Pharmacology Flashcards
1
Q
What is pharmacodynamics?
A
The biochemical, physiological + molecular effects of a drug on the body
2
Q
What is pharmacokinetics?
A
The fate of a chemical substance administered to a living organism
3
Q
What are the 4 steps of the pharmacokinetic process?
A
-Absorption
-Distribution
-Metabolism
-Excretion
4
Q
What is absorption of a drug?
A
The transfer of a drug molecule from the site of administration to the systemic circulation
5
Q
What do these acronyms stand for?
-IV
-IA
-IM
-SC
-PO
-SL
A
-Intravenous
-Intra-arterial
-Intramuscular
-Subcutaneous
-Oral
-Sublingual
6
Q
What do these acronyms stand for?
-INH
-PR
-PV
-TOP
-TD
-IT
A
-Inhaled
-Rectal
-Vaginal
-Topical
-Transdermal
-Intrathecal
7
Q
In what modes of administration does 100% of the dose reach systemic circualtion?
A
IV + IA
8
Q
What are the 3 mechanisms by which drugs can permeate across cell membranes?
A
-Passive diffusion through hydrophobic membrane (lipid soluble molecules)
-Passive diffusion through aqueous pores (small water soluble molecules)
-Carrier mediated transport (proteins transport sugars, a.a., neurotransmitters + trace metals)
9
Q
What 2 factors affect drug absorption?
A
-Lipid solubility
-Drug ionisation
10
Q
Why are ionised drugs poorly absorbed?
A
Have poor lipid solubility
11
Q
Where are weak acid drugs best absorbed?
A
Stomach
12
Q
Where are weak base drugs best absorbed?
A
Intestine
13
Q
What 5 factors affect drug absorption in the stomach?
A
-Gastric enzymes may digest drugs
-Low pH may degrade drug
-Food-full stomach slows absorption
-Gastric motility
-Previous surgery
14
Q
What is first pass metabolism?
A
Metabolism of drugs preventing them reaching systemic circulation-varies between ppl
15
Q
How does first pass metabolism occur?
A
-Drug degraded by enzymes in intestinal wall
-Absorbed from intestine into HPV + metabolism via liver enzymes
16
Q
How can you avoid first pass metabolism?
A
Give drugs by routes that avoid splanchnic circulation e.g. rectal
17
Q
What is bioavailability?
A
The proportion of a drug that reaches the systemic circulation-expressed as a % or decimal
18
Q
What is bioavailability dependent on?
A
-Extent of drug absorption
-Extent of first pass metabolism
19
Q
Give an example of a drug delivered PR
A
Diazepam suppositories for epilepsy
20
Q
Give an example of a drug delivered INH
A
Salbutamol inhaler
21
Q
Give an example of a drug delivered S/C
A
Long acting insulins for T1
22
Q
Give an example of a drug delivered TD
A
Fentanyl patches for severe chronic pain
23
Q
What compartments of the body do drugs end up in + what %
A
-ICF-35%
-Fat-20%
-Interstitial fluid-15%
-Plasma-5%
24
Q
What drug properties increase distribution?
A
-Small molecule size
-Lipophilic molecule
-Protein bound
25
What is Vd?
Volume of distribution-theoretical vol a drug will be distributed in the body
-Well distributed drugs=high Vd
26
What is the BBB?
Blood brain barrier-layer of epithelial cells with tight junctions that separates foreign substances in the blood from CNS
27
Name 3 ways drugs can reach the CNS
-Have high lipid solubility
-Be administered intrathecally
-In cases of inflammation BBB becomes leaky
28
With what patients should more care be taken when prescribing + why?
-Obese patients-drugs with small Vd not always delivered to fat-use ideal body weight rather than actual
-Septic patients-leaky blood vessels increases distribution, penetrates BBB better
-Liver impaired patients-hypoalbuminemia
-Older patients-smaller Vd of water soluble drugs=higher plasma concs
29
What are the 2 steps of metabolising a drug?
-Oxidation/reduction/hydrolysis to introduce reactive group
-Conjugation of functional group to produce hydrophilic, inert molecule
30
What enzyme is involved with most of phase 1 metabolism?
Cytochrome P450
31
What is the aim of phase 1 metabolism?
