Pharmacology 2 Flashcards
What is the law of mass action?
‘The velocity of a chemical reaction is proportional to the molecular concentrations of the reacting components’
What do k1, k2 and KD denote in the context of mass action?
k1: rate of forward (association) reaction
k2: rate of backward (dissociation) reaction
KD: dissociation constant - defines equilibrium point of overall system
What is an example of a mass action equation for a drug/receptor interaction?
D + R ⇋ DR
D: drug
R: receptor
What factors represent the forward and backward ‘pressure’ of a reaction?
When is equilibrium reached?
forward = k1 x [D][R]
backward = k2 x [DR]
Equilibrium is reached when k1[D][R] = k2[DR]
Why is KD important/useful?
It represents the constant ratio of dissociation:association for a particular interaction at equilibrium.
It permits comparison of equilibrium points for different combinations of molecules
How is affinity related to KD?
Affinity, or the affinity constant (KA) is the reciprocal of KD (1/KD)
What is fractional occupancy?
Why is it relevant?
The proportion of receptors occupied by a drug. Denoted by r
When the drug concentration is equal to the dissociation constant, then r = 0.5
Thus the dissociation constant (KD) for a D-R interaction is the concentration at which half of the receptors are occupied
Thus the relationship between KD, r and [D] is as follows:
r = [D] / KD + [D]
How is KD made more visible on graphs of drug-receptor interactions?
Using a semi-logarithmic plot results in the changes at lower values becoming more apparent and thus comparable
What is the relationship between KD and ED50?
For agonists, intrinsic activity will be related to fractional occupancy. In vitro the KD = ED50
What are the features of the semi-logarithmic plot for drug concentration and fractional occupancy/intrinsic activity?
- Sigmoid curve
- Occupancy rises with increasing [D]
What effect does increasing the KD have on the fractional occupancy curve?
Shift to the right
How are occupancy, efficacy and response related?
How can response be quantified without knowing fractional occupancy?
E = e r
E: response
e: efficacy
r: fractional occupancy
substituting into the fractional occupancy equation gives:
E = e[D] / KD + [D]
What is a full agonist?
A molecule with an efficacy of 1
What is a partial agonist?
A molecule with an efficacy of >0 but <1
What is an inverse agonist?
A molecule with efficacy <0 and ≥-1
What is Michaelis-Menten kinetics?
Describes the relationship between the concentration of a substrate [S] and the velocity of the enzyme-substrate reaction.
It is a hyperbolic relationship and a graphical representation can be used to determine the Michaelis constant (Km) which is the substrate concentration at which the velocity of the reaction is half-maximal (Vmax/2)
Michaelis-Menten equation: V = Vmax [S] / (Km + [S])
What factors may alter enzyme activity in constant environmental conditions?
By changing:
- Substrate concentration
- Km or Vmax
- Changing the amount of enzyme present
How may drugs increase enzyme activity in the body?
- Directly increasing Vmax or Km by positive allosteric modulation
- Indirectly increasing Vmax or Km through intermediary messengers
- Increasing quantity of enzyme via enzyme induction
How does insulin exhibit a direct allosteric effect?
Insulin functions as an allosteric modulator of the tyrosine kinase receptor, increasing its phosphorylating activity and mediating its intracellular actions
What is an example of an indirect positive allosteric interaction?
G-protein coupled receptor agonists indirectly activate AC through the Gα subunit of the G-protein
eg. beta adrenoceptors, D1 receptors and H2 receptors
How may drugs cause induction of enzymes?
Drug-induced increase in transcription and enzyme production
What are the CYP enzyme subtypes and their inducers?
CYP1A2: Tobacco, Omeprazole
CYP2B6/C9: Barbiturates, Rifampicin
CYP2C19: Prednisolone, Carbamazepine, Rifampicin
CYP2E1: Ethanol, Isoniazid
CYP3A4: Phenytoin, Carbamazepine, Barbiturates, Rifampicin, Glucocorticoids
What are some important drug interactions due to enzyme induction?
