VIVA: Pharmacology - General principles Flashcards
What changes would you make to the administration of IV morphine in this patient compared to a younger one and why?
Changes:
- Reduce initial dose
- Wait longer before administering a second IV dose
- Increased interval between repeat doses
Explanation:
- Elderly are often markedly more sensitive to the respiratory effects of opioid analgesics because of age-related changes in respiratory function
- Increased distribution time to the CNS due to reduced cardiac output
- Elimination half-life of morphine will be increased
- need at least one dose adjustment with correct explanation
Describe the pharmacokinetic changes that occur in the elderly
Absorption:
- Nutritional deficits
- Delayed gastric emptying (diabetics)
- Co-ingested agents (e.g. laxatives, antacids)
Distribution:
- Increased body fat
- Increased alpha-acid glycoprotein (binds bases)
- Decreased lean body mass
- Decreased body water
- Decreased serum albumin (binds weak acids)
Metabolism:
- Decreased phase 1 reactions p450*
- Decreased hepatic blood flow
- Liver disease
- CCF
- Nutritional deficiencies
Elimination:
- Reduced creatinine clearance with age*
- Decreased kidney weight as a % of young adults’
- Renal disease
- Decreased respiratory capacity
- Respiratory disease
- Polypharmacy and multiple drug interactions/toxicity
- needed to pass + one other
Give some examples of drugs commonly used in the emergency department that must have their prescribing altered in the elderly
4 relevant and plausible examples with correct associated mechanism (must include benzodiazepines and opioids):
- Benzodiazepines: liver metabolism, renal function, pharmacodynamic increased sensitivity
- Opioids: respiratory effects, pharmacodynamic increases sensitivity
- Antipsychotics: reduced lean body mass, pharmacodynamic increased sensitivity
- NSAID: increased risk of GI and renal adverse effects
- Colchicine: narrow therapeutic index, renal clearance reduced
- Other drugs with a narrow therapeutic index
- Drugs primarily renally excreted: gentamicin, acyclovir
- Digoxin loading dose: must be reduced due to decreased Vd
- Amiodarone loading: pharmacodynamic increased sensitivity
- Many drugs may interact (e.g. CYP450 inhibitors/inducers, warfarin)
- Interactions with age-related disease (e.g. B-blockers in IHD and COPD)
- Sulphurs/bactrim: adverse reactions
- Anticoagulants: increased risk of significant bleeding events with falls
- Drugs which switch to zero order kinetics (e.g. phenytoin)
Give examples of drugs where hepatic clearance does not change with age
Nitrazepam, oxazepam, salicylate, warfarin, lignocaine, prazosin
How does the pharmacokinetics of gentamicin change in the elderly?
Decreased renal excretion = increased elimination half-life
In children, what factors change with age and altered pharmacokinetics?
- Body size and composition*
- Growth of child: most doses calculated in mg/kg
- Changes in % TBW and distribution of body water (adult 60%, term neonate 70-75%, pre-term neonate 85%): influences drugs distributed in extracellular space
- Reduced fat in preterm infants (1%) compared with adults (15%)
- Decreased serum albumin in neonates (potential for increased toxicity if drugs highly protein bound)
- Risk of kernicterus with use of highly protein bound drugs in jaundiced neonates (displaces bilirubin) - Drug metabolism*:
- Reduced hepatic metabolism compared with adults
- Slow clearance and prolonged elimination half-lives - Drug excretion*:
- GFR lower in newborns than older infants (neonates 30-40% adult values, 3 weeks 50-60%, 12 months 100%)
- needed to pass
List the factors affecting placental drug transfer
2/5 needed to pass:
- Lipid solubility
- Molecular size
- Placental transporters
- Protein binding
- Placental and foetal drug metabolism
What is meant by foetal therapeutics?
Drug administration to the pregnant woman with the foetus as the target
Give examples of drugs administered as foetal therapeutics
Corticosteroids (for lung maturation)
Phenobarbitone (induces enzymes for glucuronidation of bilirubin)
Antiretrovirals (decreases HIV transmission)
Antiarrhythmics
What pharmacokinetic variables affect drug levels?
2 needed to pass:
- Absorption (e.g. small bowel abnormalities)
- Clearance (e.g. impaired renal, liver or cardiac function)
- Volume of distribution: changes in either tissue or plasma binding impact drug availability (e.g. decreased muscle mass in elderly, hypoalbuminaemia, drug interactions)
What pharmacodynamic variables affect drug dosing?
Maximum effect (Emax): vs toxicity by increasing dose beyond maximum effect
Sensitivity (EC50): e.g. hyperkalaemia decreases sensitivity to and effect of digoxin
List the factors which contribute to the variation in response to a drug
- Genetic factors* (enzyme level differences)
- Age* (extremes of age have decreased enzyme activity or decreased levels of cofactors)
- Sex (increased metabolic rate in males)
- Body mass
- Diet (induce/inhibit enzymes)
- Environmental (exposure to enzyme inducers)
- Disease states* (hepatic, pulmonary, cardiac, thyroid, inflammatory)
- Drug-drug interactions* (enzyme induction or inhibition, substrate competition)
- Liver size and function
- Circadian rhythm
- Body temperature
Also: tolerance, tachyphylaxis, idiosyncratic reaction
- 3/4 needed to pass
What mechanisms are involved in factors which cause variation in response to a drug
2/4 needed to pass:
- Alteration in concentration of drug reaching receptor (e.g. altered absorption or clearance)
- Variation in concentration of an endogenous receptor ligand (e.g. propranolol in patients with elevated vs normal endogenous catecholamines)
- Alteration in number or function of receptors (e.g. down-regulation leading to tolerance, overshoot leading to withdrawal)
- Changes in response components distal to the receptor (e.g. age, health, disease)
In the context of drug-receptor interactions, what is the difference between a full agonist and a partial agonist?