To create a reactive molecule
32
What is the aim of phase 2 metabolism?
To create a hydrophilic molecule that can then be renally excreted
33
How are drugs/metabolites excreted?
-Liquids (small polar molecules) e.g. urine, bile, sweat, tears, breast milk
-Solids (large molecules) e.g. faeces
-Gases (volatiles) e.g. expired air
34
How does glomerular filtration remove drugs?
Plasma filtered + very large drug molecules removed
35
How does active tubular secretion in the kidneys remove drugs?
Removes protein bound drugs
36
What kind of drugs does passive reabsorption in the kidneys remove?
Highly polar drugs
37
What is an advantage of PR administration?
Avoids first pass metabolism
38
What is an advantage of INH administration?
Well perfuses a large s.a.
39
What is an advantage of S/C administration?
-Faster onset than PO
-Can change formulation to control rate of absorption
40
What is an advantage of TD administration?
-Continuous drug release
-Avoids first pass metabolism
41
What is a disadvantage of PR administration?
-Variable absorption
-Patient preference
42
What is a disadvantage of INH administration?
Inhaler technique can limit effectiveness
43
What is a disadvantage of S/C administration?
Not as quick as IV
44
What is a disadvantage of TD administration?
-Only suitable for lipid soluble drugs
-Slow onset
45
What is first order kinetics?
When the rate of elimination is proportional to the plasma drug conc-metabolism processes do not become saturated-most drugs
46
What is zero order kinetics?
Rate of elimination is not proportional to the plasma drug conc-metabolism processes are saturated
47
Describe the elimination of a drug with first order kinetics
A constant % of the plasma drug is eliminated over time
48
Describe the elimination of a drug with zero order kinetics
A constant amount of the plasma drug is eliminated over time
49
What is Cmax?
Maximum plasma concentration
50
What is tmax?
Time taken to reach Cmax
51
What is clearance?
Removal of a drug by all eliminating organs
52
What is half life (t1/2) of drug elimination dependent on?
-Clearance
-Vd (large Vd takes longer to clear)
53
At what % of clearance is a drug considered 'cleared' in medical practice?
97% = 5x half lives
54
What must you consider when administering drugs with a short t1/2?
-Will need more frequent dosing
-Short t1/2 drugs may need dose weaning on cessation as risk of withdrawal symptoms
55
What does a steady state of drug delivery mean?
rate of drug input=rate of drug elimination
56
What is Css?
Drug plasma conc at a steady state
57
Why is a steady state important?
Need to deliver drug at concentration which lies between MSC (maximum safe conc) + MEC (minimum effective conc)
58
What is the purpose of a loading dose?
Decrease initial time to reach steady state-important as detrimental to wait to reach steady state
59
Name 5 drugs that require a loading dose
-Digoxin
-Vancomycin
-Teicoplanin
-Amiodarone
-Heparin
60
Give an example of a drug metabolised with zero order kinetics
Ethanol
61
Name 2 drugs with a narrow therapeutic window
-Lithium
-Digoxin
62
How to you deal with drugs that have a narrow therapeutic window?
-Monitor drug plasma levels to ensure efficacy + avoid toxicity
-Levels should be taken pre-dose
63
What is pharmacogenomics?
The use of genetic + genomic info to tailor pharmaceutical Tx to an individual
64
What is druggability?
The ability of a protein to bind to a specific drug, altering its function so it can give a therapeutic benefit to the patient
65
What is a receptor?
A component of a cell that interacts with a specific ligand + initiates a change of biochemical events leading to the ligands observed effects
66
Name 3 types of chemical that receptors help communicate + give an example for each
-Neurotransmitters e.g. acetylcholine, serotonin
-Autacoids e.g. cytokines, histamine
-Hormones e.g. testosterone, hydrocortisone
67
Name 4 types of receptor + examples
-Ligand-gated ion channel-nicotinic ACh receptor
-G protein coupled receptors-beta=adrenoceptors
-Kinase-linked receptors-growth factor receptors
-Cytosolic/nuclear receptors-steroid receptors
68
What are ligand gated ion channels?
Membrane proteins that allow ions to pass through the channel pore so cell has a change in electric charge distribution-change mediated by influx of cation/efflux of anion
69
What are GPCRs?
