Lecture 34 & 35 - Introduction to Pharmacology and pharmacokinetics concepts Flashcards
what is Pharmacology
effects of chemicals on biological entities
interaction of drugs biologically
effect of drugs
therapeutic an toxic effects
pharmacodynamics
specific to drug or drug class
pharmacokinetics
non-specific general processes
advantages and disadvantages of oral route of administration
convenient, safe, economical
cannot be used for drugs inactivated by 1st pass metabolism or that irritate the gut
advantages and disadvantages of intramuscular
suitable for suspensions and oily vehicel
rapid absorption from solutions
slow and sustained absorption from suspensions
dis - may be painful, cause bleeding at site of infection
subcutaneous - advantages and disadvantages
suitable for suspensions and pellets
cannot be used to deliver large volumes of fliof
cannot be used for drugs that irritate cutaneous tissue
intravenous - advantages and disadvantages
bypass absorption yielding immediate effect
- 100% immediate bioavailibity
- poses more risk for toxicity
buccal - advantages and disadvantages
rapidly absorbed
avoids 1st pass metabolism
dis - effect only for low doses
drugs must be water and lipid soluble
transdermal
avoids 1st pass metabolism, effective only for low doses of drug that are highly lipid soluble
inhalation
produces a localised effect
drug particles must be correct size
dependent on patient technique
intrathecal
local and rapid effects
requires expert administration
may introduce infection/toxicity
epidural
provides a targeted effect
risk of failure, risk of infection
topical
non-invasive and easy to administer
poor lipid soluble not absorbed via skin or mucous membranes
very slow absorption
types of oral preparations
tablet - compressed powder - can be coated to protect against stomach acid
capsule - solid dosage enclosed by gelatin shell
solution - dissolved in solvent
suspension - suspended in a vehicle - large amounts of drug
what processes are involved in pharmacokinetics
ADME - Absorption
distribution, metabolism and excretion
What is absorption
transfer of drug from site of administration into general or systemic circulation
What are the factors that affect oral absorption
needs to disintegrate and dissolve in the GIT content to form a solution before becoming absorbed
need to be lipid soluble to be absorbed by the gut
rate of gastric emptying determines the rate at which a drug is delivered to the small intestine.
physiochemical factors - drug-food interactions - insoluble complexes
presence of food may delay absorption
-reduce adverse effects of certain medicine eg. NSAID’s
what is the effect of pH on drug absorption
increase in pH leads to an increase in ionisation
acid - increasingly ionised
bases - increasingly unionised
What nature of the cell membrane allows drugs to cross the cell membrane?
the cell membrane has a lipophilic nature
only permits passage of uncharged fraction of any drug
What is distribution
drug is transferred reversibly from general circulation into tissues as concentrations in blood increase
from tissues into blood as concentrations in blood decrease
occurs by passive diffusion of un-ionised form across cell membrane
what happens to distribution after an IV injection
high plasma concentration and drug rapidly equilibrates with well perfused tissue giving relatively high concentrations in these tissues
Different types of drug movement
bulk flow transfer - blood transfer
diffusion transfer - molecule by molecule - short distances
lipid solubility - passive diffusion
carrier mediated transfer
What are the factors affecting drug distribution
Plasma protein binding - competition
specific drug receptor sites in tissues
regional blood flow - reduced and enhanced blood flow
how does lipid solubility and disease affect distribution?
lipid solubility - blood/brain barrier, membrane of GI tract eg, vancomycin, highly water soluble drugs eg. gentamycin
disease - liver disease can low plasma protein levels
renal disease - cause high blood urea levels
What happens in drug-protein binding
binding of drugs with albumin and glycoproteins
when a patient takes a drug that becomes highly protein bound when they are already taking a drug that is highly protein bound, the drug is displaced and increase in unbound concentrations of drug and activity
Albumin bound proteins
furosemide, ibuprofen, phenytoin, thiazides, warfarin
Glycoprotein bound
chlorpromazide, propranolol, tricyclic anti-depressants, lidocaine
what molecules can cross a cell membrane
those not bound to protein
they are crossed by: passive diffusion - high conc to low conc across ion channels transporters - membrane pores vesicle mediated transport
What is facilitated diffusion
combine with membrane bound carrier protein
movement still dependent on conc gradient
faster than passive diffusion
What is active transport
requires energy
molecule transported against conc gradient
How can molecules be transported by pinocytosis
molecules engulfed by cell membrane and vesicle is formed
vesicle moved into cell
molecule is released within cell
distribution to specific organs - brain?
blood brain barrier protects it from toxic chemicals
only lipid soluble can enter
What is the functional basis of the blood brain barrier
reduced capillary permeability
tight junctions between endothelial cells
decrease in size and pores in cell membranes
presence of surrounding astrocytes
efflux transporters - return drugs back to circulation
How does distribution work in a foetus?
cross placenta
placental blood flow is low compared to other organs - equilibriate slowly with maternal concentrations
highly polar and large
molecules dont cross
foetal liver - lower conc of metabolising enzymes
maternal elimination - processes foetal concentrations of drugs
effect of drugs given to mother close to delivery produce prolongued effect on a new born
what are the 4 aspects of drug metabolism?
