Pharmacology- Introduction to Clinical Sciences Flashcards
What is pharmacology
Pharmacology is the study of medications, or chemical compounds, which interact with various living systems, from tiny molecules to cells, to tissues and whole organisms, in order to produce a certain effect.
What are the steps involved in drug development?
Step 1 is discovery
Step 2 is preclinical research
Step 3 is clinical development
What is referred to as discovery within drug development
when a candidate compound is picked out as a possible therapeutic agent for a specific disease
What is referred to as preclinical research within drug development
When the compound is tested on cell cultures and animals, like mice and rats, mainly to see if it causes any serious harm to live organisms.
What is referred to as clinical development within drug development
Clinical trials are performed.
Tthe compound is tested on humans to see if it’s safe and effective in treating diseases.
What are the 4 phases of clinical Trials
Safety, Efficacy, Approval, and Long term
Remember “All medications need the SEAL of approval,”
What is involved in phase 1 of clinical trials
Phase I trials test the medication in a small group of healthy individuals to see if it’s Safe for humans.
What is involved in phase 2 of clinical trials
Phase II trials aim to discover more about how effective the medication is or how well it works at a certain dose. This is done by testing it on a moderately sized group of individuals affected by the condition in question
What is involved in phase 3 of clinical trials
In phase III trials, the new medication is compared to the standard treatment to find out if it’s actually just as good as or even better than the existing one. Phase III trials generally involve a much larger number of individuals. They aim to replicate the exact setting in which the medication will be administered in real life, which will then be used as the basis for Approval by regulatory organizations for the market.
What are the three names of a new medication
- Chemical: (describing the chemical structure and used in scientific studies)
- Generic (shortened version in chemical names and used by health professionals)
- Brand/Trade (given by pharmaceutical companies that make the medication)
What is involved in phase 4 of clinical trials
final phase of safety surveillance that looks for Long term or rare side effects that might have been missed. If it’s found to be unsafe, a recall and ban might be needed.
Define pharmacokinetics
Refers to the movement and modification of the medication inside the body.
In other words, it’s what the body does to this medication.
What happens once the medication is administered regarding pharmacokinetics (ADME)
- Absorption: Absorbed into circulation
- Distribution: Distributed to various tissue
- Metabolism: Metabolised or broken down
- Excretion: eliminated or excreted in urine or faeces
Define pharmacodynamics
What the medication does to the body
What happens once the medication is administered regarding pharmacodynamics
Binds to receptors or specialised proteins: surface or inside the cell
It gives rise to a signal cascade resulting in some change in the cell’s function (boosting the production of a particular type of protein or slowing down DNA replication)
What is an ideal medication
produces a single beneficial or therapeutic effect for a certain disease state
In reality, most medications produce several unwanted effects (side effects), like nausea or fatigue.
What is the therapeutic index
the ratio between the toxic dose and effective dose of a given medication
The larger the therapeutic index, the safer a medication is considered to be.
How do you calculate the therapeutic index
What does it mean if medications have a low therapeutic index
Narrow margin of safety
Require close monitoring of serum levels
Examples of medications with a low therapeutic index
warfarin
lithium
digoxin
gentamicin
phenytoin
theophylline,
What are drug-drug interactions
When 2 medications are administered together
What can happen when two drugs are administered together?
Pharmacokinetic interactions: 1 medication can alter the absorption, distribution, metabolism or excretion of another. This changes the amount available to produce the desired effect.
Pharmacodynamic interactions: medications influence each other’s effects directly e.g both increase bp
Define enzymes
Proteins that play a major role in biochemical reactions
Act as a catalyst
What is an enzyme inhibitor
a molecule that binds to an enzyme and decreases its activity. It prevents the substrate from entering the enzyme’s active site and prevents it from catalysing its reaction.
Difference between irreversible and reversible inhibitor
Irreversible inhibitors – react with the enzyme and change it chemically (e.g. via covalent bond formation)
Reversible inhibitors – bind non-covalently, and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both.
What is non-competitive inhibition?
When the inhibitory molecule binds irreversibly to the enzyme’s active site or reversibly to a different place called the allosteric site.
The net effect is that substrates can no longer bind to the active site, and it is as if the number of available enzymes has decreased.
What is competitive inhibition
can be used to decrease the affinity of the enzyme
binds to the active site instead of the substrate and usually doesn’t get metabolized - blocking the enzyme.
