Topic 10 - Pharmacology Flashcards
What is pharmacology?
The branch of medicine concerned with the uses, effects, and modes of action of drugs.
What are pharmacodynamics?
Specific to drug or drug class:
- interaction with cellular component
- concentration-effect relationship
- modification of disease progression
What are pharmacokinetics?
Non-specific, general processes:
- absorption from the site of administration
- time to onset of effect
- elimination from the body
What is the generic drug name?
Approved or official name
What is the trade/brand name of a drug?
‘Proprietary’ name is given to a drug by its
pharmaceutical producer
What is the chemical name of a drug?
Each drug has its own chemical structure
and given an appropriate chemical name
What is the use name of a drug?
Commonly drugs are categorised according
to the use for which they are prescribed
e.g. anti-hypertensives, contraceptives,
anti-inflammatories
What is the effect name of a drug?
For some drugs, the categorisation relates
to the physiological or biological response
in the body
What are the advantages of the oral route of administration?
Convenient, safe, economical
What are the disadvantages of the oral route of administration?
Cannot be used for drugs
inactivated by 1st pass metabolism
or that irritate the gut
What are the advantages of the intramuscular route of administration?
-Suitable for suspensions and oily vehicle
-Rapid absorption from solutions
-Slow and sustained absorption from
suspensions
What are the disadvantages of the intramuscular route of administration?
- May be painful
- May cause bleeding at site of injection
What are the advantages of the subcutaneous route of administration?
Suitable for suspensions and pellets
What are the disadvantages of the subcutaneous route of administration?
- Cannot be used to deliver large volumes of fluid
- Cannot be used for drugs that irritate cutaneous tissue
What are the advantages of the intravenous route of administration?
- Bypasses absorption yielding immediate effect
- 100% immediate bioavailability
What are the disadvantages of the intravenous route of administration?
Poses more risk for toxicity
What are the advantages of the buccal route of administration?
- Rapidly absorbed
- Avoids 1st pass metabolism
What are the disadvantages of the buccal route of administration?
- Effective only for low doses
- Drugs must be water and lipid soluble
What are the advantages of the transdermal route of administration?
Avoids 1st pass metabolism
What are the disadvantages of the transdermal route of administration?
Effective only for low doses of drug that
are highly lipid soluble
What are the advantages of the inhalational route of administration?
Produce a localised effect
What are the disadvantages of the inhalational route of administration?
- Drug particles must be correct size
- Dependent on patient technique
What are the advantages of the intrathecal route of administration?
Local and rapid effects
What are the disadvantages of the intrathecal route of administration?
- Requires expert administration
- May introduce infection/toxicity
What are the advantages of the epidural route of administration?
Provides a targeted effect
What are the disadvantages of the epidural route of administration?
- Risk of failure
- Risk of infection
What are the advantages of the topical route of administration?
Non-invasive and easy to
administer
What are the disadvantages of the topical route of administration?
-Poorly lipid soluble not absorbed via skin
or mucous membranes
-Very slow absorption
What are the advantages of using modified dose forms?
✓ Improved patient adherence
✓ Reduction in incidence and severity of GIT effects
✓ Improved control over
therapeutic plasma concentrations
✓ Improved treatment of chronic conditions in which steady plasma concentration required
✓ Maintenance of therapeutic action overnight
✓ Minimise adverse effects
associated with high plasma
concentrations
What are the disadvantages of using modified dose forms?
-Cost more per unit dose than conventional forms
-Possibility of unsafe over
dosage if used incorrectly or in failure of MR tablet
-Rate of transit through GIT
limits the maximum period
for which a therapeutic
response can be maintained
-Variability in physiological
factors e.g. GIT pH, enzymes,
food etc influence drug
bioavailability
What can an incorrect route of administration result in?
Adverse patient outcomes including death
What is ADME?
Absorption
Distribution
Metabolism
Excretion
What is absorption of a drug?
Transfer of the drug from the site of administration into
the general or systemic circulation
How much of an orally administered drug is absorbed in 1/3 hours?
