Pharmacology Flashcards
(211 cards)
1
Q
What are alkanes?
A
Carbon chains without any functional groups (e.g. methane, ethane, propane, butane)
2
Q
What is this functional group?
A
Alkene
3
Q
What is this functional group?
A
Amine
4
Q
What is this functional group?
A
Halide
5
Q
What is this functional group?
A
Carboxylic Acid
6
Q
What is this functional group?
A
Ketone
7
Q
What is this functional group?
A
Amide
8
Q
What is this functional group?
A
Ether
9
Q
What is this functional group?
A
Ester
Made by combining an alcohol and an acid
10
Q
What is an aromatic compound?
A
Contains a benzene ring
NOTE: a benzene ring with an alcohol group is called a phenol
11
Q
What is the chemical name for propofol?
A
2,6-di-isopropyl phenol
12
Q
Define valency.
A
The number of bonds an atom has in its uncharged state
13
Q
How can barbituric acid be modified to become an anaesthetic agent?
A
Adding an alkyl group at the C5 position produces hypnotic activity
Increasing the length of the side chain increases hypnotic potency
Substituting oxygen for sulphur at C2 (thiopentone) increases lipid solubility
14
Q
What are the two groups of volatile anaesthetics?
A
HALOGENATED HYDROCARBONS
- Halothane, trichloroethylene, chloroform
HALOGENATED ETHERS
- Enflurane, isoflurane, sevoflurane, desflurane
15
Q
What are the three components of the structure of a local anaesthetic?
A
Aromatic group
Intermediate chain
Amine group
16
Q
What are the two functional groups that can form the intermediate chain in local anaesthetic agents?
A
Ester and Amide
17
Q
Give examples of ester local anaesthetics.
A
Procaine
Cocaine
Benzocaine
Tetracaine
Chloroprocaine
18
Q
Give examples of amide local anaesthetics.
A
Bupivacaine (and levo)
Lidocaine
Prilocaine
Dibucaine
19
Q
What are the differences between the metabolism of ester and amide local anaesthetics?
A
Ester: hydrolysed quickly in the plasma by esterases
Amide: metabolised slowly by the liver
20
Q
How can the structure of local anaesthetics be altered to increase lipid solubility and protein binding?
A
Increase the bulk of the amide side chain
Add groups to the aromatic portion
21
Q
Describe the acid-base activity of amines.
A
Amines are bases as the lone pair of electrons on the nitrogen can bond with a free hydrogen to form a positively charged ammonium group
22
Q
Describe the acid-base characteristics of midazolam.
A
It contains an amine group and is, hence, a weak base with a pKa of 6.2
It is buffered in vials at a pH of 4 to ensure that it is mostly ionised and water soluble
Upon exposure to a physiological pH, it becomes mostly unionised and forms a benzodiazepine ring - this is lipid soluble and can cross the BBB to exert its effects
23
Q
What is tautomerisation?
A
When a compound rapidly interconverts between two isomeric forms (keto and enol) typically by the movement of a proton and a shift in bonding
24
Q
How does thiopental demonstrate tautomerism?
A
It is prepared in an alkaline solution (pH 10.5)
At this pH, the keto form is favoured which is water soluble
At physiological pH, it changes to its enol form which is more lipid soluble and can cross the BBB
25
Define a metal.
An element that tends to lose electrons to form positive ions and has characteristic properties such as high electric and thermal conductivity, malleability, ductility and a shiny appearance due to free-moving electrons in a metallic bond
26
Which common anaesthetic agent is an example of ionic bonding?
Sodium thiopental
27
What are some properties of ionic compounds?
High melting and boiling points due to strong forces between ions
Water soluble
Conduct electricity which is carried by ions that are free to move when the compound melts or dissolves
28
Which covalent bonds are considered polar?
When the electrons are pulled more in one direction than the other
29
Define electronegativity.
The ability of an atom to attract shared electrodesns in a chemical bond
30
What are the three main types of intermolecular interactions in a gas?
Van der Waals' forces
Dipole-Dipole attractions
Hydrogen bonding
31
What is a hydrogen bond?
