Pharmacokinetics and Pharmacodynamics Flashcards
Pharmacokinetics
Effect of the body on a drug
Pharmacodynamics
What the drug does to the body
What are the 4 processes of drug therapy?
Pharmaceutical (is drug getting to patient)
Pharmacokinetic (is drug getting to site of action)
Pharmacodynamic (is drug producing pharmacolgical effect)
Theraputic (is pharmacologic effect producing theraputic effect)
Explain the pharmaceutical process of drug therapy
Compliance: drug will be ineffective if patients are non-compliant
Bioavailability: Proportion of administered drug that reaches the systemic circulation and is available for distribution to site of action
Formulation: physical factors affecting bioavailability e.g. tablet disintigration, drug dissolution, controlled release
site of administtation: affects drug delivery to target and duration of action.
Name 4 sites of administation for drugs
Subcutaneous
Intramuscular
Sublingual
Buccal
Rectal
Vaginal
Inhalation
Transdermal
Benefit of sublingual administration
Drugs pass into the venous circulation intact, avoiding first pass metabolism in the liver. Smaller doses required.
Use of transdermal administration
Mostly patches that deliver small quantities of drug over a period of time.
What are the four components of pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
Factors affecting the rate of drug absorption
Drug absorption occurs mainly in the upper part of the small intesine. Affected by:
GI motility: delay in emptying may delay effects of painkillers. Increase in motility may mean enteric coated tablets pass through without being absorbed.
Malabsorptive sttes e.g. coeliacs
Food: can increase or decrease absorption of drugs
What is first pass metabolism?
The extent of metabolism that occurs in the liver before the drug enters the systemic circulation.
Drugs are absorbed through the gut wall and delivered to the liver via the portal circulation where they are metabolised. This affects bioavailability.
3 routes which by-pass first-pass metabolism
Sublingual
Rectal
Transdermal
Extraction ratio
Measure of how much of a drug the liver removes by first pass metabolism before it reaches the systemic circulation.
High ratio = most of the drug is metabolised after absorption
How can changes in plasma protein concentrations alter drug distribution?
Many drugs are bound to plasma proteins in solution. Drugs need to be unbound to be active - bind to cellular receptors pass into the tissue and enter the cells.
A fall in plasma protein will increase the percentage of unbound drug and therefore increase potency of the drug.
N.B. The effect this has is dependent on the % of drug that is normally bound.
Factors that can decrease the levels of drug bound to protein
renal impairment - albumin exreted, levels decrease
3rd trimester pregnancy
Hypoalbuminaemia
displacement by other drugs e.g. sulphonamides and warfarin.
Factors that affect tissue distribution
Plasma protein binding
Blood flow
Lipid solubility
Active transport
Diseases
Other drugs
Name 4 organs that excrete drugs from the body
Kidney
Lungs
Breast milk
Sweat
Tears
Bile
Saliva
Agonists
Bind to and activate the receptor. Can bring about the effect directly or indirectly.
Can be full or partial. Partial agonists produce a lower response at full receptor occupancy than full agonists.
Have maximum dose effect determined by tissue e.g. muscle shortening, once short will not get shorter even if [drug] increases
Antagonists
Bind to the receptor without stimulating it, prevent binding of other molecules.
Can be competitive or non-competitive. Non-competitive bind at allosteric sites, competitive can be overcome by increasing [agonist].
Potency
The concentration at which 50% of the maximum effect of the drug is acheived.
Efficacy
The drug which has the biggest effect/response.
Clinical effectiveness of a drug depends on efficacy
Theraputic window
[drug] needed to produce an effect relative to the [drug] which has a harmful/toxic effect.
Drug variability
Variability between patients in the dose needed for benefit vs. harm.
Can be due to genetic factors (metabolism, target sensitivity) or acquired factors (receptor expression, other diseases, [ligand])
Single individual may respond differently to the same drug at different times during treatment.
Factors that affect drug absorption
Lipid solubility: Ability to move from aq. to lipid varies with pH of medium. Most drugs are weak acids/bases and cross membranes when unionised.
Surface area: required to efficently absorb drugs, majority occurs in the small bowel
Blood flow: required for access to the tissues. Reduced flow affects the absorption.
Bioavailbility
The proportion of a dose that gets from the point of delivery to the systemic circulation unchanged.
Note: not always an indicator of activity, some drugs are precursors which are metabolised to active products.
Bioavailability affects how some drugs are delivered. If metabolised before it reaches systemic circulation then it is ineffective.
Tissue distribution
Well-perfused organs (heart, kidney, liver) accumulate drugs to a greater extent that poorly perfused tissue.
Cells with leaky junctions e.g. muscle, endothelial cells allow water-soluble substances to diffuse through easily. The BBB has tight junctions and pumps to restrict water soluble molecules. Lipid soluble drugs cross easily.
Hepatic drug metabolism
Converts lipid soluble drugs into more water soluble molecules. Usually terminates activity
Phase 1: oxidation, reduction, deamination, hydrolysis. Metabolite may retain activity. Oxidation most common, controlled by cytochrome P450 isoenzymes. Enzymes can be induced or inhibited by certain drugs
Phase 2: conjugation (glucoronate, acetate, sulphate). Metabolite lacks activity
Some drugs undergo both phase 1 and 2, some just 1 or 2.
Briefly outline renal drug excretion
Glomerular filtration: Only the free unbound drug is filtered. Extent of filtration depends upon GFR
Active secretion: Some strong acids/bases actively pumped into PCT
Passive tubular absorption: Some drugs are reabsorbed in the PCT. This is dependent on pH and lipid solubility. e.g. aspirin is a weak acid - less reabsorbed in alkaline urine.
Pharmacokinetic parameters
Half life: time required to change to amount of drug in the body by 1/2. Guide to time it takes for drug to be eliminated form the body. (In renal failure half life is prolonged). Used to measure time to steady state (5 half-lives) and loading dose
Volume of distribution: Measure of the degree to which a drug is in the circulation or tissues. Drugs with high VD are mainly in the tissues, cannot be easily removed from the body.
Clearance: Volume of blood cleared of a compund per unit time. Measure of the ability of the body to tlimate the drug.
What determines intensity of a drug’s action following parenteral administration?
Volume of distribution (governed by body composition and regional blood flow)
What determines a drug’s plasma concentration after oral administration?
Bioavailability
Rate of systemic clearance (hepatic metabolism/renal excretion)
Factors that affect oral bioavailability?
Destuction in the GIT
Absorption across the gut epithelium
First pass metabolism (avoided by iv, im or sublingual)
How does half-life affect loading dose?
Drugs with long half-lives take a long time to reach strady state (constant blood level) and have theraputic effect, therefore a a higher dose (loading dose) may be required to get a patient to have a response
Drugs with short half-lives may need a loading dose in emergencies e.g. lignocaine in arrhythmia.
Types of pharmacological action of drugs
Via a receptor to have a pharmacological effect
Via an indirect alteration of aan endogenous agonist e.g. SSRI, ACEi
Inhibition of transport processes
Enzyme inhibition e.g. NSAIDs, warfarin
Enzyme activation
How to determine choice of treatment
Consider:
Efficacy
Evidence
Adverse Effects
Effectiveness (cost)
