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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

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2
Q

What % of UK population on medication

A

48% (in 2016?)
(prescriptions have increased by 47% between 2006-2016)

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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.

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4
Q

What percentage of the human genome is estimated to be druggable

A

10-15% (with a small molecule approach)

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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

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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

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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
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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

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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

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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
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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
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12
Q

What % of drugs are GCPRs targeted by

A

> 30%

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13
Q

What kind of ligands can you have for GCPRs

A

Ligands include:
- light energy
- peptides
- lipids
- sugars
- proteins

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14
Q

GIve an example of GCPRs

A

olfactory receptors

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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

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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

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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)
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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

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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

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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?
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21
Q

Define pharmacodynamics

A

Relating to the effects of drugs and the mechanism of their action

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22
Q

Define tolerance

A

Down regulation of the receptors with prolonged use
- Need higher doses to achieve the same effect

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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.

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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

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25
Q

Types of receptor ligands (in teems of the effect they have)

A

Agonist - a compound that binds to a receptor and activates it

Antagonist - a compound that reduces/blocks the effect of an agonist

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26
Q

What is the two state model of receptor activation

A
  • describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”.
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27
Q

Can different agonists mediate the same response through different receptors?

A

Yes

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28
Q

What is intrinsic activity

A

Refers to the efficacy of a drug.

The ability of a drug-receptor complex to produce a maximum functional response

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29
Q

How can antagonists reverse effects of agonist

A

Competitive antagonism
Non-competitive antagonism

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30
Q

What are the 2 catagories of cholinergic receptor characterisation?

A

Nicotinic
Muscarinic

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31
Q

What is an agonist and an antagonist of muscarinic receptors (mAChR)

A

Agonist - muscarine

Antagonist - atropine

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32
Q

What is an agonist and an antagonist of nicotinic receptors (nAChR)

A

Agonist - nicotine

Antagonist - curare

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33
Q

Characterisations of different histamine receptors

A

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

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34
Q

What are factors governing drug action

A

Receptor-related
- affinity
- efficacy

Tissue-related
- receptor number
- signal amplification (dependant on receptor)

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35
Q

What is affinity

A

Describes how well a ligand binds to the receptor

It is a property shown by both agonists and antagonists

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36
Q

What is efficacy?

A

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

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37
Q

What happens when you block receptors

A

The response takes longer to reach the maximal point. It reduces potency.

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38
Q

What is a receptor reserve

A

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

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39
Q

Why is receptor reserve useful

A

Reduces risk of total inactivation due to a high-affinity or permanently binding antagonist

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40
Q

What occurs in signal transduction

A

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

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41
Q

What is signal amplification

A

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

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42
Q

What is allosteric modulation

A

Creating a different response by a ligand binding to a receptor at an allosteric (other) site (a site which is not the orthosteric site)

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43
Q

What is inverse agonism and why can it occur

A

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

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44
Q

What is tolerance

A

The slow reduction in agonist effect over time

caused by continuously, repeated high concentrations

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45
Q

What is desensitisation

A

Rapid reduction in agonist effect

Due to complete change in receptor (- e.g. in type 2 diabetes?)

Receptors are:
- uncoupled
- internalized
- degraded

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46
Q

Why is selective a better term than specific when referring to drug interactions

A

No compound is ever truly specific

Leads to off target effects

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47
Q

Why can non-selective drugs cause problems

A

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.

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48
Q

Define affinity

A

The extent or fraction to which a drug binds to receptors at any given drug conentration

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49
Q

What is an enzyme inhibitor?

A

A molecule that binds to an enzyme and (normally) decreases its activity

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50
Q

What does an enzyme inhibitor do?

A

It prevents the substrate from entering the enzyme’s active site and prevents it from catalysing its reaction

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51
Q

What are the classes of enzyme inhibitors?

A

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

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52
Q

Give an example of an enzyme which is in itself a drug product

A

streptokinase – a clot buster

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53
Q

What are statins?

A

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

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54
Q

What is the purpose of statins?

A

Reduce cardiovascular disease (CVD) and mortality in those who are at high risk.

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55
Q

How does RAAS increase blood pressure

A

By increasing the amount of salt and water the body retians

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56
Q

What is RAAS inhibited by, how and why?