G/guanine protein coupled receptors-act as molecular switches
70
What regulates the activity of GPCRs?
Factors that control their ability to bind to + hydrolyse GTP to GDP
71
What are kinases?
Enzymes that catalyse the transfer of phosphate groups between proteins-phosphorylation
72
How are transmembrane receptors activated?
When an extracellular ligand binds + causes enzymatic activity on the intracellular site
73
What are nuclear receptors?
Steroid hormones that work by modifying gene transcription
74
Give 2 examples where an imbalance in chemical leads to pathology
-Allergy=increased histamine
-Parkinson's=decreased dopamine
75
Give 2 examples where an imbalance with receptors leads to pathology
-Myasthenia gravis=loss of ACh receptors
-Mastocytosis=increased c-kit receptors
76
What is an agonist?
Compound that binds to a receptor + activates it
77
What is an antagonist?
Compound that reduces the effect of an agonist
78
What is the two state model of receptor activation?
Model that describes how drugs activate receptors by inducing a conformational change in the receptor from 'off' to 'on'
79
What is Emax?
The maximum response from a Tx achievable-measure of efficacy
80
How do calculate intrinsic activity?
Emax of partial agonist/Emax of full agonist
81
What is intrinsic activity?
AKA efficacy-ability of a drug-receptor complex to produce a maximum functional response
82
What is competitive antagonism?
When antagonists bind to the same site as agonists
83
What are the 2 categories of cholinergic receptor?
-Nicotinic
-Muscarinic
84
Name 4 factors that affect drug action
-Receptor affinity
-Receptor efficacy
Receptor number
-Signal amplification
85
What is affinity?
How well a ligand binds to a receptor
86
What is efficacy?
How well a ligand activates the receptor-is it possible to get a maximal response? Full vs partial agonists
87
Compare agonists + antagonists in terms of affinity + efficacy
Agonists=have affinity + efficacy
Antagonists-have affinity but zero efficacy
88
Give an example of an irreversible antagonist
Bromoacetyl alprenolol menthane (BAAM)
89
What is a full agonist?
One with high efficacy, producing a full response while occupying a relatively low proportion of receptors
90
What is a partial agonist?
One with a low intrinsic activity-can never see maximal response, even with 100% occupancy
91
What is receptor reserve?
When an agonists can produce a maximal response with only a portion of available receptors being activated
92
What can activation of a receptor do to a signal?
-Signal transduction (signalling cascade)
-Signal amplification
93
What is allosteric modulation?
Where a binding site is elsewhere on molecule to main (orthosteric) site, but a binding still alters shape of molecule
94
What is an inverse agonist?
Drug that binds to the same receptor as an agonist, but induces a pharmacological response opposite to that of the agonist
95
What is the difference between tolerance + desensitisation?
Tolerance=slower, reduction in agonist effect over time vs desensitisation=much quicker degrading
96
What is an enzyme inhibitor?
Molecule that binds to an enzyme + reduces its activity
97
What is an irreversible inhibitor?
One that forms covalent bonds with the enzyme, changing it chemically
98
What is a reversible inhibitor?
One that binds non-covalently, diff types of inhibition depending on where inhibitor binds
99
What do statins inhibit?
HMG-CoA reductase
100
How do statins work?
-Block rate-limiting step in cholesterol pathway
-Reduce levels of LDL
-Therefore reducing risk of CVD
101
What drugs are used to treat hypertension?
ACE inhibitors
102
How do ACE inhibitors reduce blood pressure?
-Inhibition of ACE, reduces production of angiotensin II
-Less ATII = less water + salt retention
-Decreases blood pressure
103
What are the 3 types of protein ports?
-Uniporters
-Symporters
-Antiporters
104
How do uniporters work?
They use energy from ATP to pull molecules in
105
How do symporters work?
They use the movement in of 1 molecule, to pull in another molecule, against a conc gradien
106
How do antiporters work?
On substance moves against it gradient, using energy from the 2nd substance moving down its gradient
107
Give an example of a symporter
Na-K-Cl-co-transporter (NKCC)
108
What does binding of the diuretic Furosemide to NKCC cause?