Strongest type of intermolecular force
Occurs when a hydrogen is bonded to a strongly electronegative atom (e.g. oxygen) forming a very polar molecule
This leads to very strong dipole-dipole interactions
32
What are the two ways in a which a covalent bond can be broken?
Homolytic Fission: each element takes one electron to form a free radical (required high temp or UV)
Heterolytic Fission: the more electronegative element takes both electrons and oppositely charged ions are formed
33
Define water solubility.
The ability of a compound to disrupt the normal attraction between water molecules in their fluid form (requires polarity)
34
What is the difference between strong and weak electrolytes?
Strong: dissociates completely in water and is VERY water soluble (e.g. NaCl)
Weak: only fraction of molecules exist as ions and can interfere with bonds between water molecules
35
Describe the acid-base activity of aspirin.
Weak acid
It has a carboxyl group
36
Describe the acid-base activity of morphine.
Weak base
It has an amine group
37
Define pKa.
The pH at which the proton donor and proton acceptor are present in equal amounts
NOTE: it is an indicator of how readily a functional group gives up or accepts a proton and becomes ionised in an aqueous environment
38
Briefly describe the pH at which weak acids and weak bases ionise.
Weak acids: ionise above their pKa
Weak bases: ionise below their pKa
39
What is the pKa of thiopental?
7.6
Functional Group: S=O
40
What is the pKa of propofol?
11
Functional Group: -OH
41
What is the pKa of etomidate?
4.2
Functional Group: -N-
42
What is the pKa of ketamine?
7.5
Functional Group: -NH-
43
What is the pKa of paracetamol?
9.4
Functional Group: -OH
44
What is the pKa of ibuprofen?
4.9
Functional Group: -COOH
45
What is the pKa of tramadol?
9.4
Functional Group: -NR3
46
What is the pKa of fentanyl?
8.4
Functional Group: -N-
47
State the Henderson-Hasselbalch equation.
This can be used to predict the ratio of ionised to unionised form of a weak acid or weak base
NOTE: for an acid, the ionised form is on TOP, for a base it is at the bottom
48
What is a buffer?
Consists of a weak acid and its conjugate base or a weak base and its conjugate acid
It is most effective at limiting pH changes around its pKa (when it has around 50% of both types)
49
What is the pKa of the carbonic acid-bicarbonate buffer system?
6.1
50
What is the pKa of the phosphate buffer system?
6.8
51
What is the main buffering system in the kidneys?
Ammonia (NH3)
Combines with H+ in the tubular cells to form ammonium ions (NH4+)
This is excreted in the urine to enable us to remove 30-40 mmol of H+ daily
NOTE: dihydrogen phosphate (HPO4= + H+ -> H2PO4) is another important urinary buffer that enables us to get rid of H+ in the urine
52
What are some methods of producing intravenous preparations for induction agents?
Propofol is prepared as an emulsion in intralipid (egg phosphatide)
Etomidate is solubilised with polyethylene glycol or intralipid
Sodium thiopental is produced as a powder under nitrogen
53
What are the three main factors that determine the extent to which a drug crosses the blood-brain barrier?
Lipid Solubility
Degree of Protein Binding
pKa
54
Why does alfentanil has a quicker onset of action than morphine?
Both are weak bases - morphine has a pKa of 7.9, and alfentanil 6.4
Morphine is 40% protein bound and alfentanil is 90%
Alfentanil has a faster onset of action because, though it has a smaller proportion of free drug, this difference is smaller than the difference between the proportion of unionised drug in the blood stream (alfentanil is 100 times less ionised than morphine)
55
Why does propofol have a faster offset than fentanyl?
Propofol's high lipid solubility and unionised state mean it enters the brain fast but also redistributes quickly and stays trapped in fat, leading to a rapid drop in plasma levels and fast offset.
Fentanyl (pKa of 8.5), though also lipid-soluble, re-enters circulation from fat more readily due to ionisation, so its effect lasts longer.
56
Which volatile agents are structural isomers of each other?
Isoflurane and Enflurane
57
What is a stereoisomer?
Same molecular formula
Same chemical structure
Different spatial configurations
TWO types: geometric and optical
58
What is a geometric stereoisomer?