Vecuronium + Phenytoin / Carbamazepine - Reduced length of blockade
Warfarin + Rifampicin / Carbamazepine - Reduced efficacy of warfarin
Ciclosporin + Rifampicin - Reduced efficacy of ciclosporin
Barbiturates + Corticosteroids - Reduced efficacy of steroids
How may drugs reduce enzyme activity?
By reducing:
- Vmax/Km or both
- Activity of second-messengers
How does allopurinol work?
Inhibition of xanthine oxidase
How may enzyme inhibition be classified?
Reversible / Irreversible
Substrate / non-substrate
What are some examples of competitive enzyme inhibitors?
- Neostigmine (AChE)
- Ramipril (ACE)
- Theophylline / Milrinone (PDE)
- NSAIDs (COX)
Describe the mechanism of ACh breakdown by AChE
Anionic / Esteratic site
- Anionic site attracts NH+ from choline end of molecule and serine residue in esteratic site binds OH of acetyl group.
- Hydrolysis breaks ester bond and releases choline.
- Rapid reaction of water with the acetylated enzyme forms acetic acid which is released from the esteratic site.
Name 3 cholinesterase inhibitors which have different mechanisms of action
Neostigmine / pyridostigmine:
- Act as substrates and bind to both sites
- Carbamylate AChE (instead of acetylating)
- Carbamyl group takes much longer to react with water, increasing occupation time at esteratic site
- Reversible, competitive
Edrophonium:
- Binds to anionic site only
- Short-acting competitive inhibitor
- Used diagnostically to confirm MG
Organophosphates:
- Binds to both sites, but after cleavage leaves esteratic site phosphorylated.
- Phosphorylated AChE reacts very slowly with water and the complex ‘ages’ with time, becoming irreversibly bound, resulting in permanent inactivity (and thus non-competitive inhibition)
Where do organophosphate molecules exert their effects?
AChE and plasma cholinesterases
How may organophosphate toxicity be treated?
Pralidoxime administered before ‘aging’ occurs (36-48h) displaces phosphate from esteratic site of AChE until sufficient time has allowed the clearance of the toxins.
Anticholinergic treatment (atropine) must be used until either the the above has been acheived or the patient has synthesised new AChE
What is an example of an organophosphate?
Parathion / malathion
-Metabolised to paraoxon / malaoxon (active compound) in vivo
What is the action of the phosphodiesterases (PDEs)?
Degrade the phosphodiester bond of cAMP and cGMP
What are the important intracellular functions of cAMP and cGMP?
cAMP:
- Activation of protein kinase A (PKA)
- Results in increased glucose metabolism, lipid metabolism and Ca2+ release
cGMP:
- Activation of protein kinase G (PKG)
- Results in SM relaxation and reduced platelet activation
How may PDEs be classified?
Non-selective / Selective
Non-selective:
- eg. Methylxanthines (Aminophylline / theophylline)
- Inhibit PDE in many tissues
- Used for effect on bronchial smooth muscle
- Side effects include positive inotropy, vasodilatation, lipolysis and platelet inhibition
Selective:
- PDE3 inhibitors (Enoximone / milrinone) are cardioselective, acting as positive inotropes
- PDE5 inhibitors (Dipyridamole / sildenafil) inhibit platelet aggregation and cause vascular SM relaxation
What is the mechanism of action of NSAIDs?
- Inhibition of cyclooxygenase (COX) which metabolises arachidonic acid into several products
- Reduces inflammation through reduced production of prostaglandins
- Aspirin is an irreversible non-selective COX inhibitor
- Other NSAIDs are reversible, though have relatively long half-lives
- Other effects of COX inhibition may be platelet inhibition, gastric ulceration and renal dysfunction
How is vitamin K recycling affected by warfarin?
What effect does enzyme inhibition have on this?
- Reduction of used (epoxide) vitamin K by Vit K epoxide reductase (VKOR) is needed for re-use (and thus activation of clotting factors)
- Warfarin inhibits VKOR and exists in 2 enantiomers, of which S-warfarin is the more potent inhibitor
- CYP2C9 metabolises S-warfarin
- CYPs 1A1, 1A2 and 3A4 metabolise R-warfarin
-As well as drugs, pharmacogenomic and genetic variants of VKOR can affect warfarin dose requirements/complications
How long does aspirin affect platelet function for?
