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PHASE 2A > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Define pharmacodynamics

A

How drugs effect the body

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2
Q

Define pharmacokinetics

A

How the body effects the drug (ADME)

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3
Q

Name 3 reasons why pharmacology is becoming such a big problem

A
  1. Age - more older people
  2. Polypharmacy - more people on more than one medication
  3. Lifestyle - ‘over the counter’ use increasing and natural remedies
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4
Q

Name 4 types of drug interaction

A
  1. Synergy
  2. Antagonism
  3. Summation
  4. Potentiation
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5
Q

What is synergistic drug interaction?

A

Drugs work together to make a combined greater effect (1+1>2)

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6
Q

Describe antagonistic drug interaction

A

2 drugs that cancel each other out (1+1=0)

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7
Q

Describe summation drug interaction

A

Drugs work together to create combined effect (1+1=2)

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8
Q

Describe potentiation drug interaction

A

Drug A has same effect it causes drug B to have an increased duration so greater effect (1+1=1+1.5)

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9
Q

Name 5 patient risk factors for drug interaction

A
  1. Polypharmacy
  2. Old age
  3. Genetic
  4. Hepatic disease
  5. Renal disease
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10
Q

Name 3 drug risk factors for drug interaction

A
  1. Narrow therapeutic index
  2. Steep dose/response curve
  3. Saturable metabolism
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11
Q

Name 4 ways to avoid drug interactions

A
  1. Prescribe rationally
  2. BNF
  3. Ward pharmacist
  4. PIL - Patient/product information leaflet
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12
Q

How does grapefruit juice effect warfarin?

A

Interacts with warfarin - affects CYP450 and its ability to bind with proteins

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13
Q

Name 4 drugs that induce Acute Kidney Injury (AKI)

A
  1. NSAIDs
  2. Gentamicin
  3. ACE Inhibitors
  4. Furosemide
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14
Q

Define pharmacology

A

Branch of medicine concerned with the uses, effects, and modes of action of drugs

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15
Q

Define ‘druggability’

A

Ability of a protein target to bind small molecules with high affinity

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16
Q

What are the most common drug targets?

A

Proteins

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17
Q

Name 4 types of drug target

A
  1. Receptors
  2. Enzymes
  3. Transporters
  4. Ion channels
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18
Q

Define receptor

A

A component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects

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19
Q

What can ligands be?

A

Exogenous –> Drugs

Endogenous –> Hormones, neurotransmitters

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20
Q

Name 2 types of neurotransmitter

A

Acetylcholine

Serotonin

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21
Q

Give 2 examples of autacoids

A

Cytokines

Histamine

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22
Q

Name 4 types of receptor

A
  1. Ligand gated ion channels
  2. G protein couples receptors
  3. Kinase-linked receptors
  4. Cytosolic/nucelar receptors
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23
Q

Explain how ligand gated ion channels work

A

Ligand binds to a ligand binding motif on surface of channel which induces transformational change to the protein
Open channel pore enabling free movement of an ion into the inside

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24
Q

Give an example of a ligand gated ion channel receptor

A

Nicotinic ACh receptor

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25
Q

How do G protein couples receptors work?

A 
G proteins (GTPases) act as molecular switch (on when bound to GDP and off when bound to GTP)
Ligands include light energy, peptise, lipids, sugars and proteins 
Majority of GPCRs interact with PLC or adenylyl cyclase (AC)
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26
Q

How do kinase-linked receptors work?

A

Transmembrane receptors activated when the binding of an extracellular ligand causes enzymatic activity on the intracellular side

  1. Signal dimer binds
  2. Kinase activity stimulated
  3. Tyrosines are phosphorylated
  4. Intracellular proteins bind to phosphor-tyroisne docking sites
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27
Q

Explain how cytosolic/nuclear receptors work

A

Zinc fingers bind to DNA and modify gene transcription

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28
Q

Give an example of a drug that uses cytosolic/nuclear receptors

A

Tamoxifen (breast cancer)

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29
Q

What kind of imbalance can lead to pathology?

A

Imbalance of chemicals or receptors

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30
Q

Name 2 conditions that can arise from an imbalance in chemicals

A
  1. Allergy –> increased histamine

2. Parkinson’s –> reduced dopamine

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31
Q

Name 2 conditions that can arise from an imbalance in receptors

A
  1. Myasthenia Gravis –> loss of ACh receptors

2. Mastocyosis –> increased c-kit receptors

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32
Q

Define agonist

A

A compound that binds to a receptor and activates it

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33
Q

Define antagonist

A

A compound that reduces the effect of an agonist

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34
Q

What shape is a log concentration agonist response curve

A

Sigmoidal

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35
Q

Define potency

A

Measure of how well a drug works

EC50 = concentration that gives half the maximal response

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36
Q

Define Efficacy (Emax)

A

Maximum response achievable form a dose

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37
Q

What is a partial agonist?

A

Even with 100% occupancy, maximal response is not seen

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38
Q

Define intrinsic activity (efficacy)

A

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

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39
Q

What is the equation for intrinsic activity?

A

IA = Emax of partial agonist/Emax of full agonist

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40
Q

What is seen on a graph if compound A is more potent than compound B?

A

Compound A has a lower concentration which provides a 50% response - lower EC50

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41
Q

What is seen on a graph if compound A is more efficacious than compound B?

A

The maximum response for compound A is greater than that of compound B

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42
Q

Name the 2 types of antagonism

A
  1. Competitive

2. Non-competitive

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43
Q

What site does a competitive antagonist bind to?

A

The same site as the agonist on the receptor

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44
Q

What site does a non-competitive antagonist bind to?

A

Binds to an allosteric (non-agonist) site on the receptor

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45
Q

What happens to the response when a competitive antagonist is added?

A

Same thing happens but a greater concentration of agonist is needed (max response can be achieved)

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46
Q

What happens to the response when a non-competitive antagonist is added?

A

The response can’t reach its maximum

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47
Q

What do cholinergic receptors respond to?

A

Neurotransmitters

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48
Q

Name the 2 categories of cholinergic receptor

A
  1. Muscarinic
  2. Nicotinic
    One is a GPCR and the other is an ion channel
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49
Q

Name an agonist for a H2 receptor

A

Histamine - contraction of ileum, acid secretion from parietal cells

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50
Q

Name a antagonist for a H2 receptor

A

Mepyrmaine

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51
Q

Name 2 categories of factors that govern drug action

A
  1. Receptor related

2. Tissue related

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52
Q

Name 2 receptor related factors that govern drug action

A
  1. Affinity

2. Efficacy

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53
Q

Define affinity

A

How well a ligand binds to the receptor

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54
Q

Define efficacy

A

How well a ligand activates the receptor

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55
Q

Is affinity shown by agonists or antagonists?

A

Shown by both

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56
Q

Is efficacy shown by agonists or antagonists?