Occurs in compounds with C=C double bonds (alkenes)
There is no rotation around this bond meaning that there are two isomers
- Cis and Trans
59
What is an example of a commonly used drug in anaesthesia that has geometric stereoisomers?
Mivacurium
60
What are optical isomers?
Occurs when four different groups are attached to the same atom (chiral centre)
Groups can be arranged in two configurations that are NON-SUPERIMPOSABLE mirror images
Paris of optical isomers are called enantiomers
61
How would two enantiomers differ in their properties?
Identical chemical and physical properties
Rotate plane polarised light in opposite directions
62
What is the different between D and L enantiomers?
Optical isomers that rotate plane polarised light in opposite directions
D (+): rotates to RIGHT
L (-): rotates to LEFT
NOTE: an equal mixture of both has no effect on plane polarised light (racemic mixture)
63
What are R and S enantiomers?
Each group around a central carbon has a priority (higher atomic number = lower priority)
The highest priority (smallest atomic number) is placed at the top, then a circle is drawn from the lowest priority to the next lowest to the next lowest
If clockwise = R
If anticlockwise = S
64
Describe the effects of the two enantiomers of ketamine.
S(+): useful IV agent
R(-): agitation, postoperative pain, emergence reactions
65
Describe the effects of the two enantiomers of bupivacaine.
S(+): prolonged local anaesthesia
R(-): convulsant and cardiotoxic
66
How does cisatracurium compare to atracurium?
Atracurium is a mixture of 10 isomers
Cisatracurium is 3 x as potent with minimal autonomic effects and histamine release (can be produced as a single isomer)
67
Which enantiomer of local anaesthetics tends to be most useful?
S
Increased vasoconstriction resulting in prolonged duration of action and less systemic absorption
Reduced cardiotoxicity
Reduced motor blockade
NOTE: this applies to bupivacaine, prilocaine, ropivacaine and mepivacaine
68
Give an example of charge neutralisation as an example of non-specific drug action.
Antacids neutralise gastric activity
Protamine is a strong base with a positive charge that neutralises the anticoagulant effect of heparin by the formation of an inactive complex that is cleared by the reticulo-endothelial system
69
What is a coordinate bond?
A type of covalent bond in which both electrons in the shared pair come from the same atom.
70
Describe the structure of metal chelating agents and how it enables them to carry out their role.
The agents have multiple oxygen, sulphur or nitrogen agents that form coordinate bonds with the metal ion
71
What does 'encapsulation' mean in the context of pharmacodynamics?
Form of chelation
Cyclodextrins are naturally occurring oligosaLccharides
Sugammadex is a modified gamma-cyclodextrin that encapsulated rocuronium and creates concentration gradient between NMJ and plasma
72
List some commonly used anaesthetic drugs that target G proteins.
Opioids
Atropine
Adrenergic drugs
73
What is the difference between ionotropic and metabotropic receptors?
Ionotropic: transmitter binding alters activity of ion channel leading to rapid synaptic transmission
Metabotropic: transmitter binding and effector are separate, coupled via G protein that alters ion channel activity, slower response time
74
What are the five families of ionotropic receptors?
Cys-Loop receptor family (e.g. nAChR)
Glutamate (e.g. NMDA)
P2X
Transient receptor potential (TRP)
Cyclic nucleotide-gated
75
Give some examples of receptor tyrosine kinases.
Insulin
IGF
VEGF
76
Describe the stimulation of nitric oxide generation and how it leads to vasodilation.
NO production is initiated by the release of inflammatory mediators which, in turn, activates endothelial NO synthase
NO, via guanylate cyclase, triggers cGMP production in smooth muscle cells resulting in blood vessel dilation
77
How can methylene blue be useful in vasodilatory shock?
Blocks soluble guanylate cyclase (thereby preventing NO-induced increase in cGMP which usually leads to vasodilation)
78
What are the two different ways in which ligands can bind to a receptor?
Orthosteric: site where endogenous activators bind
Allosteric: modulatory sites that are distinct from the active site
79
List some mechanisms through which receptors can become desensitised after prolonged exposure.
Downregulation of receptor expression
Receptor internalisation
Receptor phosphorylation
80
What is the difference between tachyphylaxis and tolerance?
