General principles of pharmacology : General principles of pharmacology
Objectives : Objectives By the end of this topic you should be able to:
Define the main terms used in pharmacology
Explain the factors that influence drug movement across membranes
Describe the key features of each of the four phases of pharmacokinetics
Explain the time course of responses to a drug
Explain why an understanding of half-life is important to drug doseing
Pharmacology - terminology : Pharmacology - terminology Drug - chemical that acts on a living process
Pharmacology - study of interaction between drugs and living organisms
Therapeutics - drugs used to diagnose, prevent and treat disease or prevent pregnancy
Pharmacopoeia - list of all authorised drugs
Toxicology - study of poisons
What are the features of an ideal drug? : What are the features of an ideal drug?
The ideal drug : The ideal drug What are features of an ideal drug?
Drug formulations : Drug formulations Tablets & capsules
convenient and commonest dosage forms but likely to be no good if the drug cannot be absorbed in the gastrointestinal tract or if the patient (e.g. a child) cannot swallow them or is unconscious
Drug formulations : Drug formulations Injections & infusions
rapid action but impractical for treating chronic (long term) illnesses
can deliver large volumes of fluids
there may be a danger of local tissue damage from toxic agents
Drug formulations : Drug formulations Pessaries & suppositories
can deliver the drug to local area where required but have limited general use
made with vehicle (eg cocoa butter) that melts at body temperature
storage - in fridge
Drug formulations : Drug formulations Solutions, suspensions & elixirs
useful for children and the elderly but are bulky and less useful if the drug is unpalatable or unstable in the presence of water
Aerosols & dry powder inhalations
good for drugs required in the lungs but can be difficult to administer the dose correctly
Drug formulations : Drug formulations Ointments, creams & paints
topical application
Transdermal patches
convenient if the dose needs to be released over a long period (e.g. hormone replacement therapy) but can cause irritation
Drug Combinations : Drug Combinations Drugs are rarely administered alone - often they are combined in a formulation with other medical and non-medical agents
this can confer special physical or chemical properties
E.g. protect from gastric pH
E.g. fast acting analgesics
Drug names : Drug names Trade or brand name
Antenex, Valium, Ducene
Generic or non-proprietary name
diazepam
Chemical name
7-chloro-1,3-dihydro-1-5-phenyl-2H-1,4-benzodiazepin-2-one
Drug names – another example : Drug names – another example Trade or brand name
Plavix
Generic or non-proprietary name
Clopidogrel hydrogen sulfate
Chemical name
methyl (+)-(S)-?-(2-chlorophenyl)-6,7-dihydrothienol[3,2-c] pyridine-5(4H)-acetate sulfate
Slide 14 :
Principles of pharmacology : Principles of pharmacology Pharmacokinetics
absorption
distribution
metabolism
excretion
Pharmacodynamics
how does the drug work-
biochemical and physiological action of drugs & how they produce these effects
What factors influence drug movement across membranes? : What factors influence drug movement across membranes? molecule size - little effect, most drugs are small
lipid solubility - nonpolar molecules move across membranes more rapidly than polar ones
ionisation – unionised molecules can cross membranes
ionised drugs use transport systems to move drugs from gut to blood and from blood to urine
Ionisation : Ionisation Strong acids & bases are ionised at all pHs
Most drugs are weak acids or bases and are ionised at physiological pH (usually pH 7.4)
Degree of ionisation depends on the pH of the solution e.g. stomach, urine
Ionisation of weak acids & bases : Ionisation of weak acids & bases
For a weak acid : For a weak acid
For a weak base : For a weak base
In summary: : In summary: Acids tend to ionise in alkaline media
? acidic drugs tend to accumulate on the alkaline side
Bases tend to ionise in acidic media
? basic drugs will accumulate on the acidic side
A question : A question Why would people who want to increase the amount of amphetamine in the body take bicarbonate to make the urine more alkaline? Alkaline urine increases the proportion of amphetamine reabsorbed from the urine into the blood
acidic urine: 78% lost in 24 h
alkaline urine: 45% lost in 24 h
Pharmacokinetics : Pharmacokinetics
Absorption : Absorption Movement of drug from site of administration to the blood
absorption influenced by
rate of dissolution (How fast does it dissolve?)
surface area of membrane
most drugs (~80%) are administered orally
Oral administration : Oral administration What factors influence absorption of drugs following oral administration?