A

Only by agonists

Antagonist have zero efficacy as they don’t activate receptors

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57
Q

Name 2 tissue related factors that govern drug action

A
  1. Receptor number

2. Signal amplification

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58
Q

How does receptor number affect drug action?

A

If more receptors available the quicker an action is
Or increase in antagonist = decrease in receptors available
Dose-response curve shifts left - drug potency is increased

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59
Q

How does signal amplification work?

A

Signal cascade –> signal amplification –> response
Can be edited by same receptor, same agonist can cause signal amplification in one tissue compared to another
Less signal amplification = reduced drug response

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60
Q

What is a receptor reserve?

A

Where an agonist needs to activate only a small fraction of the existing receptors to produce the maximal system response

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61
Q

Does a partial agonist have a receptor reserve?

A

NO - even with 100% occupancy, maximal response is not seen

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62
Q

What is allosteric modulation?

A

An allosteric ligand binds at a different site on a receptor and influences the role of an agonist

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63
Q

What is inverse agonism?

A

When a drug binds to the same receptor as an agonist but induces pharmacological response opposite to that of the agonist

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64
Q

Define tolerance

A

Reduction in drug (agonist) effect over time

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65
Q

Give 3 ways a receptor can be desensitised

A
  1. Uncoupled - agonist would be unable to interact with a GPCR
  2. Internalised - endocytosis, receptor is taken into vesicles in the cell
  3. Degraded
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66
Q

What is an enzyme inhibitor?

A

Molecule that binds to an enzyme and decreases its activity

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

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67
Q

Name the 2 types of enzyme inhibitor

A
  1. Irreversible inhibitors

2. Reversible inhibitors

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68
Q

How do irreversible inhibitors work?

A

React with enzyme and change it chemically (e.g. via a covalent bond)

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69
Q

How do reversible inhibitors work?

A

Bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzymes, the enzymes-substrate complex, or both

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70
Q

What do statins inhibit?

A

HMG-CoA reductase inhibitors

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71
Q

What step do statins block?

A

The rate limiting step - HMG-CoA –> Mevalonic acid

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72
Q

What is the purpose of statins?

A

To reduce the levels of ‘bad cholesterol’, reduce CVD and mortality in those who are at high risk

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73
Q

What do ACE inhibitors do?

A

Reduce angiotensin II production therefore reducing blood pressure

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74
Q

Give 5 symptoms of Parkinson’s disease

A
  1. Hypokinesia
  2. Tremor at rest
  3. Muscle rigidity
  4. Motor inertia
  5. Cognitive impairment
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75
Q

What does Parkinson’s effect?

A

Degenerative disease of basal ganglia - Early degeneration of dopaminergic neurones in the nigrostriatal pathway

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76
Q

How does L-DOPA improve Parkinson’s symptoms?

A

Produced from aa L-tyrosine as a precursor for neurotransmitter biosynthesis

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77
Q

Name a peripheral DDC (dopamine decarboxylase) inhibitor

A

Carbidopa

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78
Q

How do peripheral DDC inhibitors improve Parkinson’s symptoms?

A

Blocks DDC in the periphery generating more for the CNS pathway

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79
Q

What happens to L-DOPA when in the CNS?

A

L-DOPA converted to Dopamine via DOPA Decarboxylase (DDC)

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80
Q

Name 2 peripheral Catechol-O-methyl transferase (COMT) inhibitors

A
  1. Tolcapone

2. Entacapone

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81
Q

How do peripheral COMT inhibitors help improve Parkinson’s symptoms?

A

Prevents breakdown of L-DOPA generating more L-DOPA for the CNS pathway d

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82
Q

Name a central COMT inhibitor

A

Tolcapone

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83
Q

How do central COMT inhibitors help improve Parkinson’s symptoms?

A

Function within CNS to prevent dopamine breakdown

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84
Q

Name 2 monoamine oxidase B inhibitor

A
  1. Selegiline

2. Rasagiline

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85
Q

How do monoamine oxidase B inhibitors help improve Parkinson’s symptoms?

A

Prevent dopamine breakdown and increase availability

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86
Q

Name 4 central dopamine receptor agonists

A
  1. Bromocryptine
  2. Pergolide
  3. Pramipexole
  4. Ropinirole
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87
Q

How do central dopamine receptor agonists help improve Parkinson’s symptoms?

A

Antagonise dopamine receptors

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88
Q

Name the types of protein port

A

Uniporters
Symporters
Antiporters

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89
Q

How does a uniporter work?

A

Uses energy from ATP to pull molecules in

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90
Q

How does a symporter work?

A

Uses the movement in of one molecule to pull in another molecules against a concentration gradient

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91
Q

How do antiporters work?

A

One substance moves against its gradient, using energy form the second substance (mostly Na+, K+ or H+) moving down its gradient

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92
Q

Give an example of a symporter

A

Na-K-Cl co transport (NKCC)

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93
Q

Name a drug that effects NKCCs

A

Furosemide - inhibits NKCC co-transport in the ascending limb of the loop of Henle (hypertension and oedema)

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94
Q

Name 5 types of ion channel

A
  1. Epithelial sodium channels (ENaC)
  2. Voltage-gated Calcium channels
  3. Voltage-gated Sodium Channels
  4. Metabolic Potassium channels
  5. Receptor Activated Channels
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95
Q

How do ENaCs work?

A

An apical membrane-bound heterotrimeric ion channel selectively permeable to Na+ ions
Causes reabsorption of Na+ ions at the CDs of the kidney’s nephrons (also in colon, lung and sweat glands)

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96
Q

Name a drug that blocks ENaCs

A

Amiloride

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97
Q

What does Thiazide do?

A

Targets Na+/Cl- cotransporter that reabsorbs Na and Cl from tubular fluid

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98
Q

How do Voltage-gated Calcium channels work?

A

VDCC found in membrane of excitable cells (muscle, glial, neurons)
At resting membrane potential, VDCCs are normally closed
Activated (opened) at depolarised membrane potentials
Ca2+ enters the cells, resulting in activation of Ca-sensitive K channels, muscular contraction, excitation of neurons etc.

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99
Q

Name a drug that effects voltage gated calcium channels

A

Amlodipine - angioselective Ca channel blocker - inhibits movement of Ca ions into vascular smooth muscle cells and cardiac muscle cells

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100
Q

How do Voltage-gated Sodium channels work?

A

Conducts Na+ through plasma membrane
An electrical current (AP) allows the activation gates to open, allowing Na+ ions to flow into the cell causing the voltage across the membrane to increase – transmits a signal

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101
Q

Name a drug that affects voltage gated calcium channels

A

Amlodipine - angioselective Ca channel blocker - inhibits movement of Ca ions into vascular smooth muscle cells and cardiac muscle cells

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102
Q

What are the 3 main conformational states of VG Na+ channels and metabolic K+ channels in excitable cells?