Loss of sodium, chloride = potassium ions in urine
109
Name 4 types of ion channel
-Epithelial (sodium)
-Voltage-gated (calcium, sodium)
-Metabolic (potassium)
-Receptor activated (chloride)
110
Give an example of an epithelial sodium channel (ENaC)
Reabsorption of Na+ at collecting ducts of kidney's nephrons
111
Give an example of a voltage-gated calcium channel
Membrane of excitable cells (glial, muscle, neurons etc)
e.g. vascular smooth muscle cells-Ca influx causes vasoconstriction + increases bp
112
Give an example of voltage gated sodium channels
Transmission of action potential + signalling in heart
113
Give an example of voltage gated potassium channels
Insulin regulation in Islets of Langerhans
114
Give an example of a receptor-mediated (chloride) ligand ion channel
GABA A receptor
115
Describe the action of the sodium pump (Na/K ATPase)
-x 3 Na's pumped out, x2 K's into cells, against conc gradients
-Energy required comes from ATP
116
Describe the action of the stomach's proton pump
-Hydrogen potassium ATPase exchanges potassium from intestinal lumen with cytoplasmic H+
-Causes acidification of stomach + activation of pepsin
117
Name the irreversible inhibitors of cholinesterase
Organophosphates
118
Name 2 drugs that are irreversible enzyme inhibitors
-Omeprazole
-Aspirin
119
Give 3 examples of recombinant proteins in clinical use
-Insulin
-Erythropoietin
-Growth hormone
120
Name 2 naturally occurring opioids
-Morphine
-Codeine
121
Does morphine undergo first pass metabolism?
Yes-50% of morphine is metabolised by first pass metabolism if delivered orally
122
What are the repercussions of morphine undergoing first pass metabolism by the liver?
Dose should be halved if given IV, s/c, IM
123
What is diarmorphine?
Crude form of heroin-developed from morphine-more potent + crosses BBB quickly
124
How do opioids work?
They inhibit the release of pain transmitters at spinal cord + midbrain + modulate pain perception in higher centres-euphoria
125
What does sustained inhibition of the pain pathways lead to?
Tolerance + addiction
126
Name the 4 opioid receptors
-MOP (mu (μ)-opioid peptide)
-KOP (kappa opioid receptor)
-DOP (delta)
-NOP (nociceptin opioid-like receptor)
127
Which opioid agonist causes depression instead of euphoria?
Kappa
128
What kind of agonist are most opioids we use?
µ-mu
129
What is potency?
Whether a drug is strong/weak in relation to how well it binds to the receptors-binding affinity
130
What is tolerance?
Down regulation of the receptors with prolonged use-need higher doses to achieve same effect
131
What is dependence?
Phycological-craving, euphoria
Physical symptoms
132
When does opioid withdrawal start + how long does it last?
Starts within 24hrs, lasts 72hrs
133
Name 7 side effects of opioid withdrawal
-Respiratory depression
-Sedation
-Nausea + vomiting
-Constipation
-Itching
-Immune suppression
-Endocrine effects
134
What is the bioavailability for oral morphine?
50%
135
Describe the 8 steps of a synaptic impulse
-Action potential arrives at axon terminal
-Voltage-gated Ca2+ channels open
-Ca2+ enters presynaptic neuron
-Ca2+ signals to neurotransmitter vesicles
-Vesicles move to membrane + dock
-Neurotransmitters released via exocytosis
-Neurotransmitters bind to receptors
-Signal initiate din postsynaptic cells
136
What do α1 (postsynaptic)receptors do?
Vasocontriction
137
What do β1
receptors do?
Increase heart rate + contractility
137
What do α2 (presynaptic)
receptors do?
Negative feedback-suppresses norad release
137
What do β2
receptors do?
Bronchodilation
138
What do ACE inhibitors do?
Vasodilation, decreased IV remodelling
139
140
What do anti-platelet medication do?
Prevent clot formation
141
What do statins do?
Reduce cholesterol
142
What do beta blockers do?
-Decrease heart rate + contractility
-Prolong diastole-more time for coronary perfusion
-Reduce incidents of heart failure
143
What do alpha 2 agonists do?
Act as hypertensives, sedatives + analgesics
144
How do alpha 2 agonists work?
