Pharmacology Flashcards
(379 cards)
1
Q
Define pharmacodynamics
A
How drugs effect the body
2
Q
Define pharmacokinetics
A
How the body effects the drug (ADME)
3
Q
Name 3 reasons why pharmacology is becoming such a big problem
A
- Age - more older people
- Polypharmacy - more people on more than one medication
- Lifestyle - ‘over the counter’ use increasing and natural remedies
4
Q
Name 4 types of drug interaction
A
- Synergy
- Antagonism
- Summation
- Potentiation
5
Q
What is synergistic drug interaction?
A
Drugs work together to make a combined greater effect (1+1>2)
6
Q
Describe antagonistic drug interaction
A
2 drugs that cancel each other out (1+1=0)
7
Q
Describe summation drug interaction
A
Drugs work together to create combined effect (1+1=2)
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)
9
Q
Name 5 patient risk factors for drug interaction
A
- Polypharmacy
- Old age
- Genetic
- Hepatic disease
- Renal disease
10
Q
Name 3 drug risk factors for drug interaction
A
- Narrow therapeutic index
- Steep dose/response curve
- Saturable metabolism
11
Q
Name 4 ways to avoid drug interactions
A
- Prescribe rationally
- BNF
- Ward pharmacist
- PIL - Patient/product information leaflet
12
Q
How does grapefruit juice effect warfarin?
A
Interacts with warfarin - affects CYP450 and its ability to bind with proteins
13
Q
Name 4 drugs that induce Acute Kidney Injury (AKI)
A
- NSAIDs
- Gentamicin
- ACE Inhibitors
- Furosemide
14
Q
Define pharmacology
A
Branch of medicine concerned with the uses, effects, and modes of action of drugs
15
Q
Define ‘druggability’
A
Ability of a protein target to bind small molecules with high affinity
16
Q
What are the most common drug targets?
A
Proteins
17
Q
Name 4 types of drug target
A
- Receptors
- Enzymes
- Transporters
- Ion channels
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
19
Q
What can ligands be?
A
Exogenous –> Drugs
Endogenous –> Hormones, neurotransmitters
20
Q
Name 2 types of neurotransmitter
A
Acetylcholine
Serotonin
21
Q
Give 2 examples of autacoids
A
Cytokines
Histamine
22
Q
Name 4 types of receptor
A
- Ligand gated ion channels
- G protein couples receptors
- Kinase-linked receptors
- Cytosolic/nucelar receptors
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
24
Q
Give an example of a ligand gated ion channel receptor
A
Nicotinic ACh receptor
25
How do G protein couples receptors work?
```
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)
```
26
How do kinase-linked receptors work?
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
27
Explain how cytosolic/nuclear receptors work
Zinc fingers bind to DNA and modify gene transcription
28
Give an example of a drug that uses cytosolic/nuclear receptors
Tamoxifen (breast cancer)
29
What kind of imbalance can lead to pathology?
Imbalance of chemicals or receptors
30
Name 2 conditions that can arise from an imbalance in chemicals
1. Allergy --> increased histamine
| 2. Parkinson's --> reduced dopamine
31
Name 2 conditions that can arise from an imbalance in receptors
1. Myasthenia Gravis --> loss of ACh receptors
| 2. Mastocyosis --> increased c-kit receptors
32
Define agonist
A compound that binds to a receptor and activates it
33
Define antagonist
A compound that reduces the effect of an agonist
34
What shape is a log concentration agonist response curve
Sigmoidal
35
Define potency
Measure of how well a drug works
| EC50 = concentration that gives half the maximal response
36
Define Efficacy (Emax)
Maximum response achievable form a dose
37
What is a partial agonist?
Even with 100% occupancy, maximal response is not seen
38
Define intrinsic activity (efficacy)
Refers to the ability of a drug-receptor complex to produce a maximum functional response
39
What is the equation for intrinsic activity?
IA = Emax of partial agonist/Emax of full agonist
40
What is seen on a graph if compound A is more potent than compound B?
Compound A has a lower concentration which provides a 50% response - lower EC50
41
What is seen on a graph if compound A is more efficacious than compound B?
The maximum response for compound A is greater than that of compound B
42
Name the 2 types of antagonism
1. Competitive
| 2. Non-competitive
43
What site does a competitive antagonist bind to?
The same site as the agonist on the receptor
44
What site does a non-competitive antagonist bind to?
Binds to an allosteric (non-agonist) site on the receptor
45
What happens to the response when a competitive antagonist is added?
Same thing happens but a greater concentration of agonist is needed (max response can be achieved)
46
What happens to the response when a non-competitive antagonist is added?
The response can't reach its maximum
47
What do cholinergic receptors respond to?