A

Closed
Open
Inactivated

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103
Q

Name a drug that affects VG Na+ Channels

A

Lidocaine (anaesthetic) - bocks transmission of the AP and blocks signalling in the heart reducing arrhythmia

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104
Q

How do Metabolic Potassium channels work?

A

Voltage gated K+ channels are selective for K+ over other cations such as Na+
An electric current (AP) allows the activation gates to open eliciting a downstream effect
Repetitive firing of Aps increases Ca+ influx and triggers insulin secretion

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105
Q

Where are metabolic K+ channels found?

A

Pancreas - Regulate insulin - Increased glucose leads to block of ATP depend K+ channels

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106
Q

Name 3 drugs that block K+ channels

A
  1. Repaglinide
  2. Nateglinide
  3. Sulfonylurea
    Treatment of type 2 diabetes
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107
Q

How do receptor activated channels work?

A

Ligand gated ion channels (ionotropic receptors), open to allow ions to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand) such as a neurotransmitter

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108
Q

Name a receptor activated channel

A

GABA-A receptor

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109
Q

How do GABA-A receptors work?

A

Endogenous ligand is a y-aminobutyric acid (GABAG – major inhibitory neurotransmitter on the CNS)
GABAG A receptor is post synaptic, opens Cl- channels –> induces hyperpolarisation
Drugs can enhance activation of GABA A receptor by GABA (i.e. produce greater inhibition)

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110
Q

Name 2 active transport mechanisms

A
  1. Sodium pump

2. Proton pump

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111
Q

Explain the sodium pump

A

Pumps 3 Na out and 2 K into cells, against their concentration gradients
Pumping is active (energy from ATP)
Has antiporter-like activity
Creates an electrochemical gradient between a cell and its exterior
(Reverse process is spontaneous)

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112
Q

Give an example of a drug that affects sodium pump and how it does this

A

Digoxin – inhibits Na+/K+ ATPase, mainly in the myocardium
Used for AF, atrial flutter and heart failure
This inhibition causes an increase in intracellular Na –> decreased activity of the Na-Ca exchanger –> increases intracellular Ca
Lengthen the cardiac AP –> decrease in heart rate

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113
Q

Explain the proton pump

A

The gastric H/K ATPase = proton pump of the stomach
H+/K+ ATPase is a heterodimeric protein
Exchanges K form the intestinal lumen with cytoplasmic hydronium
Responsible for the acidification often stomach and the activation of the digestive enzyme pepsin

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114
Q

What group of drugs can affect proton pumps?

A

Proton-pump inhibitors (PPIs)

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115
Q

Give an example of a PPI

A

Omeprazole - inhibits acid secretion independent of cause
Irreversible inhibition of H/K ATPase
Drug half-life = 1hr but works for 2-3 days

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116
Q

Name a ACE inhibitor

A

Ramipril

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117
Q

Name 2 COX inhibitors

A

Aspirin

Paracetamol

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118
Q

What is the major group of enzymes that are involved in drug metabolism?

A

CYPs - 75% of total metabolism

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119
Q

Name 2 naturally occurring opioids

A
  1. Morphine

2. Codeine

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120
Q

Name 4 synthetic opioids

A
  1. Fentanyl
  2. Pethidine
  3. Alfentanil
  4. Remifentanil
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121
Q

Name 3 simple chemical modifications of naturally occurring opioids

A
  1. Diamorphine
  2. Oxycodone
  3. Dihydrocodeine
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122
Q

Name an antagonist to opioids

A

Naloxone

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123
Q

How much oral morphine is metabolised by first pass metabolism?

A

50%

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124
Q

What is the IV, IM, s/c dose of morphine compared to the oral dose?

A

Half the dose if it’s being given via IV etc

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125
Q

Where are the majority of opioid receptors found?

A

CNS

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126
Q

What is diamorphine also called?

A

Heroin - more potent and faster acting than morphine

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127
Q

How are opioids given when treating chronic pain?

A

Through transdermal patches

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128
Q

How do opioids work?

A

Use existing pain modulation system
Natural endorphins and enkephalins
G protein coupled receptors – act via second messengers
Inhibit the release of pain transmitters to spinal cord and midbrain – and modulate pain perception in higher centres (euphoria) – changes the emotional perception of pain

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129
Q

Name 4 types of opioid receptors

A
  1. M receptors
  2. Delta receptors
  3. Kappa receptors
  4. Nociceptin opioid-like receptors
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130
Q

Why are kappa agonists not used?

A

Cause depression rather than euphoria

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131
Q

Why do you get side effects from opioids?

A

Opioid receptors exist outside the pain system  digestive tract, respiratory control centre and mostly opioids are given systemically

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132
Q

Name 7 side effects to opioids?

A 
Addiction
Respiratory depression 
Sedation 
Nausea and vomiting 
Constipation 
Itching 
Immune suppression
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133
Q

What should be given for opioid induced depression?

A

Naloxone - opioid antagonist

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134
Q

Why should you be careful when prescribing morphine to patients with renal failure?

A

Morphine is metabolised to morphine-6-glucuronide = more potent and is renally excreted (cleared quickly)
In renal failure, it builds up and may cause respiratory depression

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135
Q

Name 7 things the parasympathetic nervous system causes

A
  1. Constricts pupil
  2. Stimulates tear and salivary glands
  3. Slows heart rate
  4. Constricts bronchi
  5. Stimulates gastric secretion and motility
  6. Contracts the bladder
  7. Stimulates erection
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136
Q

Name 7 things the sympathetic nervous system causes

A
  1. Dilates pupil
  2. Inhibits tear and salivary glands
  3. Increases heart rate and constricts arterioles
  4. Dilates bronchi
  5. Inhibits gastric secretion and motility
  6. Relaxes the bladder
  7. Stimulates ejaculation
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137
Q

Where are the ganglia located in the parasympathetic nervous system?

A

Near their targets - short post-ganglionic nerves

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138
Q

Where are the ganglia located in the sympathetic nervous system?

A

Ganglia are near the spinal cord - longer post-ganglionic nerves

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139
Q

What neurotransmitter does the PNS release at the first ganglion?

A

Acetylcholine

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140
Q

What neurotransmitter does the SNS release at the first ganglion?

A

Acetylcholine

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141
Q

What neurotransmitter does the PNS release at the target and what receptors does it act on?

A

Acetylcholine

Acts on muscarinic receptors

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142
Q

What neurotransmitter does the SNS release at the target and what receptors does it act on?

A

Noradrenaline

Act on adrenergic receptors (alpha or beta)

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143
Q

Name the 5 types of muscarinic receptor

A

M1, M2, M3, M4 nad M5

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144
Q

Where are M2 receptors mainly located?

A

Heart - activation slows heart

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145
Q

Where are M3 receptors mainly located?