75%
What are the factors affecting oral absorption?
- Particle size and formulation
- GIT Enzymes/Acid
- GIT motility
- Physicochemical factors
- Food
What is drug distribution?
The process by which the drug is transferred reversibly
How does drug distribution generally occur?
Passive diffusion of un-ionised form across the cell membrane.
What is the volume of drug distribution?
The size of a compartment which will account for the total amount
of drug in the body based on the amount in the plasma at time zero.
What is the volume of distribution used for?
- To determine the loading dose necessary for a desired blood concentration of a drug.
- Estimating a blood concentration in the treatment of an overdose
What are the factors affecting drug distribution?
- Plasma protein binding
- Specific drug receptor sites in tissues
- Regional blood flow
- Lipid solubility
- Disease
What is perfusion?
The passage of fluid through the circulatory system or lymphatic system to an organ or a tissue
What are some examples of albumin bound drugs?
- Furosemide
- Ibuprofen
- Phenytoin
- Thiazides
- Warfarin
What are some examples of glycoprotein bound drugs?
- Chlorpromazine
- Propranolol
- Tricyclic antidepressants
- Lidocaine
When are changes in protein binding significant for drugs?
When the drug is more than 90% bound to plasma proteins
When a drug is 20% bound to plasma proteins?
Reduction of 5% in bound drug
• Unbound plasma concentration increases from 80% to 85% (negligible)
When a drug is 95% bound to plasma proteins?
- Reduction of 5% in bound drug
* Unbound plasma concentration increases from 5% to 10% (significant)
What are the factors which can increase the fraction rate of unbound drug?
-Renal impairment due to rise in blood urea
-Low plasma albumin levels
-Late pregnancy
-Displacement from binding site by other drugs
-Saturability of plasma protein binding within
therapeutic range
How thick is the phospholipid bilayer?
About 10nm
What are the four aspects of 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
What are the factors which affect drug metabolism?
- First pass effect
- Hepatic blood flow
- Liver disease
- Genetic factors
- Other drugs
- Age
What is first pass metabolism?
A phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. Occurs prior to and during absorption.
What are the 4 major metabolic barriers drugs have to pass before they reach general circulation?
- Intestinal lumen
- Intestinal wall
- Liver
- Lung
How does the intestinal lumen act as a metabolic barrier to drugs?
- Digestive enzyme secreted by the mucosal cells and pancreas
- Certain enzymes break down proteins and stop them from being absorbed
How does the intestinal wall act as a metabolic barrier to drugs?
Rich in enzymes that further metabolise drugs
How does the liver act as a metabolic barrier to drugs?
Major site of drug metabolism
How does the lung act as a metabolic barrier to drugs?
Cells of the lung have high affinity for many drugs and are the Lung site of metabolism for many local hormones
What are the phases of metabolism?
- Lipophilic drug reacts (oxidation, reduction, hydrolysis).
- Forms more reactive drug, which then reacts again
- Forms hydrophilic drug
- Excreted by kidneys
What are isoenzymes?
Each of two or more enzymes with identical function but different structure.
What are enzyme inducers?
- Enhance production of liver enzymes which breakdown drugs
- Faster rate of drug breakdown
What are enzyme inhibitors?
- Inhibit production of enzymes which breakdown drugs
- Reduced rate of drug breakdown
What is the metabolism of paracetamol?
Paracetamol, conjugation -> paracetamol glucuronide, paracetamol sulphate
Paracetamol, oxidation -> N-acetyl-p-benzoquinoneimine (NAPQI)
NAPQI + glutathione -> cysteine/mercapturate derivatives
What is a possible toxic metabolite of paracetamol?
N-acetyl-p-benzoquine imine
What is bioavailability?
The proportion of a dose which actually gets into the systemic circulation
What is bioequivalence?
It means that two or more chemically or pharmaceutically equivalent products produce comparable
bioavailability characterises
What is clearance?