Tachyphylaxis: rapidly diminishing response to repeated drug administration, usually due to depletion of transmitter stores (e.g. ephedrine)
Tolerance: loss of response over longer period of time, due to transcriptional changes, bigger dose needed to achieve same effect (e.g. opioid abuse)
81
Define affinity in the context of drug-receptor interactions.
The strength with which a drug binds to a receptor
82
What is the dissociation constant with regards to drug receptor interactions?
KD can also be defined as the drug concentration at which 50% or receptors are occupied
83
Define potency.
Concentration of drug required to achieve a desired effect.
EC50 is a commonly used measure of potency: This is defined as the concentration at which a drug produces 50% of its maximal possible response
84
Define efficacy in the context of pharmacodynamics.
The maximum effect that can be expected from a drug once it has bound to the receptor. It is an intrinsic property of the drug.
Ranges from 0 (no effect) to 1 (full effect)
85
State the law of mass action.
Rate of a reaction is proportional to the concentration of the reacting elements.
86
What is the affinity constant?
Reflects the strength of the drug-receptor bond
KA = kon/koff
87
What is the dissociation constant with regards to drug receptor interactions?
This is the tendency of the drug-receptor complex to dissociate back into its components
KD = koff/kon
88
State the equation for the dissociation constant in drug-receptor interactions.
You can define KD as being equal to the dose when the drug occupies exactly 50% of the receptors at equilibrium
When [R] and [DR] are equal, they cancel out
In other words, KD is the molar concentration of a drug when 50% of its receptors are occupied at equilibrium
89
What is the difference between EC50 and ED50?
EC50: Concentration of a drug that produces a response halfway between baseline and maximum
ED50: Dose that produces a response in 50% of the population to whom it is administered
90
Define intrinsic activity of a drug.
Drug’s maximal efficacy as a fraction of the maximal efficacy achieved by a full agonist acting on the same receptor under the same conditions
91
Define functional selectivity with regards to drug action.
Having differing efficacies at a single receptor for a variety of different cellular responses
A drug, acting at the same receptor, can be an agonist, inverse agonist and antagonist simultaneously depending on the response being measured
92
What are the three mechanisms of transmembrane signalling?
G-protein coupled receptors
Enzyme linked receptors
Ion channel receptors
93
What are the three subunits of a G protein?
Alpha (activates effector molecule)
Beta
Gamma
94
List classes of commonly used drugs that act via G protein coupled receptors.
Adrenergic agents
Opioids (Gi linked)
Atropine
Angiotensin Receptor Blockers
95
Describe, in general, the activity of enzyme-linked receptors.
A transmembrane receptor where the binding of an extracellular ligand causes enzymatic activity on the intracellular side
Most active enzyme domains are kinases that phosphorylate the amino acids (serine, threonine and tyrosine) of proteins
96
Give some examples of ligand-gated ion channels.
Nicotinic acetylcholine receptor
5HT-3 receptor
NMDA
GABA
97
Give two examples of intracellular receptors.
Steroid
Thyroid hormone
98
What are the two main types of intracellular receptor?
Type 1: binds to receptors in cytoplasm or nucleus (e.g. sex hormone, cortisol)
Types 2: binds directly to DNA proteins (e.g. thyroid hormone)
99
What are the three components of an intracellular receptor?
Transcription-Activating Domain
DNA-binding Domain
Ligand-binding Domain
100
Describe the activity of steroid hormone receptors.
Associated with heat shock proteins when inactive in the cytoplasm (keeps them stabilised)
Upon hormone binding, HSP dissociated and reveals nuclear localisation sequence that allows passage of ligand-receptor complex into the nucleus
Active complex interacts with HRE via DNA binding domain, which activates gene transcription
101
Describe the mechanism of action of neostigmine.
Carbamylates the active site of acetylcholinesterase and, once bonded, it is hydrolysed like Ach but takes much longer (thus acting as a competitive inhibitor)
Increase in synaptic ACh concentration outcompetes non-depolarising NMBs
Added to glycopyrronium to offset the drug’s parasympathetic cholinergic activity (bradycardia, hypotension, bronchoconstriction)
Lasts 1-2 hours
102
List some examples of medium- to long-acting acetylcholinesterase inhibitors.