Neurotransmitters
48
Name the 2 categories of cholinergic receptor
1. Muscarinic
2. Nicotinic
One is a GPCR and the other is an ion channel
49
Name an agonist for a H2 receptor
Histamine - contraction of ileum, acid secretion from parietal cells
50
Name a antagonist for a H2 receptor
Mepyrmaine
51
Name 2 categories of factors that govern drug action
1. Receptor related
| 2. Tissue related
52
Name 2 receptor related factors that govern drug action
1. Affinity
| 2. Efficacy
53
Define affinity
How well a ligand binds to the receptor
54
Define efficacy
How well a ligand activates the receptor
55
Is affinity shown by agonists or antagonists?
Shown by both
56
Is efficacy shown by agonists or antagonists?
Only by agonists
| Antagonist have zero efficacy as they don't activate receptors
57
Name 2 tissue related factors that govern drug action
1. Receptor number
| 2. Signal amplification
58
How does receptor number affect drug action?
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
59
How does signal amplification work?
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
60
What is a receptor reserve?
Where an agonist needs to activate only a small fraction of the existing receptors to produce the maximal system response
61
Does a partial agonist have a receptor reserve?
NO - even with 100% occupancy, maximal response is not seen
62
What is allosteric modulation?
An allosteric ligand binds at a different site on a receptor and influences the role of an agonist
63
What is inverse agonism?
When a drug binds to the same receptor as an agonist but induces pharmacological response opposite to that of the agonist
64
Define tolerance
Reduction in drug (agonist) effect over time
65
Give 3 ways a receptor can be desensitised
1. Uncoupled - agonist would be unable to interact with a GPCR
2. Internalised - endocytosis, receptor is taken into vesicles in the cell
3. Degraded
66
What is an enzyme inhibitor?
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
67
Name the 2 types of enzyme inhibitor
1. Irreversible inhibitors
| 2. Reversible inhibitors
68
How do irreversible inhibitors work?
React with enzyme and change it chemically (e.g. via a covalent bond)
69
How do reversible inhibitors work?
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
70
What do statins inhibit?
HMG-CoA reductase inhibitors
71
What step do statins block?
The rate limiting step - HMG-CoA --> Mevalonic acid
72
What is the purpose of statins?
To reduce the levels of 'bad cholesterol', reduce CVD and mortality in those who are at high risk
73
What do ACE inhibitors do?
Reduce angiotensin II production therefore reducing blood pressure
74
Give 5 symptoms of Parkinson's disease
1. Hypokinesia
2. Tremor at rest
3. Muscle rigidity
4. Motor inertia
5. Cognitive impairment
75
What does Parkinson's effect?
Degenerative disease of basal ganglia - Early degeneration of dopaminergic neurones in the nigrostriatal pathway
76
How does L-DOPA improve Parkinson's symptoms?
Produced from aa L-tyrosine as a precursor for neurotransmitter biosynthesis
77
Name a peripheral DDC (dopamine decarboxylase) inhibitor
Carbidopa
78
How do peripheral DDC inhibitors improve Parkinson's symptoms?
Blocks DDC in the periphery generating more for the CNS pathway
79
What happens to L-DOPA when in the CNS?
L-DOPA converted to Dopamine via DOPA Decarboxylase (DDC)
80
Name 2 peripheral Catechol-O-methyl transferase (COMT) inhibitors
1. Tolcapone
| 2. Entacapone
81
How do peripheral COMT inhibitors help improve Parkinson's symptoms?
Prevents breakdown of L-DOPA generating more L-DOPA for the CNS pathway d
82
Name a central COMT inhibitor
Tolcapone
83
How do central COMT inhibitors help improve Parkinson's symptoms?
Function within CNS to prevent dopamine breakdown
84
Name 2 monoamine oxidase B inhibitor
1. Selegiline
| 2. Rasagiline
85
How do monoamine oxidase B inhibitors help improve Parkinson's symptoms?
Prevent dopamine breakdown and increase availability
86
Name 4 central dopamine receptor agonists
1. Bromocryptine
2. Pergolide
3. Pramipexole
4. Ropinirole
87
How do central dopamine receptor agonists help improve Parkinson's symptoms?
Antagonise dopamine receptors
88
Name the types of protein port
Uniporters
Symporters
Antiporters
89
How does a uniporter work?
Uses energy from ATP to pull molecules in
90
How does a symporter work?
Uses the movement in of one molecule to pull in another molecules against a concentration gradient
91
How do antiporters work?
One substance moves against its gradient, using energy form the second substance (mostly Na+, K+ or H+) moving down its gradient
92
Give an example of a symporter
Na-K-Cl co transport (NKCC)
93
Name a drug that effects NKCCs
Furosemide - inhibits NKCC co-transport in the ascending limb of the loop of Henle (hypertension and oedema)
94
Name 5 types of ion channel
1. Epithelial sodium channels (ENaC)
2. Voltage-gated Calcium channels
3. Voltage-gated Sodium Channels
4. Metabolic Potassium channels
5. Receptor Activated Channels
95
How do ENaCs work?
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)
96
Name a drug that blocks ENaCs
Amiloride
97
What does Thiazide do?
Targets Na+/Cl- cotransporter that reabsorbs Na and Cl from tubular fluid
98
How do Voltage-gated Calcium channels work?
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.
