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Phase 2a Lecture Notes > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

First order

A

Rate of elimination is proportional to the plasma drug concentration (processes involved in elimination do not become saturated)
A constant % of the plasma drug is eliminated over a unit of time

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2
Q

Zero order

A

Rate of elimination is NOT proportional to the plasma drug concentration (metabolism processes become saturated)
A constant amount of the plasma drug is eliminated over a unit of time

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3
Q

Cmax

A

maximum plasma concentration

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4
Q

tmax

A

time taken to reach Cmax

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5
Q

Clearance (CL)

A

removal of drug by all eliminating organs

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6
Q

Bioavailability of IV

A

100% bioavailability, absorption and tmax are not relevant

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7
Q

Half life (t1/2)

A

Dependent on clearance (CL) of drug from body by all eliminating organs (hepatic, renal, faeces, breath)
Dependent of volume of distribution (Vd) - A drug with large Vd will be cleared more slowly than a drug with a small Vd

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8
Q

When a drug considered cleared in clinical practice

A

A drug will be 97% cleared from the body after 5 x half lives

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9
Q

Relevance of t1/2 in clinical practice- drug dosing

A

short t1/2 will need more frequent dosing

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10
Q

Relevance of t1/2 in clinical practice- Organ dysfunction

A

t1/2 may be increased, Reduced CL increases t1/2, Time to Css increases (5 x t1/2), Css increases, Therefore dose reduction required

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11
Q

Relevance of t1/2 in clinical practice- Adverse drug reactions or management of toxicity

A

how long will drug take to be removed and symptoms to resolve

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12
Q

Relevance of t1/2 in clinical practice- Short t1/2 increases risk of discontinuation/withdrawal symptoms

A

drugs may need dose weaning on cessation

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13
Q

Repeat IV dosing

A

Most drugs require repeated dosing
Peaks and troughs in plasma concentration causing oscillation around the mean

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14
Q

Does repeat iv change time to Css compared to single dose of the same amount

A

Time to Css does not change (roughly 5 half lives)

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15
Q

Why is steady state important?

A

Aim for Css which lies between the Maximum safe concentration (MSC) and minimum effective concentration (MEC)

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16
Q

Method for Reducing time to steady state

A

A loading dose will speed up time to steady state

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17
Q

Zero order kinetics

A

Drugs are metabolised by an amount (e.g in mg) in a unit of time. Metabolism is dependent on mechanisms that become saturated. Elimination is irrespective of plasma concentration.

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18
Q

Zero order kinetics- is plasma concentration proportional to dose?

A

Plasma concentration is not proportional to dose. Small increases in dose may cause large increases in plasma concentration. There caution needed when adjusting doses

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19
Q

Pharmacogenomics

A

The use of genetic and genomic information to tailor pharmaceutical treatment to an individual

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20
Q

Genomics

A

The study of the genomes of individuals and organisms that examines both the coding and non-coding regions. The study of genomics in humans focuses on areas of the genome associated with health and disease

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21
Q

Pharmacogenetic approach

A
  1. Patient is diagnosed with condition x
  2. Patient’s genome used to identify most appropriate treatment and dose
  3. Patient receives optimal treatment
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22
Q

Genomic variation in Pharmacodynamics

A

variations in drug receptor
-variations in efficacy (‘on’ targets)
-increased incidence of adverse drug reactions (ADRs) (‘on’ and ‘off’ targets)

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23
Q

Pharmacology definition

A

The study of how medicines work and how they affect our bodies

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24
Q

Pharmacokinetics

A

The fate of chemical substance administered to a living organism- what the body does to the drug

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25
Q

Pharmacodynamics

A

The biochemical, physiological and molecular effect of a drug on the body- what the drug does to the body

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26
Q

3 considerations when prescribing

A

Legal, safe and effective

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27
Q

4 pharmacokinetic processes

A

Absorption, distribution, metabolism, excretion

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28
Q

Absorption

A

-Transfer of a drug molecule from site of administration to systemic circulation
-Barriers vary with route of administration
-Drugs must cross at least one membrane to reach systemic circulation (except IV and IA)

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29
Q

Routes of administration

A

IV (intravenous)
IA (intra-arterial)
IM (intramuscular)
SC (subcutaneous)
PO (oral)
SL (sublingual
INH (inhaled)
PR (rectal)
PV (vaginal)
TOP (topical)
TD (transdermal)
IT (intrathecal)

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30
Q

Routes of administration with 100% of dose reaching systemic circulation

A

IV and IA administration

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31
Q

Mechanisms for drug permeation across cell membranes

A

Passive diffusion through hydrophobic membrane
-Lipid soluble molecules
Passive diffusion aqueous pores
-Very small water soluble drugs (eg lithium)
-Most drug molecules are too big
Carrier mediated transport
-Proteins which transport sugars, amino acids, neurotransmitters and trace metals (and some drugs)

