Phase 2 - Pharmacology (ICS) Flashcards
1
Q
Definition of drug
A
A medicine or other substance which has a physiological effect when introduced to the body
2
Q
What % of UK population on medication
A
48% (in 2016?)
(prescriptions have increased by 47% between 2006-2016)
3
Q
Druggability meaning
A
The term used to describe a biological target the is known to/predicted to bind with high affinity to a drug.
The binding of a drug to a druggable target must alter the function of the target with a theraputic benefit.
4
Q
What percentage of the human genome is estimated to be druggable
A
10-15% (with a small molecule approach)
5
Q
Name types of drug targets
A
Most/all drug targets are proteins
- receptors
- enzymes
- transporters
- ion channels
Also - ligand drugs like thyroid hormone
6
Q
What is a receptor
A
A component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the observed effects caused by the ligand
They are the principal means by which chemicals communicate
not all cells will have certain druggable components
7
Q
Explain what ligands can be
A
Ligands can be exogenous (drugs) or endogenous (hormones, neurotransmitter, etc)
ligands mediate effects
- they are many and varied
- they’re a molecule that bind to another, usually
8
Q
Which chemicals are commonly associated with receptors?
A
Neurotransmitters
- e.g. acetylcholine, serotonin
Autacoids - (local) Greek “autos” (self) and “acos” (relief).
- e.g. cytokines, histamine
Hormones (slightly diff type of ligand - works intracellularly)
- e.g. testosterone, hydrocortisone
- e.g. retinoic acid, steroid hormone
9
Q
What types of receptors can you have?
A
Ligand-gated ion channels
e.g. - nicotinic ACh receptor
G protein coupled receptors (most common in human genome)
e.g. - beta-adrenoceptors
Kinase-linked receptors
e.g. - receptors for growth factors
Cytosolic/nuclear receptors (intracellular - others normally on cell surface - affect gene transcription)
e.g. - steroid receptors
10
Q
What are ligand gated ion channels and how do they work?
A
- Pore forming membrane proteins that allow ions to pass through
- results in a shift in the distribution of electric charge
- change in charge can be mediated by influx of any cation or the efflux of any anion
11
Q
What are GCPRs and how do they work?
A
- G protein coupled recptors are the largest, most diverse group of membrane receptors (in eukaryotes)
- they have 7 membrane spanning regions
- thought to make up around 4% of all genes
- G proteins (guanine nucleotide-binding proteins) are involved in transmitting signals from GCPRs
- GCPR activity is regulated by factors that control their ability to bind to/hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP)
- G proteins (GTPases) act as molecular switches
- when the ligand binds to GCPR it causes a conformational change
- G protein is recruited and this causes a cascade
- GCPR catalyses the exchange of GDP to GTP
12
Q
What % of drugs are GCPRs targeted by
A
> 30%
13
Q
What kind of ligands can you have for GCPRs
A
Ligands include:
- light energy
- peptides
- lipids
- sugars
- proteins
14
Q
GIve an example of GCPRs
A
olfactory receptors
15
Q
Give common receptor messengers, G proteins, coupled substances and secondary messengers for GCPRs
A
Receptor messengers:
- M3 (Muscarinic acetylcholine receptor M3)
- β2 (beta 2 adrenergic receptor)
G protein:
- Gq
- Gs
Coupled with:
- PLC (phospholipase C)
- AC (adenylyl cyclase)
2nd messengers:
- IP3/DAG (inositol triphosphate/diacylglycerol)
- cyclic AMP
16
Q
What are kinase-linked receptors and how do they work
A
Transmembrane receptors activated when the binding of an extracellular ligand that causes a conformational change and results in enzymatic activity intracellular side.
- receptor can have 2 components/ be made of 2 copies of a structure
Kinases catalyse phosphoylation and the substrate/ligand gains a phosphate group from an ATP molecule
17
Q
What are nuclear receptors and how do they work
A
- receptors within the cell/ on nuclear membrane
- have zinc fingers and a ligand binding site
- typically associated with steroid hormones
- ligand binding causes conformational change - activates receptor
- regulates/modifies gene transcription (can be an activator or receptor)
18
Q
Examples of how chemical/receptor imbalance can cause pathology
A
Chemical imbalance:
- allergy; increased histamine
- Parkinson’s; reduced dopamine
Receptor imbalance:
- myasthenia gravis; loss of ACh receptors
- mastocytosis; increased c-kit receptor
targeting these is a theraputic strategy
19
Q
Define potency
A
An expression of the activity of a drug in terms of the concentration or amount of the drug required to produce a defined
Whether a drug is ‘strong’ or ‘weak’ relates to how well the drug binds to the receptor, the binding affinity
20
Q
Define efficacy
A
The ability of an intervention to produce the desired beneficial effect
- can you get maximal response? do you get maximal response even if not all receptors are engaged? partial agonist?
21
Q
Define pharmacodynamics
A
Relating to the effects of drugs and the mechanism of their action
22
Q
Define tolerance
A
Down regulation of the receptors with prolonged use
- Need higher doses to achieve the same effect
23
Q
Define dependence
A
A condition in which a person takes a drug over time, and unpleasant physical/psychological symptoms occur if the drug is suddenly stopped or taken in smaller doses.
24
Q
State psychological and physical symptoms of drug dependence.
A
Psychological
- craving, euphoria
Physical
- cold-turkey (withdrawal symptoms)
- can be fatal for people especially if malnourished
25
Types of receptor ligands (in teems of the effect they have)
Agonist - a compound that binds to a receptor and activates it
Antagonist - a compound that reduces/blocks the effect of an agonist
26
What is the two state model of receptor activation
- describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”.
27
Can different agonists mediate the same response through different receptors?
Yes
28
What is intrinsic activity
Refers to the efficacy of a drug.
The ability of a drug-receptor complex to produce a maximum functional response
29
How can antagonists reverse effects of agonist
Competitive antagonism
Non-competitive antagonism
30
What are the 2 catagories of cholinergic receptor characterisation?
Nicotinic
Muscarinic
31
What is an agonist and an antagonist of muscarinic receptors (mAChR)
Agonist - muscarine
Antagonist - atropine
32
What is an agonist and an antagonist of nicotinic receptors (nAChR)
Agonist - nicotine
Antagonist - curare
33
Characterisations of different histamine receptors
H1 receptor - 481 amino acids; 56 kDa protein
- related to ALLERGIC conditions
H2 receptor - 359 amino acids; 40 kDa protein
- related to GASTRIC ACID secretion
H3 receptor - 445 amino acids; 49kDa protein
- related mostly to CNS DISORDERS (e.g. narcolepsy, ADHD, Schizophrenia, Alzheimer's)
- evidence suggests role in obesity, pain and rhinitis
H4 receptor - 390 amino acids; 44 kDa protein
- related to IMMUNE system and INFLAMMATORY conditions (e.f. rhinitis, pruritis and asthma) and inflammatory PAIN
34
What are factors governing drug action
Receptor-related
- affinity
- efficacy
Tissue-related
- receptor number
- signal amplification (dependant on receptor)
35
What is affinity
Describes how well a ligand binds to the receptor
It is a property shown by both agonists and antagonists
36
What is efficacy?