Since this is a reversible process, adding more substrate makes it possible to eventually outcompete and displace the inhibitor.
What do drug target?
receptors
ion channels
enzymes
transporters
What are receptors?
a component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects
Where are intracellular receptors located
cytoplasm or nucleus of the cell
What do intracellular receptors recognise
small, hydrophobic ligands
e.g steroids that diffuse across a phospholipid membrane
Wha happens once intracellular receptors are bound to ligand
Receptor-ligand complex attaches to specific DNA sequences that activate or inhibit specific genes.
What are cell-surface receptors
Receptors embedded into plasma membrane and bind to ligands too large or hydrophillic
What are the 3 main types of cell surface receptors?
- Ligand-gated ion channels
- G-coupled protein receptor
- Kinase-linked receptor
- Cytosolic/nuclear receptors
What are the three different protein ports
- Uniporters – use energy from ATP to pull molecules in
- Symporters – use the movement in of one molecule to pull in another molecule against a concentration gradient
- Antiporters – one substance moves against its gradient, using energy from the second substance (mostly Na+, K+ or H+) moving down its gradient
Ion channel examples
- Epithelial (sodium) – heart failure
- Voltage-gated (calcium, sodium) – nerve, arrhythmia
- Metabolic (potassium) – diabetes
- Receptor activated (chloride) – epilepsy
What are kinase-linked receptors?
Receptors for growth factors
What are cytosolic/nuclear receptors
Steroid receptors
When do ligand-gated ion channels open up?
Once bound to a specific ligand
ions: chloride, calcium, sodium, potassium passively flow into the cell, down their gradient, and trigger the signalling pathway
What end of the G coupled protein does the ligand bind to?
End sitting outside cell
What subunit is present within the G protein-coupled receptor (inside the cell), and what is it bound to?
Alpha subunit bound to GDP
What happens when a ligand binds to G protein-coupled receptor
G protein changes shape, causing the alpha subunit to release the GDP, allowing GTP to bind.
This causes the alpha subunit to detach and trigger other proteins in the signalling pathway.
Why do medications cause side effects?
Because no drug is 100% specific meaning, it could also bind to other receptors that are similar to its intended target,
What are the two main principles of how medication and receptors interact?
affinity
intrinsic activity
Define affinity
How strongly a medication binds to its receptor
The higher the affinity, the higher the potency (amount of medication needed to elicit an effect)
Define intrinsic ability
Ability to activate receptor once the medication is bound to that receptor
Define efficacy
the maximal effect the medication can produce
Describe a dose-response curve
Amount of medication given (x-axis)
The response produced (y-axis)
Define specificity
Specificity refers to a medications tendency to bind to a specific type of receptor.
Generally, a medication with a better affinity for its receptor, has a higher ..
Potency
After the medication binds to a receptor, its ability to activate the receptor is called its
intrinsic activity
When is maximum efficacy achieved
When the dosage is high enough, all available medication receptors are occupied.
What are the two major categories explaining the effect a medication has on its receptor
agonists and antagonists
Define agonist
a compound that binds to a receptor and activates it
(it essentially mimics the action of the signal ligand by binding to and activating a receptor)
Define antagonist
a compound that reduces the effect of an agonist
Agonists have _____ and ______, but antagonists have ______ and ZERO _____-
Affinity
Efficacy
affinity
Efficacy
Define signal transduction
A basic process involving the conversion of a signal from outside the cell to a functional change within the cell.
Define signal amplification
to increase the strength of a signal
What is allosteric modulation
When an allosteric ligand binds to a different site on the molecule and prevents the signal from being transmitted
Define ligand
A molecule that binds to another (usually larger) molecule
Typically binds to a receptor without activating them, but instead, decreases the receptor’s ability to be activated by another agonist.
What is the maximum effect an agonist (EMax) can produce
Determined by the no. receptors bound to an agonist (depending on dose)
Intrinsic ability
How can antagonists be further subdivided
competitive antagonists
non-competitive antagonists
What is a competitive antagonist?
Medication that reversibly binds to the same receptor site where an agonist binds but it does not activate it
The inhibition caused can be overcome when there are more ligands
How do competitive antagonists affect agonists
Decrease agonist potency
Do not affect agonist efficacy
What are non-competitive antagonists
Bind to the allosteric site, causing the shape or receptor to change so that ligand can no longer recognise it as a bonding site.
