Pharmacokinetics Flashcards
List major routes by which drugs are administered & give advantages and disadvantages Identify factors that affect drug passage across membranes determining drug distribution Identify the routes and biochemistry of Phase 1 and Phase 2 metabolism Explain how drug action can be terminated, and identify the principal routes routes of drug metabolism & excretion Define: first-pass metabolism, enterohepatic circulation, drug half-life, apparent volume of distribution, bioavailability, drug clearance.
What are the main routes of administration?
Oral Inhalational IV Dermal Sub-lingual
Describe advantages and disadvantages of each method of administration.
Oral - Easy to do at home ie. swallow pill. Has to undergo first-pass metabolism. Takes a long time to enter the systemic circulation as it has to go through gut etc.
Inhalational - Extremely fast entry into the systemic circualtion as alveoli have many capillaries and it bypasses one step in the process ie. straight into pulmonary circulation. Only about 50% penetrates deep enough into the lungs to be absorbed. Could be done easily at home.
IV - Very fast entry into systemic circulation, very high bioavailability. May require professional administration.
Sub-lingual or dermal - Not very fast. May need to be done by a professional.
What is absorption?
The passage of a drug from the site of administration to the blood plasma.
What is bioavailability?
The fraction of drug that reaches the systemic circulation as intact drug, taking into account degradation and metabolism.
In which 2 ways can drugs move around the body?
Bulk flow transfer which is the process of drugs moving around in the bloodstream.
Diffusional transfer describes the process of drugs moving over a short distance (molecule by molecule).
What are 4 ways of drugs crossing the lipid membrane?Describe them.
Pinocytosis - liquids being endocytosed
Diffusion through the lipid membrane - small uncharged polar molecules and lipid soluble molecules can diffuse through lipid membranes
Diffusion through aqueous pores - molecules smaller than 0.5nm can fit through aquaporins in the membrane and enter. Not very common as drugs < 0.5nm
Carrier proteins - molecules can be transported across the membrane by carrier proteins.
How does pH affect drug molecules?
The pH being higher or lower than the pKa will affect the ionisation of the molecule, resulting in a more lipid soluble molecule when it is non ionised.
How does pH being greater/less than pKa affect the lipid solubility of the molecule?
If the pH is lower than the pKa, the molecule will be unionised. A weak acid in an acidic environment won’t dissociate as there is already protons in the solution. A weak base in an acidic environment will accept all the free protons.
What does the pH partition hypothesis tell us?
The pH partition hypothesis indicates to us that the pH of certain body compartments will result in specific drugs being trapped in them - ion trapping. This is due to the pH changing the lipid solubility of the drugs by ionising/deionising them.
How can non lipid soluble drugs gain access to certain tissues?
Carrier transport systems. They are present in membranes to control the transport of endogenous molecules, but drugs may interact with them and be transported across the membrane despite not being lipid soluble.
Where are the most important carrier protein systems relating to drug action?
Renal tube (for reabsorption into tubule at excretion)
Biliary tract
Blood-brain barrier
GI Tract - allows access to the bloodstream for orally administered drugs
What are the advantages and disadvantages of administering drugs for local effect?
It can delivered directly to the site of action
You can deliver a high local concentration without worrying about systemic effects
However, it is rare for a drug to have only local effects as most tissues have good blood supply - and most drugs are somewhat lipid soluble so can enter the systemic circulation.
Which factors influence tissue distribution?
Regional Blood Flow
Plasma Protein Binding
Capillary Permeability
Tissue Localisation
Describe how Plasma protein binding effects tissue distribution.
When they reach the systemic circulation, most drugs bind to plasma proteins. Albumin is particularly good at binding acidic drugs. The amount of drug bound to plasma proteins is dependent on the amount of free drug, affinity for protein binding site, and plasma protein conc. Binding capacity = free drug conc. x number of binding sites. The extent of plasma protein binding is largely due to the different affinities of plasma protein binding sites. Only free drugs can diffuse out of the blood
Describe the effect of capillary permeability on tissue distribution.
Most capillaries are continuous where they have gap junctions, and lipid soluble molecules can diffuse into the capillaries. Less lipid soluble molecules which are big can be transported in by carrier proteins. The blood brain barrier has tight junctions which make it very difficult to access. The liver has a discontinuous capillary structure which has big gaps between cells, making it easy for drugs to access. The glomerulus has a fenestrated capillary system which means it has small circular windows within endothelial cells that allow the passage of small molecular weight substances.