Describes how well a ligand activates the receptor
Agonists can have high or low efficacy (depending on the intensity of the downstream response)
Antagonists block receptor signalling so they have ZERO efficacy
37
What happens when you block receptors
The response takes longer to reach the maximal point. It reduces potency.
38
What is a receptor reserve
It refers to instances where agonists activate only a small fraction of existing receptors to produce the maximal system response
This only relates to full agonists in a given tissue. A partial agonist can never have a receptor reserve as the maximal response will not be seen even when 100% of receptors are occupied
39
Why is receptor reserve useful
Reduces risk of total inactivation due to a high-affinity or permanently binding antagonist
40
What occurs in signal transduction
The steps from the activation of the receptor to the displayed response. It involves a signelling cascade.
Activation of a receptor can elicit differing responses
41
What is signal amplification
The amplification of a signal as it moves along the signalling cascade
Activation of the same type of receptor by the same type of agonist can elicit a different response in different tissues
42
What is allosteric modulation
Creating a different response by a ligand binding to a receptor at an allosteric (other) site (a site which is not the orthosteric site)
43
What is inverse agonism and why can it occur
When a drug that binds to the same receptor as an agonist, induces a pharmacological response opposite to that of the agonist.
can be due to receptor protein changing shape slightly or due to being a different ligand
44
What is tolerance
The slow reduction in agonist effect over time
caused by continuously, repeated high concentrations
45
What is desensitisation
Rapid reduction in agonist effect
Due to complete change in receptor (- e.g. in type 2 diabetes?)
Receptors are:
- uncoupled
- internalized
- degraded
46
Why is selective a better term than specific when referring to drug interactions
No compound is ever truly specific
Leads to off target effects
47
Why can non-selective drugs cause problems
Various versions/subtypes of the same type of receptor exist in different areas in the body and a non-selective receptor would affect all of them
e.g. isoprnaline is a non-selective β-adrenoceptor agonist used for bradycardia (slow heart rate), heart block, and rarely for asthma. It affects both the receptors in heart and lungs.
48
Define affinity
The extent or fraction to which a drug binds to receptors at any given drug conentration
49
What is an enzyme inhibitor?
A molecule that binds to an enzyme and (normally) decreases its activity
50
What does an enzyme inhibitor do?
It prevents the substrate from entering the enzyme's active site and prevents it from catalysing its reaction
51
What are the classes of enzyme inhibitors?
Irreversible inhibitors usually 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.
Partially reversible
52
Give an example of an enzyme which is in itself a drug product
streptokinase – a clot buster
53
What are statins?
A class of major lipid-lowering medications that reduces the levels of “bad cholesterol” for the primary prevention of cardiovascular disease
HMG-CoA reductase inhibitors
Blocks rate-limiting step (catelysed by HMG-CoA) in cholesterol pathway
54
What is the purpose of statins?
Reduce cardiovascular disease (CVD) and mortality in those who are at high risk.
55
How does RAAS increase blood pressure
By increasing the amount of salt and water the body retians
56
What is RAAS inhibited by, how and why?
Inhibited by Angiotension Converting Enzyme inhibitors (ACE inhibitors) IN ORDER TO reduce blood pressure.
It functions by reducing angiotensin II production by blocking ACE
57
What were the names of 1st and 2nd generation ACE inhibitors respectively?
Captopril
Enalaprilat (Enalapril)
58
How can the ACE system be hijacked?
SARS-CoV-2 uses ACE2 as an entry receptor
59
Give an example of a disease where enzymes can target multiple steps in the biosynthetic pathways? Give the proportion of the population affected by this disease.
Parkinson's disease
Affects one person in every 500
(1:100 in over 60s)
60
What are the symptoms of Parkinson's
Hypokinesia – motor movement↓
Tremor at rest
Muscle rigidity, Motor inertia
Cognitive impairment
Degenerative disease of basal ganglia
Early degeneration of dopaminergic neurons in the nigrostriatial pathway leading to autonomic dysfunction and dementia
61
What is the name of the key substrate in Parkinson's and where does it come from
L-DOPA
produced from the amino acid L-Tyrosine as a precursor for neurotransmitter biosynthesis - crosses the Blood Brain Barrier
62
How can Parkinson's be treated?
Peripheral DDC Inhibitor (Carbidopa, Benserazide)
- reduces dopamine in peripheral (DDC converts l-dopa to dopamine in the periphery) THUS
- reduces degradation of l-dopa in peripheral THUS
- increases dopamine in brain
Peripheral COMT inhibitor (Tolcapone, Entacapone)
- prevents breakdown of L-DOPA to 3-methyl DOPA
- generates more l-dopa for CNS
Central COMT inhibitors (Tolcapone)
- reduces conversion of dopamine to 3MT in CNS
- increases dopamine in CNS
Mono Amine Oxidase B inhibitor (Selegiline, Rasagiline)
- prevents breakdown of dopamine to DOPAC in CNS
- increases availability of dopamine in CNS
Central Dopamine Receptor Agonists (Bromocrytine, Pergolide, Pramipexole, Ropinirole, Rotigotine)
- Antagonise dopamine receptors in CNS
- These are NOT enzyme inhibitors
EVIDENCE of how many therapeutic options for one specific pathway
63
Types of ion transporters
Passive (no energy required)
- Symporter
- Na/K/2Cl , NaCl
- Channels
- Na, Ca, K, Cl
Active (requires energy)
- ATP-ases
- Na/K, K/H
64
What are the 3 main types of protein ports in cell membranes?
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. (typically moving in same direction)
Antiporters: one substance moves against its gradient, using energy from the second substance (mostly Na+, K+ or H+) moving down its gradient. (typically moving in opposite directions)
65
Give an example of a symporter and the drug that can affect it
The Na-K-Cl cotransporter (NKCC) is a protein that transports Na, K, and Cl into cells
- Move ions in the same direction
Predominantly functions in organs that secrete fluids. E.g. in kidney
Furosemide (a loop diuretic - used for hypertension and edema)
Acts by inhibiting the luminal NKCC in the thick ascending limb of the loop of Henle
Binding to the NKCC causes sodium, chloride, and potassium loss in urine
66
Where can ion channels exist
In many tissues, especially excitable tissues
67
Give types of ion channels and the conditions related to their dysfunction
Epithelial (Sodium) – heart failure
Voltage-gated (Calcium, Sodium) – nerve, arrhythmia
Metabolic (Potassium) – diabetes
Receptor Activated (Chloride) - epilepsy
68
What is an epithelial (sodium) channel (ENaC) - function and associated drugs
An (apical) membrane-bound heterotrimeric (structure is two sets of three proteins) ion channel selectively permeable to Na+ ions
Causes reabsorption of Na+ ions at the collecting ducts of the kidney's nephrons (also in colon, lung and sweat glands - plays a role in fluid reabsorption in the lungs)
Blocked by the high affinity diuretic amiloride (often used with Thaizide).