High concentrations of full agonist can evoke a maximal response, but partial agonists cannot evoke maximal response at any concentration
Under what circumstances can a partial agonist act as an antagonist?
In the presence of a full agonist (e.g. buprenorphine)
In relation to drug concentration and responses, what is the EC50?
EC50 is the concentration at which an agonist produces half its maximal effect
What are spare receptors?
The concentration of an agonist producing a maximum response may not result in occupancy of full complement of receptors; these receptors are said to be “spare”
May be temporal or in number
Dose-response curve for an irreversible antagonist:
- A = no antagonist
- B = low dose antagonist; still get maximum effect because receptors still in excess of required for effect
- C = largest concentration of antagonist to produce maximum effect; therefore no spare receptors
- D+E = high concentrations of antagonists which diminish maximum response
What is an antagonist?
Receptor antagonists bind to receptors but do not activate them
The primary action of antagonists is to prevent agonists from activating receptors
What is the difference between a competitive and non-competitive antagonist?
Competitive antagonist:
- In the presence of increasing concentration of antagonist, higher concentrations of agonist are needed to produce a given effect
- E.g. propranolol and noradrenaline/adrenaline
Irreversible or non-competitive antagonist:
- Bind via covalent bonds or just binding so tightly to receptor so that the receptor is unavailable for agonist
- Duration of action of antagonist depends on the rate of turnover of receptor-antagonist molecules
- Reduces maximal effect of agonist but may not effect the EC50
- E.g. phenoxybenzamine vs adrenaline
What type of antagonist is naloxone?
Competitive
What effect does a competitive antagonist have on the concentration-effect curve?
Shifts the agonist vs effect curve to the right (higher concentrations of agonist are needed to overcome a competitive antagonist)
Give an example of an antagonist
Competitive: naloxone, flumazenil, propranolol, isoprenaline, naltrexone, nalmefene
Irreversible: phenoxyenzamine, MAOI
How does an irreversible antagonist alter the concentration effect curve for a drug? Draw to demonstrate. What happens to EC50?
Reduced maximum effect
EC50 may not alter
How does a competitive antagonist alter the concentration effect curve for a drug? Draw to demonstrate. What happens to EC50?
EC50 increased
Maximum effect not changed
Can you define potency?
Amount of drug required to produce an effect* of certain intensity
Refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect
Dependent on affinity of drug for receptor and the number of receptors available
- needed to pass
Can you define efficacy?
Maximal effect a drug can produce* when all receptors are occupied, irrespective of the concentration required to produce that response (or irrespective of dose)
Determined by the drug’s mode of interactions with receptors or by characteristics of the receptor-effector system involved
- needed to pass
Show the difference between efficacy and potency by drawing graded dose response curves
A and B have similar potency
A and B are more potent than C which is more potent than D for mild to moderate responses/effects
A, C and D have similar efficacy and greater efficacy than B
B is a partial agonist (producing less than full response despite full receptor occupancy)
Compare the potency of morphine to fentanyl
Fentanyl 100x more potent (0.1mg fentanyl = 10mg morphine)
Draw a concentration-response curve showing 2 drugs with the same potency but different efficacy
X and Z have similar efficacies
X and Y have similar potencies
X and Y are more potent than Z
What factors affect a drug’s efficacy?
3/6 to pass:
- Affinity of receptor for drug
- Drug-receptor interaction
- Route of administration
- Absorption
- Distribution through the body
- Clearance from the blood or site of action
What factors influence the potency of a drug?
Potency is affected by the affinity of receptors for binding the drug, and the coupling efficiency
What are the steps in activation of a second messenger?
Method of transmembrane signalling*
Drug binds to a receptor on extracellular side plasma membrane*
Triggers activation of G protein on cytoplasmic side*
Activated G protein changes an enzyme or ion channel*
This changes concentration of intracellular second messenger which mediates a response
- needed to pass
Give an example of a second messenger and the type of response it produces
Name 1 and some knowledge of a response to pass:
1. cAMP:
- Via adenylate cyclase
- Mobilisation of fat and carbohydrates
- Conservation of water by kidney
- Increases rate and contractility of heart
- Ca2+ regulation
- Adrenal hormone regulation, relaxation of smooth muscle
2. Ca2+ and phosphoinositides
3. cGMP:
- Via transmembrane guanylyl cyclase (atrial natriuretic peptide) or NO which binds to a cytoplasmic guanylyl cyclase
- GTN
- Sodium nitroprusside
- Inhibition of phosphodiesterase -> results in increased cGMP (e.g. sildenafil)
Describe the 3 major steps in a second messenger stystem
- Cell surface receptor for an extracellular ligand
- Intracytoplasmic activation of a G-protein
- Activation of an effector (e.g. adenylate cyclase) with production of the second messenger (e.g. cAMP)
Give an example of a drug that acts via a GPCR
B agonists: B adrenoceptor -> Gs protein -> adenylcyclase -> increased cAMP
(Other examples: glucagon, thyrotropin, histamine, serotonin, ACh, opioids)
- correct example to pass, with extra marks for describing components
What is the significance of spare receptors?
Increasing the number of receptors coupled to an effect can allow lower concentrations of agonist to still produce a given proportion of maximal response (tissue thus more sensitive)