Activation of inactive drug
Production of active drug with increased activity from active drug
Inactivation of active drugs
Change in the nature of the activity
Factors affecting drug metabolism
first pass effect hepatic blood flow liver disease genetic factors -acetylation status other drugs age (impaired hepatic enzyme activity) - elderly and children below 6 months
First pass metabolism
stomach, SI, LI and lungs
- oral and inhalation
occurs prior to and during absorption
intestinal lumen - digestive enzymes secreted by the mucosal cells and pancreas. some break down proteins so are not absorbed
intestinal wall - rich in enzymes - further metabolism
liver - major site
lung - high affinity for many drugs and are the site for many local hormones
Describe the 2 phases of metabolism?
Phase 1 - oxidation, reduction and hydrolysis
form more reactive products, sometimes toxic (lipophilic - fat soluble)
Phase 2 - conjugation
usually form inactive and readily excretable products (becomes hydrophilic water soluble to be excreted)
Cytochrome PF50
Large family of enzymes and individual one is called isoenzyme
different types of cyt P450
Paracetamol poisoning
predominantly metabolised by Phase 2 metabolism
when overdosed - phase 2 becomes too saturated
body tries to metabolise through oxidation (phase 1 mechanism) - produces toxic metabolite - n-acetyl-p benzoquinone imine
damages kidneys and liver
Antidote for paracetamol poisoning and how?
n-acetylcysteine enhances phase 2 metabolism
DRUGS THAT UNDERGO SUBSTANTIAL FIRST PASS METABOLISM
Aspirin Glyceryl trinitrate Levodopa Lidocaine Morphine Propanolol Salbutamol Verapamil
ENZYME INDUCING DRUGS
Enhance the production of liver enzymes which break down drugs
Faster rate of drug breakdown
Larger dose of affected drug needed to get the same clinical effect
examples of enzyme inducing drugs
Phenytoin Phenobarbitone Carbamazepine Rifampicin Griseofulvin Chronic alcohol intake Smoking
ENZYME INHIBITING DRUGS
Inhibit the enzymes which break down drugs
Decreased rate of drug breakdown
Smaller dose of affected drug needed to produce the same clinical effect
BIOAVAILABILITY
Bioavailability is the proportion of a dose which actually gets into the systemic circulation
factors affecting bioavailablity
Pharmaceutical Preparation
Particle size, composition of formulation
- Physicochemical Interactions
Other drugs or food may interact with or inactive the drug - Patient Factors
Malabsorption syndromes, gastrointestinal motility - Pharmacokinetic interactions and first-pass metabolism
Clerance of a drug
This is the measure of the removal of drug from the body or the volume of plasma completely emptied of drug per unit time
This includes metabolic as well as renal and biliary clearance
Clearance does not indicate the amount being removed but the volume of plasma (or blood) from which the drug is completely removed or cleared in a given time period.
half life of a drug
take taken for concentration to reduce by half
What is half life increased by?
Diminished renal plasma flow e.g. heart failure
Addition of a second drug that displaces the first from albumin thereby increasing the volume of distribution of the drug
Decreased extraction ratio as seen in renal disease
Decreased metabolism as seen in liver disease
drug elimination
fluids - urine, bile, sweat, tears, milk
solids - hair, faeces
gases - important for volatile compounds
Elimination via the kidney
- free drug enters GF
- Active secretion in PCT
- Passive reabsorption of lipid soluble, unionised drug - DCT
- Ionised lipid insoluble drug into urine
What does elimination via the kidney depend on
blood flow to kidney
GFR
Active secretion of drugs into tubule at the start
passive reabsorption back into the tubule
SIGNIFICANCE OF ALTERED RENAL FUNCTION
Care with renally excreted drugs
Care with drugs with a narrow therapeutic index
Example: digoxin
Care with drugs which produce active metabolites
Care with drugs that may further reduce renal function
what is used to evaluate renal function
creatinine - produced by muscle
estimation of creatinine clearnace estimates clearance of drugs filtered at glomerulus
COCKCROFT GAULT EQUATION
Estimated Creatinine Clearance in mL/min
= (140-Age) x Weight x Constant
Serum Creatinine
egfr
eGFR uses serum creatinine, age, sex and race (for African-Caribbean patients)
This is normalised to a body surface area of 1.73m2 and derived from a specific formula.
Absolute GFR = eGFR x individual’s body surface area /1.73
drug monitoring
clinical effectMeasuring BP, pain reduction etc
biological effect - prothrombin time for warfarin, glucose for insulin etc
plasma concentrations when relevant
Therapeutic index
ratio of:
Dose that causes toxicity
Dose that produces desired effect
efficacy vs toxicity
