VIVA: Pharmacology - General principles Flashcards
What changes would you make to the administration of IV morphine in an elderly 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)
Describe the two main mechanisms that account for the “spare receptor” phenomenon?
Temporal: prolonged effect after transient binding
Numerical: limited substrate with excess receptors
What is the effect on the dose-response curve of an agonist with increasing concentrations of an irreversible antagonist?
Curve is shifted to the right with increasing agonist concentrations until eventually only a submaximal effect is achieved
What variables influence the extent and rate at which a drug is absorbed?
Need 3 to pass:
1. Route of administration: PO, SC, SL, PR
2. Nature of absorbing surface:
- Cell membrane: single layer of intestinal epithelial cells compare to several layers of skin cells
- Surface area: lung, small intestine, stomach
3. Blood flow: blood flow enhances absorption SL vs SC
4. Drug solubility: lipid soluble drugs
5. Drug formulation: i.e. enteric coatings
Explain why aspirin absorption is enhanced by the low pH in the stomach
Aspirin is an acidic drug (pKa 2.98) relatively unionised in the stomach and more ionised in the small intestine (i.e. more lipid soluble and therefore absorbed more readily from stomach)
How does ionisation of a drug affect its solubility?
Drug exist as weak acids or weak bases and in the body they are either ionised or un-ionised:
- Ionised (charged polar) are water-soluble
- Unionised (non-polar) are lipid-soluble
What is first-pass metabolism?
After absorption of an orally ingested drug, portal blood delivers drug to liver:
- Metabolised in gut wall
- Metabolised in portal blood
- Metabolised by liver
- Excreted into bile
Before reaching systemic circulation
I.e. bioavailability of a drug is reduced
- basic definition + some changes of drug to pass
How can you increase bioavailability? Give an example
- Different route of administration*
- E.g. IV, IM/SC, SL, inh, transdermal
- Can give PR although may still have some first pass metabolism as only 50% bypasses the liver - Depending on properties of the drug:
- Increase absorption (hydrophilic, lipophilic, actively pumped into gut)
- Administer as prodrug - Increase dose*
- needed to pass
Give an example of a drug which undergoes first pass metabolism
Morphine undergoes extensive first-pass metabolism in the liver (and to some extent in the gut wall)
What is bioavailability?
Fraction of unchanged drug* reaching the systemic circulation* following administration by any route
- needed to pass
What factors affect bioavailability?
- Extent of absorption*
- Drug properties (e.g. too hydrophilic or lipophilic = decreased absorption)
- Gut factors (e.g. reverse transporter associated with p-glycoprotein pumps drug back to gut lumen, or gut wall metabolism = decreased absorption) - First pass metabolism*
- Metabolism by liver before it reaches systemic circulation
- Small additional effect if drug has biliary excretion - Rate of absorption
- Determined by site of administration and drug formulation
- needed to pass (with reasonable explanation of each)
What is the bioavailability of ibuprofen?
High*:
- Weak organic acid
- Well-absorbed rapidly *
- Minimal first pass metabolism *
- needed to pass
What is drug biotransformation?
Drug metabolism to allow drugs to become inactive or by increasing excretion* by making them more hydrophilic, or by metabolising them to less active agent
- needed to pass
Describe phase 1 and phase 2 reactions
Phase 1:
- Unmasking functional group* (-OH, -NH2, -SH) to produce a more polar metabolite
- Includes oxidation, deamination, hydrolysis, reduction
Phase 2:
- Conjugation with endogenous substrate* to become highly polar conjugate
- Reactions include glucuronidation, acetylation, sulfation, methylation and glutathione conjugation
- Catalysed by different transferase enzymes
Phase 1 and 2 can occur alone, sequentially or simultaneously
Metabolites can be more active or toxic than parent drugs
- needed to pass
How is suxamethonium metabolised?
Rapid phase 1 hydrolysis* by butyrylcholinesterase (pseudocholinesterase)* in liver and plasma
- either of these needed to pass
Why may a patient have a prolonged paralysis following suxamethonium?
Genetically deficient in butyrylcholinesterase so slowed metabolism
Can you give an example of a drug-drug interaction?
Must give an example with a correct mechanism, mechanisms including:
- Induction of inhibitors (e.g. miconazole, a CYP450 2C9 inhibitor, and warfarin, a CYP450 2C9 substrate)
- Protein binding (e.g. drug with higher affinity for protein binding, warfarin and clofibrate)
- Renal clearance (e.g. thiazide diuretics and lithium)
- Pharmacodynamic interactions (e.g. insulin and glucagon)
What is meant by enzyme induction?
Drug causes an increased rate of synthesis or decreased rate of degradation of enzyme, resulting in:
- Accelerated substrate metabolism*
- Decreased pharmacological action* of the inducer or a co-administered drug
- needed to pass
What are the sites of drug biotransformation?