A

Inhibited by Angiotension Converting Enzyme inhibitors (ACE inhibitors) IN ORDER TO reduce blood pressure.

It functions by reducing angiotensin II production by blocking ACE

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57
Q

What were the names of 1st and 2nd generation ACE inhibitors respectively?

A

Captopril

Enalaprilat (Enalapril)

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58
Q

How can the ACE system be hijacked?

A

SARS-CoV-2 uses ACE2 as an entry receptor

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59
Q

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.

A

Parkinson’s disease

Affects one person in every 500
(1:100 in over 60s)

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60
Q

What are the symptoms of Parkinson’s

A

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

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61
Q

What is the name of the key substrate in Parkinson’s and where does it come from

A

L-DOPA

produced from the amino acid L-Tyrosine as a precursor for neurotransmitter biosynthesis - crosses the Blood Brain Barrier

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62
Q

How can Parkinson’s be treated?

A

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

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63
Q

Types of ion transporters

A

Passive (no energy required)
- Symporter
- Na/K/2Cl , NaCl
- Channels
- Na, Ca, K, Cl

Active (requires energy)
- ATP-ases
- Na/K, K/H

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64
Q

What are the 3 main types of protein ports in cell membranes?

A

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)

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65
Q

Give an example of a symporter and the drug that can affect it

A

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

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66
Q

Where can ion channels exist

A

In many tissues, especially excitable tissues

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67
Q

Give types of ion channels and the conditions related to their dysfunction

A

Epithelial (Sodium) – heart failure
Voltage-gated (Calcium, Sodium) – nerve, arrhythmia
Metabolic (Potassium) – diabetes
Receptor Activated (Chloride) - epilepsy

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68
Q

What is an epithelial (sodium) channel (ENaC) - function and associated drugs

A

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

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69
Q

Voltage-gated (Calcium) channels - where are they found and function

A

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.

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70
Q

What is an action potential

A

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.

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71
Q

How are voltage-gated (calcium) channels inhibited and why

A
  • 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
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72
Q

Voltage gated (sodium) channels - function

A

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.

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73
Q

Which drug inhibits voltage gated Na channels

A

Lidocaine (anaesthetic) blocks transmission of the action potential. Also blocks signaling in the heart reducing arrhythmia.

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74
Q

Voltage gated (Potassium) Channels - structure and how do they function

A

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)

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75
Q

What is the purpose of voltage gated K channels

A

Regulate insulin in Pancreas: β Islets of Langerhans

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76
Q

Name drugs that inhibit K+ channel, how they function, and what they are used for

A

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

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77
Q

Receptor mediated (Chloride) channels - structure, function, example of receptor

A

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

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78
Q

Which drug is used to increase permeability of ligand gated channels to chloride and what does it do

A

Barbiturates

enhance activation of GABA A receptor - produces greater inhibition

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79
Q

What’s another name for receptor-mediated (chloride ) channels

A

ionotropic receptors

ligand-gated

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80
Q

What are Sodium pumps, what do they do, for what purpose

A

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

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81
Q

What inhibits Sodium pumps, how does it work, what is it used for

A

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

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82
Q

What is proton pump in stomach, what does it do, for what purpose

A

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.

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83
Q

What drugs target stomach proton pumps, what do they do, for what purpose

A

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)

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84
Q

Half-life of omeprazole? How long does it work for?

A

half-life 1h, but works for 2-3 days

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85
Q

What is an alternative anti ulcer therapy other than omeprazole (don’t think i actually need to know)

A

H2-receptor antagonists (binds to histamine receptors)

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86
Q

Examples of irreversible inhibitors of cholinesterase

A

Insecticides (Diazinon)

Nerve gases (Sarin)

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87
Q

What 5 of hospital admissions due to pesticide? How many deaths worldwide per year?

A

80%

200, 000 deaths worldwide per year

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88
Q

Examples of muscarinic symptoms caused by organophosphates

A

salivation, defaecation, urination, bradycardia , hypotension

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89
Q

Examples of nicotinic symptoms caused by organophosphates

A

twitching, servere weakness paralysis, diaphragm

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90
Q

Examples of CNS symptoms caused by organophosphates

A

Confusion, loss of reflexes, convulsions, coma

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91
Q

What are organophosphates?

A

Organophosphorus substances used as insecticides and nerve gases - typically irreversible acetylcholinesterase inhibitors

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92
Q

Examples of irreversible enzyme inhibitors?