99
Name a drug that effects voltage gated calcium channels
Amlodipine - angioselective Ca channel blocker - inhibits movement of Ca ions into vascular smooth muscle cells and cardiac muscle cells
100
How do Voltage-gated Sodium channels work?
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
101
Name a drug that affects voltage gated calcium channels
Amlodipine - angioselective Ca channel blocker - inhibits movement of Ca ions into vascular smooth muscle cells and cardiac muscle cells
102
What are the 3 main conformational states of VG Na+ channels and metabolic K+ channels in excitable cells?
Closed
Open
Inactivated
103
Name a drug that affects VG Na+ Channels
Lidocaine (anaesthetic) - bocks transmission of the AP and blocks signalling in the heart reducing arrhythmia
104
How do Metabolic Potassium channels work?
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
105
Where are metabolic K+ channels found?
Pancreas - Regulate insulin - Increased glucose leads to block of ATP depend K+ channels
106
Name 3 drugs that block K+ channels
1. Repaglinide
2. Nateglinide
3. Sulfonylurea
Treatment of type 2 diabetes
107
How do receptor activated channels work?
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
108
Name a receptor activated channel
GABA-A receptor
109
How do GABA-A receptors work?
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)
110
Name 2 active transport mechanisms
1. Sodium pump
| 2. Proton pump
111
Explain the sodium pump
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)
112
Give an example of a drug that affects sodium pump and how it does this
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
113
Explain the proton pump
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
114
What group of drugs can affect proton pumps?
Proton-pump inhibitors (PPIs)
115
Give an example of a PPI
Omeprazole - inhibits acid secretion independent of cause
Irreversible inhibition of H/K ATPase
Drug half-life = 1hr but works for 2-3 days
116
Name a ACE inhibitor
Ramipril
117
Name 2 COX inhibitors
Aspirin
| Paracetamol
118
What is the major group of enzymes that are involved in drug metabolism?
CYPs - 75% of total metabolism
119
Name 2 naturally occurring opioids
1. Morphine
| 2. Codeine
120
Name 4 synthetic opioids
1. Fentanyl
2. Pethidine
3. Alfentanil
4. Remifentanil
121
Name 3 simple chemical modifications of naturally occurring opioids
1. Diamorphine
2. Oxycodone
3. Dihydrocodeine
122
Name an antagonist to opioids
Naloxone
123
How much oral morphine is metabolised by first pass metabolism?
50%
124
What is the IV, IM, s/c dose of morphine compared to the oral dose?
Half the dose if it's being given via IV etc
125
Where are the majority of opioid receptors found?
CNS
126
What is diamorphine also called?
Heroin - more potent and faster acting than morphine
127
How are opioids given when treating chronic pain?
Through transdermal patches
128
How do opioids work?
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
129
Name 4 types of opioid receptors
1. M receptors
2. Delta receptors
3. Kappa receptors
4. Nociceptin opioid-like receptors
130
Why are kappa agonists not used?
Cause depression rather than euphoria
131
Why do you get side effects from opioids?
Opioid receptors exist outside the pain system digestive tract, respiratory control centre and mostly opioids are given systemically
132
Name 7 side effects to opioids?
```
Addiction
Respiratory depression
Sedation
Nausea and vomiting
Constipation
Itching
Immune suppression
```
133
What should be given for opioid induced depression?
Naloxone - opioid antagonist
134
Why should you be careful when prescribing morphine to patients with renal failure?
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
135
Name 7 things the parasympathetic nervous system causes
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
136
Name 7 things the sympathetic nervous system causes
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
137
Where are the ganglia located in the parasympathetic nervous system?
Near their targets - short post-ganglionic nerves
138
Where are the ganglia located in the sympathetic nervous system?
Ganglia are near the spinal cord - longer post-ganglionic nerves
139
What neurotransmitter does the PNS release at the first ganglion?
Acetylcholine
140
What neurotransmitter does the SNS release at the first ganglion?
Acetylcholine
141
What neurotransmitter does the PNS release at the target and what receptors does it act on?
Acetylcholine
| Acts on muscarinic receptors
142
What neurotransmitter does the SNS release at the target and what receptors does it act on?
Noradrenaline
| Act on adrenergic receptors (alpha or beta)
143
Name the 5 types of muscarinic receptor
M1, M2, M3, M4 nad M5
144
Where are M2 receptors mainly located?
Heart - activation slows heart
145
Where are M3 receptors mainly located?
Glandular and smooth muscles - cause bronchoconstriction, sweating, salivary gland secretion
146
What nervous system do muscarinic agonists stimulate?
Parasympathetic nervous system
147
Name a muscarinic agonist and explain what it does?
Pilocarpine - stimulates salivation, contracts iris smooth muscles (treat glaucoma)
148
What do muscarinic antagonists do to the parasympathetic nervous system?
De-stimulate it by blocking muscarinic receptors
149
What do muscarinic antagonists do to the parasympathetic nervous system?