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32
Q

Factors affecting drug absorption

A

Lipid solubility
Drug ionisation

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33
Q

Factors affecting oral drug absorption

A

Drug ionisation
Stomach
Intestine

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34
Q

How does drug ionisation affect drug absorption

A

-Ionised drug has poor lipid solubility and therefore is poorly absorbed
-Most drugs are weak acids or weak bases with ionisable groups
-Proportion of ionisation depends on pH of the aqueous environment
-Weak acids - best absorbed in stomach. Weak bases - best absorbed in intestine

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35
Q

How does the stomach affect oral drug absorption

A

Gastric enzyme, low pH (may lead to drug degraded), food (full stomach slower absorption), gastric motility, previous surgery

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36
Q

How does the intestine affect oral drug absorption

A

Drug structure (Lipid soluble/unionised molecules diffuse down concentration gradient however large or hydrophilic molecules are poorly absorbed) Medicine formulation (changes rate of absorption), P-glycoprotein

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37
Q

How does first pass metabolism affect drug absorption

A

Degradation by enzymes in intestinal wall
Absorption from intestine into hepatic portal vein and metabolism via liver enzymes
Degree of first pass metabolism can vary between individuals
Avoid by giving via routes that avoid sphlanchnic circulation (eg rectal)
Proportion of administered dose which reaches the systemic circulation: bioavailability (F)

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38
Q

First pass metabolism

A

metabolism of drugs preventing them reaching systemic circulation

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39
Q

Bioavailability (F)

A

Proportion of administered drug which reaches the systemic circulation (% or fraction), variation with route of administration and between individuals

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40
Q

IS bioavailability affect by the rate of absorption

A

Not affected by rate of absorption

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41
Q

Pros and cons of rectal (PR)

A

Pros: Local administration, avoids 1st pass metabolism, nausea and vomiting
Cons: Absorption can be variable, patient preference

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42
Q

Pros and cons of Inhaled (Inh)

A

Pros: Well perfused over large SA, local administration
Cons: Inhaler technique can limit effectiveness

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43
Q

Pros and cons of Subcutaneous (S/V)

A

Pros: Faster onset that PO (oral), formulation can be changed to control rate of absorption
Cons: Not as rapid as IV

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44
Q

Pros and cons of Transdermal (TD)

A

Pros: Provides continuous drug release, avoids 1st pass metabolism
Cons: Only suitable for lipid soluble drugs, slow onset of action

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45
Q

Four compartments in the body

A

Fat (20%), Interstitial fluid (15%), Plasma (5%), Intracellular fluid (35%)

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46
Q

Bioavailability of oral dose of morphine

A

50% of oral (enteral) morphine is metabolised by first pass metabolism
Halve the dose if giving it s/c, IM, IV (parenterally) etc

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47
Q

Morphine and kidney failure

A

Morphine is problematic in patients with reduced renal function due to the risk of accumulation of active metabolites and therefore is generally avoided

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48
Q

How do Opioids Work?

A

Opioid drugs simply use the existing pain
modulation system
Natural endorphins (endogenous morphine) and enkephalins
G protein coupled receptors - act via second messengers
Inhibit the release of pain transmitters at spinal cord and midbrain - and modulate pain perception in higher centres - euphoria - changes the emotional perception of pain

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49
Q

Opioid Receptors examples

A

MOP, KOP, DOP and NOP

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50
Q

Potency

A

Whether a drug is ‘strong’ or ‘weak’ relates to how well the drug binds to the receptor,
the binding affinity

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51
Q

Efficacy

A

Is it possible to get a maximal response with the drug or not?
Or even if all the receptor sites are occupied do you get a ceiling response?
The concept of full or partial agonists

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52
Q

Tolerance

A

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

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53
Q

Opioid withdrawal

A

Starts within 24 hours, lasts about 72 hours

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54
Q

Side effects of opioids

A

Respiratory Depression
Sedation
Nausea and Vomiting
Constipation
Itching
Immune Suppression
Endocrine Effects

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55
Q

Opioid Induced Respiratory Depression treatment

A

Naloxone via IV, beware naloxone has a short half life so multiple doses over a period of time may be need

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56
Q

Sympathetic nervous system

A

Fight or flight-An acute stress response is a physiological reaction that occurs in response to a perceived harmful event

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57
Q

Parasympathetic nervous system

A

Activities that occur when the body is at rest, especially after eating

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58
Q

Sympathetic vs Parasympathetic nervous system

A

Not typically either/or, rather a continuum/balance between the 2

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59
Q

High thortacic or cervical spinal injury

A

The sympathetic nerves in the spine are damaged, Vagus nerve is undamaged, unopposed parasympathetic innervation causes bradycardia. Loss of sympathetic tone causes vasodilation and hypotension. Risk of loss of sensation so patient unable to perceive pain ie could have ruptured spleen but patient would be unaware

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60
Q

Recap on synapes

A

When an action potential, or nerve impulse, arrives at the axon terminal, it activates voltage-gated calcium channels in the cell membrane. Ca2+, which is present at a much higher concentration outside the neuron than inside, rushes into the cell. The Ca2+ allows synaptic vesicles to fuse with the axon terminal membrane, releasing neurotransmitter into the synaptic cleft.