Act pre-synaptically to reduce amount of noradrenaline released
145
Give an example of a β2 agonsist
Salbutamol
146
Name a drug that stimulates all sympathetic receptors
Adrenaline
147
Give an example of an α1 agonist
Phenylephrine
148
How does organophosphate poisoning work?
Inhibits acetylcholinesterase-stops breakdown of ACh-accumulates + overstimulates nicotinic + muscarinic receptors
149
What are the symptoms of organophosphate poisoning ?
-Increased saliva + tear production
-Diarrhoea
-Nausea + vomiting
-Sweating
-Muscle tremors
-Confusion
150
How does atropine help with organophosphate poisoning?
It competes with ACh at muscarinic receptors
151
How many muscarinic receptors are there?
5-M1-M5
152
Describe nicotinic receptors
-Ligand gated ion channels
-Action increases membrane permeability to Na+, K+
153
What are the 3 subgroups of nicotinic receptors?
-Ganglionic
-Neuromuscular
-CNS
154
What are the nicotinic signs of acetylcholinesterase inhibitor toxicity?
Monday = Mydriasis
Tuesday = Tachycardia
Wednesday = Weakness
Thursday = Hypertension
Friday = Fasciculations
155
What are the muscarinic signs of acetylcholinesterase inhibitor toxicity?
D = Defecation/diaphoresis
U = Urination
M = Miosis
B=Bronchospasm/bronchorrhea
E = Emesis
L = Lacrimation
S = Salivation
156
Name a drug that blocks parasympathetic action
Atropine
157
What is a drug interaction?
When a substance alters the expected performance of a drug
158
Name the 2 types of drug interaction + what they are
Pharmacodynamic-drug effects same target
Pharmacokinetic-drug affects absorption, distribution, metabolism/excretion of another drug
159
name the 2 types of pharmacodynamic drug interaction
-Synergistic
-Antagonistic
160
Give an example of a beneficial pharmacodynamic drug interaction
Amlodopine + ramipril (both for hypertension) synergistic interaction-causes hypotension
161
What are the risks of a pharmacokinetic absorption interaction?
Drug affects rate/extent of absorption of another drug
Bad if rapid effect needed + reduces steady state levels
162
How can pharmacokinetic interactions reduce drug distribution?
-Only unbound drugs are distributed from plasma vol
-Interactions can cause competition for protein binding
163
Give an example of a pharmacokinetic distribution interaction
Warfarin displaced by Amiodarone=warfarin has bigger effect on patient
164
What substrates does CYP3A4 process?
simvastatin, warfarin, DOACs (apixaban, rivaroxaban etc), carbamazepine, diltiazem
165
What enzyme processes ibuprofen + warfarin?
CYP2C9
166
What does CYP2D6 process?
Codeine + warfarin
167
What does CYP1A2 process?
caffeine, paracetamol, theophylline, warfarin
168
What enzyme metabolises omeprazole + phenytoin?
CYP2C19
169
Name 4 important drug-food interactions
-Grapefruit juice
-Milk
-High vitamin K foods
-Cranberry juice
170
Describe the potential drug interaction with grapefruit juice
It is a CYP3A4 inhibitor so should be avoided for warfarin + statin patients
171
Describe the potential drug interaction with milk
Milk forms insoluble complex with Ca-affects absorption of some drugs eg. doxycycline, levothyroxine, ciprofloxacin
172
Describe the potential drug interaction with high vitamin K foods (spinach, kale, avocado etc)
These foods oppose action of warfarin
173
Describe the potential drug interaction with cranberry juice
It's a CYP2C9 inhibitor so should be avoided by patients on warfarin
174
How should you manage drug interactions?
Moderate-additional monitoring-bloods, observation etc
High risk-initiate alternative, suspend interacting drug
175
What are P-glycoproteins?
Drug transporter proteins-remove toxic substances from cells
176
What is an ADR?
Adverse drug reaction-a response to a medicinal product/combination of products, which is noxious + unintended
177
How do ADRs affects patients?
-Reduced QofL
-Poor compliance
-Reduced confidence in clinicians
-Unnecessary Tx/investigations
178
How do ADRs affect the NHS?