The measure of the removal of drug from the body
or the volume of plasma completely emptied of drug per unit time. 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.
What is drug half life?
Time taken for the concentration to reduce by half
What is the half-life of a drug 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
What does drug elimination via the liver depend on?
- blood flow to the liver
- activity of the enzymes in the liver
- liver enzymes will alter the drug to form metabolites which are inactive, active or more potent than the drug
What are the steps of elimination via the kidney?
- Filtration
- Reabsorption
- Secretion
- Excretion
How is renal function evaluated?
Estimation of creatinine clearance, estimates clearance of drugs filtered at the glomerulus.
(Creatinine is produced in skeletal muscle excreted by the kidneys. Neither passively reabsorbed or actively excreted)
What is the cockroft gault equation?
-Estimated creatinine clearance
Serum Creatinine
How is absorption affected in children?
Unreliable in neonates and greater transcutaneous absorption
How is absorption affected in the elderly?
In general unchanged
How is distribution affected in children and the elderly?
Fat components of body mass tends to be proportionately greater,
acting as a reservoir
How is metabolism of drugs affected in children?
Reduced capacity due to
immature liver in infants – drug effects prolonged or excessive
How is metabolism of drugs affected in the elderly?
Slight reduction due to impaired liver function, so drug effects more pronounced and longer lasting
How is excretion of drugs affected in children?
Reduce capacity due to immature kidneys in infants
How is excretion of drugs affected in the elderly?
Reduction due to impaired
glomerular filtration rate
What are the general mechanisms of drug action?
- Action on receptors
- Action on synapses
- Enzyme action
- Inhibit cell transport
What is an agonist?
Drug that binds to receptors and initiates a cellular
response.
-high affinity and efficacy
What are partial agonists?
Act on the same receptor but do not produce the same maximal response
What are inverse agonists?
Acts on the same receptor but produces an opposite effect
What is an antagonist?
Drug that binds to receptors but does not initiate a cellular response.
-affinity but no efficacy
What is a competitive antagonist?
Binds to the same site as the agonist but does not activate it
What is a non-competitive antagonist?
Binds to an allosteric site
to prevent activation of the receptor
What is affinity?
The degree to which a substance tends to combine with another
What is efficacy?
The ability to produce a desired or intended result
What are receptors?
Macromolecules involved in the chemical signalling between and within cells.
Cell activity changes once stimulated.
What is potency?
Dose of drug needed to produce a biological effect
What are the 4 receptor families?
- Ligand-gated ion channels
- G-protein coupled receptors
- Enzume-linked receptors
- Intracellular receptors
What are ligand-gated ion channels?
A group of transmembrane ion channel proteins which open to allow ions to pass through the membrane in response to the binding of a ligand such as a neurotransmitter.
What are some examples of ligand-gated ion channels?
- Glutamate
- Serotonin
- Dopmaine
- Acetylcholine
What are G-protein-coupled receptors?
These receptors are linked to their responses by regulatory Guanosine Triphosphate (GTP)-binding proteins or G proteins. This complex induces conformational change in the G-protein.
What is the use of second messengers?
To allow signals in conduction to be amplifies
What are two examples of enzymes that produce second messengers?
- Adenyl cylase (involved in activation of protein kinase)
- Phospholipase C (involved in production of inositol truphosphate (IPS3)and diacyglycerol (DAG))
How is gastric acid secretion stimulated?
- Histamine
- Acetylcholine
- Gastrin
What does the activation of H2 receptors potentiate?
Gastrin induced acid secretion
Enhances cAMP
What are receptor kinases?
-Activate cascades of intracellular signals
-Most are receptor tyrosine-kinases and are activated by
growth factors
What are nuclear receptors?
- The receptor is entirely intracellular
- Ligand must be lipid soluble
- Primary targets are transcription factors
What is the function of acetylcholine?
Enables muscle action,
learning and memory
What problems are caused by imbalance of acetylcholine?
Low levels – Alzheimer’s disease
What is the function of noradrenaline?