Thaizide targets Na+Cl− cotransporter that reabsorbs Na and Cl from tubular fluid
- Used as a anti-hypertensive
69
Voltage-gated (Calcium) channels - where are they found and function
Voltage-gated ion channels (VDCC) are found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.)
At physiologic or resting membrane potential, VDCCs are normally closed.
Activated (i.e., opened) by depolarized membrane potentials.
Ca2+ enters the cell, resulting in activation of Ca-sensitive K channels, muscular contraction, excitation of neurons etc.
70
What is an action potential
A momentary change in electrical potential on the surface of a nerve or muscle cell, that occurs when it is stimulated, resulting in the transmission of an electrical impulse.
71
How are voltage-gated (calcium) channels inhibited and why
- AMLODIPINE is an angioselective Ca channel blocker
* inhibits influx of Ca ions across cell membrane into vascular smooth muscle cells and cardiac muscle cells - inhibits contraction.
- has a greater effect on vascular smooth muscle
- causes vasodilation and reduction of peripheral vascular resistance
- prevents excessive constriction in coronary arteries
* LOWERS BLOOD PRESSURE
72
Voltage gated (sodium) channels - function
Allows influx of Na+ through plasma membrane when activation gates are opened by action potential.
- increases voltage across membrane
- transmits a signal
In excitable cells voltage-gated Na+ channels have three main conformational states: closed, open and inactivated.
73
Which drug inhibits voltage gated Na channels
Lidocaine (anaesthetic) blocks transmission of the action potential. Also blocks signaling in the heart reducing arrhythmia.
74
Voltage gated (Potassium) Channels - structure and how do they function
6 - transmembrane spanning with intracellular component and extracellular p-loop
Voltage gated channels that are selective for K+ over other cations
- Allow influx of K+ when activation gates opened by action potential
have three conformational states: closed, open and inactivated
(>40 known human voltage-gated potassium channel alpha subunits)
75
What is the purpose of voltage gated K channels
Regulate insulin in Pancreas: β Islets of Langerhans
76
Name drugs that inhibit K+ channel, how they function, and what they are used for
Repaglinide, nateglinide and sulfonylureal
Increased glucose blocks ATP dependent K+ channels.
Repetitive firing of action potentials increases Ca+ influx and triggers insulin secretion
These drugs block K+ channels and thus stimulate insulin secretion
Used to treat type II diabetes
77
Receptor mediated (Chloride) channels - structure, function, example of receptor
Composed of 2 beta, 2 alpha and 1 gamma subunit
When a ligand (e.g. a neurotransmitter like GABA) binds to the receptor it opens and allows efflux of chloride.
- inhibitory effect
E.g. GABA A receptor
78
Which drug is used to increase permeability of ligand gated channels to chloride and what does it do
Barbiturates
enhance activation of GABA A receptor - produces greater inhibition
79
What's another name for receptor-mediated (chloride ) channels
ionotropic receptors
ligand-gated
80
What are Sodium pumps, what do they do, for what purpose
They are a type of ATPase (Na/K ATPase)
It actively pumps out 3 N ions and simultaneously pumps in 2 K ions. Antiporter-like activity (both substances moving against conc. grad)
This creates an electrochemical gradient between inside and outside the cells and is used to re-establish membrane potential in excitable tissue
81
What inhibits Sodium pumps, how does it work, what is it used for
Digoxin
Inhibits Na/K ATPase, mainly in myocardium which causes increase in intracellular Na. This promotes activity of Na-Ca exchanger so intracellular Ca increases.
Lengthens cardiac action potential - decreased heart rate.
Used to treat atrial fibrillation, atrial flutter, heart failure
82
What is proton pump in stomach, what does it do, for what purpose
H+/K+ ATPase - a heterodimeric (composed of 2 similar but different components) protein (product of 2 genes)
Exchanges potassium from intestinal lumen with cytoplasmic hydronium (form of H+ in aqueos solution)
Receptor-mediated acid secretion in stomach and activates pepsin.
83
What drugs target stomach proton pumps, what do they do, for what purpose
Proton-pump inhibitors (PPIs) - e.g. omeprazole
Inhibit acid secretion by irriversible inhibition of H/K ATPase - anti ulcer theraputics
Omeprazole metabolised at acid pH so delivered via enteric coated granules (increase bioavailability)
84
Half-life of omeprazole? How long does it work for?
half-life 1h, but works for 2-3 days
85
What is an alternative anti ulcer therapy other than omeprazole (don't think i actually need to know)
H2-receptor antagonists (binds to histamine receptors)
86
Examples of irreversible inhibitors of cholinesterase
Insecticides (Diazinon)
Nerve gases (Sarin)
87
What 5 of hospital admissions due to pesticide? How many deaths worldwide per year?
80%
200, 000 deaths worldwide per year
88
Examples of muscarinic symptoms caused by organophosphates
salivation, defaecation, urination, bradycardia , hypotension
89
Examples of nicotinic symptoms caused by organophosphates
twitching, servere weakness paralysis, diaphragm
90
Examples of CNS symptoms caused by organophosphates
Confusion, loss of reflexes, convulsions, coma
91
What are organophosphates?
Organophosphorus substances used as insecticides and nerve gases - typically irreversible acetylcholinesterase inhibitors
92
Examples of irreversible enzyme inhibitors?
Omeprazole
Aspirin (COX inhibitor)
93
What is pharmacokinetics
study of drug metabolism
- occurs through specialised enzymatic systems
94
Why is metabolism of drugs important?
The rate of metabolism determines the duration and intensity of a drug's pharmacologic action
It generates compounds that are (often inactivated and) more readily excreted (works in liver and kidney)
95
What are xenobiotics
Compounds foreign to an organism's normal biochemistry, such any drug or poison
96
What is bioavailability of a drug?
the fraction (%) of an administered drug that reaches the systemic circulation.
If a drug can’t reach its intended site of action then it will have limited therapeutic utility
97
What factors need to be considered in pharmacokinetics
Absorption, Metabolism, Distribution, Excretion
98
What is cytochrome p450, where are they found, function, purpose
Primarily membrane associated monooxidase proteins - major enzymes involved in drug metabolism (accounts for ~75% total metabolism)
located in the inner membrane of mitochondria OR in endoplasmic reticulum
Deactivate most drugs - directly OR by facilitated excretion from body (usually by urine)
Bioactivate many substances.
Metabolise thousands of endogenous and exogenous chemicals.