-Increased admissions
-Longer stays
-GP appts
-Inefficient use of medication
179
What are the 7 classification of ADRs?
Augmented
Bizarre
Chronic/continuing
Delayed
End of use/withdrawal
Failure of Tx
Genetic
180
What is the most common type of ADR?
Augmented
181
What is an augmented ADR + example?
Exaggerated effect of drugs pharmacology at a therapeutic dose-not normally life threatening
e.g. bleeding with anticoagulants
182
What is a bizarre ADR + example?
Not related to pharmacology/dose-serious illness/mortality, symptoms don't always resolve when drug stopped e.g. anaphylaxis with penicillin
183
What is a chronic ADR + example?
ADR that continues after drug stopped e.g. osteonecrosis of jaw with bisphosphonates
184
What is a delayed ADR + example?
ADR becomes apparent some time after drug stopped e.g. leucopenia with chemotherapy
185
What is a end of use ADR + example?
ADR develops after drug stopped e.g. insomnia after stopping benzodiazepine
186
What is a failure of Tx ADR + example?
Unexpected Tx failure, could be drug/food-drug interaction or due to poor compliance e.g. failure of bisphosphonate due to taking with food
187
What is a genetic ADR + example?
Drug causes irreversible damage to genome e.g phocomelia in children of women taking thalidomide
188
What is another way to classify ADRs?
DoTS
189
What does DoTS stand for?
-Dose-relatedness
-Timing
-Susceptibility
190
Name the 3 dose-related types of ADR
-Hypersusceptibility-dose is subtherapeutic
Collateral/side effects-ADRs at therapeutic doses
-Toxic effects-ADRs at higher than therapeutic levels
191
What are the 6 time stages for ADRs?
-Rapid-rapid administration
-First dose-1st dose only
-Early-only early in Tx-resolves
-Intermediate-Occurs after some delay
-Late-risk increases with exposure
-Delayed-reaction some time after initial exposure
192
Name 4 groups/populations with higher susceptibility for ADRs
-Age
-Gender
-Disease states
-Physiological states
193
How are ADRs identified?
In stages of drug development:
-Pre-clinical
-Clinical trial
-Post-marketing surveillance
-Pharmacovigilance
194
What symbol in the BNF/SPC/on patient info leaflet indicates a drug is under post-marketing surveillance?
Black triangle
195
What body oversees ADRs?
MHRA (Medicines and Healthcare products Regulatory Agency)
196
What is the yellow card system?
Voluntary + confidential reporting system for ADRs
197
What is a GSL drug?
General sales list drug
198
What is a POM drug?
Prescription only medication
199
What is a P drug?
Pharmacy medication
200
What are 2 genetic variations that can increase risk for ADRs
-Variation in expression of CYP450 enzymes (altered metabolism)
-HLA (human leucocyte antigen) alleles can increase risk of immune mediated idiosyncratic ADRs
201
What is hypersensitivity?
Objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects
202
What causes acute anaphylaxis?
Prior exposure to antigen/drug causes IgE antibodies to form
-IgE attaches to mast cells/leucocytes, expressed as cell surface receptors
-Re-exposure causes mast cell degranulation + release of histamine, prostaglandins, leukotrienes, platelet activating factor etc
203
What is type 1 hypersensitivity?
Acute anaphylaxis
204
What is a type 2 hypersensitivity reaction?
-Drug/metabolite combines with protein
-Body treats it as foreign + forms antibodies
-Antibodies combine with antigens + complement activations damages cells
205
What is a type 3 hypersensitivity reaction?
-Antigen-antibody complex forms + activates complement
-Small blood vessels damaged/blocked
-Leucocytes attracted to site of reaction + release inflammatories
206
What is a type 4 hypersensitivity reaction?
-Antigen-specific receptors develop on T-lymphocytes
-Later administration leads to local/tissue allergic reaction e.g. contact dermatits
207
What is non-immune anaphylaxis?
Clinically identical to normal anaphylaxis but needs no prior exposure, due to to mast cell degranulation
208
What does adrenaline do?
-Vasoconstriction, increases BP + coronary perfusion
-Stimulates beta1-adrenoreceptors
-Reduces oedema
-Reduces release of inflammatory mediators