Helps control alertness,
mood. Increases heart rate
What problems are caused by imbalance of noradrenaline?
Low level – depression
High levels - insomnia
What is the function of dopamine?
Influences movement,
attention and emotion
What problems are caused by imbalance of dopamine?
Low levels – Parkinson’s disease
High levels – Schizophrenia
What is the function of GABA?
Major inhibitory neurotransmitter
What problems are caused by imbalance of GABA?
Low levels - anxiety
What is GABA?
Gamma Amino Butyric Acid
What is the function of GABA?
Affects sleep, mood,
hunger and arousal
What problems are caused by imbalance of GABA?
Low levels – depression
How so SSRIs work?
Block the reuptake of serotonin
How do TCAs work?
Block the reuptake of both serotonin and noradrenaline
What is the lock and key concept?
Enzyme and substrate bind temporarily to form enzyme-substrate complex
What are NSAIDs?
Non-Steroidal Anti-Inflammatory Drugs
eg. Ibuprofen, Aspirin
What does Cox1 (constitutional) result in?
-Cytoprotective prostaglandins
(Protect gastric mucosa, Protect renal perfusion)
-Thromboxanes
(Aid platelet aggregation)
What does Cox2 (inducible) result in?
-Inflammatory prostaglandins
Recruit inflammatory cells (inflammation, vasodilation), Sensitise skin pain receptors (pain)
What are ACE inhibitors?
Angiotensin Converting Enzymes
inhibit enzymes
What are some examples of Calcium Channel Blockers?
- Amlodipine
- Diltiazem
- Verapamil
How do calcium channel blockers work?
Bind to calcium channels on smooth muscles, blocking the influx of calcium causes smooth muscle relaxation and decreased heart rate
What are the 3 classes of CCBs?
- Dihydropyridines
- Phenylalkylamine
- Benzothiazepine
What are Dihydropyridines selective against?
Most smooth muscle selective
What are selective Phenylalkylamines against?
Selective to myocardium and less effective as
a vasodilator
What are selective Benzothiazepines against?
Has both cardiac depressant and vasodilator
actions
What is the general structure of local anaesthetics?
-A lipid-soluble
hydrophobic aromatic group and a charged, hydrophilic
amine group.
-The bond between these two groups determines the class of the drug, and may be amide or ester.
What are some examples of amide local anaesthetics?
- Lignocaine
- Bupivacaine
- Prilocaine
What are some examples of ester local anaesthetics?
- Cocaine
- Amethocaine
How are amides as local anaesthetics?
Relatively stable and hypersensitivity reactions
are rare
How are esters as local anaesthetics?
Rapidly hydrolysed and the breakdown product
PABA (para amino benzoic acid) is associated
with allergic and hypersensitive reactions
Which is more easily broken: ester linkage or amide bond?
Ester linkage (meaning ester drugs cannot be stored for as long as amides)
How do local anaesthetics work?
Disrupt ion channel function within the neurone cell
membrane preventing the transmission of the neuronal action potential.
What are adverse effects associated with local anaesthetics?
-Block sodium channels in the conduction system of the heart. This can cause
myocardial depression and vasodilatation.
-Affect the CNS. Stimulation
causes restlessness and at high doses, convulsions.
-Addition of adrenaline causes constriction of peripheral
blood vessels, lessening the distribution, prolonging
action and producing a relatively bloodless field.
How are esters (except cocaine) broken down?
Rapidly by plasma
esterases to inactive compounds and consequently have a
short half life.
How are amides broken down?
Metabolised hepatically by amidases. This is a
slower process, hence their half-life is longer and they can accumulate if given in repeated doses or by infusion.
How is prilocaine metabolised?
Extra-hepatically
What is the ceiling in drug concentration?
Lowest dose that
produces maximal effect
What is the threshold in drug concentration?
Dose that produces a
just-noticeable effect
What is the ED50 in drug concentration?
Dose that produces
50% of maximum response