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61
Q

Sympathetic NS receptors

A

Alpha1- postsynaptic- vasoconstriction
Alpha 2- presynaptic- -ve loop, supresses noradrenaline release
Beta 1- Increase HR and contractility
Beta 2- Bronchodilation
1 heart, 2 lungs

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62
Q

Metaraminol and noradrenaline as vasopressors

A

vasoconstrictor of choice for the short-term management of acute hypotension and can be administered by peripheral intravenous catheter. simulate alpha 1 receptors

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63
Q

Veins used for central line

A

internal jugular, common femoral, and subclavian veins

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64
Q

Alpha blockers

A

Block the effect of the sympathetic nervous system on the blood vessels causing vasodilation

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65
Q

ACE inhibtors

A

vasodilationor

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66
Q

Anti-platelet

A

prevent clot formation

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67
Q

Statin

A

reduce cholesterol

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68
Q

Betablockers

A

Blocks the effect of the sympathetic NS on the earth, decreases HR and contractility, decrease workload for the cardiac muscle

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69
Q

Beta 2 agonists

A

Acute asthma attacks, stimulates beta 2 receptors, causes bronchodilation, reduces symptoms of asthma attack

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70
Q

Alpha 2 agonists

A

Act presynaptically to reduce the amount of noradrenaline released. They form a -ve loop of the sympathetic NS.

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71
Q

Phenylephrine

A

alpha 1 agonist, major action is systemic and pulmonary arterial vasoconstriction

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72
Q

Nicotinic Cholinergic Receptors

A

Nicotinic
(pre-ganglionic, SNS and PNS)
Ligand gated ion channels
Action increases membrane permeability to Na+, K+
Subgroups Ganglionic, Neuromuscular and CNS

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73
Q

Muscarinic Cholinergic Receptors

A

Muscarinic
(7 transmembrane helical, G protein coupled)
M1 - CNS, higher cognitive
M2 - Cardiac
M3 - Exocrine Glands and smooth muscle
M4 - CNS only
M5 - CNS only

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74
Q

nicotinic signs of acetylcholinesterase inhibitor toxicity

A

Monday = Mydriasis
Tuesday = Tachycardia
Wednesday = Weakness
Thursday = Hypertension
Friday = Fasciculations

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75
Q

muscarinic effects of organophosphate poisonings

A

DUMBELS:
D = Defecation/diaphoresis
U = Urination
M = Miosis
B = Bronchospasm/bronchorrhea
E = Emesis
L = Lacrimation
S = Salivation

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76
Q

Drug targets

A

Most drugs target proteins
-receptors, enzymes, transporters, ion channels

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77
Q

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. Ligands can be exogenous (drugs) or endogenous (hormones, neurotransmitter, etc)

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78
Q

Type of receptors

A

-Ligand-gated ion channels ie nicotinic ACh receptor
-G protein coupled receptors ie beta-adrenoceptors
-Kinase-linked receptors ie receptors for growth factors
-Cytosolic/nuclear receptors ie steroid receptors

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79
Q

Ligand gated ion channels

A

pore-formingmembrane proteinsthat allowionsto pass through the channel pore so that the cell undergoes a shift inelectric chargedistribution

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80
Q

G protein coupled receptors (GPCRs)

A

largest and most diverse group of membrane receptors in eukaryotes. (the have 7 membrane spanning regions). Targeted by >30% of drugs. Ligands include light energy, peptides, lipids, sugars, and proteins.

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81
Q

How do GPCRs work?

A

-G proteins(guanine nucleotide-binding proteins) are a family of proteins involved in transmitting signals from GPCRs
-Their activity is regulated by factors that control their ability to bind to and hydrolyzeguanosine triphosphate(GTP) toguanosine diphosphate(GDP)
-G proteins (GTPases) act as molecular switches. (on ligand binding, GPCRs catalyse the exchange of GDP to GTP*)

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82
Q

Kinase-linked receptors

A

-Kinasesare enzyme that catalyze the transfer of phosphate groups between proteins - process is known as phosphorylation.
-The substrate gains a phosphate group ”donated” by ATP
-Transmembrane receptors activated when the binding of an extracellular ligand causes enzymatic activity on the intracellular side.

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83
Q

Nuclear receptors

A

Ligand-activated transcription factors that regulate key functions in reproduction, development, and physiology. Work by modifying gene transcription.

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84
Q

Pathology example of chemical imbalances

A

-allergy; increased histamine
-Parkinson’s; reduced dopamine

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85
Q

Pathology example of Receptors imbalances

A

-myasthenia gravis; loss of ACh receptors
-Mastocytosis (Mast cells); increased c-kit receptor

86
Q

Agonist Receptor ligands

A

a compound that binds to a receptor and activates it

87
Q

Antagonist Receptor ligands

A

a compound that reduces the effect of an agonist

88
Q

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”.