99
Characteristics of autonomic nervous system
Involuntary
Involves an enteric nervous system as well (both sympathetic and parasympathetic)
Conveys all outputs to body from cns except for voluntary stuff
100
Cholinergic and adrenergic meanings
Cholinergic - relates to acetylcholine
Adrenergic - relates to adrenaline
101
Characteristics of sympathetic nervous system
2 nerve system
Gre-ganglion - lateral horn (T1-L2)
Gre-ganglion fibre synapses with post-ganglion nerve at sympathetic chain ganglion (both pre- and post-ganglionic fibres are long)
Travels through white and grey rami communicantes respectively
102
Characteristics of parasympathetic nervous sytem
2 nerves
Cranial nerve nuclei: 3, 7 ,9, 10
Sacral outflow: t12/L1, exit at S2-S4
Ganglia in/adjacent to effector organs
Pre-ganglionic: long, post-ganglionic: short
103
Functions of parasympathetic and sympertetic systems.
Related to fight/flight and rest/relax
Parasympathetic:
constrict pupil
simulate saliva
slow heartbeat
bronchoconstriction
stimulates peristalsis and secretion
stimulates release of bile
bladder contraction (detrusor)
Sympathetic:
dilate pupil
ihibit saliva
increased heartbeat
bronchodilation
inhibits peristalsis and secretion
conversion of glycogen to glucose
secretion of adrenaline and noradrinaline
inhibits bladder contraction
104
What are the 2 main neurotransmitters in autonomic system
ACh (acetylcholine)
Noradrenaline
105
Where does ACh act
muscarinic pre-ganglion reseptors in both sympathetic and parasympathetic systems
nicotinic post-ganglionic receptors in parasympathetic system
106
Where does noradrenaline act
on alpha and beta adreno post-ganglionic receptors in sympathetic system
107
What are exceptions to the ACh/noradrenaline generalisation
Sweat glands function sympathetically but use ACh in postganglion
NO is released in parasympathetic termini in blood vessels
108
Which parts of the nervous system do nicotine and muscarine affect?
Nicotine stimulates both autonomic nervous systems
Muscarine activates muscarinic - paraysmpathetic response.
Muscarine poisoning has parasympathetic action (except for sweating which is actually sympathetic)
109
Examples of NANC (non-adrenergic, non-cholinergic autonomic transmitters)
nitric oxide and vasoactive intestinal peptide
(parasympathetic)
ATP and neuropeptide Y (sympathetic system)
110
How many muscarinic receptors are there and what type of receptor are they
5
GPCRs (G protein coupled receptors)
111
Where are M1 receptors found
mainly in brain
112
Where are M2 receptors found and function
mainly in heart.
SA node (decreases heart rate), decrease conduction velocity at AV node (increases pr interval)
113
M3 receptor location and function
glandular and smooth muscle
Resp system - produce mucus, bronchoconstriction
GI - more saliva, gut mobility and biliary secretion
Sweating in skin (sympathetic but uses muscarinic)
Urinary - detrusor contraction, relaxation of internal sphicter
Eye - myosis, increases drainage, causes tears
114
M4/5 receptor location
mainly in CNS
115
Example of muscarinic agonists
Pilocarpine:
stimulates salivation (may be useful after
radiotherapy, or in Sjogren’s syndrome). Activating the parasympathetic nervous system.
* Contracts iris smooth muscle, so may be used to treat glaucoma by facilitating drainage of aqueous humour
* Side effects would be to slow the heart
116
Examples of muscarinic antagonists
Atropine - increases heart rate, treats brady-arrhythmias and AV node block
hyoscine - M3 antagonist - treat resp secretion and symptoms of bowel obstruction in pallitive care
117
Drugs to treat bronchoconstriction, how they work, side effects
Short-acting: ipratropium bromide (atrovent)
Long-acting: LAMAs such as tiotropium, glycopyrrhonium
- block M3 receptor (anti-cholinergics or anti-muscarinics)
Selectivity by drug delivery mechanisms (inhalers) and receptor selectivity (e.g. tiotropium relatively selective for M3 receptors).
Side effects: tachycardia, dry mouth, urinary retention, make glaucoma worse
118
Examples of anticholinergics
Solifenacin - treats overactive bladder
Short acting anticholinergics to open up the pupil to allow
eye examination
Mebeverine for IBS (prevents intestinal colic and spasm)
119
What is ACh involved in outside the autonomic syste,
memory:
anticholinergics worsen memory, and acetylcholinesterase inhibitors may be useful for treatment of dementia
Anti-emetic actions (e.g. hyoscine for travel sickness)
Also innervates skeletal muscle
120
What does acetylcholinesterase do
Breaks down ACh at synapses - Terminates neuronal transmission and prevents ACh dispersal
121
Drugs related to ACh
Botulinum toxin (botox) prevents ACh release: cosmetic and antispasmodic uses.
Nicotinic (N1) blockers such as pancuronium and suxamethonium inhibit ACh to inhibit muscle activity and induce relaxation in surgery.
* Suxamethonium is broken down by acetylcholinesterase, so is contraindicated in rare patients with low levels of this enzyme
122
Role of ACh in myasthenia gravis and treatment
Autoimmune destruction of nicotinic ACh receptors results in muscle weakness
Give anti-acetylcholinesterase to increase the amount of acetylcholine available to
cause signalling
123
Examples of anti-cholinergic side effects. Why does this happen?
In the brain, anticholinergics worsen memory and may cause confusion
Peripherally, may get constipation, drying of the mouth, blurring of the vision, worsening of glaucoma
Many drugs have some anticholinergic activity
124
Examples of drugs wiith antigolinergic side effects
Tricyclic antidepressants,
some early antihistamines,
some anti-emetics (prochlorperazine)
125
What drug can be used to counteract side effect of bradycardia from anticholinesterases?