De-stimulate PNS by blocking muscarinic receptors
150
Name 6 muscarinc antagonists that act within the autonomic system
```
Atropine
Hyoscine
Ipratopium bromide
Tiotropium
Solifenacin
Mebeverine
```
151
What is Atropine used for?
Treat life threatening bradycardia and cardiac arrest
| Prevents bradycardia and BP drop
152
What is Hyoscine used for?
Used in palliative care - particularly to antagonise parasympathetic given secretions
153
Name a Short Acting Muscarinic Antagonist (SAMA)
Ipratropium bromide - treats bronchoconstriction by blocking M3 receptors
154
Name a Long Acting Muscarinic Antagonist (LAMA)
Tiotropium
155
What is Solifenacin used in the treatment of?
An overactive bladder
156
Give an example of a nicotinic blocker that is used during surgery
Pancuronium or suxamethonium - inhibit ACh to inhibit muscle activity and induce relaxation in surgery
157
Why does myasthenia graves result in muscle weakness?
Autoimmune destruction of nicotinic ACh receptors
158
Give 6 side effects of muscarinic antagonists
1. Worsen memory
2. Confusion
3. Constipation
4. Dry mouth
5. Blurring of vision
6. Worsening of glaucoma
159
What is the precursor to noradrenaline?
Dopamine
160
What is the precursor to adrenaline?
Noradrenaline
161
Where is noradrenaline released from?
Sympathetic nerve fibre ends
162
Where is adrenaline released from?
Adrenal glands
163
Name 5 types of adrenergic receptors
```
Alpha 1
Alpha 2
Beta 1
Beta 2
Beta 3
```
164
What is the main agonist for Alpha 1 receptors?
Noradrenaline
165
What does stimulation on Alpha 1 receptors cause?
Contracts smooth muscle - vasoconstriction (pupil, blood vessels)
166
What is the main agonist for Alpha 2 receptors?
Noradrenaline and adrenaline act on it equally
167
What does stimulation on Alpha 2 receptors cause?
Can cause mixed effects on smooth muscle
Can lower BP and cause vasodilation
Presynaptic inhibition - inhibits NAd release
E.g. Clonidine
168
What is the main agonist for Beta 1 receptors?
Noradrenaline = Adrenaline
169
What does stimulation on Beta 1 receptors cause?
Increases the heart rate and chronotropic and inotropic effects
Increases renin secretion
170
What is the main agonist for Beta 2 receptors?
Adrenaline
171
What does stimulation on Beta 2 receptors cause?
Relaxes smooth muscle - lifesaving in asthma and can delay onset of premature labor
Bronchodilation and vasodilation
172
What is the main agonist for Beta 3 receptors?
Noradrenaline
173
What does stimulation on Beta 3 receptors cause?
Enhances lipolysis and relaxes the detrusor muscle of the bladder
174
Give 2 side effects of beta agonists
1. Can classy tachycardia
| 2. Affects glucose metabolism in the liver
175
Name an Alpha Blocker (antagonist)
Doxazosin - blocks Alpha 1 to lower BP
| Tamsuloin - blocks Alpha 1A in prostate to help treat prostatic hypertrophy
176
Name 4 Beta blockers
1. Propanolol
2. Atenolol
3. Bisoprolol
4. metoprolol
177
What affects does Propanolol have and how?
Blocks Beta 1 and 2 receptors
| Slows heart rate and reduces tremor
178
What receptor does Atenolol act on and where does it cause an effect?
Beta 1 receptor selective
| Main effect on the heart
179
Give 6 uses of beta blockers
1. Angina
2. MI prevention
3. High BP
4. Anxiety
5. Arrhythmias
6. Heart failure
180
Give 7 side effects of beta blockers
1. Tiredness
2. Cold extremities
3. Erectile dysfunction
4. Bronchoconstriction
5. Bradycardia
6. Hypoglycaemia
7. Cardiac depression
181
Define Allergy
Abnormal response to harmless foreign material
182
Define Atopy
Tendency to develop allergies - inherited tendency to exaggerated IgE response to antigen
183
How many types of hypersensitivity are there in the Gell and Coombes classification?
4
184
What immunoglobulin is Type 1 hypersensitivity related to?
IgE - immunological memory to something causing an allergic response
Mast cells degranulate on re-exposure releasing inflammatory mediators
185
Give 3 examples of Type 1 reactions
1. Acute anaphylaxis
2. Hayfever
3. Asthma
186
How do you treat hayfever?
Prevent exposure
Antihistamines
Reduction in local inflammation (steroids)
Desensitisation
187
Explain Type 2 hypersensitivity
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
Give 3 examples of Type 2 hypersensitivity reactions
Goodpastures syndrome
Mycoplasma pneumonia
Graves' disease
189
Explain Type 3 reactions
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
Give 3 examples of Type 3 reactions
Farmers lung
SLE
Post-streptococcal gastroenteritis
191
What are Type 4 reactions mediated by?