89
Q

Partial agonists

A

Ligands that bind to the agonist recognition site but trigger a response that is lower than that of a full agonist at the receptor, ie Emax is lower than 100%

90
Q

Efficacy

A

Efficacy (Emax) is the maximum response achievable

91
Q

Intrinsic activity

A

Intrinsic activity(IA)refers to the ability of a drug-receptor complex to produce a maximum functional response

92
Q

Intrinsic activity calc

A

Intrinsic Activity = Emax of partial agonist ÷ Emax of full agonist

93
Q

Competitive antagonism

A

Antagonist binds to same site as agonist

94
Q

Factors governing drug action

A

-Receptor-related
-affinity
-efficacy
-Tissue-related
-receptor number
-signal amplification

95
Q

affinity

A

Describes how well a ligand binds to the receptor, property shown by both agonists and antagonists

96
Q

Do both agonists and antagonists have affinity

A

Yes, both do

97
Q

Do both agonists and antagonists have efficacy

A

No, agonist do have efficacy, however antagonists do not. Antagonists do not cause a cellular response

98
Q

Irreversible antagonists

A

Once bound to receptors, it wont come off the receptors

99
Q

Receptor reserve

A

Spare receptors. Some agonists needs to activate only a small fraction of the existingreceptors to produce the maximal system response. This holds for a full agonist in a given tissue (reserve can be large or small depending tissue). No receptor reserve for a partial agonist.

100
Q

Signal amplification

A

Some drugs can act on the same receptors on different tissues and cause a different size of response. Not all signalling cascades are the same

101
Q

Allosteric modulation

A

When agonist binds to one site (orthostertic site) and allosteric ligand binds to a second (allosteric site), but both lead to same response

102
Q

Inverse agonism

A

When a drug that binds to the same receptor as anagonistbut induces a pharmacological response opposite to that of theagonist

103
Q

Tolerance

A

-reduction in agonist effect over time
-continuously, repeatedly, high concentrations
- result of chronic use of drug (slow process)

104
Q

Desensitization

A

rapidly system becomes uncoupled, so fails to get a response
-uncoupled
-internalized
-degraded

105
Q

Specificity or selectivity

A

Specific- no compound is ever truly specific
Selective- better term to describe enhanced activity for certain receptors

106
Q

Enzyme inhibitor

A

Molecule that binds to anenzymeand (normally) decreases itsactivity. An enzyme inhibitor prevents the substratefrom entering the enzyme’sactive site and prevents it fromcatalyzingits reaction

107
Q

Two types of enzyme inhibitors

A

-Irreversible inhibitors usually react with the enzyme and change it chemically (e.g. viacovalent bondformation).
-Reversible inhibitors bindnon-covalentlyand different types of inhibition are produced depending on whether these inhibitors bind to theenzyme, the enzyme-substrate complex, or both.

108
Q

Examples of enzyme inhibitors

A

Statins- block rate limiting step of cholesterol pathway
ACE inhibitors- inhibits angiotensin converting enzyme which convents angiotensin 1 to 2, reducing BP

109
Q

Blood brain barrier (BBB)

A

Highly selective semi-permeable membrane barrier that separates the circulating blood from the brain

110
Q

Drug and 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

111
Q

3 types of Protein ports

A

Uniporters, Symporters, Antiporters

112
Q

Uniporters

A

use energy from ATP to pull molecules in.

113
Q

Symporters

A

use the movement in of one molecule to pull in another molecule against a concentration gradient. ie Na-K-Cl co-transporter (NKCC)- ions move in the same direction so organ can secrete fluid

114
Q

Antiporters

A

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

115
Q

Ion channels example and pathology

A

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

116
Q

Epithelial (Sodium) channel (ENaC)

A

membrane-bound heterotrimeric (two set 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). Blocked by the high affinity diuretic , used as a anti-hypertensive

117
Q

Voltage-gated (Calcium) channels (VDCC)

A

found in the membrane of excitable cells. At physiologic or resting membrane potential, VDCCs are normally closed. They are activated at depolarized membrane potentials . Ca2+ enters the cell, resulting in activation of Ca-sensitive K channels, muscular contraction, excitation of neurons etc

118
Q

Targeting VDCCs with Amlodipine

A

Amlodipine is an angioselective Ca channel blocker that inhibits the movement of Ca ions into vascular smooth muscle cells and cardiac muscle cells. This inhibits the contraction of cardiac muscle and vascular smooth muscle cells
Amlodipine inhibits Ca ion influx across cell membranes, with a greater effect on vascular smooth muscle cells
Causes vasodilation and a reduction peripheral vascular resistance, thus lowering blood pressure. Also prevents excessive constriction in the coronary arteries

119
Q

Voltage gated (Sodium) Channels

A

Conducts Na+ through plasma membrane. Classified according to the trigger that opens them- “Voltage-gated” or “ligand-gated”. Three main conformational states: closed, open and inactivated. AP allows gates to open, allowing Na+ions to flow into the cell causing the voltage across the membrane to increase – transmits a signal.