Noradrenaline (tho this can cause peripheral vasocontriction which can be a problem for people with vessel disease like diabete)
Also antimuscarinics (same group as inhaler drug)
126
Name most important catecholamines
Noradrenaline: released from sympathetic nerve fibre ends, beloved in the management of shock in the intensive care unit
Adrenaline: released from the adrenal glands (fight and flight, management of anaphylaxis) (and in brain - locus serrulius - concentration and attention)
Dopamine (the precursor of adrenaline and noradrenaline)
127
Agonists, Mechanism and Consequence for Alpha 1 adreno receptors
Noradrenaline more than adrenaline
increases intracellular calium, Gq signelling
contracts smooth muscle (pupil, blood vessels)
vasoconstrictio (mainly skin and splanchnic)
used for low BP and to counteract anasthesia
128
Agonists, Mechanism and Consequence for Alpha 2 receptors
Noradrenaline and adrenaline can equally affect
Gi signalling, inhibition of cAMP generation
Mixed effects on smooth muscle, reduces vascular tone and BP
129
Agonists, Mechanism and Consequence for Beta 1 receptors
Noradrenaline and adrenaline can equally affect
Gs, raises cAMP
Chronotropic and inotropic effects on heart
130
Agonists, Mechanism and Consequence for Beta 2 receptors
Adrenaline much more than noradrenaline
Gs, raises cAMP
Relaxes smooth muscle (delays premature labour, asthma)
131
Agonists, Mechanism and Consequence for Beta 3 receptors
Noradrenaline more than adrenaline
Gs, raises cAMP
Enhances lipolysis, relaxes bladder detrusor
132
Example of alpha 2 agonist
clonidine - used in ADHD to help concentration, aso lowers BP
133
Where are alpha 2 receptors found
Barin and peripheral
134
Examples of use of adrenaline and noradrenaline as treatment
Adrenaline given intramuscularly (or via IV in serious cases) for anaphylactic shock
Noradrenaline given IV for septic shock in ITU setting
135
Examples of alpha blockers (atagonists)
Doxazosin - lowers BP
Phenoxybenainamine - treats phaeochromocytoma (vascular tumour of adrenal medulla - irregular secretion of chatecholamines)
Tamsulosin - treats prostatic hypertrophy (works on alpha 1A subtype) - can cause dilatation of venous capacitance vessels which can cause dizziness and uwell feeling
136
Are there any notable clinically significant alpha 2 blockers?
No
137
What does beta 1 activation cause
increase heart rate and chronotropic effects, and may increase risk of arrhythmias
Also affects carbohydrate and lipid metabolism (esp. glucose metabolism in liver)
138
Effect of beta 2 activation
Muscle relaxation - life saving in asthma and COPD
- can delay premature labour (tocolysis)
Side effect: tremor, hyperglycemia, tachyarrythmia
139
Function of beta 3 agonists
Can reduce over-active bladder symptoms
Also affects carbohydrate and lipid metabolism (esp. glucose metabolism in liver)
140
Side effects of beta adrenergic agonism
tachcycardia, increase in stroke volume, renin release (increase vascular tone), lipolysis and hyperglycaemia
141
Uses of beta blockers
* Angina
* MI prevention
* High blood pressure
* Arrhythmias
* Heart failure
* Anxiety
142
Side effects of beta blockers
* Cardiac depression
* Bradycardia
* Cold extremities
* Bronchoconstriction
* Hypoglycaemia
* Tiredness
143
Location of beta-2 receptors and their roles when activated
Bronchi - bronchodilation
Bladder wall - inhibits micturition
Uterus - inhibits labour
Skeletal muscles - increases contraction speed (can induce tremor)
Pancreas - increase insulin and glucagon secretion
144
What can beta blockers do
Reduce heart rate, stroke volume (SV) and myocardial oxygen demand and help remodel heart failure
I.E.
Lower blood pressure, reduce cardiac work and treat arrythmias
145
What can be used as an antidote for beta -blocker overdose
Glucagon
increases heart rate and myocardial contractility irrespective of prescence of beta blocker - bypass beta-adrenergic receptor site
146
Examples of beta blockers
* Propranolol and metoprolol: blocks beta 1 and beta 2.
Slows heart rate, reduce tremor, but may cause wheeze (caution in asthma)
* Atenolol and Bisoprolo: beta 1 selective, main effects on heart.
147
Examples of drugs with less direct effects relating to NAd
Methyldopa:
- last resort antihypertensive
- useful in pre-eclampsia and eclampsia that blocks NAd synthesis
MAOIs prevent NAd breakdown (anti-depressants)
148
A patient with well controlled COPD has prostatic hypertrophy and bladder instability
They get cardiac disease (angina, occasional atrial fibrillation)
They get admitted with pneumonia and septic shock and get wheezy
They are penicillin allergic and get anaphylaxis
They have a cardiac arrest
They eventually go home on inhalers and tablets
M3 antagonist and B2 agonist for COPD
Alpha agonist for hypertrophy
B3 agonist for bladder instability
Beta 1 blocker for cardiac disease
NAd for septic shock
Beta agonists for wheeze
Adrenaline for anaphylaxis
Atropine for bradycardia (from cardiac arrest)
149
What does opium contain
Some codine and around 25% morphine
150
Why should you never give codine to breastfeeding mothers or children?
Codine is a pro-drug that is inactive iuntil it is metabolised into morphine
Breastfeeding mothers and children have higher metabolism and it gets into breast milk and it can kill the baby
151
What is the oral bioavailability of morphine
50% of oral (enteral) morphine is metabolised by the first pass metabolism by liver
152
How long does it take for oral morphine to work
around 1-2 hours
153
What difference in dose would there between enteral and parenteral morphine administration?
As 50% of oral dose is metabolised in first pass metabolism, the oral/enteral doe would be double what would be given parenterally (subcutaneous, IV etc.)
154
How long does a single dose of morphine last?
around 3-4 hours
(single dose is usually 10mg orally; 5mg subcutaneously)
155
What type of morphine is used in pallative care
Slow release preparations that release twice a day
(MST Conntinus)
156
How long does it take a sub-cutaneous morphine dose to work
1/2 hour
peaks at 1 hours
157
How can analgesia be delivered? Which is fastest
Subcutaneous
Intramuscular
IV (fastest - works almost instantaneously)
IV PCA (Patient controlled analgesia)
Epidural/CSF
Trans-dermal patches for lipid soluble drugs (e.g. fentanyl)
Fentanyl lollipops are also used for kids
158
Issues associated with patient controlled analgesia
people (visitors) may press button too many times,
morphine can build up due to blockage, can have everything coming in at once
- things in place to try stop this
159
What are the major issues with morphine
It is highly addictive and can cause respiratory depression
There is a very fine difference between a dose that sufficiently eases pain and a fatl dose
160
Which vitamin is required for blood clotting
vitamin K - Prothrombin is vitamin K-dependant
may need to be given to individuals on blood thinners if they are bleeding extensively
161
what is diamorphine, its characteristics
Transformation of morphine to diacetylmorphine (AKA heroin)
* More potent and faster acting
(crosses the blood-brain barrier quickly)
* Invented by Bayer in 1898 and promoted as an over the counter non-addictive alternative to morphine
162
When was controlled drugs (CDs) legislation started
1920s
163
What is current CD legislation
Misuse of Drugs Act 1971
* Opioids - Class A drugs
* Practical issues:
- Secure storage - double-locked, nurses check twice a day
- CD books - two signatures needed
* Prescription regulations for TTOs (to take out medication for patients who are leaving hospital care)
164
Examples of synthetic and semi-synthetic opioids
1911 - dihydrocodeine
1916 - oxycodone
1939 - pethidine
Modern - more specific and potent
- fentanyl, alfentanyl, remifentanyl
165
characteristics of dihydrocodeine
about 1.5x more potent than codeine - already metabolized so works in pretty much everyone
166
characteristics of oxycodone
developed to try and reduce dependence - about
1.5x as potent as morphine
- reformulated in the 1980s as oxycontin (a
slow release formulation) and marketed for non-cancer pain in the US -
leading to huge problems with addiction (started in appalachian mining communities)
167
what are fentanyl and varients used for
- very potent (50x stronger than heroin)
used as trans dermal patches for chronic cancer pain, in ITU and as anasthesia
168
When does opioid withdrawal start? lasts how long?
