Basic principles Flashcards
What are the four aspects of pharmacokinetics?
- absorption
- distribution
- metabolism
- excretion
What is pharmacodynamics?
the concentration of a drug at its site of action and the resulting pharmacological effects and blood stream/tissue concentrations
Describe the concept of ‘volume of distribution’
- extent of distribution of the drug across the body (space that can contain the drug)
- usually correlates with roughly with the area it is ‘distributed’ too
(e.g. aminoglycosides disperse largely to the ECF, 20% is the approx Vd) - not usually a ‘range’ as cannot be sepcified in the body per se
What are the two main factors that effect Vd
- distribution across the body (e.g. muscle, fat etc)
- the extent of tissue binding
What is drug clearance?
The measure of the body to eliminate the drug
Equation = rate of elimination / concentration
What does the term bioavailability refer to?
- active pharmaceutical component that enters the systemic circulation (i.e. the bloodstream)
*oral medications - this would be absorption and first pass metabolism
What is the purpose of a loading dose?
This enables reaching an intended concentration instantaneously. The loading dose is obtained from the V(d)
*a maintenance dose is required to keep meeting this concentration
What is the PK parameter that determines the maintainence dose rate
Clearance
Why is the half life important?
Helps determine the dosing interval and the time needed to reach steady state
What is zero order elimination?
This is here concentrations of a drug fall at a constant rate (e.g. ethanol)
What is first order elimination?
Elimination depends on a concentration-dependent relationship
What is steady state and how is it calculated?
- medication must be supplied at at equal rate towards its elimination at a given concentration
- maintainence dose rate = clearance x steady state concentration
True or false - volume of distribution only describes the proportion of unbound drug
False - includes protein bound or unbound drug
What is the formula for half life
T(1/2) =0.693 Vd / CL
If high Vd, high half life
If high CL, low half life
If there is a drop in albumin, would this affect protein binding of drugs?
Unlikely to as clearance is dependent on free drug clearance
What types of drugs traverse lipid membranes - ionised or unionised?
Unionized
What is P glycoprotein?
It is the efflux transporter protein that helps in transporting drugs to various organs
In the gut, PGP pumps drugs back into the lumen, decreasing their absorption
Describe the concept of systemic clearance
Describe how liver metabolism of drugs occurs
1) biotransformation of a parent drug to one or more metabolites
2) excretion of unchanged drug in the bile
3) both
*hard to measure directly, so often calculated by systemic clearance - renal clearance
What is the formula for half life?
T(1/2) =0.7 x V / clearance
List 3 factors that alter absorption
- lack of gut absorption
- too lipophilic (can’t cross water layer adjacent to cell) or hydrophilic (can’t cross lipid membrane)
- P glycoprotein - this pumps drug put of gut wall cells
What is first pass elimination/metabolism
This is when the drug is metabolised by the liver before moving to the systemic circulation
Determined by extraction ratio = liver clearance / hepatic blood flow
What is the most important parameter in defining a steady state drug dosage regime?
Clearance
What is the equation for dosing rate?
Dosing rate = clearance x target concentration
Explain how the ageing process can affect absorption?
Consequence of decreased blood flow to the tissues, GIT and alteration in stomach pH
*clinical application of this - some medications may enhance this effect
» use of omeprazole may lower gastric pH subsequently affecting B12 absorption
» inconsistent eating habits (e.g. a high protein meal with phenytoin results in less absorption due to a higher amount of drug becoming protein bound
» reduction of subcut and transdermal meds due to reduced blood flow
Explain the difference between first pass and phase I metabolism
- first pass - metabolism of a drug prior to reaching the systemic circulation
- phase I - early reactions that break down drugs
In the ageing process, how is first pass metabolism affected?
- first pass reduced as part of the ageing process (resulting in a HIGHER peak concentration) - good examples of this are amitriptyline, verapamil, opiods
In the ageing process, how is phase I metabolism affected?
- reduced
- clinical application - decreased clearance of metabolised medications (e.g. warfarin)
*note no affect on peak concentration
Is renal clearance affected by the ageing process?
- not confirmed evidence wise - unsure if reduced renal clearance related to pathophysiology vs. ageing
Describe the half life and Vd of ampicillin
- short half life (<1.5 hour) and therefore a low volume of distribution
*this is enabled by glomerular filtration and renal tubular secretion
What is the electrolyte disturbance associated with ampicillin?
sodium
What is the role of anticholinergics?
- block/inhibit the neurotransmitter acetylcholine at central and peripheral nerve synapses
- downstream effect of blocking the parasympathetic nervous system
- two main receptors - antimuscarinic and nicotinic
Outline the key adverse effects of anticholinergic medications at toxic levels
Central (CNS blockage)
- agitation/confusion/delerium
- seizures
Peripheral (various)
- hyperthermia
- flushed/tachycardia
- reduced gut motility, urinary retention
- blurred vision, NARROW angle glaucoma
What are some key contraindications for anticholinergics?
- some conditions make elderly people more susceptible to anticholinergic activity (e.g. dementia)
- elderly Px - increased permeability of BBB
Explain why in a patient with AD, anti-cholinergic medications would not be useful
- in mild-mod dementia - cholinergic medication may be used
*anti-cholinergics could offset this - example - donepazil
What is the concept of high anticholinergic load?
This is where there can be a cumulative, sedative effect of taking multiple medications with anticholinergic properties
What is the risk associated with switching a patient from a biologic to a biosimilar medication?
- potential initiation of anti-drug antibodies
*possibility to make the biologic and biosimilar medication ineffectie
List 3 drugs that are common CYP3A4 inducers
- carbemazipine
- phenytoin
- rifampin
- dexamethasone
How is hydrocortisone metabolised and what drugs should be avoided to prevent an addisonian crisis?
- via CYP3A4
- any inducers could reduce the plasma concentration of hydrocortisone (e.g, carbemazipine)
What will happen to a patient on ketoconazole and hydrocortisone?
increased levels of hydrocortisone as ketoconozole is an inhibitor of CYP3A4
List 3 drugs that are inhibitor enzymes