A

Glandular and smooth muscles - cause bronchoconstriction, sweating, salivary gland secretion

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146
Q

What nervous system do muscarinic agonists stimulate?

A

Parasympathetic nervous system

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147
Q

Name a muscarinic agonist and explain what it does?

A

Pilocarpine - stimulates salivation, contracts iris smooth muscles (treat glaucoma)

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148
Q

What do muscarinic antagonists do to the parasympathetic nervous system?

A

De-stimulate it by blocking muscarinic receptors

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149
Q

What do muscarinic antagonists do to the parasympathetic nervous system?

A

De-stimulate PNS by blocking muscarinic receptors

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150
Q

Name 6 muscarinc antagonists that act within the autonomic system

A 
Atropine 
Hyoscine
Ipratopium bromide 
Tiotropium 
Solifenacin
Mebeverine
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151
Q

What is Atropine used for?

A

Treat life threatening bradycardia and cardiac arrest

Prevents bradycardia and BP drop

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152
Q

What is Hyoscine used for?

A

Used in palliative care - particularly to antagonise parasympathetic given secretions

153
Q

Name a Short Acting Muscarinic Antagonist (SAMA)

A

Ipratropium bromide - treats bronchoconstriction by blocking M3 receptors

154
Q

Name a Long Acting Muscarinic Antagonist (LAMA)

A

Tiotropium

155
Q

What is Solifenacin used in the treatment of?

A

An overactive bladder

156
Q

Give an example of a nicotinic blocker that is used during surgery

A

Pancuronium or suxamethonium - inhibit ACh to inhibit muscle activity and induce relaxation in surgery

157
Q

Why does myasthenia graves result in muscle weakness?

A

Autoimmune destruction of nicotinic ACh receptors

158
Q

Give 6 side effects of muscarinic antagonists

A
  1. Worsen memory
  2. Confusion
  3. Constipation
  4. Dry mouth
  5. Blurring of vision
  6. Worsening of glaucoma
159
Q

What is the precursor to noradrenaline?

A

Dopamine

160
Q

What is the precursor to adrenaline?

A

Noradrenaline

161
Q

Where is noradrenaline released from?

A

Sympathetic nerve fibre ends

162
Q

Where is adrenaline released from?

A

Adrenal glands

163
Q

Name 5 types of adrenergic receptors

A 
Alpha 1 
Alpha 2 
Beta 1 
Beta 2
Beta 3
164
Q

What is the main agonist for Alpha 1 receptors?

A

Noradrenaline

165
Q

What does stimulation on Alpha 1 receptors cause?

A

Contracts smooth muscle - vasoconstriction (pupil, blood vessels)

166
Q

What is the main agonist for Alpha 2 receptors?

A

Noradrenaline and adrenaline act on it equally

167
Q

What does stimulation on Alpha 2 receptors cause?

A

Can cause mixed effects on smooth muscle
Can lower BP and cause vasodilation
Presynaptic inhibition - inhibits NAd release
E.g. Clonidine

168
Q

What is the main agonist for Beta 1 receptors?

A

Noradrenaline = Adrenaline

169
Q

What does stimulation on Beta 1 receptors cause?

A

Increases the heart rate and chronotropic and inotropic effects
Increases renin secretion

170
Q

What is the main agonist for Beta 2 receptors?

A

Adrenaline

171
Q

What does stimulation on Beta 2 receptors cause?

A

Relaxes smooth muscle - lifesaving in asthma and can delay onset of premature labor
Bronchodilation and vasodilation

172
Q

What is the main agonist for Beta 3 receptors?

A

Noradrenaline

173
Q

What does stimulation on Beta 3 receptors cause?

A

Enhances lipolysis and relaxes the detrusor muscle of the bladder

174
Q

Give 2 side effects of beta agonists

A
  1. Can classy tachycardia

2. Affects glucose metabolism in the liver

175
Q

Name an Alpha Blocker (antagonist)

A

Doxazosin - blocks Alpha 1 to lower BP

Tamsuloin - blocks Alpha 1A in prostate to help treat prostatic hypertrophy

176
Q

Name 4 Beta blockers

A
  1. Propanolol
  2. Atenolol
  3. Bisoprolol
  4. metoprolol
177
Q

What affects does Propanolol have and how?

A

Blocks Beta 1 and 2 receptors

Slows heart rate and reduces tremor

178
Q

What receptor does Atenolol act on and where does it cause an effect?

A

Beta 1 receptor selective

Main effect on the heart

179
Q

Give 6 uses of beta blockers

A
  1. Angina
  2. MI prevention
  3. High BP
  4. Anxiety
  5. Arrhythmias
  6. Heart failure
180
Q

Give 7 side effects of beta blockers

A
  1. Tiredness
  2. Cold extremities
  3. Erectile dysfunction
  4. Bronchoconstriction
  5. Bradycardia
  6. Hypoglycaemia
  7. Cardiac depression
181
Q

Define Allergy

A

Abnormal response to harmless foreign material

182
Q

Define Atopy

A

Tendency to develop allergies - inherited tendency to exaggerated IgE response to antigen

183
Q

How many types of hypersensitivity are there in the Gell and Coombes classification?

A

4

184
Q

What immunoglobulin is Type 1 hypersensitivity related to?

A

IgE - immunological memory to something causing an allergic response
Mast cells degranulate on re-exposure releasing inflammatory mediators

185
Q

Give 3 examples of Type 1 reactions

A
  1. Acute anaphylaxis
  2. Hayfever
  3. Asthma
186
Q

How do you treat hayfever?

A

Prevent exposure
Antihistamines
Reduction in local inflammation (steroids)
Desensitisation

187
Q

Explain Type 2 hypersensitivity

A

Ig bound to cell surface antigens
Drug or metabolite combines with protein
Body treats it as foreign protein and forms antibodies (IgG, IgM)
Caused by transfusion reactions or autoimmune disease

188
Q

Give 3 examples of Type 2 hypersensitivity reactions

A

Goodpastures syndrome
Mycoplasma pneumonia
Graves’ disease

189
Q

Explain Type 3 reactions

A

Involve immune complexes
Antigen and antibodies form large complexes and activate complement
Leucocytes attracted to the site of reaction release pharmacologically active substances leading to an inflammatory process

190
Q

Give 3 examples of Type 3 reactions

A

Farmers lung
SLE
Post-streptococcal gastroenteritis

191
Q

What are Type 4 reactions mediated by?

A

T cell mediated reaction

Formation of granulomas in a slow process

192
Q

Name 3 examples of Type 4 reactions

A

TB
Contact dermatitis
Sarcoidosis

193
Q

Name 2 types of asthma

A

Extrinsic - atopy, occupational

Intrinsic - often late onset - nasal polyposis, aspirin sensitive

194
Q

Name the 2 phases of bronchoconstriction

A

Immediate - IgE/mast cell mediated

Late Phase - T cell mediated

195
Q

How do you treat asthma?