Liver*
GIT
Lung
Skin
Kidneys
- needed to pass + two others
Does biotransformation generally result in more or less active metabolites?
Usually less active (detoxification; e.g. paracetamol)
May frequently result in metabolites with residual pharmacological activity (e.g. nordiazepam) or even enhanced activity (activation; e.g. morphine-6-glucuronide)
- need concept and at least one example to pass
What is drug clearance?
Clearance is:
- Measure of the ability of the body to eliminate a drug
- Rate of elimination in relation to the concentration, OR volume of plasma cleared of a drug per unit time
- Clearance = rate of elimination / concentration
What factors affect clearance?
Concentration*:
- Dose
- Bioavailability
Elimination*:
- Specific organ function and blood flow
- Protein binding
- Major sites of elimination are kidneys and liver; therefore factors that affect these organs’ function and blood flow will have the most effect
- needed to pass + one factor for each
What is the difference between capacity-limited and flow-dependent drug elimination?
Capacity-limited is saturable (zero order kinetics)*:
- Clearance varies depending on drug concentration
- E.g. aspirin, phenytoin, ethanol
Flow-dependent is non-saturable (first order kinetics)*:
- Most of drug is cleared on first pass of blood through an organ, so elimination depends on the rate of drug delivery to the organ (and hence on blood flow)
- Plasma protein binding and blood cell partitioning may also play a small role
- E.g. amitriptyline, imipramine, labetalol, lignocaine, morphine, verapamil
- needed to pass
Which organs are involved in drug clearance?
Two main organs are kidney and liver*
Others include blood, muscle, lung
CL (systemic) = CL (liver) + CL (kidney) + CL (other)
- needed to pass
What factors affect renal clearance?
Renal function*
Renal blood flow*
Plasma protein binding
Ionisation
- needed to pass
Name drugs that are predominantly cleared by the kidneys
Ampicillin
Gentamicin*
Vancomycin
Digoxin
Enalapril
Metformin
Lithium
- needed to pass + two others
Name two drugs that have hepatic clearance and explain why this is important
Lignocaine
Morphine
Propranol
Pethidine
Drugs with high hepatic elimination may only be suitable for parenteral administration or have significant dosing variations depending on the route of administration
What factors determine drug half-life?
Volume of distribution and clearance*
Half-life = (0.693 x Vd)/CL
Vd and clearance change with disease states including cardiac, hepatic and renal failure
- needed to pass
What formula describes drug clearance?
Ratio of rate of elimination of a drug to its concentration in blood/plasma
CL = rate of elimination / concentration
Can you name any drugs that have flow-dependent elimination?
Hepatic flow-dependent elimination (one example needed to pass):
- Lignocaine
- Propranolol
- Verapamil
- Morphine
- Pethidine
(May Vary Pending Liver flow: Morphine, Verapamil, Propranolol/Pethidine, Lignocaine)
What is the relationship between clearance and the dosing frequency of a drug?
2/3 needed to pass:
1. Knowing the clearance of a drug will allow the dosage to be worked out to achieve the target concentration:
- To maintain steady state, the dosing rate (“rate in”) must equal the rate of elimination (“rate out”)
2. Maintenance dose needs to be adjusted for disease state which affects clearance (e.g. renal failure)
3. Dosing rates (mg/hr) = rate of elimination (steady state) = CL x target concentration
Give an example of dosage adjustment for impaired clearance
Gentamicin and digoxin in renal failure
Loading dose is not affected but maintenance dose must be reduced or dosage interval increased
What is the role of the cytochrome P450 enzyme system?
Part of biotransformation system to detoxify drugs and other substrates*
Acts by oxidation (phase 1 reaction) *: one molecule of oxygen is consumed per molecule of substrate
Makes substrate more polar and therefore easier to excrete or conjugate in a phase 2 reaction
Acts on a large number of lipophilic substrates with low specificity
Relies on two enzymes: cytochrome P450 and cytochrome P450 reductase (plus oxygen and NADPH as cofactors)
Cytochrome P450 is a haemo-protein * and is active in its oxidised (ferric, Fe3+) state
- needed to pass
What is the mechanism of cytochrome P450 enzyme induction and give examples?
Enhanced rate of synthesis and/or reduced rate of degradation of CYP450 enzymes*
Specific examples:
- CYP450 2B1: barbiturates
- CYP450 3A: steroids, macrolides, anticonvulsants
- CYP450 2E1: isoniazid, chronic ethanol
- CYP450 1A1: pollutants (aromatic hydrocarbons in tobacco smoke)
Examples by mechanism:
- Enhanced synthesis: dexamethasone, phenobarbitol
- Reduced degradation: clotrimoxazole, ethanol
CYP450 inducers:
- Carbamazepine
- Rifampicin
- Alcohol (chronic): CYP450 2E1
- Phenobarbitone: CYP450 2B1
- Glucocorticoids: CYP450 3A
- Griseofulvin
- Phenytoin
- Sulfonylureas
- St John’s Wort
- need one mechanism and two examples to pass
What are the effects of oxidation on a drug?