MEDIUM
- Neostigmine
- Pyridostigmine (used to treat myasthenia gravis)
- Physostigmine (used to treat glaucoma)
LONG
- Ecothiopate (lasts weeks and includes sarin and VX nerve gases)
103
What can toxic doses of long-acting acetylcholinesterase inhibitors cause?
SLUDE syndrome (salivation, lacrimation, urination, defecation and emesis)
E.g. organophosphate poisoning
Treated with atropine or pralidoxime
104
Which neuromuscular blockers would neostigmine prolong the duration of action of?
Suxamethonium and Mivacurium
Due to inhibition of plasma cholinesterases
105
Describe the mechanism of action of carbonic anhydrase inhibitors.
Act on the proximal convoluted tubules
They are non-competitive inhibitors of the enzyme affecting the sodium-H+ exchange, thus alkalinising the urine and causing a metabolic acidosis
106
What are the three types of COX enzymes?
COX1: constitutive and found in most cells
COX2: inducible and normally undetectable in normal tissues but is found in abundance in macrophages and other inflammatory cells
COX3: CNS variant of COX1 (site of action of paracetamol)
107
Give an example of a selective COX inhibitor.
Parexocib - COX-2
108
Describe the synthesis pathway for adrenaline and noradrenaline.
109
Where are the two types of monoamines found?
MAO-A: cerebral cortex (areas of serotoninergic transmission), liver, pulmonary vasculature, GI tract, placenta
MAO-B: striatum and globus pallidus (noradrenaline), platelets
NOTE: MAO-A present from birth, MAO-B develops afterwards
110
List some non-selective MAO inhibitors.
Phenelzine
Hydracarbazine
111
List some selective MAO-A inhibitors.
Moclobemide
Pirlindole
112
List some selective MAO-B inhibitors.
Selegiline
Rasagiline
113
What are some risks associated with MAO inhibitors?
Hypertensive crises (due to raised catecholamines)
Serotonin syndrome
114
List some reversible inhibitors of monoamine oxidase.
Methylene blue
Moclobemide
Brofaromine
115
State the Michaelis-Menten equation.
NOTE: Km = 1/2 Vmax
116
Give an example of a non-competitive enzyme inhibitor.
Cyanide (cytochrome oxidase in the electron transport chain)
117
Describe the action of acetylcholinesterase.
AChE has an anionic site which attracts a quaternary ammonium moiety and an esteratic site which binds to the ester group in ACh
Breakdown of ACh releases choline, and then it is hydrolysed to release acetic acid
118
Describe the mechanism of action of pralidoxime.
Binds to the anionic site and cleaves the phosphate-ester bond – this makes the organophosphate dissociate from AChE
119
Describe the action of phosphodiesterase.
PDE hydrolyses cAMP and cGMP
cAMP normally increases PKA activity which opens L-type calcium channels
Therefore, PDE inhibitors increase cAMP levels leading to a positive inotropic effect
120
A reduction in which prostaglandins mediates the anti-inflammatory and anti-pyretic effects of NSAIDs?
Decrease PGE2 and PGF2-alpha
121
Which antibiotic also has inhibitory effects on the MAO enzyme?
Linezolid - reversible MAO inhibitor
122
What are the different types of G protein linked to GPCRs?
Gs stimulates and Gi inhibits adenylyl cyclase which regulates cAMP formation
Gq activates phospholipase C which breaks down phosphatidylinositol bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3) leading to increased calcium release in the cell
123
Give examples of phase 1 reactions.
Oxidation, reduction and hydrolysis
124
Give examples of phase 2 reactions.
Glucuronidation (MOST COMMON), sulfation, acetylation and methylation
125
Which CYP enzyme metabolises lidocaine?
CYP1A2
CYP3A4
126
Which CYP enzyme metabolises propranolol?
CYP1A2
CYP2C19
127
Which CYP enzyme metabolises warfarin?
CYP2C9
128
Which CYP enzyme metabolises NSAIDs?
CYP2C9
129
Which CYP enzyme metabolises phenytoin?
CYP2C9
CYP2C19
130
Which CYP enzyme metabolises codeine?
CYP2D6
131
Which CYP enzyme metabolises sevoflurane and isoflurane?