starts in 24 hours
lasts around 72 hours
169
How do naturally occuring opioids work
Inhibit release of pain transmitters at spinal cord and midbrain and modulate pain perception in higher centres (creates euphoria)
- changes emotion perception of pain in brainstem/blocks pain
170
What is the natural purpose of opioids
Descending inhibition of pain
Part of the fight or flight response
- Never designed for sustained activation
171
What does sustained activation of the pain modulation/descending inhibitory pathway do
leads to tolerance and addiction (psychological craving and physical withdrawal)
172
names of opioid receptors
mu (greek letter m for morphine), delta and kappa
nociceptin opioid-like receptors
- MOP, KOP, DOP, NOP
173
which species' have main opioid receptors
all vertebrates
174
Which receptor do all present opioid drugs work on
mu - they are µ agonists
175
What effect does kappa agonism have
depression (NOT euphoria)
176
Where are opioid receptors mainly found in the body
embedded in outer membrane of neurons
177
Side effects of opioids
Respiratory Depression
Sedation
Nausea and Vomiting
Constipation
Itching
Immune Suppression
Endocrine Effects
Different patients have quite a range of sensitivity to opioids (especially older people) - start with a small
dose and titrate up as necessary
178
Why do opioids have side effects
Opioid receptors exist outside the pain system
e.g.: digestive tract, respiratory control centre
We can sometimes deliver opioids epidurally, but for the most part we have to
give them systemically
179
What do you do when faced with a case of opioid induced respiratory depression
* Call for help
* ABC
* Naloxone
* IV is fastest route
* If there is enough time Titrate to effect - don’t have to give it all at once - dilute 1ml in 10ml saline
One ampoule of a drug is usually about the right adult dose - if you think you need to open more than one - check with a colleague first
* Short half-life of naloxone - beware drug
addict overdoses in A&E, they might try to leave after initial treatment but the naloxone wears off and they get ill again
- give depo and then via IV to make sure it continues to work
180
Which drug is given to counter opioid induced respiratory depression
Naloxone
181
Issues of using opioids for non-cancer pain
- lose effectiveness quickly
- highly addictive
* In one large study 50% of patients who were on opioids for non-cancer pain at
12 weeks were still on them 5 years later
- addiction can lead to manipulative behaviour
182
Where is opioid addiction more common in the UK
Socially deprived areas
183
What is the MHRA (medicine and healthcare products regulatory agency) advice for prescribing opioids for chronic non-cancer pain
* Before prescribing opioids, discuss with the patient the risks and features of tolerance, dependence, and addiction - use short term courses
* Agree a treatment strategy and plan for end of treatment
* Warnings have been added to the drug labels and packaging of opioids to
support patient awareness
* At the end of treatment, taper dosage slowly to reduce the risk of
withdrawal effects - may take weeks
184
What is codine metabolised to morphine by
cytochrome CYP2D6
185
pharmacogenetics of codeine metabolism
* CYP2D6 activity is decreased in 10-15% of the Caucasian population
* + CYP2D6 is absent in a further 10% of this population
* Codeine will have a reduced or absent effect in these individuals
* CYP2D6 is overactive in 5% of this population - these individuals may be at
increased risk of respiratory depression with codeine - due to this it is not licensed for children under 12
186
What is morphine metabolised to
morphine 6 glucuronide
- which is more potent than morphine and is renally excreted
187
What issues can morphine use in patients with renal failure cause? What precautions need to be taken
In renal failure it will build up and may cause respiratory depression
In patients with < 30% renal function (creatinine clearance < 30) reduce dose and timing interval
- use something like oxycodone with different metabolic pathway
if in doubt, please ask - or look at the acute pain guidance on the intranet
188
What is another example of an opioid pro-drug (not codeine)
Tramadol - a weak opioid agonist, slightly stronger than codeine
metabolised by CYP2D6 to o-desmethyl
tramadol to be active - and therefore won’t be effective in about 10% of patients
189
Secondary effect of tramadol
a serotonin and nor-epinephrine reuptake inhibitor
- can be useful for chronic pain
190
Issues with tramadol side effects
interacts with SSRIs, tricyclic antidepressants and MAOIs, sometimes fatally
Recent increase in the number of deaths associated with tramadol as a substance of misuse - now a controlled drug - stricter controls on it’s
long term prescription - avoid prescribing except in the very short term
191
What is an adverse drug reaction (ADR)
Unwanted or harmful reaction following administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug.