A

Omeprazole

Aspirin (COX inhibitor)

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93
Q

What is pharmacokinetics

A

study of drug metabolism

  • occurs through specialised enzymatic systems
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94
Q

Why is metabolism of drugs important?

A

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)

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95
Q

What are xenobiotics

A

Compounds foreign to an organism’s normal biochemistry, such any drug or poison

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96
Q

What is bioavailability of a drug?

A

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

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97
Q

What factors need to be considered in pharmacokinetics

A

Absorption, Metabolism, Distribution, Excretion

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98
Q

What is cytochrome p450, where are they found, function, purpose

A

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.

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99
Q

Characteristics of autonomic nervous system

A

Involuntary
Involves an enteric nervous system as well (both sympathetic and parasympathetic)
Conveys all outputs to body from cns except for voluntary stuff

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100
Q

Cholinergic and adrenergic meanings

A

Cholinergic - relates to acetylcholine
Adrenergic - relates to adrenaline

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101
Q

Characteristics of sympathetic nervous system

A

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

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102
Q

Characteristics of parasympathetic nervous sytem

A

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

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103
Q

Functions of parasympathetic and sympertetic systems.

A

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

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104
Q

What are the 2 main neurotransmitters in autonomic system

A

ACh (acetylcholine)
Noradrenaline

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105
Q

Where does ACh act

A

muscarinic pre-ganglion reseptors in both sympathetic and parasympathetic systems

nicotinic post-ganglionic receptors in parasympathetic system

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106
Q

Where does noradrenaline act

A

on alpha and beta adreno post-ganglionic receptors in sympathetic system

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107
Q

What are exceptions to the ACh/noradrenaline generalisation

A

Sweat glands function sympathetically but use ACh in postganglion

NO is released in parasympathetic termini in blood vessels

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108
Q

Which parts of the nervous system do nicotine and muscarine affect?

A

Nicotine stimulates both autonomic nervous systems

Muscarine activates muscarinic - paraysmpathetic response.
Muscarine poisoning has parasympathetic action (except for sweating which is actually sympathetic)

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109
Q

Examples of NANC (non-adrenergic, non-cholinergic autonomic transmitters)

A

nitric oxide and vasoactive intestinal peptide
(parasympathetic)

ATP and neuropeptide Y (sympathetic system)

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110
Q

How many muscarinic receptors are there and what type of receptor are they

A

5

GPCRs (G protein coupled receptors)

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111
Q

Where are M1 receptors found

A

mainly in brain

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112
Q

Where are M2 receptors found and function

A

mainly in heart.

SA node (decreases heart rate), decrease conduction velocity at AV node (increases pr interval)

113
Q

M3 receptor location and function

A

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
Q

M4/5 receptor location

A

mainly in CNS

115
Q

Example of muscarinic agonists

A

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
Q

Examples of muscarinic antagonists

A

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
Q

Drugs to treat bronchoconstriction, how they work, side effects

A

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
Q

Examples of anticholinergics

A

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
Q

What is ACh involved in outside the autonomic syste,

A

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
Q

What does acetylcholinesterase do

A

Breaks down ACh at synapses - Terminates neuronal transmission and prevents ACh dispersal

121
Q

Drugs related to ACh

A

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
Q

Role of ACh in myasthenia gravis and treatment

A

Autoimmune destruction of nicotinic ACh receptors results in muscle weakness

Give anti-acetylcholinesterase to increase the amount of acetylcholine available to
cause signalling

123
Q

Examples of anti-cholinergic side effects. Why does this happen?

A

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
Q

Examples of drugs wiith antigolinergic side effects

A

Tricyclic antidepressants,
some early antihistamines,
some anti-emetics (prochlorperazine)

125
Q

What drug can be used to counteract side effect of bradycardia from anticholinesterases?

