate compounds.
What are prodrugs?
Drugs that are activated by metabolism.
What can metabolism result in?
Loss of pharmacological activity
Increase in pharmacological activity (prodrugs)
Production of toxic metabolites
What are metabolising enzymes divided into?
Families and sub-families.
Do metabolising enzymes always have specific substrates?
No- they often are more open to various so that they can metabolise different drugs.
What happens during Phase I metabolism?
Polar groups are exposed on or introduced to a molecule. Oxidation, reduction or hydrolysis- this increases the polarity of the compound and provides a site of action for Phase II metabolism.
In what stage of metabolism are polar groups exposed on or introduced to a molecule?
What reactions are involved in Phase I metabolism?
Why do oxidation/reduction/hydrolysis reactions occur in Phase I metabolism?
To increase the polarity of the compound and provide a site of action for Phase II metabolism.
What are the most important family of metabolising enzymes called?
What are Cytochrome P450 enzymes?
The most important family of metabolising enzymes.
What does the isoform of Cytochrome P450 determine?
What are the three most important isoforms of the Cytochrome P450 family?
What is CYP3A4?
Major isoform involved in the metabolism of various drugs. Responsible for pre-systemic metabolism.
What isoform of Cytochrome P450 is responsible for pre-systemic metabolism?
What is CYP2D6?
Responsible for metabolism of antidepressants/antipsychotics and conversion of codeine into morphine.
What isoform of Cytochrome P450 is responsible for metabolism of psychological disease drugs?
What isoform of Cytochrome P450 is responsible for the conversion of codeine into morphine?
What isoform shows reduced/absent expression seen in 5-10% of the population?
What must be considered regarding reduced expression of CYP2D6 in psychiatric patients?
Reduced/absent expression of CYP2D6 in smoking psychiatric patients.
What isoform of Cytochrome P450 is majorly induced by smoking?
What is CYP1A2?
Majorly induced by smoking.
What is enzyme induction?
Enzyme induction occurs when an enzyme is stimulated by another factor (e.g. alcohol/smoking).
How does enzyme inhibition affect drug metabolism?
May cause reversible or irreversible binding to an enzyme.
What is pharmacogenetics?
The ability of genetics to cause major effects on pharmacological therapies.
What may pharmacogenetics variation result in?
Increased/decreased activity of particular enzymes
What isoform of Cytochrome P450 commonly shows pharmacogenetic variation?
CYP2D6- over 70 polymorphisms known.
How does drug metabolism alter in children?
Drug metabolising enzymes are often less efficient in paediatric patients.
How does drug metabolism alter in the elderly?
Parameters such as plasma proteins, lean body mass and liver weight all decrease significantly and so affect drug metabolism. Chronic disease is also more common.
How does gender affect drug metabolism?
Sex-based differences are found in all areas of pharmokinetics (absorption, distribution, metabolism and elimination)- this means that responsiveness to certain drugs is different for men and women.
How does race affect drug metabolism?
Many differences in Cytochrome P450 isoforms.
What can drug formulation allow?
Can be formulated to allow selective targeting of a tissue site or to avoid pre-systemic metabolism, or to allow 24 hour access.
What determines the drug delivery system?
Dose / frequency / timing
What should dosing regimes take into account?
What does oral delivery involve?
Tablets/oral suspensions/capsules/modified release tablets etc.
Where does absorption occur in oral delivery?
What are solutions and suspensions useful for?
Administration of drugs in patients with swallowing difficulties.
What are suspensions?
Dispersions of coarse drug particles in a liquid phase, dose can be contained in a small volume, good for insoluble drugs
What is the rate-determining step in tablet absorption?
What do enteric coated tablets do?
Enteric coating delays the disintegration of the tablet until it reaches the small intestine, this can protect the drug from stomach acid or protect the stomach from the drug.
What do prolonged/delayed-release tablets do?
Useful in disorders that require a prolonged therapy, maintains therapeutic range, reduces need for frequent dosing therefore compliancy is improved.
What are prodrugs?
Prodrugs are synthesised inactive derivatives of an active drug which requires to be metabolically activated after administration.
What are the advantages of prodrugs?
Prologation of the duration of action
Avoidance of drug degradation in the gut
What is buccal/sublingual administration?
Sublingual tablets are small and dissolve slowly under the tongue or in the buccal cavity- tongue/cheek.
What is rectal administration useful in?
Administration in patients who have trouble swallowing; bypasses first pass metabolism.
What is the vaginal route of administration useful in?
What is the injection-based delivery system used for?
Produce fast systemic effects through bypassing first-pass metabolism. Can be administered in unconscious patients.
Can injection-based delivery systems by administered in unconscious patients?
When are IV drugs given?
- A rapid onset of action is required
- Careful control of plasma levels is required
- A drug has a short half-life
What is an intramuscular injection?
When a drug is administered into the muscle mass.
What is a subcutaneous injection?
Dermal administration- e.g. insulin.
How does the transdermal delivery system work?
Patches on skin used to administer drugs- seen in nicotine therapies for anti-smoking.
How does administration through inhalation work?
Inhalation is commonly used to deliver drugs directly to the lung for local effect or to achieve a systemic effect (i.e. anaesthetics). This has many advantages when used to treat systemic diseases such as asthma.
What are the disadvantages of inhalation administration?
Patient must be educated on how to use administration device and also must be compliant.
What is the carrier-based delivery system?
Delivery system based on administration using secondary objects such as micelles/nanoparticles etc.
What do monoclonal antibodies do?
Act directly when binding to a cancer specific antigen and induce the immunological response to cancer cells. Have been modified for the delivery of a toxin, cytokine or other drug.
What carrier induces the immunological response?
What does liposomal drug delivery lead to?
What is nanoparticle administration technology?
Using nanotechnology, the drug can be targeted to a precise location which would increase effectiveness and reduce the chances of possible side effects.
There is more specific drug targeting and delivery, a reduction in toxicity while maintaining the therapeutic efficiency.
What is an adverse drug effect?
Any response to a drug which is unintended and occurs at normal therapeutic dosage.
How is adverse drug effect onset classified?
Acute- within an hour
Sub-acute- within a day
Latent- within 2 days
How long does acute onset of adverse drug effects take?
Within an hour.
How long does sub-acute onset of ADRs take?
Within a day.
How long does latent onset of ADRs take?
Within 2 days.
How is ADR severity classified?
Mild (no change in therapy)
Moderate (requires change, hospitalisation)
What are the classifications of ADR?
Augmented Bizarre Chronic Delayed End of treatment Failure of therapy
What are predisposing factors for ADRs?
Polytherapy, sex, age, renal/hepatic disfunction.
How are augmented ADRs classified?
Normal but augmented responses to pharmacological actions of the drug (predictable/dose-dependant).
Due to excess pharmacological action.
What are augmented ADRs caused by?
Excess pharmacological activity.
What are the 2 types of augmented ADR?
How are bizarre ADRs classified?
Bizarre, unpredictable, rare, cause serious illness and death- unrelated to dose and not readily reversed.
More common in macromolecules, hypersensitive patients and HLA transplant status.
How are chronic ADRs classified?
Related to the duration of treatment as well as the dose- does not occur with a single dose and is semi-predictable.
How are delayed ADRs classified?
Occurs a long time after treatment
Seen through carcinogenesis in patient or teratogenesis in the children of patients.
How are end of treatment ADRs classified?
Occurs when the treatment has stopped, especially following long-term usage. Seen in rebound phenomena within alcoholism.
How are failure of treatment ADRs classified?
Common dose-related, often caused by drug interactions.