- Has to be noxious and unpleasant
192
What % of hospital admissions, issues in inpatients and deaths are caused by ADRs
6 -7% of all hospital admissions
Occur in 10-20% of hospital inpatients
2% patients admitted with an ADR die
Cause deaths in 0.1% of medical and 0.01% of surgical inpatients
5th most common cause of hospital death
193
To what % does WHO say ADRs are preventable
WHO state 60% of ADRs are preventable
194
Negative impacts of ADRs on patients
Adversely affect patients' quality of life
Increase costs of patient care
Preclude use of that drug in most patients, although the ADR may occur in only a few patients
May mimic disease
Very common cause of death, behind heart disease, cancer and stroke
195
Examples of past ADRs
Salvarsan - caused jaundice in 1922 while treating syphilis
Elixiar sulanilamide with solvent diethylene glycol - 107 died from acute renal failure (1937)
Thalidomide - caused phocomelia (1959-61)
196
When was the food, drug and cosmetic act passed in the US
1938
197
What is a side effect
an unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment
- often minor and predictable
198
Side effect vs ADR
Side effect can be beneficial
- side effect can be used to describe minor and predictable ADRs e.g. constipation with opiates
ADRs:
- never beneficial
199
Examples of beneficial side effects
In men:
PDE5 inhibitors improve urinary flow (for things like erectile dysfunction)
Minoxidil for hypertension led to hair growth
200
Name the catagories of types of effects produced by ADRs
Toxic effects (beyond therapeutic range)
Collateral effects (within therapeutic range)
Hyper-susceptibility effects (below therapeutic range)
201
When can toxic ADR effects occur
If dose is too high
If drug excretion is reduced by renal/hepatic function
Due to interaction with other drugs
202
Examples of ADR toxic effects
Nephrotoxicity or ototoxicity (hearing/balance problems) with high doses of aminoglycosides e.g. gentamicin
Dysarthria (difficulty speaking) and ataxia (balance/coordination issues) with lithium toxicity
Cerebellar signs and symptoms with xs phenytoin
203
When do collateral effects occur (ADRs)
At standard theraputic doses
204
Examples of ADR collateral effects
Beta blockers causing bronchoconstriction
Broad spectrum antibiotics causing clostridium difficile and pseudomembranous colitis (inflammation of colon due to C difficile overgrowth)
205
When do hypersusceptibility reactions occur (ADRs)
At sub theraputic doses
e.g. anaphylaxis from penicillin
206
What is the range of severity of ADRs
- Mild e.g. nausea, drowsiness, urticaria
TO
- severe e.g. resp. depression, catastrpohic haemorrhage, anaphylaxis, neutropenia (low neutrophil count)
207
Risk factors for ADRs
Patient risk:
- Gender (F>M)
- Elderly
- Neonates
- Polypharmacy (21% 5 or more drugs)
- Genetic predisposition
- Hypersensitivity/allergies
- Hepatic/renal impairment
- Adherence problems
Drug risk:
- Steep dose-response curve
- Low therapeutic index
- Commonly causes ADR’s
Prescriber risks:
- may not consider potential drug interactions if tired
208
Causes for ADRs
- Pharmaceutical variation
- Receptor abnormality
- Abnormal biological system unmasked by drug
- Abnormalities in drug metabolism
- Immunological
- Drug-drug interactions
- Multifactorial
209
Example of pharmacytical variation causing ADRs
eosinophilia-myalgia syndrome with L-tryptophan (had a pharmacutical contaminant from company making it)
210
Example of receptor abnormality causing ADRs
malignant hyperthermia with general anaesthetics
211
Example of ADR due to abnormal biological system unmasked by drug
primaquine induced haemolysis in patients deficient in glucose 6-phosphate dehydrogenase
212
Example of ADR due to abnormalities in drug metabolism
isoniazid induced peripheral neuropathy in people deficient in the enzyme N-acetyl transferase (that is, those who are slow acetylators)
213
Example of ADR due to immunological reasonons
penicillin induced anaphylaxis
214
Example of ADR caused by drug interactions
increased incidence of hepatitis when isoniazid is prescribed with rifampicin
215
Example of ADR causde by multifactorial reasons
halothane hepatitis
216
What types of time dependant reactions can you have with ADRs
- Rapid reactions
- First dose reactions
- Early reactions
- Intermediate reactions
- Late reactions
- Delayed reaction
217
Example of rapid ADR
red man syndrome due to histamine release with rapid administration of vancomycin
218
Example of first does ADR
hypotension from ACE inhibitors
219
Example of early ADR
nitrate induced headache
220
Example of early ADR
nitrate induced headache
221
Example of early ADR
nitrate induced headache
222
Example of intermediate ADR
delayed immunological reactions such as Stevens-Johnson syndrome (flu like symptoms, painful ras and necrolysis of top layer of skin) with carbamazepine
223
Examples of late ADR
adverse effects of corticosteroids,
seizures on withdrawal of long term benzodiazepines
224
Example of delayed ADR
Thalidomide causes phocomelia in children born to those pregnant individuals
225
Rawlins Thompson classification of ADRs
Type A (Augmented pharmacological)– predictable, dose dependent, common (morphine and constipation, hypotension and antihypertensive) 80% of all ADRs
Type B (Bizarre or idiosyncratic)– not predictable and not dose dependent (anaphylaxis and penicillin)
Type C (Chronic/continuous) – (osteoporosis and steroids)
Type D (Delayed) – (malignancies after immunosuppression)
Type E (End of treatment) – occur after abrupt drug withdrawal (eg opiate withdrawal syndrome)
Type F (Failure of therapy) – (Failure of OCP in presence of enzyme inducer)
226
ways to asses ADRs
Rawlins Thompson classification
DoTS
227
Characteristics of a Type A ADR
Extension of primary effect
- (bradycardia and propranolol, hypoglycaemia and insulin, haemorrhage due to anticoagulants, respiratory depression and opiates)
Secondary effect - (bronchospasm with propranolol B2 blocking effect)
High morbidity, low mortality
Excludes drug abuse and overdose
228
Charcteristics of Type B ADRs
Not predictable or related to pharmacology
Not dose dependant
Can’t be readily reversed
Less common but often serious; Life threatening
Low morbidity, high mortality
Can be idiosyncrasy
Can be allergy or hypersensitivity (I-IV hypersensitivity)
229
What % of ADRs are Type B
10-15%
230
What is idiosyncrasy
Inherent abnormal response to drug
- a genetic abnormallity
- rare but serius
231
What kind of abnormalities cause an idiosyncrasy
- enzyme deficiency
- abnormal receptor activity
232
example of enzyme dificiency related idiosyncrasy
X-linked enzyme Glucose 6 phosphate dehydrogenase (G6PD) deficiency + primaquine →haemolysis and haemolytic anaemia
233
example of abnormal receptor activity related idosyncrasy
Malignant hyperpyrexia with general anaesthetics. Sudden huge rise in calcium concentration → increase in muscle contraction → increase in metabolic activity → rise in body temperature
234
Examples of types of hypersensitivity reactions
- Type 1: immediate anaphylactic - IgE eg penicillin allergy
- Type 2: cytotoxic antibody IgG, IgM eg methyl dopa - and haemolytic anaemia
- Type 3: eg procainamide induced lupus
- Type 4: delayed hypersensitivity T cell eg contact dermatitis
235
Characteristics of Type C ADR
Uncommon
Related to cumulative dose
Time related
236
Example of type C ADR
Steroids and osteoporosis
Analgesic nephropathy
Colonic dysfunction due to laxatives
237
Characteristics of type D ADR
Uncommon
Usually dose related
Shows itself some time after the use of the drug
238
Examples of type D ADRs
Teratogenesis – drugs taken in the first trimester eg thalidomide
Carcinogenesis eg cyclophosphamide and bladder cancer
239
Overview of thalidomide scare
Use 1959-1961 for its mild sedative effects and morning sickness
Animal tests did not include effects in pregnancy
Major effects on day 35-50 of pregnancy
Most commonly limb defects
>10,000 children affected
This led to tougher testing and drug approval
240
Characteristics of type E ADR
Uncommon
Occurs soon after drug withdrawn
241
Examples of type E ADR
Opiate withdrawal
Glucocorticoid abruptly withdrawn leads to adrenocortical insufficiency
Withdrawal seizures when anticonvulsants are stopped
242
Characteristics of type F ADR
Common
Dose related
Often cause by drug interactions
243
Examples of type F ADR
Failure of oral contraceptive pill with enzyme inducers
Failure of therapeutic effect in patients taking warfarin leading to CVA (cerebral vascular accident)
244
When should we suspect an ADR?
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
245
What should be done in response to an ADR?