- Non-selective irreversible COX inhibitor
- Acetylates COX for duration of platelet lifespan (5-10 days)
Other than aspirin, what are some more examples of irreversible enzyme inhibiting drugs?
Older non-selective MAOIs:
- Phenelzine
- Tranylcypromine
What enzymes do the following drugs affect? Allopurinol Aminophylline Aspirin Enalapril Methyldopa Edrophonium Benzylpenicillin Selegiline
All inhibit: Allopurinol - Xanthine oxidase Aminophylline - PDE Aspirin - COX Enalapril - ACE Methyldopa - DOPA decarboxylase Edrophonium - AChE Ben-pen - Bacterial wall peptidase Selegiline - MAO
Name the most important CYP subtypes that are inhibited and their associated important inhibitors
CYP1A2: Fluvoxamine
CYP2C9: Fluconazole, Amiodarone
CYP2C19: Lansoprazole, Omeprazole
CYP2D6: Fluoxetine, Paroxetine, Quinidine
-Note not subject to induction
CYP3A4: Clarithromycin, Grapefruit juice, Ketoconazole, Verapamil
What are some important drug interactions due to P450 inhibition?
Beta-blockers + Verapamil / Diltiazem - Bradycardia, asystole, hypotension
Warfarin + Amiodarone - Increased bleeding risk
Ciclosporin + Grapefruit - Risk of toxicity
NSAIDs + paroxetine - Increased bleeding risk
Terfenidine + Clarithromycin - TdP
Buprenorphine + Ketoconazole - Risk of toxicity
How may a drug reduce adenylyl cyclase activity?
Give an example
Gi-coupled receptor activation leads to a reduction in AC activity
Eg. mu-Opioid receptor agonists
Give an example of a drug that inhibits Gs GPCRs?
Beta blockers
Give an example of a class of drugs that are therapeutic enzymes
Fibrinolytics (plasminogen activators):
- Streptokinase
- Urokinase
- Alteplase
What is the mechanism of action of hyaluronidase?
How is it used clinically?
Degrades hyaluronic acid, which holds tissues together
Used mixed with LA in ophthalmic regional blocks to increase diffusion.
What is an unwanted drug effect?
‘Any noxious or unintended reaction to a drug that has been given at a standard dose by an approved route for the prevention, treatment or diagnosis of a condition’
What type of adverse drug reactions may occur in anyone?
- Overdose
- Side effects
- Interactions
What types of ADRs may occur only in susceptible individuals?
- Intolerance
- Idiosyncrasy (genetically determined abnormal reaction)
- Allergy and pseudoallergy
What is the gene affected in suxamethonium apnoea?
How common is it?
Plasma pseudocholinesterase E1a gene
4% of caucasians carry an abnormality - more common in Asian/Middle-Eastern people and less common in Africans
What are some common P450 genetic abnormalities?
CYP2D6:
- metabolises codeine, tramadol, ondansetron and beta-blockers
- Genetic variation may increase codeine metabolism (Saudi Arabian / Ethiopian) or decrease metabolism (Chinese). Low metabolism may result in poor analgesia.
CYP2C19:
-Affects metabolism of diazepam and TCAs. Found mostly in Chinese populations
What is the significance of G6PD gene abnormality?
Causes haemolytic anaemia in susceptible individuals
Most common in Mediterranean, African and Asian populations. Affects use of sulphonamides and nitrofurantoin
What is the abnormality responsible for acute intermittent porphyria?
Porphobilinogen deaminase deficiency
Most common in Switzerland, Sweden and the Netherlands. Affects barbiturate and nitrofurantoin use.
How are ADRs traditionally classified?
What classifications have been added?
