Download L8 Pharmacology PPt - Moodle

Responding to ill Health
Life Science
Pharmacology
Abinoam Jr. (2007)
https://commons.wikimedia.org/wiki/File:Comprimidos.jpg
1
Learning Outcomes
1. Define the terms- pharmacodynamics,
pharmacokinetics. Outline the different stages in
pharmacokinetics, including first-pass metabolism.
2. Outline the concepts of drug half-life, steady state and
therapeutic range.
3. Define and give an example of analgesics & antibiotics.
Briefly explain their physiological effects and
summarise common side effects of these drugs.
2
Pharmacology (revision)
What is pharmacology?
The study of how chemical agents affect the tissues or cells of
the body
What is a drug?
Any chemical agent that affects the tissues or cells of the body
3
Pharmacokinetics and Pharmacodynamics
(revision)
2 branches of pharmacology
• Absorption
Pharmacokinetics
• what the body does to drugs
• Distribution
• Metabolism
• Excretion
Pharmacodynamics
• what drugs do to the body (their mechanism or mode
of action)
Insulin
• binds to specific receptors on target (liver, muscle, fat) cells
• increases glycogen storage - lowers blood glucose
4
First-pass effect (revision)
• Oral drugs absorbed from GI tract sent to liver through hepatic
portal vein
• Drugs partially metabolised by the liver enzymes before entering
general circulation
• If “first-pass” metabolism is extensive, very little drug survives to
reach the systemic circulation – need other route of
administration
UWS Staff (2015)
Drug plasma levels
Concentration of drug in plasma over time
depends on:
– Route of administration
– Rate of metabolism
– Rate of excretion
6
Drug plasma levels - administration
140
Intravenous
120
Plasma Drug Concentration
100
80
Intramuscular
60
Oral
40
20
0
0
20
40
60
80
100
120
140
160
Time
UWS Staff (2015)
Drug plasma levels
• speed of drug metabolism & excretion is
important clinically
• a rapidly metabolised/ excreted drug needs
– higher dose
– possibly more frequent administration
• measure of speed of removal of drug from
plasma = HALF LIFE
8
Elimination Half-life
140
Plasma Drug Concentration
120
100
80
60
40
Half-life
20
0
0
20
40
60
80
Time
• Time taken for plasma drug concentration to fall to half the starting value
• Half-life is characteristic of a particular drug
• Drug half-lives vary from minutes → days.
UWS Staff (2015)
Drug elimination half-life
Plasma drug concentration
100
Plasma Drug Concentration v Time
(showing half-life determination)
Can you determine the plasma drug
concentrations after 40 minutes
and 60 minutes?
50
?
??
0
0
Half-life
20
40
60
80
Time (minutes)
UWS Staff (2015)
Different drugs have different elimination half-lives
100
Plasma drug concentration
Three drugs with different half-lives
50
?
0
0
Half-life
20
40
60
80
Time (minutes)
• slow metabolism/excretion – long half-life
• rapid metabolism/excretion – short half-life
• important in determining frequency of administration
UWS Staff (2015)
Dosing regimes
Drugs only effective if:
• present at target site at high enough concentration
• maintained at target site for sufficient time
• actual concentration and time needed depend on:
– drug
– clinical situation
• adrenaline (cardiac rhythm) – seconds/minutes
• antibiotics - days
• dose must be correct to maintain blood levels within specific limits –
Therapeutic range
Dosing regimes & therapeutic range
UWS Staff (2015)
Repeated drug doses
Dosing intervals for a particular drug
depend on both:
• Half –life
– Short half-life - frequent administration
– Long half-life - less frequent
• Therapeutic range
14
Dosing intervals
• Which dosing
frequency is
best?
• Which dosing
frequency is
too low?
UWS Staff (2015)
Steady state
• Eventually (if dosing frequency
great enough) plateau reached
- steady state
• Drug input &
excretion/metabolism roughly
equal
• Large initial dose (loading
dose) followed by smaller
repeated (maintenance) doses
 steady state more quickly
• Age, genetic factors & health
affect pharmacokinetics, also
drug interactions
Loading dose
administered to
achieve therapeutic
range, prior to
maintenance doses
UWS Staff (2015)
Variability in patient response
Patient response is influenced by:
– Body weight / Surface Area
Different volume of body fluids
 different concentration of drug in the body
 different response
– Age
• Very young / elderly may show different response to norm:
– Liver & renal function
– Interactions (e.g. with alcohol)
• 2 different drugs: each can influence handling of / response to the other
– Pregnancy
• Changes in blood volume, plasma protein levels, cardiac output
– Illness
• Liver & renal function
17
Pharmacodynamics
How do drugs work (mechanism of action)?