T cell mediated reaction
| Formation of granulomas in a slow process
192
Name 3 examples of Type 4 reactions
TB
Contact dermatitis
Sarcoidosis
193
Name 2 types of asthma
Extrinsic - atopy, occupational
| Intrinsic - often late onset - nasal polyposis, aspirin sensitive
194
Name the 2 phases of bronchoconstriction
Immediate - IgE/mast cell mediated
| Late Phase - T cell mediated
195
How do you treat asthma?
Steroids
Symptomatic relief
Antihistamines
Anti-IgE
196
Define adverse drug reaction
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
Define side effect
Unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment
198
Name 3 categories adverse drug reactions can be classified into
1. Toxic effects (beyond therapeutic range)
2. Collateral effects (within therapeutic range)
3. Hyper-susceptibility (below therapeutic range)
199
When can toxic effect drug reaction occur?
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
Give an example of when a collateral effect drug reaction can occur
Occurs when given standard therapeutic doses
| Beta blockers during bronchoconstriction
201
Name examples of hyper-susceptibility effect drug overdoses
Occurs when given sub therapeutic doses
| Anaphylaxis and penicillin
202
Give 4 symptoms of mild ADRs
1. Nausea
2. Drowsiness
3. Itching
4. rash
203
Give 4 symptoms of severe ADRs
1. Respiratory depression
2. Neutropenia
3. Catastrophic haemorrhage
4. Anaphylaxis
204
When can time independent reactions occur and give an example of one?
Occur at any time during treatment
| E.g. INR increase when erythromyocin administered with warfarin
205
Name 6 times of time dependent drug reactions
1. Rapid reactions
2. First dose reactions
3. Early reactions
4. Intermediate reactions
5. Late reactions
6. Delayed reactions
206
Name the types of adverse drug reactions in Rawlins Thompson classification
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
Describe Type A ADRs
Predictable
Dose dependent
Common
Extension of primary effect (bradycardia and propranolol)
Secondary effect (bronchospasm with propranolol B2 blocking effect)
208
Descrive Type B ADRs
```
Not predictable
Not dose dependent
Can't readily be reverse
Life threatening
Can be idiosyncrasy
Can be allergy or hypersensitivity
```
209
Give an example of a Type B ADR
Anaphylaxis
210
What are Type C ADRs due to?
Osteoporosis and steroids
| Analgesic nephropathy
211
Give an example of a Type D ADR
Malignancies after immunosuppression
Thalidomide causing adverse effects on foetus when taken while pregnant
Carcinogenesis
212
When do Type E ADRs occur?
After abrupt drug withdrawal
| E.g. Opiate withdrawal syndrome
213
Describe idiosyncrasy
Inherent abnormal repose to a drug
| Genetic abnormality, enzyme deficiency
214
What does DoTS mean?
Dose related (toxic, collateral, hyper-susceptibility)
Timing
Patient Susceptibility
Relates to what ADR occurs
215
Name 8 patient risk factors for ADRs
1. Gender (F>M)
2. Elderly
3. Neonates
4. Polypharmacy
5. Genetic predisposition
6. Hypersensitivity/allergies
7. Hepatic/renal impairment
8. Adherence problems
216
Name 3 drug risk factors for ADRs
1. Steep dose-response curve
2. Low therapeutic index
3. Commonly causes ADRs
217
Name another risk factor for ADRs
Prescriber risks
218
Name 7 causes of ADRs
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
When should we suspect an ADR?
Symptoms soon after a new drug is started
Symptoms after a dosage increase
Symptoms disappear when the drug is stopped
Symptoms reappear when the drug is restarted
220
What are the most common drugs that have ADRs?
```
Antibiotics
Anti-neoplastics
Cardiovascular drugs
Hypoglycemics
NSAIDS
CNS drugs
```
221
Name 6 common ADRs
1. Confusion
2. Nausea
3. Balance problems
4. Diarrhoea
5. Constipation
6. Hypotension
222
Give 3 ways to avoid ADRs
1. Avoid drug interactions
2. Don't prescribe inappropriate medications
3. Don't prescribe unnecessary medications
223
What does the Medicines and Healthcare Regulatory Agency (MHRA) do?
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
What are yellow cards used for?
To report ADRs
225
Define hypersensitivity
Objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects and may be caused by immunological (allergic) and non-immunological mechanisms
226
What inflammatory mediators do mast cells release when they undergo degranulation?
Histamine, prostaglandins, leukotrienes, platelet activating factors, cytokines and proteases
227
Name 3 groups of risk factors for hypersensitivity
1. Medicine factors
2. Host factors
3. Genetic factors
228
Name 4 host risk factors for hypersensitivity
1. Females > Males
2. EBV, HIV
3. Previous drug reactions
4. Uncontrolled asthma
229
Name 2 genetic risk factors for hypersensitivity
1. Certain HLA groups
| 2. Acetylator status
230
Name 7 clinical criteria for an allergy to a drug
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
Define anaphylaxis
A severe, life-threatening, generalised or systemic hypersensitivity reaction
232
What is anaphylaxis characterised by?
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
What immunoglobulin is anaphylaxis mediated by?