CYP2E1
132
Which CYP enzyme metabolises midazolam?
CYP3A4
Also metabolises temazepam and diazepam
133
Which CYP enzyme metabolises fentanyl and alfentanil?
CYP3A4
134
Which commonly used anaesthetic drugs are metabolised by CYP2D6?
Codeine
Tramadol
Flecainide
TCAs
Metoclopramide
Ondansetron
Haloperidol
Risperidone
135
List some common inhibitors of CYP1A2.
Cimetidine
Ciprofloxacin
Erythromycin
Amiodarone
136
List some common inhibitors of CYP2C9.
Fluconazole
Amiodarone
Sertraline
Metronidazole
137
List some common inhibitors of CYP2C19.
Esomeprazole
Citalopram
Voriconazole
138
List some common inhibitors of CYP2D6.
Fluoxetine
Paroxetine
Citalopram
Amiodarone
Cimetidine
139
List some common inhibitors of CYP3A4.
Amiodarone
Macrolides
Azoles
Diltiazem
Verapamil
Grapefruit juice
140
Describe the mechanism of action of streptokinase, alteplase and urokinase.
Induces the conversion of plasminogen to plasmin, thereby promoting clot destruction
141
Which commonly used drug induces CYP1A2?
Omeprazole
142
Which commonly used drugs induce CYP2C9?
Barbiturates
Rifampicin
143
Which commonly used drugs induce CYP2C19?
Rifampicin
Prednisolone
Carbamazepine
144
Which commonly used drugs induce CYP2E1?
Ethanol
Isoniazid
145
Which commonly used drugs induce CYP3A4?
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Steroids
146
What genotypes cause suxamethonium apnoea?
Normal plasma cholinesterase is E1u whilst atypical is E1a
Heterozygote E1u, E1a will have effect of 30 mins
Homozygous atypical will have an effect of more than 2 hours
There are rare variants E1f (fluoride) and E1s (silent)
The silent variant has almost no capacity to hydrolyse suxamethonium resulting in paralysis lasting several hours
NOTE: drug is eventually cleared by non-specific esterases
147
What is a pseudoallergic drug reaction?
Some clinical manifestations that are similar to allergic reactions driven by histamine release but they are NOT immunologic
148
What are Type A and Type B adverse drug reactions?
Type A (Augmented): related to the pharmacological effects of the drug and are usually dose related (e.g. hypotension with propofol)
Type B (Bizarre): unpredictable and NOT dose-related (e.g. MH)
Extended classification: C (Chronic), D (Delayed), E (End of Use), F (Failure)
149
What are the three components of the DOTS classification of unwanted drug effects?
Dose-Relatedness (at normal dose or overdose)
Time-Relatedness (during treatment, or independent of duration)
Susceptibility (e.g. age, sex)
150
Outline the Coombs' classification of allergic reactions.
I: IgE-Mediated Allergy (e.g. anaphylaxis)
II: Cytotoxic, Antibody Dependent (e.g. AIHA)
III: Immune Complex-Mediated (e.g. rheumatoid arthritis)
IV: Cell-Mediated (e.g. contact dermatitis)
151
What are the most common triggers for intraoperative anaphylaxis?
Antibiotics (particularly Teicoplanin)
Muscle relaxants
Chlorhexidine
Blue Dye
152
List factors affecting absorption of a drug.
Drug formulation
Route of administration
Physicochemical properties (e.g. solubility, ionisation)
Local blood flow
153
List some commonly used drugs that undergo high rates of hepatic first pass metabolism.
Morphine
Midazolam
Lidocaine
Aspirin
GTN
154
Define bioavailability.
The fraction of an administered drug that reaches the systemic circulation intact and is, therefore, available to act at the site of action
155
How is bioavailability calculated?
Calculating the area under the curve which describes the blood concentration against time following administration of a drug via a defined route
For drugs taken orally:
Bioavailability = AUC(PO)/AUC(IV)
156
What proportion of total body mass is water?
60%
157
What proportion of total body water is intracellular vs extracellular?
Intracellular: 2/3
Extracellular: 1/3
NOTE: 3/4 of extracellular fluid is interstitial fluid, 1/4 intravascular and the rest is transcellular
158
Define drug distribution.