2/3 needed to pass:
- More polar
- More easily excreted
- May be inactivated
Define drug elimination half-life
Time required to change the amount of drug in the body by half during elimination*
Half-life = (0.693 x Vd) / clearance
Drug concentration 50% after one half-life, >90% after four half-lives
- needed to pass
How does knowledge of a drug’s half-life help us clinically?
2 needed to pass:
- Determine dosing regimens
- Determine time to decay after dose/overdose
- Determine time to steady state after dose change
What disease states can affect elimination half-life?
Liver, renal or cardiac disease
What disease state could affect the elimination half-life of morphine?
Liver or renal disease
What is first-order elimination kinetics?
A constant fraction/percentage of the drug is eliminated per unit time*
Rate of elimination is proportional to the amount of drug in the body*
Half-life is constant
Most drugs are eliminated this way
- needed to pass
How do zero-order kinetics differ from first-order kinetics?
A constant amount of drug is eliminated per unit time
Rate of elimination is constant and is independent of drug
There is capacity-limited clearance or mechanisms have been saturated in overdose
Give some examples of drugs with zero-order kinetics
Ethanol
Phenytoin
Salicylates
Theophylline
Thiopentone (at high doses)
What routes of drug administration are there?
Enteral*: oral, buccal, sublingual, rectal
Parenteral: subcut, IM, IV, intrathecal, epidural
Inhalational
Topical
- needed to pass + three non-enteral
What factors affect the rate of drug absorption from the small intestine?
Must mention drug factors and gut factors to pass:
1. Ionisation status of drug:
- Alkaline intestinal pH (7-8) favours absorption of unionised basic drugs
2. Intestinal motility:
- Increased motility leads to reduced transit time and therefore reduced drug absorption
3. Gut surface area
4. Blood flow
5. Solubility of drug
6. Formulation of drug
What are potential disadvantages of rectal drug administration?
1/3 needed to pass:
- Erratic absorption because of rectal contents
- Local drug irritation
- Uncertainty of drug retention
To which routes of drug administration is first pass effect most important?
Oral
Rectal (only 50% of dose absorbed into systemic circulation)
What is the formula for the extraction ratio?
ER = CL(liver) / Q where Q = hepatic blood flow (90L/hr in 70kg adult)
What disease states can affect drug half-life?
Factors affecting Vd:
- Malnutrition
- Albumin levels
- Change in muscle mass or fat distribution
- Oedema
- Ascites
- Effusions
Factors affecting clearance:
- Poor nutrition
- Renal disease*
- Hepatic disease
- Heart disease (decreased CO)
- need two Vd factors, and renal plus one other for clearance
Give examples of drug administration that bypass the first pass effect
2 needed to pass:
- All injections
- GTN (patches, spray and sublingual tabs)
- Transdermal fentanyl
- Rectal (partially)
Define the volume of distribution of a drug
Need either definition or formula to pass:
- Defined as the volume in which the amount of drug in the body would need to be uniformly distributed to produce the observed concentration in blood, plasma or water
- Vd = amount of drug in body / concentration
How is it possible for a drug to have a Vd of 2500L in an adult?
Higher concentrations in extravascular tissues than in blood (e.g. lipid soluble)
Not homogeneously distributed
Give an example of a drug with a high Vd
High (>70L/70kg):
- Morphine*
- Chloroquine
- Digoxin*
- Clonidine
- Fluoxetine
- Tricyclic antidepressants*
- B-blockers*
- Diazepam*
- Cyclosporin
- one of these needed to pass
Give an example of a drug with a low Vd
Low (approximating ECF/TBW):
- Aspirin*
- Frusemide*
- Most antibiotics* (gentamicin, amoxicillin, cephalexin)
- Tolbutamide
- Phenytoin*
- Valproate
- Lithium*
- Warfarin
- Theophylline
- Indomethacin
- Sulphamethoxazole
- one of these needed to pass
What is the importance of Vd in the overdose situation?
Drugs with large Vd (e.g. TCAs) cannot be dialysed whereas drugs with a low Vd (ASA, lithium) can
What factors affect volume of distribution?
Drug factors*:
- Lipid solubility
- pKa
- pH
- Protein binding
Patient factors*:
- Age
- Gender
- Disease state
- Body composition (fat distribution)
- Blood flow
- two from each needed to pass
If a drug is distributed in TBW, what is its Vd?
TBW: 0.6L/kg or 42L/70kg