Irreversible change or dissociates very slowly
How do non-competitive antagonists affect agonists
Decrease agonist efficacy
Do not affect agonist potency
Difference between full agonists and partial agonists
Full agonists: produce a maximal response
Partial agonists: produce submaximal response
What happens when there is persistent flooding of receptors with the same agonist at the same dose
The ability of the agonist to produce that response drops
Acts as a defence mechanism preventing overstimulation of agonists
Desensitisation vs tolerance
Desensitisation or tachyphylaxis
-happens rapidly
-can occur with an initial dose
Tolerance
-happens more gradually
-typically happens with repeated doses
Mechanisms of desensitisation and tolerance
Drug administration
swallowed by the mouth or orally
injected into a vein or intravenously
injected into a muscle or intramuscularly
inhaled into the lungs
sprayed into the nose or nasally
applied onto the skin or cutaneously
What is absorption
process of moving the medication from the site of administration into the circulation
will need to cross one or more cell membranes before it reaches the circulation except intravenously
How can molecules move across cell membrane
Passive transport: Subdivided into facilitated and passive diffusion
Active transport
Endocytosis
What does facilitated diffusion transport
Larger, water-soluble, and polar medications move across the membrane through transport proteins like channels and carrier proteins.
What does passive diffusion transport
small, lipid-soluble, and nonpolar medications move across the membrane, from an area of high concentration to low concentration
What is active transport
medication is transported against their concentration gradient
involves specific carrier proteins that use ATP as a fuel to pump medications into the cell
What is endocytosis
The cell membrane invaginates and swallows up the medication forming vesicles
What is the rate of absorption vs extent of absorption
How quick
How much
What does the rate/extent of absorption depend on?
pH of environment
Surface area available
Blood supply to the absorption site
Presence of food or other material in GI tract
Where is weakly acidic medication better absorbed?
Better in an acidic environment in the proximal duodenum
Where is weakly basic medication better absorbed
Better in an alkaline environment in the distal ileum
What happens when a medication is taken in by mouth
Absorbed through the small intestine’s walls and transported into the liver via the portal vein.
Once in the liver, hepatic enzymes work on the medication to metabolize it (first-pass metabolism or first-pass effect)
Enters circulation
What are the four major metabolic barriers when drugs are taken orally
Intestinal lumen
Intestinal wall
Liver
Lungs
What are the problems with the oral administration of drugs?
Undergo extensive first-pass metabolism - concentration in the bloodstream decreases, meaning once the site of action is reached won’t produce desired effect.
How can you bypass the first- pass effect
Offer alternate routes of administration as medications go straight into systemic circulation
Pros and Cons of Intradermal and subcutaneous absorption
Pros:
* Avoids barrier of stratum corneum
* Small volume can be given
* Use for local effect or to deliberately limit the rate of absorption
Con:
* Mainly limited by blood flow
What does intramuscular absorption depend on
blood flow and water solubility
Limitations of inhalational absorption
- Large SA and blood flow but limited by risks of toxicity to alveoli and delivery of non-volatile drugs
- Largely restricted to volatiles such as general anaesthetics and locally acting drugs such as bronchodilators in asthma
Why are asthma drugs given as a powder or aerosol
Because its non-volatile
What is a common reversible binding
With plasma protein albumin
What drugs can pass from blood to brain easily
Lipid soluble
How are drugs removed from the brain?
by diffusion into plasma
active transport in the choroid plexus
elimination in the CSF
What does and does not cross the placenta
Large molecules do not cross
Lipid soluble drugs cross
- Foetal liver has low levels of drug-metabolizing enzymes, so relies on maternal elimination
Define bioavailability
Bioavailability or F is actually the fraction of an orally administered medication that eventually reaches the circulation in the unchanged form
What is the bioavailability of intravenously administered drugs?