A

Steroids
Symptomatic relief
Antihistamines
Anti-IgE

196
Q

Define adverse drug reaction

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 unintended

197
Q

Define side effect

A

Unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment

198
Q

Name 3 categories adverse drug reactions can be classified into

A
  1. Toxic effects (beyond therapeutic range)
  2. Collateral effects (within therapeutic range)
  3. Hyper-susceptibility (below therapeutic range)
199
Q

When can toxic effect drug reaction occur?

A

If dose is too high
Drug excretion is reduced by impaired renal or hepatic function
By interaction with other drugs
E.g. nephrotoxicity with gentamicin

200
Q

Give an example of when a collateral effect drug reaction can occur

A

Occurs when given standard therapeutic doses

Beta blockers during bronchoconstriction

201
Q

Name examples of hyper-susceptibility effect drug overdoses

A

Occurs when given sub therapeutic doses

Anaphylaxis and penicillin

202
Q

Give 4 symptoms of mild ADRs

A
  1. Nausea
  2. Drowsiness
  3. Itching
  4. rash
203
Q

Give 4 symptoms of severe ADRs

A
  1. Respiratory depression
  2. Neutropenia
  3. Catastrophic haemorrhage
  4. Anaphylaxis
204
Q

When can time independent reactions occur and give an example of one?

A

Occur at any time during treatment

E.g. INR increase when erythromyocin administered with warfarin

205
Q

Name 6 times of time dependent drug reactions

A
  1. Rapid reactions
  2. First dose reactions
  3. Early reactions
  4. Intermediate reactions
  5. Late reactions
  6. Delayed reactions
206
Q

Name the types of adverse drug reactions in Rawlins Thompson classification

A
  1. Type A - Augmented pharmacological
  2. Type B - Bizarre or idiosyncratic
  3. Type C - Chronic
  4. Type D - Delayed
  5. Type E - End of treatment
  6. Type F - Failure of therapy
207
Q

Describe Type A ADRs

A

Predictable
Dose dependent
Common
Extension of primary effect (bradycardia and propranolol)
Secondary effect (bronchospasm with propranolol B2 blocking effect)

208
Q

Descrive Type B ADRs

A 
Not predictable 
Not dose dependent 
Can't readily be reverse 
Life threatening 
Can be idiosyncrasy
Can be allergy or hypersensitivity
209
Q

Give an example of a Type B ADR

A

Anaphylaxis

210
Q

What are Type C ADRs due to?

A

Osteoporosis and steroids

Analgesic nephropathy

211
Q

Give an example of a Type D ADR

A

Malignancies after immunosuppression
Thalidomide causing adverse effects on foetus when taken while pregnant
Carcinogenesis

212
Q

When do Type E ADRs occur?

A

After abrupt drug withdrawal

E.g. Opiate withdrawal syndrome

213
Q

Describe idiosyncrasy

A

Inherent abnormal repose to a drug

Genetic abnormality, enzyme deficiency

214
Q

What does DoTS mean?

A

Dose related (toxic, collateral, hyper-susceptibility)
Timing
Patient Susceptibility
Relates to what ADR occurs

215
Q

Name 8 patient risk factors for ADRs

A
  1. Gender (F>M)
  2. Elderly
  3. Neonates
  4. Polypharmacy
  5. Genetic predisposition
  6. Hypersensitivity/allergies
  7. Hepatic/renal impairment
  8. Adherence problems
216
Q

Name 3 drug risk factors for ADRs

A
  1. Steep dose-response curve
  2. Low therapeutic index
  3. Commonly causes ADRs
217
Q

Name another risk factor for ADRs

A

Prescriber risks

218
Q

Name 7 causes of ADRs

A
  1. Pharmaceutical variation
  2. Receptor abnormality
  3. Abnormal biological system unmasked by drug
  4. Abnormalities in drug metabolism
  5. Immunological
  6. Drug-drug interactions
  7. Multifactorial
219
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

220
Q

What are the most common drugs that have ADRs?

A 
Antibiotics
Anti-neoplastics
Cardiovascular drugs
Hypoglycemics
NSAIDS
CNS drugs
221
Q

Name 6 common ADRs

A
  1. Confusion
  2. Nausea
  3. Balance problems
  4. Diarrhoea
  5. Constipation
  6. Hypotension
222
Q

Give 3 ways to avoid ADRs

A
  1. Avoid drug interactions
  2. Don’t prescribe inappropriate medications
  3. Don’t prescribe unnecessary medications
223
Q

What does the Medicines and Healthcare Regulatory Agency (MHRA) do?

A

Responsible for approving medicines and devices for use

Watch over medicines and devices and take actions to protect the public promptly if there is a problem

224
Q

What are yellow cards used for?

A

To report ADRs

225
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 immunological (allergic) and non-immunological mechanisms

226
Q

What inflammatory mediators do mast cells release when they undergo degranulation?

A

Histamine, prostaglandins, leukotrienes, platelet activating factors, cytokines and proteases

227
Q

Name 3 groups of risk factors for hypersensitivity

A
  1. Medicine factors
  2. Host factors
  3. Genetic factors
228
Q

Name 4 host risk factors for hypersensitivity

A
  1. Females > Males
  2. EBV, HIV
  3. Previous drug reactions
  4. Uncontrolled asthma
229
Q

Name 2 genetic risk factors for hypersensitivity

A
  1. Certain HLA groups

2. Acetylator status

230
Q

Name 7 clinical criteria for an allergy to a drug

A
  1. Does not correlate with pharmacological properties of the drug
  2. No linear relation with dose (tiny dose can cause severe effects)
  3. Reaction similar to those produced by other allergens
  4. Induction period of primary exposure
  5. Disappearance on cessation
  6. Re-appears on re-exposure
  7. Occurs in a minority of patients on the drug
231
Q

Define anaphylaxis

A

A severe, life-threatening, generalised or systemic hypersensitivity reaction

232
Q

What is anaphylaxis characterised by?

A
  1. Sudden onset and rapid progression of symptoms
  2. Life throning airway, breathing and circulation problems
  3. Usually with skin and/or mucosal changes
233
Q

What immunoglobulin is anaphylaxis mediated by?

A

IgE

234
Q

Describe non immune anaphylaxis

A

Sue to direct mast cell degeneration
No prior exposure needed
Clinically identical and treatment is the same

235
Q

Name 6 features if anaphylaxis

A
  1. Rash/urticaria
  2. Swelling of lips, face, oedema
  3. Wheeze/SOB
  4. Hypotension (anaphylactic shock)
  5. Cardiac arrest
  6. Respiratory arrest
236
Q

Describe the management of anaphylaxis

A 
Commence basic life support - ABC 
ADRENALINE IM 550 mg
High flow oxygen 
IV fluids
IV antihistamine (chlorphenamine 10mg) 
IV hydrocortisone 
Repeat Adrenaline if symptoms don't improve after 5 mins
237
Q

How does Adrenaline help treat anaphylaxis?