IgE
234
Describe non immune anaphylaxis
Sue to direct mast cell degeneration
No prior exposure needed
Clinically identical and treatment is the same
235
Name 6 features if anaphylaxis
1. Rash/urticaria
2. Swelling of lips, face, oedema
3. Wheeze/SOB
4. Hypotension (anaphylactic shock)
5. Cardiac arrest
6. Respiratory arrest
236
Describe the management of anaphylaxis
```
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
How does Adrenaline help treat anaphylaxis?
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
What are the most common triggers for anaphylaxis?
```
Food - nuts, milk, fish
Drugs - NSAIDs, antibiotics
Insect stings
General anaesthetic
Contrast agents
Other - latex, hair dye
```
239
What are the steps in an allergic response?
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
Which compound causes blood vessel dilation and vascular leakage in an allergic response?
Histamine
241
How can immune function be assessed?
Looking at neutrophil numbers, morphology and flow cytometry
Looking at B and T cell subsets, number and responses to vaccines
Genetic studies
242
Give 3 examples of chronic inflammatory diseases
1. Rheumatoid arthritis
2. Crohn's disease
3. TB
243
Name 3 conventional therapies used in managing chronic inflammatory diseases
1. NSAIDs
2. Disease modifying anti rheumatic drugs (DMARDs)
3. Steroids
244
How do NSAIDs work in relieving inflammation?
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
What is a disadvantage of long term NSAID use?
Can cause gastric bleeding - inhibit COX 1 which is needed for prostaglandin synthesis and prostaglandins are needed for gastric mucus production
246
What is the result of recombination in the Ig region?
Class switching
247
Describe the process of class switching
```
Antigen engagement and T cell help result in class switching
A different Fc region is used and there is affinity maturatoin
```
248
Give an example of a ligand gated ion channel
Nicotinic ACh receptor
249
Give an example of a GPCR
Muscarinic and beta-2 adrenoreceptors
250
Give an example of a kinase linked receptors
Receptors for growth factors
251
Give an example of a cytosolic/nuclear receptor
Steroid receptors (steroid affect transcription)
252
Would an antagonist shift a dose-repose curve to the left or right?
Shift it right - drug becomes less potent
253
What is the function of COX1 and COX2
They cyclise and oxygenate arachidonic acid and produce prostaglandin H2
254
Define pro-drugs and give an example of one
Drugs that need to be activated enzymatically
| E.g. ACE inhibitors, enalapril
255
How do ACE inhibitors work?
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
Describe how ACh is synthesised
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
Describe the action of competitive antagonists at the NMJ
They block ACh receptors
| Competitive antagonists are muscle relaxants
258
Describe the catecholamine synthesis
Tyrosine --> L-DOPA --> Dopamine --> Noradrenaline --> Adrenaline
259
What would a Beta-1 adrenergic antagonist do?
Reduce CO and renin secretion
260
Describe a type C adverse drug reaction
Chronic
| Occurs after long term therapy
261
Describe a Type D adverse drug reaction
Delayed
| Occurs many years after treatment
262
What is the treatment for a type A adverse drug reaction?
Reduce the dose
263
What is the treatment for a type B adverse drug reaction?
Withdraw drug immediately
264
What is morphine metabolised to?
Morphine-6-glucuronide
265
What might u receptors be found?
In the epidural space and CSF
266
Describe the dose-response curve for morphine
As the dose increase response increases
| Initially rapid and then it plateaus - NOT sigmoidal
267
What are the 3 actions fo NSAIDs
1. Anti-inflammatory
2. Analgesic
3. Antipyrexic
AAA
268
What are the 4 components of Pharmacokinetics?
Absorption
Distribution
Metabolism
Elimination/excretion
269
Define absorption in terms of pharmacokinetics
Process of transfer from the site of administration into the general or systemic circulation
270
Name 10 routes of administration of drugs
```
Oral
Intravenous
Intraarterial
Intramuscular
Subcutaneous
Inhalation
Topics
Sublingual
Rectal
Intrathecal
```
271
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?
IV and IA injections
272
Drugs acting at intracellular sites must also cross the cell membrane, how may they do this?
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
Briefly describe the passive diffusion through the lipid layer of drugs being absorbed to intracellular sites
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
What type of molecules can diffuse through pores or ion channels in the bilayer to enter a cell?
Very small, water soluble molecules (e.g. lithium)
275
Name an ATP-binding cassette (ABC)
P-gp --> multi drug resistance (MDR1) - removes a wide range of drugs from cytoplasm to the extracellular side
276
What type of molecules are usually taken up by pinocytosis?
Endogenous macromolecule and can be used in uptake of recombinant therapeutic proteins (e.g. amphotericin)
277
Why is drug ionisation so important?
Ionisable groups are essential for the mechanism of action of most drugs as ionic forces are part of the ligand receptor interaction
278
If drugs are in their ionised from are they water or lipid soluble?
Water soluble
279
If drugs are in their unionised from are they water or lipid soluble?
Lipid soluble
280
What is the pKa?