1 or 100%
What is the bioavailability of an oral medication
Define distribution
movement of a medication from the circulation into the body tissues
What do the rate and extent of distribution depend on
Blood supply
Size and polarity
Degree of plasma protein binding
The apparent volume of distribution
What is drug ionisation
The basic property of most drugs that are either weak acids or weak bases
Essential for the mechanism of action of most drugs as ionic forces are part of the ligand-receptor interaction
Ionized form is regarded as the most water soluble, and un-ionised as lipid-soluble
What is the apparent volume of distribution (Vd)
the hypothetical volume that accommodates all of the medication in the body, if the concentration throughout was the same as in plasma
We assume that the medication is distributed evenly throughout the body
How to calculate Vd
What is metabolism
Process of converting a medication into a less or more active form. These forms are also known as metabolites
What is a prodrug
Medication that needs to be metabolised into an active form within the body before it can produce the desired effect.
Where do the phases of drug metabolism occur
Mainly in the liver
It might occur in the lungs, kidneys, and small intestine walls but to a much lesser extent
Which enzyme carries out a Phase 1 reaction in the hepatocyte
CYP450
Where can you find CYP450 enzyme?
endoplasmic reticulum
mitochondria.
What do the enzymes CYP… do?
Converts non-polar, lipid-soluble medications into more polar, water-soluble metabolites via oxidation, hydrolysis or reduction
What are Phase 2 reactions
Conjugation reactions - when medications or metabolites are joined with another compound: methyl/acetyl/sulfa/glutathione/glucuronic acid.
These reactions create highly polar, water-soluble metabolites that cannot diffuse through cell membranes very easily, so they are trapped in the urine and eliminated by the kidneys
Variability in the rate of metabolic reactions
Genes
Age
Liver disease
Medications
Foods & Supplements
Define elimination
Removal of medication from body
Done by either metabolism or excretion
Mostly through urination
How can medications be filtered within the kidney
- Filtered through the glomerulus
- Through the proximal convoluted tubule, it gets secreted into the tubular lumen
- Travels towards the distal convoluted tubule
How do polar (water soluble) medications get filtered in the proximal convoluted tubule of the kidney
Active secretion in the proximal convoluted tubule
How do non-polar (lipid soluble) medications get filtered in the proximal convoluted tubule of the kidney
Passive diffusion in the proximal convoluted tubule
How do non-polar (lipid soluble) medications get filtered in the distal convoluted tubule of the kidney
Can passively diffuse back into the peritubular circulation
How do polar (water soluble) medications get filtered in the distal convoluted tubule of the kidney
Get trapped inside the tubular fluid
What property of urine affects the elimination
Acidity (pH)
Chemical properties of medication
Aside from kidneys, where can the excretion of medications take place
Bile: absorbed in the GI tract, enter the enterohepatic circulation and leave through faeces
Faeces: Not absorbed from the GI tract and directly passed into the faeces
Exhaled air: inhaled anaesthetics eliminated by the lungs
Also: Breast milk, sweat, saliva, tears
What is clearance (CL)
Volume of plasma cleared of a medication per unit of time
What is total clearance?
Sum of various clearance routes
What is the rate of elimination determined by
Elimination kinetics:
Most eliminated through first-order kinetics
What is first-order kinetics?
Rate of elimination is directly proportional to the concentration of that medication in the body.
What is first-order kinetics?
Rate of elimination is directly proportional to the concentration of that medication in the body.
What does first-order kinetics also show us?
Half-life = Time required for the plasma conc of the medication to be reduced by half
- T1/2 = 0.693k (0.693=In2)
Which medication gets eliminated through zero-order kinetics
phenytoin
warfarin
aspirin.
the absolute amount, or milligrams eliminated per unit of time stays the same, but the fraction eliminated changes
What are the routes of administration
Enteral
Parenteral
Topical
What is the most common form of medication being administered?
Enteral administration (medication administered through the GI tract)
E.g
peroral administration (mouth)
sublingual administration (under tongue)
buccal administration (between gums and inner lining of cheeks)
rectal administration (rectum)
What is parenteral administration
Bypasses GI tract (pump medication directly into circulation)
Intravenously
Subcutaneously
Intramuscularly
What is topical administration
Medication is applied directly upon a particular area of the skin or mucous membrane to achieve a local effect
e.g. antifungal creams to treat athlete’s foot.
Choosing the route of administration depends on
Chemical properties (stability, ability to cross barriers of absorption)
Urgency of situation
What properties of a perorally administered medication need to have
Resist tough, acidic conditions within the stomach
Readily pass through the walls of the intestines into the blood.
What are the benefits of IV administration
Allows medications that are less stable to be directly administered into the bloodstream
Medication that has a major first-pass effect can be directly administered into the bloodstream.