A

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
Q

Name most important catecholamines

A

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
Q

Agonists, Mechanism and Consequence for Alpha 1 adreno receptors

A

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
Q

Agonists, Mechanism and Consequence for Alpha 2 receptors

A

Noradrenaline and adrenaline can equally affect

Gi signalling, inhibition of cAMP generation

Mixed effects on smooth muscle, reduces vascular tone and BP

129
Q

Agonists, Mechanism and Consequence for Beta 1 receptors

A

Noradrenaline and adrenaline can equally affect

Gs, raises cAMP

Chronotropic and inotropic effects on heart

130
Q

Agonists, Mechanism and Consequence for Beta 2 receptors

A

Adrenaline much more than noradrenaline

Gs, raises cAMP

Relaxes smooth muscle (delays premature labour, asthma)

131
Q

Agonists, Mechanism and Consequence for Beta 3 receptors

A

Noradrenaline more than adrenaline

Gs, raises cAMP

Enhances lipolysis, relaxes bladder detrusor

132
Q

Example of alpha 2 agonist

A

clonidine - used in ADHD to help concentration, aso lowers BP

133
Q

Where are alpha 2 receptors found

A

Barin and peripheral

134
Q

Examples of use of adrenaline and noradrenaline as treatment

A

Adrenaline given intramuscularly (or via IV in serious cases) for anaphylactic shock

Noradrenaline given IV for septic shock in ITU setting

135
Q

Examples of alpha blockers (atagonists)

A

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
Q

Are there any notable clinically significant alpha 2 blockers?

A

No

137
Q

What does beta 1 activation cause

A

increase heart rate and chronotropic effects, and may increase risk of arrhythmias

Also affects carbohydrate and lipid metabolism (esp. glucose metabolism in liver)

138
Q

Effect of beta 2 activation

A

Muscle relaxation - life saving in asthma and COPD
- can delay premature labour (tocolysis)

Side effect: tremor, hyperglycemia, tachyarrythmia

139
Q

Function of beta 3 agonists

A

Can reduce over-active bladder symptoms

Also affects carbohydrate and lipid metabolism (esp. glucose metabolism in liver)

140
Q

Side effects of beta adrenergic agonism

A

tachcycardia, increase in stroke volume, renin release (increase vascular tone), lipolysis and hyperglycaemia

141
Q

Uses of beta blockers

A
  • Angina
  • MI prevention
  • High blood pressure
  • Arrhythmias
  • Heart failure
  • Anxiety
142
Q

Side effects of beta blockers

A
  • Cardiac depression
  • Bradycardia
  • Cold extremities
  • Bronchoconstriction
  • Hypoglycaemia
  • Tiredness
143
Q

Location of beta-2 receptors and their roles when activated

A

Bronchi - bronchodilation

Bladder wall - inhibits micturition

Uterus - inhibits labour

Skeletal muscles - increases contraction speed (can induce tremor)

Pancreas - increase insulin and glucagon secretion

144
Q

What can beta blockers do

A

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
Q

What can be used as an antidote for beta -blocker overdose

A

Glucagon

increases heart rate and myocardial contractility irrespective of prescence of beta blocker - bypass beta-adrenergic receptor site

146
Q

Examples of beta blockers

A
  • 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
Q

Examples of drugs with less direct effects relating to NAd

A

Methyldopa:
- last resort antihypertensive
- useful in pre-eclampsia and eclampsia that blocks NAd synthesis

MAOIs prevent NAd breakdown (anti-depressants)

148
Q

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

A

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
Q

What does opium contain

A

Some codine and around 25% morphine

150
Q

Why should you never give codine to breastfeeding mothers or children?

A

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
Q

What is the oral bioavailability of morphine

A

50% of oral (enteral) morphine is metabolised by the first pass metabolism by liver

152
Q

How long does it take for oral morphine to work

A

around 1-2 hours

153
Q

What difference in dose would there between enteral and parenteral morphine administration?

A

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
Q

How long does a single dose of morphine last?

A

around 3-4 hours

(single dose is usually 10mg orally; 5mg subcutaneously)

155
Q

What type of morphine is used in pallative care

A

Slow release preparations that release twice a day

(MST Conntinus)

156
Q

How long does it take a sub-cutaneous morphine dose to work

A

1/2 hour

peaks at 1 hours

157
Q

How can analgesia be delivered? Which is fastest

A

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
Q

Issues associated with patient controlled analgesia

A

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
Q

What are the major issues with morphine

A

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
Q

Which vitamin is required for blood clotting

A

vitamin K - Prothrombin is vitamin K-dependant

may need to be given to individuals on blood thinners if they are bleeding extensively