120
Q

Targeting Voltage gated (Sodium) Channels

A

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

121
Q

Voltage gated (Potassium) Channels

A

Voltage-gated K+ channels are selective for K+. Present in many “excitable” tissues. They can be closed, open or inactivated. An electric current (action potential) allows the activation gates to open eliciting a downstream effect.

122
Q

Targeting Voltage gated (Potassium) Channels

A

Increased glucose leads to block of ATP dependent K+ channels in Beta Islets of Langerhans. Repetitive firing of action potentials increases Ca+ influx and triggers insulin secretion. Repaglinide, Nateglinide and Sulfonylureal lower blood glucose levels by blocking K+ channels to stimulate insulin secretion.
Used for treatment of type II diabetes

123
Q

Receptor-mediated (Chloride)

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 an example is GABA -A Receptor

124
Q

Targeting Receptor-mediated (Chloride)

A

Drugs can increased permeability of channel to chloride causing increased response, enhance activation of receptors or drugs can block complex, blocking the channel from opening

125
Q

Sodium Pump (Na/K ATP-ase)

A

It has antiporter-like activity (moves both molecules against their concentration gradients. Forward process is an active process so requires energy from ATP. Pumps 3 Na ions out for every 2 K ions in and creates a electrochemical gradient. Reverse process is spontaneous

126
Q

Targeting Sodium Pump (Na/K ATP-ase)

A

Digoxin is used for atrial fibrillation, atrial flutter, and heart failure. It inhibits the Na+/K+ ATPase, mainly in the myocardium. This inhibition causes an increase in intracellular Na, resulting in decreased activity of the Na-Ca exchanger and increases intracellular Ca. This lengthens the cardiac action potential, which leads to a decrease in HR.

127
Q

Proton Pump (K/H ATP-ase)- Stomach

A

The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach. It exchanges K+ with H+. Responsible for the acidification of the stomach and the activation of the digestive enzyme pepsin.

128
Q

Targeting Proton Pump (K/H ATP-ase)- Stomach

A

PPIs are potent inhibitors of acid secretion. Omeprazole (1st in class) - inhibits acid secretion independent of cause. Irreversible inhibition of H/K ATP-ase - drug half-life 1h, but works for 2-3 days

129
Q

Organophosphates as Irreversible Enzyme Inhibitors

A

Organophosphates are irreversible enzyme inhibitors of cholinesterase (enzyme that rapidly breaks down the neurotransmitter, acetylcholine) such as Insecticides (Diazinon) or Nerve gases (Sarin).

130
Q

Xenobiotics

A

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

131
Q

Xenobiotic metabolism importance for drug function

A

The metabolic breakdown of drugs occurs through specialized enzymatic systems. Works through biotransformation and is of ancient origin. The rate of metabolism determines the duration and intensity of a drug’s pharmacologic action

132
Q

Process of drug development

A
  1. lead compound identification
  2. pre-clinical research
  3. filing for regulatory status
  4. clinical trials on humans
  5. Regulation and marketing
133
Q

Stereoisomers

A

Have the same molecular formula and sequence of bonded atoms, but differ in the three-dimensional orientations of their atoms in space. Can change activity and change effectiveness

134
Q

Pharmacokinetic issues for immunotherapy

A
  1. Immunoglobulin (IgG MW 150kD) – not filtered by kidney
  2. FcRn Receptor - systemic receptors which absorb IgG into cells protecting them from metabolism
  3. Mouse antibodies not substrates for human FcRn receptor – result shorter half-life in man than human antibodies.
135
Q

Recombinant Proteins

A

Recombinant proteins are proteins encoded by recombinant DNA that has been cloned in an expression vector that supports expression of the gene and translation of messenger RNA

136
Q

Recombinant Proteins in Clinical Use

A

Insulin, Erythropoetin, Growth hormone, Interleukin 2, Gamma interferon, Interleukin 1 receptor antagonist

137
Q

Steroids action

A

Work through activating nuclear hormone receptors

138
Q

Protein Kinase Inhibitors

A

Targeted to specific mutations

139
Q

Gene Therapy

A

introduction of normal genes into cells in place of missing or defective ones in order to correct genetic disorders

140
Q

High-throughput screening (HTS)

A

use of automated equipment to rapidly test thousands to millions of samples for biological activity at the model organism, cellular, pathway, or molecular level

141
Q

Rational drug design

A

The process of finding new medications based on the knowledge of a biological target

142
Q

Drug interaction

A

occurs when a substance alters the expected performance of a drug

143
Q

Pharmacodynamic drug interaction

A

Occur when drugs have an effect on the same target or physiological system.
-are either synergistic or antagonistic
-Due to drugs acting on the same drug receptor(s) or physiological system
-Generally predictable (related to pharmacology of drug)
-Highly selective drugs are less likely to be problematic

144
Q

Pharmacokinetic drug interaction

A

Occur when a drug affects the pharmacokinetics (absorption, distribution, metabolism or excretion) of another drug

145
Q

Pharmacodynamic interactions example

A
  • Synergistic- act on same receptors with same actions- increased risk of ADRs
  • Synergistic- act on same system with same actions- increased risk of ADRs or maybe be beneficial
  • Antagonistic- act on same receptors with opposite actions- increased risk of ADRs
146
Q

Are all drug interactions harmful?