Peroral medications
Take less time to get absorbed in the GI tract
Effect is much slower than IV
Easier to take at home
What form of drug administration is preferred in emergency situations and surgical procedures?
IV administration
What is the dosing regimen
Determines the frequency of administration (dosing interval) and the amount administered (dose)
What does the dose regimen affect?
The onset of action: time it takes for the medication to start working and produce an effect
Duration of action: total length of time medication produces and effect
What are the three main types of dosing
Single dosing
Continuous infusion
Intermittent dosing regimen
What is single dosing
Only one dose of a medication is administered
What is a continuous infusion?
Medication is infused intravenously at a constant rate
How is the steady state of medication determined in continuous infusion
By half-life (time needed for plasma conc to be reduced by 50%)
4-5 half-lives to reach a steady state
What is the maintenance dose for a continuous infusion regimen
The dose required to maintain a steady state
What is an intermittent dosing regimen?
A certain dose of medication is administered at regular time intervals
How is the maintenance dose calculated for an intermittent dosing regimen
What is the loading dose and, when is it given, how is it calculated
The large dose is given at the beginning of a treatment course to rapidly reach the peak plasma concentration.
Given in life-threatening situations or medications with long half-lives
The loading dose is then dropped to lower maintenance doses, maintaining the steady-state plasma concentration.
What do maintenance dose and loading dose depend on?
Clearance rate
Bioavailability
Volume of distribution
Define druggability
The ability of a protein target to bind small molecules with high affinity (sometimes called ligandability).
Define stereoisomers
have the same molecule formula and sequence of bonded atoms, but differ in the 3D orientations of their atoms in space
Drug development
- Medicines from plants
- Inorganic elements
- Organic molecules
- Bacteria/fungi/moulds
- Stereoisomers
- Immunotherapy antibodies: Vaccinations for hep B, influenza, tetanus, mumps
- Medicines from animals
- Gene therapy
Clinical use of recombinant proteins
- Insulin
- Erythropoietin
- Growth hormone
- Interleukin 2
- Gamma interferon
- Interleukin 1 receptor
What is gene therapy
- Gene therapy consists of a recombinant nucleic acid used in or administered to a human being to regulate, replace, add or delete a genetic sequence
- Its effect relates directly to the recombinant nucleic acid sequence it contains or to the product of the genetic expression of this sequence
What is the rational drug design, and what does it consist of?
Process of finding new medications based on the knowledge of a biological target.
-The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule
-Involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and, therefore, will bind to it
-Relies on the knowledge of the 3D structure of the biomolecular target – structure-based drug design
Define inverse agonist
a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist
Define selectivity
the degree to which a dose of a drug produces the desired effect in relation to adverse effects
What are the different types of drug interactions
Synergetic (1+1>2)
Antagonistic (1+1=0)
Summation (1+1=1)
Potentiation (1+1=1+1.5)
Define synergy
interaction of drugs such that the total effect is greater than the sum of the individual effects (1+1>2)
What is antagonism
an antagonist is a substance that acts against and blocks an action (2 drugs opposed to each other) (1+1=0)
What is summation
different drugs used together to have the same effect as a single drug would (1+1=1)
What is potentiation
enhancement of one drug by another so that the combined effect is greater than the sum of each one alone (1+1=1+1.5)
What are the risk factors for drug interactions
- Narrow therapeutic index
- Steep dose/response curve
- Saturable metabolism
Define drugs
a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body
What are some proteins that drugs target
- Receptors
- Enzymes
- Transporters
- Ion channels
Name an example of an exogenous receptor.
Drugs (extrinsic)
Name an example of an endogenous receptor.
hormones, neurotransmitters (intrinsic)
What are some of the ways by which chemicals communicate via receptors
neurotransmitters (acetylcholine, serotonin)
autacoids (cytokines, histamine)
hormones (testosteragonistone, hydrocortisone).