Reversible transfer of a drug from one location to another
159
Define volume of distribution.
The theoretical volume that an administered drug would have to occupy, assuming a uniform distribution in the body, to produce the concentration of drug found in the plasma
In other words, based on the dose that we've given and the measured concentration in the plasma, what volume of fluid have we diluted that initial dose in?
160
State the equation for the volume of distribution of a drug.
Volume of Distribution = Administered Dose/Plasma Concentration
161
List key factors that affect drug distribution.
Molecular size
Charge and pKa
Regional blood flow
Concentration gradient
Lipid solubility
Protein binding
162
What are the main plasma proteins that bind to drugs?
Albumin and alpha-1 acid glycoprotein (ACG)
Albumin is alkaline so tends to bind to weakly acidic drugs (e.g. warfarin)
ACG is acidic and tends to bind to weakly alkaline drug (e.g. lidocaine)
163
Which well-known drug is particularly sensitive to changes in plasma protein binding?
Phenytoin (albumin concentration)
164
How does plasma protein binding affect volume of distribution?
Drugs that bind strongly to plasma proteins remain in the bloodstream, leading to higher plasma concentrations and less distribution into tissues. This results in a lower volume of distribution (Vd).
165
How does tissue protein binding affect volume of distribution?
If highly bound to tissue proteins (e.g. receptors), the Vd will be high because most of the drug is held outside of the vascular space so plasma concentration is lower than if the drug was distributed across the compartments
166
What is the only volatile anaesthetic agent that is not an ether?
Halothane - halogenated hydrocarbon
167
How does the structure of isoflurane vs enflurane affect their activity?
The altered position of fluorine atoms makes isoflurane less water soluble and more lipid soluble, meaning that it is less susceptible to metabolism than enflurane
168
Define MAC.
The minimum alveolar concentration of an inhaled anaesthetic agent at steady-state that prevents reactive movement to a standard surgical stimulus (skin incision) in 50% of non-premedicated subjects at 1 atmosphere
169
What is the MAC of isoflurane?
1.2%
170
What is the MAC of sevoflurane?
2%
171
What is the MAC of desflurane?
6.6%
172
List some factors that increase MAC.
Patient Factors
- Children
- Hyperthermia
- Hyperthyroidism
- Hypernatraemia
Pharmacological Factors
- Catcholamines and sympathomimetics
- Chronic opioid use
- Chronic alcohol use
- Acute amphetamine intake
173
List some factors that decrease MAC.
Patient Factors
- Elderly
- Pregnancy
- Hypothermia
- Hypothyroidism
- Hypotension
Pharmacological Factors
- Acute opioid use
- Acute alcohol intake
- Sedatives
174
Define partition coefficient.
Ratio of the amount of a substance present in one phase compared with another where the two phases are of equal volume and exist in equilibrium
175
What is the oil: gas partition coefficient of halothane?
224
176
What is the oil: gas partition coefficient of enflurane?
98
177
What is the oil: gas partition coefficient of isoflurane?
91
178
What is the oil: gas partition coefficient of sevoflurane?
53
179
What is the oil: gas partition coefficient of desflurane?
19
180
What is the blood: gas partition coefficient of halothane?
2.4
181
What is the blood: gas partition coefficient of enflurane?
1.9
182
What is the blood: gas partition coefficient of isoflurane?
1.4
183
What is the blood: gas partition coefficient of sevoflurane?
0.69
184
What is the blood: gas partition coefficient of desflurane?
0.42
185
What factors determine the alveolar partial pressure achieved by an anaesthetic agent?
Inspired concentration of anaesthetic drug
Minute ventilation/fresh gas flow
Functional residual capacity
Blood: gas partition coefficient
186
Describe the FA/FI graph for volatile anaesthetics.
A faster rate of rise (steeper curve) equates to a faster onset of action (due to a faster rise in the alveolar partial pressure)
Drugs with a low blood: gas partition coefficient reach equilibrium more quickly (I.e. have a more rapid rise in the FA/Fi ratio)
187
What is the blood: gas coefficient of nitrous oxide?
0.47
188
What is the Meyer-Overton hypothesis?