A

Vasoconstriction - increases peripheral vascular resistance, increases BP and coronary perfusion
Positive inotropic and chronotropic effect on the heart
Reduces oedema and bronchodilates
Attenuates further release of mediators from mast cells and basophils

238
Q

What are the most common triggers for anaphylaxis?

A 
Food - nuts, milk, fish
Drugs - NSAIDs, antibiotics 
Insect stings
General anaesthetic 
Contrast agents 
Other - latex, hair dye
239
Q

What are the steps in an allergic response?

A

Allergen/threat is identified -> high affinity IgE receptors cross link -> IgE binds -> Mast cells are activated -> granules released -> histamine and cytokines. Cytokines induce a TH2 response

240
Q

Which compound causes blood vessel dilation and vascular leakage in an allergic response?

A

Histamine

241
Q

How can immune function be assessed?

A

Looking at neutrophil numbers, morphology and flow cytometry
Looking at B and T cell subsets, number and responses to vaccines
Genetic studies

242
Q

Give 3 examples of chronic inflammatory diseases

A
  1. Rheumatoid arthritis
  2. Crohn’s disease
  3. TB
243
Q

Name 3 conventional therapies used in managing chronic inflammatory diseases

A
  1. NSAIDs
  2. Disease modifying anti rheumatic drugs (DMARDs)
  3. Steroids
244
Q

How do NSAIDs work in relieving inflammation?

A

NSAIDs inhibit COX 1 and 2. COX 2 is needed for prostaglandin synthesis. Prostaglandins are responsible for inflammation and pain. Therefore NSAIDs reduce symptoms of inflammation and pain

245
Q

What is a disadvantage of long term NSAID use?

A

Can cause gastric bleeding - inhibit COX 1 which is needed for prostaglandin synthesis and prostaglandins are needed for gastric mucus production

246
Q

What is the result of recombination in the Ig region?

A

Class switching

247
Q

Describe the process of class switching

A 
Antigen engagement and T cell help result in class switching 
A different Fc region is used and there is affinity maturatoin
248
Q

Give an example of a ligand gated ion channel

A

Nicotinic ACh receptor

249
Q

Give an example of a GPCR

A

Muscarinic and beta-2 adrenoreceptors

250
Q

Give an example of a kinase linked receptors

A

Receptors for growth factors

251
Q

Give an example of a cytosolic/nuclear receptor

A

Steroid receptors (steroid affect transcription)

252
Q

Would an antagonist shift a dose-repose curve to the left or right?

A

Shift it right - drug becomes less potent

253
Q

What is the function of COX1 and COX2

A

They cyclise and oxygenate arachidonic acid and produce prostaglandin H2

254
Q

Define pro-drugs and give an example of one

A

Drugs that need to be activated enzymatically

E.g. ACE inhibitors, enalapril

255
Q

How do ACE inhibitors work?

A

Angiotensinogen is converted to angiotensin 1 via renin
Angiotensin 1 is then converted to angiotensin 2 via ACE
ACE inhibitors prevents angiotensin 1 binding and so you don’t get angiotensin 2 formation
(Angiotensin 2 is a vasoconstrictor and so ACEi can be used in the treatment of hypertension)

256
Q

Describe how ACh is synthesised

A

Acetyl CoA, choline and choline acetyl trasnferase combine to form acetylcholine. Ach is taken up into a vesicle in the presynpatic cleft and will be released following Ca2+ influx

257
Q

Describe the action of competitive antagonists at the NMJ

A

They block ACh receptors

Competitive antagonists are muscle relaxants

258
Q

Describe the catecholamine synthesis

A

Tyrosine –> L-DOPA –> Dopamine –> Noradrenaline –> Adrenaline

259
Q

What would a Beta-1 adrenergic antagonist do?

A

Reduce CO and renin secretion

260
Q

Describe a type C adverse drug reaction

A

Chronic

Occurs after long term therapy

261
Q

Describe a Type D adverse drug reaction

A

Delayed

Occurs many years after treatment

262
Q

What is the treatment for a type A adverse drug reaction?

A

Reduce the dose

263
Q

What is the treatment for a type B adverse drug reaction?

A

Withdraw drug immediately

264
Q

What is morphine metabolised to?

A

Morphine-6-glucuronide

265
Q

What might u receptors be found?

A

In the epidural space and CSF

266
Q

Describe the dose-response curve for morphine

A

As the dose increase response increases

Initially rapid and then it plateaus - NOT sigmoidal

267
Q

What are the 3 actions fo NSAIDs

A
  1. Anti-inflammatory
  2. Analgesic
  3. Antipyrexic
    AAA
268
Q

What are the 4 components of Pharmacokinetics?

A

Absorption
Distribution
Metabolism
Elimination/excretion

269
Q

Define absorption in terms of pharmacokinetics

A

Process of transfer from the site of administration into the general or systemic circulation

270
Q

Name 10 routes of administration of drugs

A 
Oral 
Intravenous
Intraarterial 
Intramuscular 
Subcutaneous 
Inhalation 
Topics
Sublingual 
Rectal 
Intrathecal
271
Q

Which routes of administration mean that the drug does not have to cross even 1 membrane in its passage from site of administration to the general circulation?

A

IV and IA injections

272
Q

Drugs acting at intracellular sites must also cross the cell membrane, how may they do this?

A
  1. Passive diffusion through the lipid layer
  2. Diffusion through pores or ion channels
  3. Carrier mediated processes (facilitated diffusion/active transport)
  4. Pinocytosis
273
Q

Briefly describe the passive diffusion through the lipid layer of drugs being absorbed to intracellular sites

A

Drugs can move passively down a concentration gradient
Need to have degree of lipid solubility to cross phospholipid bilayer directly (e.g. steroids)
Rate of diffusion is proportional to concentration gradient, the area and permeability of the membrane Rate of diffusion is inversely proportional to the thickness of the membrane

274
Q

What type of molecules can diffuse through pores or ion channels in the bilayer to enter a cell?

A

Very small, water soluble molecules (e.g. lithium)

275
Q

Name an ATP-binding cassette (ABC)

A

P-gp –> multi drug resistance (MDR1) - removes a wide range of drugs from cytoplasm to the extracellular side

276
Q

What type of molecules are usually taken up by pinocytosis?

A

Endogenous macromolecule and can be used in uptake of recombinant therapeutic proteins (e.g. amphotericin)

277
Q

Why is drug ionisation so important?

A

Ionisable groups are essential for the mechanism of action of most drugs as ionic forces are part of the ligand receptor interaction

278
Q

If drugs are in their ionised from are they water or lipid soluble?