161
Q

what is diamorphine, its characteristics

A

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
Q

When was controlled drugs (CDs) legislation started

A

1920s

163
Q

What is current CD legislation

A

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
Q

Examples of synthetic and semi-synthetic opioids

A

1911 - dihydrocodeine

1916 - oxycodone

1939 - pethidine

Modern - more specific and potent
- fentanyl, alfentanyl, remifentanyl

165
Q

characteristics of dihydrocodeine

A

about 1.5x more potent than codeine - already metabolized so works in pretty much everyone

166
Q

characteristics of oxycodone

A

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
Q

what are fentanyl and varients used for

A
  • very potent (50x stronger than heroin)

used as trans dermal patches for chronic cancer pain, in ITU and as anasthesia

168
Q

When does opioid withdrawal start? lasts how long?

A

starts in 24 hours

lasts around 72 hours

169
Q

How do naturally occuring opioids work

A

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
Q

What is the natural purpose of opioids

A

Descending inhibition of pain
Part of the fight or flight response
- Never designed for sustained activation

171
Q

What does sustained activation of the pain modulation/descending inhibitory pathway do

A

leads to tolerance and addiction (psychological craving and physical withdrawal)

172
Q

names of opioid receptors

A

mu (greek letter m for morphine), delta and kappa

nociceptin opioid-like receptors
- MOP, KOP, DOP, NOP

173
Q

which species’ have main opioid receptors

A

all vertebrates

174
Q

Which receptor do all present opioid drugs work on

A

mu - they are µ agonists

175
Q

What effect does kappa agonism have

A

depression (NOT euphoria)

176
Q

Where are opioid receptors mainly found in the body

A

embedded in outer membrane of neurons

177
Q

Side effects of opioids

A

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
Q

Why do opioids have side effects

A

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
Q

What do you do when faced with a case of opioid induced respiratory depression

A
  • 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
Q

Which drug is given to counter opioid induced respiratory depression

A

Naloxone

181
Q

Issues of using opioids for non-cancer pain

A
  • 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
Q

Where is opioid addiction more common in the UK

A

Socially deprived areas

183
Q

What is the MHRA (medicine and healthcare products regulatory agency) advice for prescribing opioids for chronic non-cancer pain

A
  • 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
Q

What is codine metabolised to morphine by

A

cytochrome CYP2D6

185
Q

pharmacogenetics of codeine metabolism

A
  • 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
Q

What is morphine metabolised to

A

morphine 6 glucuronide
- which is more potent than morphine and is renally excreted

187
Q

What issues can morphine use in patients with renal failure cause? What precautions need to be taken

A

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
Q

What is another example of an opioid pro-drug (not codeine)

A

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
Q

Secondary effect of tramadol

A

a serotonin and nor-epinephrine reuptake inhibitor
- can be useful for chronic pain

190
Q

Issues with tramadol side effects

A

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
Q

What is an adverse drug reaction (ADR)

A

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
Q

What % of hospital admissions, issues in inpatients and deaths are caused by ADRs

A

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
Q

To what % does WHO say ADRs are preventable

A

WHO state 60% of ADRs are preventable

194
Q

Negative impacts of ADRs on patients

A

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
Q

Examples of past ADRs

A

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
Q

When was the food, drug and cosmetic act passed in the US

A

1938

197
Q

What is a side effect

A

an unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment
- often minor and predictable

198
Q

Side effect vs ADR

A

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
Q

Examples of beneficial side effects

A

In men:
PDE5 inhibitors improve urinary flow (for things like erectile dysfunction)
Minoxidil for hypertension led to hair growth

200
Q

Name the catagories of types of effects produced by ADRs

A

Toxic effects (beyond therapeutic range)

Collateral effects (within therapeutic range)

Hyper-susceptibility effects (below therapeutic range)

201
Q

When can toxic ADR effects occur

A

If dose is too high
If drug excretion is reduced by renal/hepatic function
Due to interaction with other drugs

202
Q

Examples of ADR toxic effects

A

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
Q

When do collateral effects occur (ADRs)

A

At standard theraputic doses

204
Q

Examples of ADR collateral effects

A

Beta blockers causing bronchoconstriction

Broad spectrum antibiotics causing clostridium difficile and pseudomembranous colitis (inflammation of colon due to C difficile overgrowth)

205
Q

When do hypersusceptibility reactions occur (ADRs)