A

No, Some drug interactions can be beneficial!

147
Q

Pharmacokinetic drug interactions (absorption)

A

One drug affects the rate (Limited clinical relevance, unless rapid effect required) or extent of absorption of another drug (Can result in ineffective treatment, reduced steady state levels)

148
Q

Pharmacokinetic drug interactions (absorption) example

A

-Drugs which alter pH of GI tract
-Formation of insoluble drug complexes
-P-glycoprotein induction/inhibition

149
Q

Pharmacokinetic interactions (distribution)

A

-Only unbound drug will be distributed from plasma volume
-Interactions can occur when drugs compete for protein binding

150
Q

Example of Pharmacokinetic interactions (distribution)

A

Warfarin is highly protein bound (~99%)
1% unbound and pharmaceutically active
Amiodarone displaces warfarin from albumin to create unbound warfarin molecules
Change of 99% bound to 98% bound = free drug doubles from 1% to 2%

151
Q

Pharmacokinetic drug interactions (metabolism)

A

Kidneys excrete hydrophilic molecules
Lipophilic molecules are metabolised to create a hydrophilic metabolite
Cytochrome P450 (CYP450) enzymes are responsible for majority of phase 1 metabolic reaction
Most significant CYP enzymes for drug metabolism: 3A4, 2C9, 2C19, 1A2, 2D6

152
Q

Pharmacokinetic drug interactions (metabolism) Enzyme inducer vs inhibitor

A

Enzyme Inducer- ↑ expression of enzyme> ↑ metabolism of enzyme substrate
Enzyme Inhibitor- ↓ expression of enzyme> ↓ metabolism of enzyme substrate

153
Q

Pharmacokinetic drug interactions (metabolism) Enzyme inducer vs inhibitor- Effect on substrate

A

Inducer= reduced levels- subtherapeutic, treatment failure
Inhibitor= Increased levels- ADRs, toxicity

154
Q

Pharmacokinetic drug interactions (metabolism) Enzyme inducer vs inhibitor- Timeframe of interaction

A

Inducer= 1-2 weeks, longer
Inhibitor= Days, shorter

155
Q

Pharmacokinetic drug interactions (elimination)

A

Limited clinical relevance in practice
Competition for renal tubular secretion
Drugs transported by OAT (organic anion transporters) and OCT (organic cation transporters)

156
Q

Important drug-food interactions examples

A

Grapefruit juice is a CYP3A4 inhibitor (avoided by patients taking warfarin, statins)
Milk can affect absorption of some drugs due to insoluble complex formed with Ca (eg. doxycycline, levothyroxine, ciprofloxacin)
Action of warfarin (vitamin K antagonist) is opposed by foods high in vitamin K (kale, spinach, broccoli, avocado)
Cranberry juice is a CYP2C9 inhibitor (should be avoided by patients taking warfarin

157
Q

Identifying and avoiding drug interactions

A

Look out for high risk drugs
Look out for high risk patients

158
Q

Should you report clinically significant drug interactions?

A

Yes, Drug interactions which have caused a clinically significant ADR should be reported

159
Q

High risk drugs for drug interactions

A

Obtain complete drug history (DHx), Enzyme inducers, inhibitors and substrates, Drugs with a narrow therapeutic index, High risk/critical medicines and New drugs (e.g. biologics) - little data

160
Q

High risk patients for drug interactions

A

Polypharmacy, Kidney or liver impairment, Extremes of age

161
Q

How to manage drug interactions

A

Avoid combination- Initiate an alternative drug
-Temporarily suspend interacting drug
-Permanently stop interacting drug
Proceed with caution- Additional monitoring (bloods, observations, vigilance for ADRs)
Procced- no actions required

162
Q

Mr K (86 year old male) is brought to A&E by his daughter after falling at home and hurting his wrist. He has recently started taking codeine for pain relief.
Which of his regular medicines would interact with codeine to increase his risk of falls?
Aspirin
Metformin
Morphine
Omeprazole
Ramipril

A

Morphine- duplication of agonism at opioid receptors

163
Q

Adverse Drug Reaction (ADR)

A

A response to a medicinal product, or combination of medicinal products, which is noxious and unintended

164
Q

Wider impact of ADRs

A

For patients: -Reduced Quality of life, Poor compliance, Reduced confidence in clinicians and the healthcare system, Unnecessary investigations or treatments
For the NHS: -Increased hospital admissions, Longer hospital stays, GP appointments, Inefficient use of medication

165
Q

Classification of ADRs- ABCDEFG

A

Augment, bizarre, chronic/couniting, delayed, end of use/withdrawal, failure of treatment, genetic