First pass metabolism : First pass metabolism After a drug is absorbed from GIT, it is delivered to the liver via the portal circulation
Orally administered drugs metabolised in the liver therefore undergo first pass hepatic metabolism From: http://www.nature.com/nrd/journal/v2/n3/box/nrd1032_BX3.html
Parenteral administration : Parenteral administration intravenous injections & infusions
intramuscular injections
subcutaneous injections
inhalation sublingual
topical
rectal
other specialised routes eg into joints or spine
Bioavailablity : Bioavailablity The amount of drug that actually reaches the systemic circulation as a % of the administered dose
IV administration = 100%
Oral & other routes - varies
Distribution : Distribution distribution is influenced by 3 factors:
blood flow
how much drug actually reaches target site
ability to leave blood
only free (i.e. unbound drug can leave blood)
special case: blood-CSF barrier is only permeable to lipid soluble drugs
ability to enter target organ
Drug-protein complexes : Drugs, like other body chemicals, can be bound reversibly to proteins (eg albumin) Drug-protein complexes From: Lehne ( 2002) Pharmacology for Nursing Care
% Protein binding [interest only] : % Protein binding [interest only]
Metabolism : Metabolism Metabolism occurs predominantly in the liver
Other sites – plasma, GIT, lungs
2 main types of biochemical processes – Phase I and Phase II
Phase I – catabolic reactions
Tends to make more chemically reactive products
Uses cytochrome (CYP) P450 family of enzymes
Phase II – anabolic (synthetic) reactions
Conjugation reactions that tend to result in inactive products
Consequences of metabolism : Consequences of metabolism makes the drug more water soluble to increase renal excretion
pentobarbital ? pentobarbital alcohol
Slide 34 : Inactivates the drug
procaine ? PABA
Increase or change the action
codeine ? morphine
Activate a prodrug
Levodopa ? dopamine
Alter toxicity
paracetamol ? hepatotoxic compound
Special considerations in metabolism of drugs : Special considerations in metabolism of drugs Age
infants and elderly
Induction of drug-metabolising enzymes
accelerates drug metabolism
First pass effect
Hepatic inactivation of oral drugs
Nutritional status
deficiency of co-factors used in metabolism
Competition between drugs
If they use the same metabolic pathway can reduce metabolism of one or both drugs
Renal excretion : Renal excretion Steps in renal excretion:
glomerular filtration - all free, small drugs are filtered
passive reabsorption - lipid soluble drugs can pass back into blood & are difficult to excrete
active secretion - 'pumps' compounds from blood to urine. Competition for transporter can slow excretion e.g. probenacid slows penicillin excretion
Factors affecting renal excretion : Factors affecting renal excretion pH dependent ionisation
Why might aspirin overdose treatment involve making the urine more alkaline?
Competition for active tubular resorption
E.g. penicillin excretion can be delayed by concomitant excretion of probenecid
Age
New borns have immature kidneys
Non-renal excretion : Non-renal excretion Breast milk
lipid soluble drugs can enter milk
may affect infant
Bile
reabsorption from bile termed enterohepatic recirculation
Eg digoxin and morphine
Lungs
for volatile compounds
Sweat, tears, faeces
minor & not therapeutically important:
Summary : Summary Note central role of liver and kidney in these processes
Time course of responses : Time course of responses once administered, a drug enters the blood and reaches peak concentration, then the concentration decreases again as it is cleared (metabolised and excreted)
the faster the clearance the less time it will remain in body
determines how frequently a drug needs to be given
Slide 41 :
Half-life (t½) : Half-life (t½) Since the concentration of drug at the site of metabolism and excretion determines the amount cleared, the clearance rate is often expressed as the half-life
Half life = time taken to reduce concentration of drug by 50%
may be altered by age, weight, liver or kidney disease, drug interactions
useful for calculating intervals for repeat doses
some drugs don't have a half-life - a constant amount is excreted per unit time e.g. alcohol
Slide 43 :
Slide 44 : From: Lehne ( 2002) Pharmacology for Nursing Care
Half-life : Half-life Different drugs in a therapeutic class may have different half-lives.
Example: hypnotics
short half-life used for those who have difficulty falling a sleep
longer half-life used for those with early morning insomnia
Sustained release preparations artificially increase half-life
Drugs with long half-lives can be problematic – why?
Repeat doses : Repeat doses By giving repeated doses at particular time intervals, administration keeps up with clearance and a steady concentration can be achieved
Slide 47 : Fluctuations in plasma concentration can be reduced by:
infusions
decrease dose and increase frequency
Plateau is normally reached after 4-5 half-lives
problem if half-life is long e.g. diazepam, takes a long time to reach therapeutic doses
can give ‘bolus’ dose - often a double dose to reach plateau more rapidly, or give injection then take orally
can be a problem as adverse effects more common with higher dose
Slide 48 : Same dose (4 units) is given at each t½ (1 h)
After 4-5 t½ there is little variation between the min and max concentrations From: http://cpharm.vetmed.vt.edu/VM8314/kineticsnotes2001WithPics.htm
Slide 49 :
Therapeutic index : Therapeutic index Large therapeutic index = safer drug
If a drug has a large therapeutic index, there is little chance of accidentally reaching toxic concentrations
Eg penicillin
If drug has a small therapeutic index, then plasma levels must be monitored closely to prevent toxic concentrations
Eg gentamicin, lithium, digoxin
Slide 51 : From: Lehne ( 2002) Pharmacology for Nursing Care