A

At sub theraputic doses

e.g. anaphylaxis from penicillin

206
Q

What is the range of severity of ADRs

A
  • Mild e.g. nausea, drowsiness, urticaria

TO

  • severe e.g. resp. depression, catastrpohic haemorrhage, anaphylaxis, neutropenia (low neutrophil count)
207
Q

Risk factors for ADRs

A

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
Q

Causes for ADRs

A
  • Pharmaceutical variation
  • Receptor abnormality
  • Abnormal biological system unmasked by drug
  • Abnormalities in drug metabolism
  • Immunological
  • Drug-drug interactions
  • Multifactorial
209
Q

Example of pharmacytical variation causing ADRs

A

eosinophilia-myalgia syndrome with L-tryptophan (had a pharmacutical contaminant from company making it)

210
Q

Example of receptor abnormality causing ADRs

A

malignant hyperthermia with general anaesthetics

211
Q

Example of ADR due to abnormal biological system unmasked by drug

A

primaquine induced haemolysis in patients deficient in glucose 6-phosphate dehydrogenase

212
Q

Example of ADR due to abnormalities in drug metabolism

A

isoniazid induced peripheral neuropathy in people deficient in the enzyme N-acetyl transferase (that is, those who are slow acetylators)

213
Q

Example of ADR due to immunological reasonons

A

penicillin induced anaphylaxis

214
Q

Example of ADR caused by drug interactions

A

increased incidence of hepatitis when isoniazid is prescribed with rifampicin

215
Q

Example of ADR causde by multifactorial reasons

A

halothane hepatitis

216
Q

What types of time dependant reactions can you have with ADRs

A
  • Rapid reactions
  • First dose reactions
  • Early reactions
  • Intermediate reactions
  • Late reactions
  • Delayed reaction
217
Q

Example of rapid ADR

A

red man syndrome due to histamine release with rapid administration of vancomycin

218
Q

Example of first does ADR

A

hypotension from ACE inhibitors

219
Q

Example of early ADR

A

nitrate induced headache

220
Q

Example of early ADR

A

nitrate induced headache

221
Q

Example of early ADR

A

nitrate induced headache

222
Q

Example of intermediate ADR

A

delayed immunological reactions such as Stevens-Johnson syndrome (flu like symptoms, painful ras and necrolysis of top layer of skin) with carbamazepine

223
Q

Examples of late ADR

A

adverse effects of corticosteroids,

seizures on withdrawal of long term benzodiazepines

224
Q

Example of delayed ADR

A

Thalidomide causes phocomelia in children born to those pregnant individuals

225
Q

Rawlins Thompson classification of ADRs

A

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
Q

ways to asses ADRs

A

Rawlins Thompson classification

DoTS

227
Q

Characteristics of a Type A ADR

A

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
Q

Charcteristics of Type B ADRs

A

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
Q

What % of ADRs are Type B

A

10-15%

230
Q

What is idiosyncrasy

A

Inherent abnormal response to drug
- a genetic abnormallity
- rare but serius

231
Q

What kind of abnormalities cause an idiosyncrasy

A
  • enzyme deficiency
  • abnormal receptor activity
232
Q

example of enzyme dificiency related idiosyncrasy

A

X-linked enzyme Glucose 6 phosphate dehydrogenase (G6PD) deficiency + primaquine →haemolysis and haemolytic anaemia

233
Q

example of abnormal receptor activity related idosyncrasy

A

Malignant hyperpyrexia with general anaesthetics. Sudden huge rise in calcium concentration → increase in muscle contraction → increase in metabolic activity → rise in body temperature

234
Q

Examples of types of hypersensitivity reactions

A
  • 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
Q

Characteristics of Type C ADR

A

Uncommon
Related to cumulative dose
Time related

236
Q

Example of type C ADR

A

Steroids and osteoporosis
Analgesic nephropathy
Colonic dysfunction due to laxatives

237
Q

Characteristics of type D ADR

A

Uncommon
Usually dose related
Shows itself some time after the use of the drug

238
Q

Examples of type D ADRs

A

Teratogenesis – drugs taken in the first trimester eg thalidomide
Carcinogenesis eg cyclophosphamide and bladder cancer

239
Q

Overview of thalidomide scare

A

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
Q

Characteristics of type E ADR

A

Uncommon
Occurs soon after drug withdrawn

241
Q

Examples of type E ADR

A

Opiate withdrawal
Glucocorticoid abruptly withdrawn leads to adrenocortical insufficiency
Withdrawal seizures when anticonvulsants are stopped

242
Q

Characteristics of type F ADR

A

Common
Dose related
Often cause by drug interactions

243
Q

Examples of type F ADR

A

Failure of oral contraceptive pill with enzyme inducers

Failure of therapeutic effect in patients taking warfarin leading to CVA (cerebral vascular accident)

244
Q

When should we suspect an ADR?