List some imbalances of chemicals in the body
- Allergy: increased histamine
- Parkinson’s: reduced dopamine
List some imbalances of receptors in the body
- Myasthenia gravis: loss of ACh receptors
- Mastocytosis: increased c-kit receptor
How are cholinergic receptors activated
When they bind to the neurotransmitter acetylcholine (Ach)
What are the subtypes of cholinergic receptors
Nicotinic
Muscarinic
How can the nervous system be subdivided
What composes the autonomic nervous system relay
Includes 2 neurons:
-preganglionic neurons (cell bodies in nuclei throughout the spinal cord)
-postganglionic neurons (cell bodies in ganglia out of the spinal cord)
What do preganglionic neurons in the sympathetic nervous system release? What do they bind to?
Ach
Nicotinic receptors on the cell membrane of postganglionic cell bodies
What do postganglionic neurons in the sympathetic nervous system release? What do they bind to?
Release adrenaline/noradrenaline -> Bind to adrenergic receptors on the plasma membrane of the target organ cells.
Sometimes release Ach -> Bind to muscarinic receptors on the plasma membrane of the target organ cell
What are adrenaline and noradrenaline collectively known as?
Catecholamines
What do postganglionic neurons in the parasympathetic nervous system release? What do they bind to?
Ach -> Muscarinic receptors on the plasma membrane of target organ cells
What do preganglionic neurons in the parasympathetic nervous system release? What do they bind to?
Ach -> Nicotinic receptors on postganglionic cell bodies
What is a neuromuscular junction
The site where a motor neuron axon comes into contact with skeletal muscle fiber
In the somatic nervous system, what neurotransmitter is released and what are the receptors involved
A motor neuron receives electrical impulses from the brain triggering small vesicles containing Ach into the neuromuscular joint.
These bind to nicotinic receptors on skeletal muscle
This causes skeletal muscle contraction
How many main subtypes of muscarinic receptors are there?
5
M1, M2, M3, M4, M5
What kind of receptors are muscarinic receptors
G coupled receptors
Where can you find M1 receptors?
Mainly in brain
Where can you find M2 receptors
Mainly in the heart (their activation slows the heart, so we can block these)
Where can you find M3 receptors
glandular and smooth muscle. (cause bronchoconstriction, sweating, salivary gland secretion
How do adrenergic receptors become activated
When they bind to the neurotransmitter catecholamine
What are catecholamines involved in
Trigger fight or flight response
Stimulate our organs by the sympathetic nervous system
What does the sympathetic nervous system do?
Involved in fight or flight response
Increase heart rate
Increase blood pressure
Decrease digestion
What does the parasympathetic nervous system do?
“rest and digest”
Slows heart rate
Increases digestion
What adrenergic receptors become activated when bound to noradrenaline (norepinephrine)
Alpha 1
Alpha 2
Beta 1
What adrenergic receptors become activated when bound to adrenaline (epinephrine)
Alpha 1 & 2
Beta 1& 2 & 3
List the things that cholinergic and adrenergic pharmacology is responsible for:
- Control of blood pressure: raise it in shock, lower it in hypertension
- Control of heart rate; speed up lethal bradycardias, slow down dangerous tachycardias
- Anaesthetic agents; muscle relaxants
- Regulation of airway tone; treat life-threatening bronchospasm
- Pressures in the eye; prevent glaucoma causing blindness
- Control of GI function; diarrhoea and constipation
Describe parasympathetic ganglia
Short postganglionic nerves,
Long pre-ganglionic nerve
Describe postganglionic ganglia
Short preganglionic nerves,
Long postganglionic nerve
How does anticholinergic drug activity affect the brain and other parts of the body
Brain: worsen memory and may cause confusion
Other parts of the body: constipation, drying of the mouth, blurring of the vision, worsening of glaucoma
Describe the action of alpha agonists
Alpha 1 activators raise blood pressure -> vasoconstrict
Alpha 2 activators lower blood pressure -> vasodilate
Describe the action of beta-agonists
Beta 1 activation will increase heart rate and chronotropic effects and may increase the risk of arrhythmias.
Beta 2 activation is life-saving in asthma and can delay the onset of premature labour
Beta 3 agonists can reduce over-active bladder symptoms.
What do beta blockers do?