166
Q

ADRs- Type A (Augmented)

A

Most common type of ADR (80%)
Exaggerated effect of drugs pharmacology at a therapeutic dose
Often not life threatening
Dose dependent and reversible upon withdrawing the drug
Examples: AKI with ACE inhibitors, Bradycardia with betablockers, Hypoglycaemia with gliclazide, insulin, Respiratory depression with opiates, Bleeding with anticoagulants

167
Q

ADRs- Type B (Bizarre)

A

Not related to pharmacology of drug
Not dose related
Can cause serious illness or mortality
Symptoms do not always resolve upon stopping drug
Examples: Anaphylaxis with penicillins, Tendon rupture with quinolone antibiotics, Steven Johnson Syndrome with IV vancomycin

168
Q

ADRs- Type C (Chronic/continuing)

A

ADRs that continue after the drug has been stopped
Examples: Osteonecrosis of the jaw with bisphosphonates
Heart failure with pioglitazone

169
Q

ADRs- Type D (Delayed)

A

ADRs that become apparent some time after stopping the drug
Examples: Leucopenia with chemotherapy

170
Q

ADRs- Type E (End of use/withdrawal)

A

ADR develops after the drug has been stopped
Examples: Insomnia after stopping benzodiazepine, Rebound tachycardia after stopping beta-blocker, Nasal congestion after stopping xylometolazine nasal spray

171
Q

ADRs- Type F (Failure of treatment)

A

Unexpected treatment failure
Could be due to drug-drug interaction or drug-food interaction
Poor compliance with administration instructions
Examples: Failure of oral contraceptive pill due to St John’s Wort, Failure of DOAC due to enzyme inducer (eg carbamazepine), Failure of bisphosphonate due to taking with food

172
Q

ADRs- Type G (Genetic)

A

Drug causes irreversible damage to genome
Examples: Phocomelia in children of women taking thalidomide

173
Q

ADRs- DoTS

A

Dose-relatedness
Timing
Susceptibility
More complex than ABCDE, but provides more detail.
Useful for those working in pharmacovigilance, undertaking research or developing medicines

174
Q

ADRs- DoTS - Dose-relatedness

A

-Hypersusceptibility: ADRs at subtherapeutic doses (eg anaphylaxis with penicillins)
-Collateral effects (side effects): ADRs at therapeutic doses (eg hypokalaemia with loop diuretic)
-Toxic effects: ADRs at subpratherapeutic doses (eg liver damage with paracetamol)

175
Q

ADRs- DoTS - Timing

A

Time independent: ADRs which can develop during any time during treatment (often due to clinical changes in the patient)
Time dependent- Rapid (Due to rapid administration), first does (1st dose only), early (occurs early during treatment but resolve as treatment progresses), intermediate (occurs after some delay), Late (Risk increases with prolonged or repeated exposure), delayed (occur some time after exposure or after drug withdrawal)

176
Q

DoTS - Susceptibility

A

Certain patient groups/populations may have a specific susceptibility to ADRs from a drug
-Age (anticholinergics in elderly patients)
-Gender (metoclopramide in females)
-Disease states (eg diclofenac in CVD)
-Physiological states (eg phenytoin in pregnancy)

177
Q

How are ADRs identified?

A

-Pre-clinical testing (computer models, cells and toxicity testing in animals)
-Clinical trial data (pre-marketing evaluation)
-Post marketing surveillance
-Pharmacovigilance

178
Q

Toxicity testing

A

Testing in animals before being given to humans

179
Q

Pre-marketing evaluation

A

Prior to the thalidomide disaster there was no need for manufacturers to demonstrate the efficacy or safety of a drug
MHRA (Medicines Healthcare Regulatory Authority) is responsible for monitoring drug safety (from clinical trial stage and post-marketing)

180
Q

3 stages of clincal trial

A

Phase 1 is the first stage of research, testing for general safety with a small volunteer group. Phase 2 tests how well the treatment works on a larger volunteer group, dose finding. Phase 3 evaluates how effective the treatment is in comparison to current treatments, gold standard RCTs

181
Q

Limitations of pre-marketing evaluation

A

Low patient numbers
Exclusion of specific patient groups (many at high risk of ADRs): Elderly, frail, Polypharmacy, multimorbid, Severe organ dysfunction, Neonatal and paediatric population
ADRs with incidence over 1% will generally be identified (most likely Type A)
Less common ADRs (including Type B) are less likely to be identified

182
Q

Black triangle medicines

A

Medicines subject to post marketing surveillance are indicated by a black triangle:

183
Q

Post marketing surveillance

A

After product licence is granted by MHRA medicines are subject to post marketing surveillance (usually at least 5 years). Full ADR profile is unlikely to be understood once the drug is in widespread clinical use

184
Q

Pharmacovigilance

A

process and science of monitoring the safety of medicines and taking action to reduce the risks and increase the benefits of medicines

185
Q

Yellow Card System Pros and Cons

A

Pros- confidential, no fear of litigation, quick to submit, accessible to all (HCP and patients)
Cons- Under-reporting (%% of ADRs and 10% of serious are reported), relies on HCPs recognising ADRs, data does not indicate incidence

186
Q

What ADRs are reported?