A

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
Q

What should be done in response to an ADR?

A

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
Q

Most common drugs to have ADRs

A

Antibiotics
Anti-neoplastics
Cardiovascular drugs
Hypoglycaemics
NSAIDS
CNS drugs

247
Q

Most common systems to be affectd bby ADRs

A

GI
Renal
Haemorrhagic (vascular)
Metabolic
Endocrine
Dermatologic

248
Q

Common ADRs

A

Confusion
Nausea
Balance problems
Diarrhea
Constipation
Hypotension

249
Q

How can ADRs be avoided? And what % are considered to be preventable

A

30-50% are preventable

Take care to consider rug interactions
Do not prescribe Inappropriate medication
Do not prescribe medicationif not not necessary

250
Q

How is information on ADRs gathered

A

Pre-clinical phase 1 trials
Clinical phase 1 to 3 trials
Post marketing surveillance
Yellow card reporting

251
Q

What do the MHRA do

A

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
Q

What is the yellow card scheme

A

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
Q

What types of things do you report on a Yellow Card

A

All suspected reactions for
- herbal medicines
- black triangle ▼ drugs

All serious suspected reactions for
- established drugs, vaccines and contrast media
- drug interactions

254
Q

What is a serous reaction

A

A reaction that:
- is fatal
- is life threatening
- is disabling or incapacitating
- results in hospitalisation
- prolongs hospitalisation

255
Q

What is a black triangle drug

A

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
Q

Why report ADRs?

A
  • 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
Q

Who can report on a Yellow Card

A

Doctors, dentists, coroners, pharmacists, nurses, including midwives and health visitors, radiographers, optometrists.

Patients (also parent or carers - since 2005)

258
Q

Which 4 critical pieces of information must be included on a Yellow card report

A

Suspected drug(s)
Suspect reaction(s)
Patient details
Reporter details

(Also add any additional useful information)

259
Q

Background for how allergic reactions can occur

A

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
Q

Common target organs of allergy

A

Skin
respiratory tract
GI tract
blood
blood vessels

261
Q

Most common drugs to cause allergic reactions

A

Antibiotics and NSAIDS/aspirin

262
Q

How and why should you double check with a patient who states they have an allergy

A

Ask the patient what actually happened to make them believe they were allergicthey may have misinterpreted an intolerence for allergy

263
Q

Define hypersensitivity

A

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
Q

What % of people have anaphylaxis at some point in life

A

0.05-2

265
Q

Overview of how a type 1 hypersensitivity (acute anaphylactic)reaction works

A
  • 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
Q

How fast does anaphylaxis occur

A

within minutes
- lasts 1-2 hours

267
Q

What physiological reactions does anaphylaxis cause

A

Vasodilation
Increased vascular permeability
Bronchoconstriction
Urticaria
Angio-oedema

268
Q

What are the 2 most common deaths associated with anaphylactic exposure

A

Drug anaphylaxis is most common form of death from anaphylaxis

Insect venom second most common cause

269
Q

What % of people have biphasic anaphylactic response

A

1-20%

270
Q

Basic overview of how type 2 hypersensitivity reactions occur

A

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
Q

Basic overview of type 3 hypersensitivity reaction

A

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
Q

Basic overview of type 4 reaction

A

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
Q

Overview of non-immune anaphylaxis

A

Previously called Anaphylactoid reactions
Due to direct mast cell degranulation
No prior exposure
Clinically identical

274
Q

Main features of anaphylaxis

A

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
Q

How many deaths per year from anaphylaxis in the UK

A

20

276
Q

Clinical criteria for allergy to drug

A

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
Q

Methotrexate mechanism of action

A

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
Q

Methotrexate side effects

A

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

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