The potency of an inhalational anaesthetic is directly proportional to its lipid solubility—the more lipid-soluble the agent, the more potent it is.
189
Explain the concentration effect.
When using high concentrations of nitrous oxide during induction, its rapid absorption into the blood (20-30 times more soluble than N2) causes a decrease in alveolar volume (as n2 diffuses out much more slowly).
The volume loss concentrates the remaining gases and raises their partial pressures, leading to a more rapid onset of action
190
Explain the second gas effect.
Refers to accelerated uptake of an inhalational anaesthetic when administered with N2O.
N2O is rapidly absorbed which reduces alveolar volume (concentration effect) and concentrates the remaining gases.
The initial drop in pressure in the alveolus will draw more anaesthetic agent from the dead space. Together, this increases the alveolar partial pressure of the second gas resulting in faster onset of anaesthesia.
191
List some patient factors that affect the onset of inhalational anaesthesia.
Minute ventilation (higher = faster onset)
Cardiac output (lower = faster onset)
FRC (lower = faster onset)
Cerebral blood flow (higher = faster onset)
192
List some factors that increase FRC.
Asthma
Emphysema
PEEP
Age
193
List some factors that decrease FRC.
Lying flat
Obesity
Pulmonary oedema/fibrosis
Pregnancy
Increased abdominal pressure/distension
194
Why might hyperventilation reduce the onset time of an inhalational anaesthetic agent?
Decreases pCO2 which results in reduced cerebral blood flow
195
Describe the appearance of inhalational agent washout curves.
F(AE) = partial pressure of anaesthetic agent in the lungs when the vaporiser is turned off
NOTE: you can't use FA/FI because FI at this point is 0
196
Define context-sensitive half-time.
The time taken for plasma concentration of a drug to fall by half after cessation of an infusion designed to maintain a steady plasma concentration, where context refers to the duration of the infusion
197
Which measure is used instead of context-sensitive half-time for volatile anaesthetic agents?
This is because wake-up usually occurs when the alveolar concentration is around 90% lower than maintenance
198
Which enzyme metabolises volatile agents in the liver?
CYP2E1
Oxidation produces halogen ions and trifluoroacetic acid (TFCA) which can cause hepatitis
NOTE: CYP2E1 is induced by ethanol
199
What percentage of halothane is metabolised in the liver?
20%
200
What percentage of sevoflurane is metabolised in the liver?
3-5%
NOTE: metabolised to hexafluoro-isopropanol
201
What percentage of enflurane is metabolised in the liver?
2%
202
What percentage of isoflurane is metabolised in the liver?
0.2%
203
What percentage of desflurane is metabolised in the liver?
0.02%
204
What is the most metabolised ether anaesthetic agent?
Sevoflurane
3-5% metabolised to produce inorganic fluoride which can cause nephrotoxicity
205
What proportion of the NHS carbon footprint comes from volatile anaesthetics?
5%
NOTE: 75% from nitrous oxide
206
Which volatile agent has the most significant impact on the environment?
Desflurane (persists in the atmosphere for 14 years)
207
What measures have been taken to minimise the environmental impact of anaesthesia?
Agent choice (sevoflurane < desflurane)
Avoiding nitrous oxide
Low-flow anaesthesia
BIS monitoring to avoid excessive dosing of inhalational anaesthesia
TIVA
208
Define the hepatic extraction ratio.
Fraction of drug which is removed during one pass of the blood through the liver
HER = (Ci - Co)/Ci
Ci: drug concentration in the blood entering the organ
Co: drug concentration in the blood leaving the organ
209
State the equation for hepatic clearance.
Hepatic Clearance = Hepatic Blood Flow x Hepatic Extraction Ratio
210
What are the differences between flow- and capacity-dependent elimination?
Flow-Dependent: for drugs with a high HER > 0.7, dependent on hepatic blood flow (e.g. propofol)
Capacity-Dependent: for drugs with low HER < 0.3, dependent on metabolising capacity of the hepatocytes and on protein binding (e.g. warfarin, phenytoin)
211
Renal excretion of a drug is the sum of which three mechanisms?
Renal Excretion = (Glomerular Filtration + Tubular Secretion) - Reabsorption