Type A / B
Type A (Augmented)
- 85-90% of ADRs
- Commony dose related and related to the pharmacological effect of the drug
- May be primary (exaggerated drug response) or secondary (unrelated to desired effect)
Type B (Bizarre)
- 10-15%
- Unpredicted, not dose related
- eg. sux apnoea, MH, porphyria
Added-
Type C (Cumulative)
-Cumulative dose and time related
-Eg. propofol infusion syndrome
Type D (Delayed)
- Time related (but also to dose)
- Fluoride nephrotoxicity
- Trichloroethylene carcinogenesis
Type E (End of use) -withdrawal
Type F (Failure)
- Common, dose related
- Often caused by interactions, eg. OCP failure with inducers
What is the DoTS classification for ADRs?
- Dose-relatedness
- Supra-/standard/sub-therapeutic doses - Time-relatedness
- Rapid/ early/ intermediate/ late/ delayed
- First dose reactions - Susceptibility
- Sex
- Genetics
- Age
- Physiological variation
- Disease
- Exogenous factors
How may risk factors for immune drug reactions be classified?
- Patient factors
- Drug factors
- Exacerbating factors
Summarise the Coombs’ Types of immune reaction
Type I:
- Allergy
- IgE-mediated
Type II:
- Cytotoxic, antibody-dependent
- IgM, IgG, Complement mediated
Type III:
- Immune complex mediated
- IgG, Complement mediated
Type IV:
- Cell-mediated
- Lymphocyte mediated
How does the World Allergy Organisation classify immune drug reactions?
Immediate / Delayed
Delayed is >1h from exposure
How may allergies be diagnosed?
- Skin prick tests
- RAST
- Mast cell tryptase
- Provocation tests
How may drug interactions be classified?
Pharmaceutical incompatibility:
- Physical/chemical incompatibility
- Neutralisation
- Precipitation
- Chelation
- Absorption
Pharmacokinetic interactions
-ADME
Pharmacodynamic interactions
- Summation / Potentiation / Synergism / Antagonism
- Direct / Indirect
How may hypokalaemia interact with drugs?
Increased myocardial instability -> increased risk of arrhythmia with catecholamines + anticholinergics
May be caused by :
- Diuretics
- Corticosteroids
- Insulin
How may hyperkalaemia interact with drugs?
Reduced cardiac automaticity
May be caused by:
- Sux
- K+ sparing diuretics
How may hyponatraemia interact with drugs?
Potentiation of LAs
May be caused by:
- Diuretics
- Sulphonylurea
How may hypernatraemia interact with drugs?
May be caused by
- Mannitol
- Sodium bicarb
- Hypertonic saline
How may hypomagnesaemia interact with drugs?
May cause cardiac arrhythmia
May be caused by:
- Diuretics
- Laxatives
How may hypermagnesaemia interact with drugs?
Bradycardia, AV block
May prolong neuromuscular block
May cause peripheral vasodilation
List the commonly used herbal medications relevant to anaesthesia and their effects
Echinacea:
- Said to improve immune system
- Modulates cytokines & stimulates macrophages and NK cells
- Avoid co-administration of hepatotoxic drugs
Ephedra:
- CNS stimulant, weight loss drug, asthma treatment
- Sympathomimetic (may contribute to tachyphylaxis)
- Caution with other sympathomimetics
- Arrhythmia with halothane
Garlic:
- Treatment of HTN, hyperlipidaemia and atherosclerosis
- Antiplatelet effects
- Caution if bleeding risk
Ginger:
- Anti-inflammatory, antiemetic
- Inhibit 5-HT, GI stimulant
- Caution if bleeding risk
Gingko biloba:
- Neuroprotective, improved blood flow
- Free radical scavenger
- Antiplatelet effects
- Caution if bleeding risk
Ginseng:
- Mood enhancer, aphrodisiac
- Sympathomimetic
- Caution if bleeding risk
- Hypoglycaemic effect
- Caution with other sympathomimetics
St John’s Wort:
- Antidepressant
- Induces CYP3A4 + 2C9
- Possible MAOI type effects
- Increased risk of serotonergic crisis
- Sedative effect
Valerian:
- Anxiolytic, hypnotic
- Potentiates GABAergic system
- Potential for withdrawal phenomena
- Reduces anaesthetic requirement