A

Any ADR caused by black triangle medicine
Serious ADRs: Caused hospitalisation, Prolonged hospitalisation, Life threatening, Causing disability or death, Causing congenital abnormalities, Deemed medically significant
Unlicensed uses: Unlicensed medicines, Off label uses, Herbal medicines, Illicit drugs, Reactions at unlicensed doses (toxicity)

187
Q

Who is at increased risk of ADRs

A

Atopic individuals, children/neonates, extreme weights, reduced drug clearance, females, polypharmacy, advanced age, genetic variations

188
Q

Pharmacogenomics

A

Genetic variation can increase risk of ADRs, In most cases genomic risk factors will be unknown (for now)

189
Q

Prescribing to reduce risk of ADRs

A

Rationalise: Stop unnecessary medicines, Thorough and complete DHx (avoid interactions/duplication), Optimise dose (indication, weight, organ dysfunction, interacting drugs), Pre-empt ADRs and consider prophylaxis (eg PPI with long term steroids
Patient counselling: How to take (consider patients with cognitive impairment), Side effects to expect and/or side effects to report
Appropriate monitoring
Clear and timely communication between care providers (TTOs, outpatient clinic letters, IT systems)

190
Q

Allergic reactions to drugs

A

Interaction of drug/metabolite/or non drug element with patient and disease. Subsequent re-exposure. Exposure may not be medical

191
Q

Example of target organs of allergy

A

Skin, resp tract, GI tract, blood and blood vessels

192
Q

Drug 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

193
Q

Is Anaphylaxis immunological or non-immunological?

A

Can be either, Anaphylaxis can be immunological (IgE modulated) or non-immunological

194
Q

Immediate <1hr Drug hypersensitivity

A

urticarial, anaphylaxis

195
Q

Delayed >1hr Drug hypersensitivity

A

other rashes, hepatitis, cytopenias

196
Q

Type 1 Hypersensitivity

A

Type 1 – IgE mediated drug hypersensitivity,acute anaphylaxi, Prior exposure to the antigen/drug

197
Q

Type 2 Hypersensitivity

A

Type 2 – IgG mediated cytotoxicity

198
Q

Type 3 Hypersensitivity

A

Type 3 – Immune complex deposition

199
Q

Type 4 Hypersensitivity

A

Type 4 – T cell mediated

200
Q

Anaphylaxis

A

Occurs within minutes and lasts 1-2 hours
Vasodilation, Increased vascular permeability, Bronchoconstriction, Urticaria, Angio-oedema
Drug anaphylaxis majority of deaths due to anaphylaxis
Insect venom most common cause followed by medications
1-20% have biphasic response

201
Q

Type 2 reactions – antibody dependant cytotoxicity

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

202
Q

Type 3 reactions – immune complex mediated

A

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
Includes glomerulonephritis, vasculitis,

203
Q

Type 4 reaction – Lymphocyte mediated

A

Antigen specific receptors develop on T-lymphocytes
Subsequent admin, adminstration leads to local or tissue allergic reaction
E.g. contact dermatitis
E.g. Stevens Johnson syndrome

204
Q

Non immune anaphylaxis

A

Due to direct mast cell degranulation.
Some drugs recognised to cause this
No prior exposure
Clinically identical

205
Q

Anaphylaxis – main features

A

Exposure to drug, immediate rapid onset
Rash (absent in 10-20%)
Swelling of lips, face, oedema, central cyanosis
Wheeze / SOB
Hypotension (Anaphylactic shock)
Cardiac Arrest

206
Q

Common causes of anaphylaxis

A

Food, stings, drugs taken orally or injected

207
Q

Anaphylaxis ABCDE

A

Airway, Breathing, Circulation, Disability, Exposure

208
Q

Management of anaphylaxis

A

Commence basic life support. ABC
Stop the drug if infusion
Adrenaline IM 500micrograms(300mcg epi-pen)
High flow oxygen
IV fluids – aggressive fluid resuscitation
If anaphylactic shock may need IV adrenaline with close monitoring
Antihistamines not first line treatment but can be used for skin symptoms

209
Q

Most important drug in anaphylaxis

A

Adrenaline IM 500micrograms(300mcg epi-pen)

210
Q

Adrenaline function

A

Vasoconstriction - increase in peripheral vascular resistance, increased BP and coronary perfusion via alpha1-adrenoceptors
Stimulation of Beta1-adrenoceptors positive ionotropic and chronotropic effects on the heart
Reduces oedema and bronchodilates via beta2-adrenoceptors
Attenuates further release of mediators from mast cells and basophils by increasing intracellular c-AMP and so reducing the release of inflammatory mediators

211
Q

Receptors adrenaline acts on

A

Alpha 1+2, Beta 1+2

212
Q
A

Phase 2a Lecture Notes (14 decks)

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