Dissociation/ionisation constant
| pH at chick half go the substance is ionised and half in unionised
281
How does the pH of the medium affect ionisation of drugs?
Weak acids are best absorbed in regions of high acidity (stomach)
Weak bases are best absorbed in alkaline conditions (intestine)
282
Is aspirin a weak acid or base?
Aspirin is a weak acid
283
How does a raised gastric pH affect the uptake of aspirin?
Reduces uptake of aspirin from the stomach so reduces the bioavailability
284
Why is the small intestine an ideal environment for oral administrated drug uptake?
Large SA and high blood flow gives rapid and completes absorption of oral drugs
285
What do oral drugs have to overcome before reaching the systemic circulation?
Drug structure
Drug formulation
Gastric emptying
First pass metabolism
286
Why do oral drugs have to overcome drug structure before reaching systemic circulation?
Drugs need to be lipid soluble to be absorbed from gut
| Highly polarised drugs tend to be only partially absorbed
287
Why do oral drugs have to overcome drug formulation before reaching systemic circulation?
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
Why do oral drugs have to overcome gastric emptying before reaching systemic circulation?
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
How many metabolic barriers to oral drugs have to pass to reach systemic circulation?
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
What drugs can be given transcutaneously?
Potent and non-irritant drugs
| Slow and continued absorption useful with transdermal patches
291
What 2 factors do intramuscular drugs depend on?
1. Blood flow
| 2. Water solubility
292
How does an increase in blood flow or water solubility effect intramuscular drug uptake?
Enhances removal of drug from the injection site
293
What kind of drugs are administrated by inhalation?
Volatiles - general anaesthetics and bronchodilators
294
Define distribution in terms of pharmacokinetics
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
How does distribution occur?
By passive diffusion across cell membrane for most lipid soluble drugs
296
Where are proteins/large molecules active?
Only in the plasma compartment (5L)
297
Where are water soluble molecules active?
Plasma and interstitial compartments (5L + 15L)
298
Where are lipid soluble molecules active?
Only in the intracellular fluid (45L)
299
What happens when a drug binds to a protein reversibly?
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
What happens when a drug binds to a protein irreversibly?
Drug cannot re-enter circulation - equivalent to elimination
E.g. cytotoxic chemo with DNA
301
How quickly can drugs pass from the blood to the brain?
Lipid soluble - quickly
| Water soluble - enter slowly
302
What transporters return drug molecules from the brain to the circulation?
Efflux transporters
303
How are drugs removed from the brain?
Diffusion into plasma
Active transport into the choroid plexus
Elimination in CSF
304
What type of drugs can readily cross the placenta?
Lipid soluble drugs
305
How the foetal liver metabolise drugs well?
Low level of drug metabolising enzymes so it relies on maternal elimination
306
Where is a drug eliminated from?
Plasma compartment
307
Why is metabolism essential?
Need to convert lipid soluble products into water soluble products that can be readily removed
308
Where are pro-drugs activated?
Liver
309
What is the aim of a phase 1 metabolism reaction?
To make the drug a more polar metabolite
310
How is a phase 1 reaction carried out?
Unmasking or adding a functional group by oxidation, reduction or hydrolysis (-OH, NH2, -SH, -COOH)
311
Briefly explain a reduction phase 1 reaction
Hydrogen is added to saturate unsaturated bonds
312
Briefly explain a hydrolysis phase 1 reaction
Split amide and ester bonds
313
What is the most common phase 1 reaction?
Oxidation
314
Explain a oxidation phase 1 reaction
Hydroxylation - add -OH
Dealkylation - remove -CH side chains
Deamination - remove -NH
Hydrogen removal
315
What is an oxidation phase 1 reaction usually catalysed by
Cytochrome P450
316
Give the main features of cytochrome P450
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
What can induce P450 enzymes and what does this result in?
Smoking and alcohol
| More rapid drug metabolism as a result
318
What can inhibit P450 enzymes and what does this result in?
Drugs and foods
| Drug lasts longer/nor eliminated as fast
319
What enzyme is ethanol metabolised by?
Alcohol dehydrogenase
320
What are phase 2 metabolism reactions?
Coagulation reactions - involved formation of a covalent bond = glucuronidation
321
When are phase 2 reactions used?
When a drug is very hydrophobic
322
What is the aim of phase 2 reactions?
To make the drug more hydrophilic
323
What enzyme is involved in phase 2 reactions?
Glucuronosyltransferase (UGT) = microsomal enzyme
324
How are most drugs excreted?
Through renal and/or hepatic excretion
325
In what forms can drugs be excreted?
Molecule is expelled in liquid, solid or gaseous forms
326
What compounds are excreted as fluids?
Low molecular weight polar compounds (urine, bile, sweat, tears, breast milk)
327
What compounds are excreted as solids?
Faecal elimination is important for high molecular weight compounds excreted in bile
328
What compounds are excreted as gaseous compounds
Expired air important for volatiles
329
What is first order kinetics?
rate is directly proportional to the concentration of the drug (rate ∝ [drug])
330
What is second order kinetics?