Assess if urgent action is required
Take a history
Review medication history
Review the adverse effect profile of suspected drug
Modify dose, stop or swap
Report
246
Most common drugs to have ADRs
Antibiotics
Anti-neoplastics
Cardiovascular drugs
Hypoglycaemics
NSAIDS
CNS drugs
247
Most common systems to be affectd bby ADRs
GI
Renal
Haemorrhagic (vascular)
Metabolic
Endocrine
Dermatologic
248
Common ADRs
Confusion
Nausea
Balance problems
Diarrhea
Constipation
Hypotension
249
How can ADRs be avoided? And what % are considered to be preventable
30-50% are preventable
Take care to consider rug interactions
Do not prescribe Inappropriate medication
Do not prescribe medicationif not not necessary
250
How is information on ADRs gathered
Pre-clinical phase 1 trials
Clinical phase 1 to 3 trials
Post marketing surveillance
Yellow card reporting
251
What do the MHRA do
They are the Medicines and Healthcare products Regulatory Agency
Responsible for approving medicines and devices for use
Watch over medicines and devices and take actions (e.g. drug withdrawal) to protect the public promptly if there is a problem
252
What is the yellow card scheme
World's first ADR reporting scheme - from 1964
Collects spontaneous reports
Collects suspected adverse drug reactions
Is a voluntary reporting scheme (tho docters are expected to report)
253
What types of things do you report on a Yellow Card
All suspected reactions for
- herbal medicines
- black triangle ▼ drugs
All serious suspected reactions for
- established drugs, vaccines and contrast media
- drug interactions
254
What is a serous reaction
A reaction that:
- is fatal
- is life threatening
- is disabling or incapacitating
- results in hospitalisation
- prolongs hospitalisation
255
What is a black triangle drug
Any medication undergoing additional monitering
It is assigned to any preparation that:
- contains a new active substance; new medicines or vaccines authorised on or after January 2011
- is a biological medicine, such as a vaccine or a medicine derived from plasma (blood);
- has been given a conditional approval or approved under exceptional circumstances
- the company that markets the medicine is required to carry out additional studies: for instance, to provide more data on long-term use of the medicine, or on a rare side effect seen during clinical trials.
256
Why report ADRs?
- Important for patient safety
- To identify ADRs not identified in clinical trials
- To identify new ADRs ASAP
- To compare drugs in the same therapeutic class
- To identify ADRs in ‘at risk’ groups
257
Who can report on a Yellow Card
Doctors, dentists, coroners, pharmacists, nurses, including midwives and health visitors, radiographers, optometrists.
Patients (also parent or carers - since 2005)
258
Which 4 critical pieces of information must be included on a Yellow card report
Suspected drug(s)
Suspect reaction(s)
Patient details
Reporter details
(Also add any additional useful information)
259
Background for how allergic reactions can occur
Interaction of drug/metabolite/or non drug element with patient and disease
Subsequent re-exposure (for the allergy to actually occur)
Exposure may not be medical e.g. penicillin in dairy products
- Most of the UK population has penicillin antibodies but few react clinically
260
Common target organs of allergy
Skin
respiratory tract
GI tract
blood
blood vessels
261
Most common drugs to cause allergic reactions
Antibiotics and NSAIDS/aspirin
262
How and why should you double check with a patient who states they have an allergy
Ask the patient what actually happened to make them believe they were allergicthey may have misinterpreted an intolerence for allergy
263
Define hypersensitivity
objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects’ and may be caused by immunologic (allergic) AND non‐immunologic mechanisms
264
What % of people have anaphylaxis at some point in life
0.05-2
265
Overview of how a type 1 hypersensitivity (acute anaphylactic)reaction works
- Prior exposure to the antigen/drug
- IgE antibodies formed after exposure to molecule
- IgE becomes attached to mast cells or leucocytes, - expressed as cell surface receptors
- Re-exposure causes mast cell degranulation and release of pharmacologically active substances such as histamine, prostaglandins, leukotrienes, platelet activating factor etc
266
How fast does anaphylaxis occur
within minutes
- lasts 1-2 hours
267
What physiological reactions does anaphylaxis cause
Vasodilation
Increased vascular permeability
Bronchoconstriction
Urticaria
Angio-oedema
268
What are the 2 most common deaths associated with anaphylactic exposure
Drug anaphylaxis is most common form of death from anaphylaxis
Insect venom second most common cause
269
What % of people have biphasic anaphylactic response
1-20%
270
Basic overview of how type 2 hypersensitivity reactions occur
Drug or metabolite combines with a protein
Body treats it as foreign protein and forms antibodies (IgG, IgM)
Antibodies combine with the antigen and complement activation damages the cells e.g. methyl-dopa-induced haemolytic anaemia, pemphigus
271
Basic overview of type 3 hypersensitivity reaction
This is immune complex mediated
Antigen and antibody form large complexes and activate complement
Small blood vessels are damaged or blocked
Leucocytes attracted to the site of reaction release pharmacologically active substances leading to an inflammatory process
E.g. glomerulonephritis, vasculitis,
272
Basic overview of type 4 reaction
Lymphocyte mediated
Antigen specific receptors develop on T-lymphocytes
Subsequent admin, adminstration leads to local or tissue allergic reaction
E.g. contact dermatitis, Stevens Johnson syndrome
273
Overview of non-immune anaphylaxis
Previously called Anaphylactoid reactions
Due to direct mast cell degranulation
No prior exposure
Clinically identical
274
Main features of anaphylaxis
Exposure to drug, immediate rapid onset
Rash (absent in 10-20%)
Swelling of lips, face, oedema, central cyanosis
Wheeze / SOB (short of breath)
Hypotension (Anaphylactic shock)
Cardiac Arrest
275
How many deaths per year from anaphylaxis in the UK
20
276
Clinical criteria for allergy to drug
Does not correlate with pharmacological properties of the drug
No linear relation with dose (tiny dose can cause severe effects)
Reaction similar to those produced by other allergens
Induction period of primary exposure
Disappearance on cessation
Re-appears on re-exposure
Occurs in a minority of patients on the drug
277
Methotrexate mechanism of action
It inhibits the folate pathway (esp dihydrofolate reductase) -> inhibits neucleotide synthesis
It does also subesquently cause more folate excretion -> folate deficiency hence why folate supllementation is given with MTX
278
Methotrexate side effects
Most commonly GI:
- N+V
- mucosal ulcers
- loss of appetitie
- stomach pain/indigestion
- diarrhoea
- headaches
- fatigue, malaise
- hair loss (more mils)
HEPATOTOXICITY -> raised aminotransferases
- jaundice
Lung inflam -> persitent cough, dyspnoe
Renal issues -> oedema, oligouria
Immunocompromicse -> increased infection
Clotting dysfunction (thrombocytopenia) -> bleeding, haematuria/haematemesis, bruising
Treatogenic