A

Water soluble

279
Q

If drugs are in their unionised from are they water or lipid soluble?

A

Lipid soluble

280
Q

What is the pKa?

A

Dissociation/ionisation constant

pH at chick half go the substance is ionised and half in unionised

281
Q

How does the pH of the medium affect ionisation of drugs?

A

Weak acids are best absorbed in regions of high acidity (stomach)
Weak bases are best absorbed in alkaline conditions (intestine)

282
Q

Is aspirin a weak acid or base?

A

Aspirin is a weak acid

283
Q

How does a raised gastric pH affect the uptake of aspirin?

A

Reduces uptake of aspirin from the stomach so reduces the bioavailability

284
Q

Why is the small intestine an ideal environment for oral administrated drug uptake?

A

Large SA and high blood flow gives rapid and completes absorption of oral drugs

285
Q

What do oral drugs have to overcome before reaching the systemic circulation?

A

Drug structure
Drug formulation
Gastric emptying
First pass metabolism

286
Q

Why do oral drugs have to overcome drug structure before reaching systemic circulation?

A

Drugs need to be lipid soluble to be absorbed from gut

Highly polarised drugs tend to be only partially absorbed

287
Q

Why do oral drugs have to overcome drug formulation before reaching systemic circulation?

A

Capsule or tablet must disintegrate and dissolve to be absorbed
This must occur rapidly
Some are formulated to modified release and some have an enteric coating

288
Q

Why do oral drugs have to overcome gastric emptying before reaching systemic circulation?

A

Rate of gastric emptying determines how soon a drug taken orally is delivered to small intestine
Can be slowed by food or drugs
Can be faster is you’ve had plastic surgery

289
Q

How many metabolic barriers to oral drugs have to pass to reach systemic circulation?

A

4:

  1. Intestinal lumen - enzymes that split peptide, ester and glycosidic bonds
  2. Intestinal wall - cellular enzymes, bowel surgery
  3. Liver - major site of drug metabolism
  4. Lungs
290
Q

What drugs can be given transcutaneously?

A

Potent and non-irritant drugs

Slow and continued absorption useful with transdermal patches

291
Q

What 2 factors do intramuscular drugs depend on?

A
  1. Blood flow

2. Water solubility

292
Q

How does an increase in blood flow or water solubility effect intramuscular drug uptake?

A

Enhances removal of drug from the injection site

293
Q

What kind of drugs are administrated by inhalation?

A

Volatiles - general anaesthetics and bronchodilators

294
Q

Define distribution in terms of pharmacokinetics

A

Process by which the drug is transferred reversibly from the general circulation to the tissues as the blood concentration increases and then returns from the tissues to the blood when the blood concentration falls

295
Q

How does distribution occur?

A

By passive diffusion across cell membrane for most lipid soluble drugs

296
Q

Where are proteins/large molecules active?

A

Only in the plasma compartment (5L)

297
Q

Where are water soluble molecules active?

A

Plasma and interstitial compartments (5L + 15L)

298
Q

Where are lipid soluble molecules active?

A

Only in the intracellular fluid (45L)

299
Q

What happens when a drug binds to a protein reversibly?

A

Binding lowers the free concentration of drug and can act as a depot releasing the bound drug when the plasma concentration drops through redistribution or elimination
E.g. Albumin

300
Q

What happens when a drug binds to a protein irreversibly?

A

Drug cannot re-enter circulation - equivalent to elimination
E.g. cytotoxic chemo with DNA

301
Q

How quickly can drugs pass from the blood to the brain?

A

Lipid soluble - quickly

Water soluble - enter slowly

302
Q

What transporters return drug molecules from the brain to the circulation?

A

Efflux transporters

303
Q

How are drugs removed from the brain?

A

Diffusion into plasma
Active transport into the choroid plexus
Elimination in CSF

304
Q

What type of drugs can readily cross the placenta?

A

Lipid soluble drugs

305
Q

How the foetal liver metabolise drugs well?

A

Low level of drug metabolising enzymes so it relies on maternal elimination

306
Q

Where is a drug eliminated from?

A

Plasma compartment

307
Q

Why is metabolism essential?

A

Need to convert lipid soluble products into water soluble products that can be readily removed

308
Q

Where are pro-drugs activated?

A

Liver

309
Q

What is the aim of a phase 1 metabolism reaction?

A

To make the drug a more polar metabolite

310
Q

How is a phase 1 reaction carried out?

A

Unmasking or adding a functional group by oxidation, reduction or hydrolysis (-OH, NH2, -SH, -COOH)

311
Q

Briefly explain a reduction phase 1 reaction

A

Hydrogen is added to saturate unsaturated bonds

312
Q

Briefly explain a hydrolysis phase 1 reaction

A

Split amide and ester bonds

313
Q

What is the most common phase 1 reaction?

A

Oxidation

314
Q

Explain a oxidation phase 1 reaction

A

Hydroxylation - add -OH
Dealkylation - remove -CH side chains
Deamination - remove -NH
Hydrogen removal

315
Q

What is an oxidation phase 1 reaction usually catalysed by

A

Cytochrome P450

316
Q

Give the main features of cytochrome P450

A

Microsomal enzyme that is present in the SER\Uses heme group to oxidise a substance
Requires energy and molecular oxygen
Creates products that are more water soluble

317
Q

What can induce P450 enzymes and what does this result in?

A

Smoking and alcohol

More rapid drug metabolism as a result

318
Q

What can inhibit P450 enzymes and what does this result in?

A

Drugs and foods

Drug lasts longer/nor eliminated as fast

319
Q

What enzyme is ethanol metabolised by?

A

Alcohol dehydrogenase

320
Q

What are phase 2 metabolism reactions?

A

Coagulation reactions - involved formation of a covalent bond = glucuronidation

321
Q

When are phase 2 reactions used?

A

When a drug is very hydrophobic

322
Q

What is the aim of phase 2 reactions?

A

To make the drug more hydrophilic

323
Q

What enzyme is involved in phase 2 reactions?

A

Glucuronosyltransferase (UGT) = microsomal enzyme

324
Q

How are most drugs excreted?

A

Through renal and/or hepatic excretion

325
Q

In what forms can drugs be excreted?

A

Molecule is expelled in liquid, solid or gaseous forms

326
Q

What compounds are excreted as fluids?

A

Low molecular weight polar compounds (urine, bile, sweat, tears, breast milk)

327
Q

What compounds are excreted as solids?

A

Faecal elimination is important for high molecular weight compounds excreted in bile

328
Q

What compounds are excreted as gaseous compounds

A

Expired air important for volatiles

329
Q

What is first order kinetics?

A

rate is directly proportional to the concentration of the drug (rate ∝ [drug])

330
Q

What is second order kinetics?

A

Rate is directly proportional to the square of the concentration of the drug (rate ∝ [drug]2)

331
Q

What is third order kinetics?