Rate is directly proportional to the square of the concentration of the drug (rate ∝ [drug]2)
331
What is third order kinetics?
Rate is directly proportional to the cube of the concentration of the drug (rate ∝ [drug]3)
332
What is zero order kinetics?
Rate is unrelated to the concentration of the drug
333
Define half life
Time taken for a concentration o reduce by one half
334
Define bioavailability
Fraction of the administered drug that reaches the systemic circulation unaltered
335
What is the bioavailability of IV drugs?
1 as 100% of the drug reached circulation
336
What does the rate of distribution of water soluble drugs depend on?
Rate of passage across membranes
337
What does the rate of distribution of lipid soluble drugs depend on?
Blood flow to tissues that accumulate drug
338
Why is the extent of drug distribution clinically important?
Determines total amount of drug that has to be administered to produce a particular plasma concentration (apparent volume of distribution)
339
What is the apparent volume of distribution (Vd)?
Total amount of drug in the body (dose) / plasma concentration fo drug
340
Define clearance (CL)
Volume o blood or plasma cleared of drug per unit time (ml/min)
341
What is clearance a measure of?
Efficiency
342
If a drug has a high Vd, what will its plasma concentration be like?
Low plasma concentration
343
What is an equation for renal clearance?
CL = rate of appearance in urine / plasma concentration
344
What is used as a marker substance in the kidney?
Creatinine
345
What are the adult renal clearance values?
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
What percentage of the cardiac output is hepatic blood flow?
12%
347
Define Hepatic extraction ratio (HER)
Proportion of drug removed by one passage through the liver
348
If there is a high HER, what is the clearance limited by?
Perfusion limited (hepatic blood flow)
349
If there is a low HER, what is the clearance limited by?
Diffusion limited - process is slow and not efficient with a low amount removed
350
How do low HER drugs increase their clearance rate?
Cause liver to produce more enzymes
351
At what point does liver failure effect drug metabolism?
Once at least 70% of functioning liver is lost
352
Name 4 drugs with active metabolites
1. Prednisone
2. Codeine
3. Diamorphine
4. L-DOPA
5. Cortisone
6. Morphine
353
Why are repeat drug doses used?
To maintain a constant drug concentration int he blood and at the site of action for the therapeutic effect
354
What is steady state (Css)?
Balance between drug input and elimination
| infusion dosage = rate of elimination from plasma
355
If a drug has a slow elimination rate how quickly is steady state reached?
A logn time to reach Css and it will accumulate high plasma concentration before elimination rate rises to match drug infusion
356
What is a loading dose?
High initial dose which 'loads' the system and shortened the time to steady state
(loading dose = Css x Vd)
357
Name 3 things that the chemical properties of a drug can influence?
1. Administration
2. Distribution
3. Elimination
358
What equation can be used to determine the degree of ionisation at a specific pH?
Henderson Hasselbach
| pH = log[A-]/[HA] + pKa
359
In terms of ionisation, what happens to Aspirin in the stomach?
Aspirin is a week acid and so becomes less ionised in the stomach due to the low gastric pH
360
What is the effect of an increase in pH on a weak acid?
Weak acid will become more ionised
361
What is the effect of an increase in pH on a weak base?
Weak base will become less ionised
362
If a drug had a high Vd what would that tell us about the drug?
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
What are 2 ways by which drugs can be eliminated in the kidneys?
1. Glomerular filtration
| 2. Active secretion
364
What are the possible danger of kidney damage with regards to renal clearance ?
Results in decreased renal clearance and so there is a danger of accumulation, our dosage and toxicity
365
Give 3 advantages of IV infusion
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
Give 3 disadvantages of IV infusion
1. Expensive.
2. Needs constant checking.
3. Calculation error likely.
367
Name 2 approaches to drug design
1. Chance
| 2. Rational drug design
368
By what method was penicillin developed?
Fermentation
369
Name 3 other drugs developed by the process of fermentation
1. Lovastatin (statin)
2. Cyclosporine (immunosurpressent)
3. Ivermectin (broad spectrum antibiotic)
370
What form of drugs, D or L, do biological systems use?
The L amino acids (R form)
371
Name 2 drugs designed by the rational drug design approach
1. Propranolol - B-antagonist used in treatment for hypertension
2. Cimetidine - H2-antagonist used in treatment of peptic ulcers
372
Name 3 recombinant proteins in clinical use
1. Insulin
2. Erythropetin
3. Groth hormone
4. Interleukin 2
373
What are therapeutic antibodies based on?
Monoclonal antibody technology
374
How are monoclonal antibodies produced?
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
Name 2 types of second generation monoclonal antibodies
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
What does gene therapy involve?
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
What is combinatorial chemistry?
Biochemical modification of natural products
378
What is High Throughput Screening?
Screening the biological activity of compounds to analyse whether one has clinical efficacy
379
What can High Throughput Screening not establish?
Bioavailability
Pharmacokinetic
Toxicology