Lower blood pressure (reduction in cardiac output reduction in central sympathetic outflow activity),
Reduce cardiac work
Treat arrhythmias
Uses of beta blockers
Angina
MI prevention
High blood pressure
Heart failure
What are the side effects of beta blockers
- Tiredness
- Bronchoconstriction
- Bradycardia
- Cardiac depression
Define potency
whether a drug is ‘strong’ or ‘weak’ relates to how well the drug binds to the receptor, the binding affinity
Define efficacy
the concept of full or partial agonists
Define tolerance
Down-regulation of the receptors with prolonged use. Need higher doses to achieve the same effect
Define dependence
psychological – craving, euphoria
When does opioid withdrawal
starts within 24 hours, lasts about 72 hours
What % of oral morphine is metabolised by the first-pass metabolism
50%
Halve the dose is given IM/IV
What are three controlled drug (CDs) legislation
- Misuse of drugs act 1971
- Opioids - class A drugs
- Practical issues :
- secure storage
- CD books - two signatures needed
How do opioids work?
- Descending inhibition of pain
- Part of the fight or flight response
- Never designed for sustained activation
- Sustained activation leads to tolerance and addiction
Opioids and pharmacodynamics
- Review of pain pathways – opioid drugs simply use the existing pain modulation system
- Natural endorphins and enkephalins
- G protein-coupled receptors – act via second messengers
- Inhibit the release of pain transmitters at the spinal cord and midbrain – and modulate pain perception in higher centres – euphoria – changes the emotional perception of pain
Side effects of opioids (9)
- Opioid receptors exist outside the pain system e.g. digestive tract, the respiratory control centre
- We can sometimes deliver opioids epidurally, but for the most part, we have to give them systemically
- Respiratory depression
- Sedation
- Nausea and vomiting
- Constipation
- Itching
- Immune suppression
- Endocrine effects
What is morphine metabolised into
Morphine is metabolized to morphine 6 glucuronide
What can morphine lead to and why?
- Morphine is metabolized to morphine 6 glucuronide, which is more potent than morphine and is renally excreted. With normal renal function, this is cleared quickly
- In renal failure, it will build up and may cause respiratory depression
When do you have to be careful when administering morphine
- How do you overcome this?
If patients have <30% renal function (creatinine clearance <30).
-Reduce dose and timing interval.
What are the 4 key takeaway points from administering opioids which you have to be made aware of?
- Oral bioavailability – 50% oral morphine
- Titrate the dose to suit the patient
- Potential for respiratory depression
- Potential for addiction – be very careful before starting strong opioids for chronic backache etc.
Define allergy
an abnormal response to harmless foreign material
What are the clinical indications related to allergy (5)
- Epithelial – eczema, itching, reddening
- Excessive mucus production
- Airway constriction
- Abdominal bloating, vomiting, diarrhoea
- Anaphylaxis
What are the cells involved in an allergic reaction
o Mast, eosinophil, lymphocytes, dendritic
o Smooth muscle, fibroblasts, epithelia
What are the mediators involved in an allergic reaction
o Cytokines, chemokines, lipids, small molecules
What kind of reaction is a hypersensitivity type 1-3 reaction
antibody-mediated reaction
What reaction is an allergic reaction
Type 1 hypersensitivity reaction
What does an allergic reaction involve?
Involves recognition of an antigen by primed IgE immunoglobulin on mast cells.
How do plasma cells become primed specifically towards a particular allergen (sensitised towards particular allergen)
Involves first contact or first exposure to a particular benign antigen such as pollen, food, drugs
The antigen is picked up and expressed by APC on the cell surface.
The APC will carry the allergen to nearby lymphoid tissue, where sensitisation begins. APC presents to T helper cell.
T helper cells activate B cells to differentiate into plasma cells via IL-21
IL 4 stimulates the B cells to class switch from IgD to IgE. Causes plasma cells to become IgE-secreting plasma cells primed specifically towards the particular allergen
IgE sits on the receptors of mast cells containing histamine and basophils
When does sensitisation regarding an allergic reaction begin?
When there is an initial exposure to an antigen
What happens to subsequent exposure to an allergen in an allergic reaction (early phase)
Bound IgE on mast cells and basophils will recognise the allergen. The allergen cross-links IgE on mast cells.
This activates cells to degranulate, releasing granules of histamine.
Results in vasodilation and increased vascular permeability causing oedema and erythema to local tissues
Increased vascular permeability allows the extravasation of neutrophils and other acute inflammatory cells.