A

Rate is directly proportional to the cube of the concentration of the drug (rate ∝ [drug]3)

332
Q

What is zero order kinetics?

A

Rate is unrelated to the concentration of the drug

333
Q

Define half life

A

Time taken for a concentration o reduce by one half

334
Q

Define bioavailability

A

Fraction of the administered drug that reaches the systemic circulation unaltered

335
Q

What is the bioavailability of IV drugs?

A

1 as 100% of the drug reached circulation

336
Q

What does the rate of distribution of water soluble drugs depend on?

A

Rate of passage across membranes

337
Q

What does the rate of distribution of lipid soluble drugs depend on?

A

Blood flow to tissues that accumulate drug

338
Q

Why is the extent of drug distribution clinically important?

A

Determines total amount of drug that has to be administered to produce a particular plasma concentration (apparent volume of distribution)

339
Q

What is the apparent volume of distribution (Vd)?

A

Total amount of drug in the body (dose) / plasma concentration fo drug

340
Q

Define clearance (CL)

A

Volume o blood or plasma cleared of drug per unit time (ml/min)

341
Q

What is clearance a measure of?

A

Efficiency

342
Q

If a drug has a high Vd, what will its plasma concentration be like?

A

Low plasma concentration

343
Q

What is an equation for renal clearance?

A

CL = rate of appearance in urine / plasma concentration

344
Q

What is used as a marker substance in the kidney?

A

Creatinine

345
Q

What are the adult renal clearance values?

A

Renal blood flow is 18% of cardiac output = 1L/min
Renal plasma flow is 60% of blood flow = 600 ml/min
Glomerular filtration is 12% of renal blood flow = 130 ml/min

346
Q

What percentage of the cardiac output is hepatic blood flow?

A

12%

347
Q

Define Hepatic extraction ratio (HER)

A

Proportion of drug removed by one passage through the liver

348
Q

If there is a high HER, what is the clearance limited by?

A

Perfusion limited (hepatic blood flow)

349
Q

If there is a low HER, what is the clearance limited by?

A

Diffusion limited - process is slow and not efficient with a low amount removed

350
Q

How do low HER drugs increase their clearance rate?

A

Cause liver to produce more enzymes

351
Q

At what point does liver failure effect drug metabolism?

A

Once at least 70% of functioning liver is lost

352
Q

Name 4 drugs with active metabolites

A
  1. Prednisone
  2. Codeine
  3. Diamorphine
  4. L-DOPA
  5. Cortisone
  6. Morphine
353
Q

Why are repeat drug doses used?

A

To maintain a constant drug concentration int he blood and at the site of action for the therapeutic effect

354
Q

What is steady state (Css)?

A

Balance between drug input and elimination

infusion dosage = rate of elimination from plasma

355
Q

If a drug has a slow elimination rate how quickly is steady state reached?

A

A logn time to reach Css and it will accumulate high plasma concentration before elimination rate rises to match drug infusion

356
Q

What is a loading dose?

A

High initial dose which ‘loads’ the system and shortened the time to steady state
(loading dose = Css x Vd)

357
Q

Name 3 things that the chemical properties of a drug can influence?

A
  1. Administration
  2. Distribution
  3. Elimination
358
Q

What equation can be used to determine the degree of ionisation at a specific pH?

A

Henderson Hasselbach

pH = log[A-]/[HA] + pKa

359
Q

In terms of ionisation, what happens to Aspirin in the stomach?

A

Aspirin is a week acid and so becomes less ionised in the stomach due to the low gastric pH

360
Q

What is the effect of an increase in pH on a weak acid?

A

Weak acid will become more ionised

361
Q

What is the effect of an increase in pH on a weak base?

A

Weak base will become less ionised

362
Q

If a drug had a high Vd what would that tell us about the drug?

A

This would indicate that the drug was highly lipid soluble and that most of the drug had moved into the intracellular space, less was in the plasma

363
Q

What are 2 ways by which drugs can be eliminated in the kidneys?

A
  1. Glomerular filtration

2. Active secretion

364
Q

What are the possible danger of kidney damage with regards to renal clearance ?

A

Results in decreased renal clearance and so there is a danger of accumulation, our dosage and toxicity

365
Q

Give 3 advantages of IV infusion

A
  1. Steady state plasma levels are maintained.
  2. Highly accurate drug delivery.
  3. IV infusion can be used for drugs that would be ineffective when administered via an alternative route.
366
Q

Give 3 disadvantages of IV infusion

A
  1. Expensive.
  2. Needs constant checking.
  3. Calculation error likely.
367
Q

Name 2 approaches to drug design

A
  1. Chance

2. Rational drug design

368
Q

By what method was penicillin developed?

A

Fermentation

369
Q

Name 3 other drugs developed by the process of fermentation

A
  1. Lovastatin (statin)
  2. Cyclosporine (immunosurpressent)
  3. Ivermectin (broad spectrum antibiotic)
370
Q

What form of drugs, D or L, do biological systems use?

A

The L amino acids (R form)

371
Q

Name 2 drugs designed by the rational drug design approach

A
  1. Propranolol - B-antagonist used in treatment for hypertension
  2. Cimetidine - H2-antagonist used in treatment of peptic ulcers
372
Q

Name 3 recombinant proteins in clinical use

A
  1. Insulin
  2. Erythropetin
  3. Groth hormone
  4. Interleukin 2
373
Q

What are therapeutic antibodies based on?

A

Monoclonal antibody technology

374
Q

How are monoclonal antibodies produced?

A

Mouse is immunised against the antigen of interest
B cells are isolated to check they are producing antibodies against the antigen
If desired antibody is being produced, mouse spleen is removed
B cells in the spleen are removed and cultured along with myeloma tumour cells (these cells can divide indefinitely but cannot produce antibodies)
Solution is added to fuse the B cells with the tumour cells to produce hybridomas (fused cells) that can divide indefinitely and produce antibodies
The hybridomas are cloned and undergo clonal expansion
The monoclonal antibodies produced are extracted and used for clinical purposes

375
Q

Name 2 types of second generation monoclonal antibodies

A
  1. Chimeric antibodies - mix of human and mouse antibody, can illicit immune response
  2. Humanised antibodies - 3 hypervariable regions, less likely to illicit immune response
376
Q

What does gene therapy involve?

A

Delivery of nucleic acid polymer to cell sing viral vector

Therapeutic gene administered to treat effects of mutated gene and suppresses mutated gene expression

377
Q

What is combinatorial chemistry?

A

Biochemical modification of natural products

378
Q

What is High Throughput Screening?

A

Screening the biological activity of compounds to analyse whether one has clinical efficacy

379
Q

What can High Throughput Screening not establish?

A

Bioavailability
Pharmacokinetic
Toxicology

PHASE 2A (16 decks)

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