• usually by binding to a specific protein in or on cells
• binding results in a biological response
Biological
Effect
+
Drug
Protein
• Drug target
• Drug receptor
UWS Staff (2015)
Pharmacodynamics
Drug Targets
e.g. Receptor proteins on the surface of cells
• Proteins designed to respond to natural molecules
(hormones, neurotransmitters)
• Activation changes the activity of the cell
Drugs may be designed to bind to these
receptors
• Shape of drug molecules “fits” into receptor
Endogenous hormones or
neurotransmitter
Drugs can mimic the effect
(agonist)
Binds to then activates
a receptor
Change in cell activity
Or drugs can fit into the
receptor but not activate it
(but block endogenous agents)
Hottuna080 (2013)
https://commons.wikimedia.org/wiki/File:Lock_and_key.png
20
adapted by UWS Staff (2105)
Drug Classes
Agonists
Hormone
• Drugs that activate the receptor,
bringing about the “natural”
change in the cell
Drug
• Mimic natural ligand e.g.
hormone
• Adrenaline (hormone)
• β-adrenoreceptor agonists (drug)
UWS Staff (2015)
Drug Classes
Antagonists
– Do not activate the
receptor
– Block binding by
“natural” activators
– Prevent activation
of the receptor
– e.g. beta-blockers
antagonist
UWS Staff (2015)
Specificity of drug binding
Drug X
Drug Y
Drug Z
binds B
binds A
SIDE
EFFECTS!
SPECIFIC
Receptor A
Cell
A
Receptor B
Cell
B
UWS Staff (2015)
Analgesics
Analgesia (an- “without”; algesia – “the sensation of pain”)
• Tissue damage  pain receptors stimulated
• “message”  cortex of brain interpreted as pain
2 major pharmacological groups of analgesics:
• Opioids act on CNS
• Non-opioids:
e.g. NSAIDS & paracetamol act on site of tissue damage
NSAID – Non-Steroidal Anti-Inflammatory Drug)
24
NSAIDS & paracetamol
• Tissue damage  inflammatory response
• Brought about by e.g. prostaglandins, make pain
receptors more sensitive to pain
• Cyclooxygenase (COX) enzymes needed to make
prostaglandins
• NSAIDS inhibit COX enzymes (NB mechanism of
paracetamol not entirely clear)
• Therefore reducing sensitivity of pain receptors &
reducing pain
25
Perception of pain
• After tissue injury, “pain message” peripheral nerves
 spinal cord  brain
• Can this message pathway can be blocked ???
• Endorphins (and others) - body’s “natural” painkillers
• Gentle rubbing eases pain by stimulating touch
receptors → blocks passage of pain signals at synapses
• Drugs?
• Opioid analgesics mimic action of endorphins
26
Opioid action
UWS Staff (2015)
Opioid side effects
• Euphoria (high)
• Sedation (Morpheus)
• Respiratory depression
• Chronic use
– dependence
• Cross placenta
– respiratory depression in newborn.
28
Other mechanisms
• Local anaesthetics (e.g. for use in
dental surgery or epidural
administration during childbirth)
• Other classes of analgesics do not act
through previously mechanisms (e.g.
flupirtine, amitriptyline and gabapentin)
and are not discussed here.
29
WHO analgesic ladder
Discussed further by HNM staff
STEP 3
strong-moderate pain
strong opioid (e.g.
morphone) ±nonopioid ±adjuvant
adjuvant
STEP 2
Mild-moderate pain
Weak opioid (e.g.
codeine) ±nonopioid ±adjuvant
adjuvant
STEP 1
Mild pain
Non-opioid
(e.g. paracetamol,
aspirin or other
NSAIDs) ±adjuvant
Modified from WHO, UWS Staff (2015)
Antibiotics
• Antibacterials (drugs used to treat bacterial infection)
• Bacteriocidal
• Bacteriostatic
Problems
• Selective toxicity (should be toxic to bacteria but not to
patient)
• Resistance (many bacteria now able to survive drug
treatment)
31
Mechanisms of action
1. Inhibition of cell wall synthesis
•Penicillins, cephalosporins
•Prevent cell wall formation as cells divide
•Drug activity relies on a β-lactam ring
•Some bacteria produce an enzyme β-lactamase 
antibiotic resistant
•Side effect - allergy!
Vaccinationist (2013)
https://commons.wikimedia.org/wiki/File:Hetacillin_structure.svg
32
Mechanisms of action
2. Inhibition of DNA or protein synthesis
• Prevent bacteria dividing
• Cells cannot synthesise essential components
transcription
DNA
translation
mRNA
protein
UWS Staff (2015)
Author: Kendrick Johnson
https://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png
Wiki commons
Antibiotic mechanisms
34
Other drug mechanisms
Where else do drugs act?
• Ion channels
• local anaesthetics (block sodium channels)
• Transport molecules
• antidepressants (block neurotransmitter transport)
• Enzymes
– ACE (protease) inhibitor - hypertension
• Nucleic acid interference
e.g. DNA replication blocked
• anti-cancer (chemotherapy) drugs, as well as antibiotics
Drug Interactions
• People often take more than one drug
• Different drugs may interact causing changes in
their activity
– Interactions may affect pharmacokinetics (absorption,
distribution, metabolism, excretion)
– Interactions may affect pharmacodynamics - drugs effects
on the body
• Beneficial interactions
– e.g. cytotoxic ‘cocktail’ for cancer chemotherapy
• Adverse interactions
36
Adverse drug interaction
e.g. sulphonamides and warfarin
• Interactions in plasma changing protein (albumin) binding
• Albumin binding creates drug ‘reservoir’
• Interaction ↑ free warfarin to dangerous levels
UWS Staff (2015)
Sources of Information
• Pharmacology
textbooks
• British National
Formulary
www.bnf.org
38