This all happens within minutes of exposure to the allergen
What happens to subsequent exposure to an allergen in an allergic reaction (late phase)
Occurs hours after exposure to the allergen
Other mediators are synthesised after the cells degranulate
These mediators cause the following :
-increased vascular permeability
-bronchospasm
-attracts eosinophils to tissues immediately
List 5 allergic diseases
- Anaphylaxis
- Allergic asthma
- Contact dermatitis
- Insect venom
- Food allergies
What is anaphylaxis
acute allergic reaction to an antigen to which the body has become hypersensitive
a most severe form of type 1 hypersensitivity
What are some symptoms of anaphylaxis?
Hypotension
Oedema of the lips and neck
Severe bronchoconstriction
Tachycardia
Management of anaphylaxis
- Commence basic life support
- Adrenaline – IM 500µg
- High-flow oxygen
What does adrenaline do once administered regarding anaphylaxis
- Vasoconstriction – increase in peripheral vascular resistance, increased BP and coronary perfusion
- Stimulation of beta1-adrenoceptors positive ionotropic and chronotropic effects on the heart
- Reduces oedema and bronchodilates via beta2-adrenoceptors
What are the clinical criteria for allergy to the drug
It does not correlate with the pharmacological properties of the drug
No linear relation with dose (a tiny dose can cause severe effects)
Reactions similar to those produced by other allergens
The induction period of primary exposure
Disappearance on cessation
Define atopy
immediate hypersensitivity reactions with both an environmental trigger and a strong familial predisposition
What are the potential reasons leading to atopy (4)
- Dysfunction of barrier leading to enhanced antigen exposure
- Increased uptake and presentation
- T-cell dysregulation
- Hyperesponsive to tissue mediators
Define adverse drug reaction
unwanted or harmful reactions following the administration of drugs or combination of drugs under normal conditions of use and is suspected to be related to the drug
Define side effects
an unintended effect of a drug-related to its pharmacological properties and can include unexpected benefits of treatment
What is the severity of adverse drug reactions
- Can be mild e.g. nausea, drowsiness, itching rash
- Can be severe e.g. respiratory depression, neutropenia, catastrophic haemorrhage, anaphylaxis
What is an example of an adverse drug reaction
- Beta-blockers
- Bradycardia and heart block are the primary adverse effects
- Bronchospasm is a secondary pharmacological adverse effect
Adverse drug reactions – Rawlins Thompson classification
Type A – (augmented pharmacological) – predictable, dose-dependent, common
Type B – (bizarre or idiosyncratic) – not predictable and not dose-dependent
Type C – (chronic) – osteoporosis and steroids
Type D – (delayed) – malignancies after
immunosuppression
Type E – (end of treatment) – occurs after abrupt drug withdrawal.
Type F – (failure of therapy) – failure of the oral contraceptive pill in the presence of enzyme inducer
What are the causes of an adverse drug reaction
- Pharmaceutical variation
- Receptor abnormality
- Drug-drug interactions
When do you suspect an adverse drug reaction
- Symptoms soon after a new drug is started
- Symptoms after a dosage increase
- Symptoms disappear when the drug is stopped
- Symptoms reappear when the drug is restarted
Common side effects of an adverse drug reaction
- Confusion
- Nausea
- Balance problems
- Diarrhoea
- Constipation
- Hypotension
What is the Yellow card Scheme
The first ADR reporting scheme
Collects spontaneous reports
Acts as an ‘early warning system’ for the identification of previously unrecognised reactions
Provides information about factors which predispose patients to ADRs
Continual safety monitoring of a product throughout its life span as a therapeutic agent
What are the four critical pieces to include on a yellow card
- Suspected drug
- Suspect reaction
- Patient details
- Reporter details
Mechanism of a paracetamol overdose
Hepatic mechanism to N -acetyl-p-benzoquinone-imine (NAPQI) - highly toxic
In normal doses, NAPQI combines with thiols to produce nontoxic metabolites
In overdose, thiol stores are depleted and NAPQI accumulates
What is the clinical effect of paracetamol (acetaminophen) overdose
hepatic injury and potentially fulminant liver failure
What is the antidote to a paracetamol overdose?
Give N-acetyl-cysteine (NAC)
-Detoxifies and decreases the production of NAPQI
-Very effective when given early -within 8 hours of ingestion
What are anticoagulants and antiplatelet drugs supposed to treat?
Thrombotic disorders or unwanted clots inside a blood vessel leading to a heart attack or stroke
Name a platelet aggregation inhibitor.
Aspirin
