General Pharmacology 21 to 30
What factors determine the difference in drug metabolism between individuals?
Genetic – enzyme level differences
Diet – induce / inhibit enzymes
Environmental – exposure to enzyme inducers
Age – extremes have decreased enzyme activity or decreased levels of cofactors
Sex – increased metabolic rate in males
Drug-drug interactions – enzyme induction or inhibition, substrate competition
Disease states – hepatic, pulmonary, cardiac, thyroid, inflammatory
Liver size & function
3 of 4 bold to pass
What is meant by 'enzyme induction'?
Prompt: What effect does it have on metabolism?
Prompt: What effect does this have on the pharmacological action of the drug?
Drug causes an increased rate of synthesis or decreased rate of degradation of enzyme causing:
accelerated substrate metabolism
decreased pharmacological action of the inducer or a co-administered drug.
Bold to pass
List the various molecular mechanisms of transmembrane signalling.
1. Lipid soluble ligand crosses membrane and binds to intracellular receptor.
2. Transmembrane receptor protein with ligand binding to extracellular domain regulating intracellular enzymatic activity
3. Transmembrane receptor protein that binds and stimulates protein tyrosine kinase
4. Ligand-gated transmembrane ion channels
5. Transmembrane receptor protein, G protein, intracellular second messenger
Describe 3 mechanisms to pass
Describe the function of the system involving G proteins.
Transmembrane signally system with 3 separate components. Extracellular ligand binds to specific cell surface receptor. This receptor then activates G protein located on cytoplasmic surface of membrane. Activated G protein changes activity of effector element (enzyme or ion channel) leading to a change in concentration of second messenger.
Bold concepts to pass
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 ie Reduces bio-availability of a drug
Pass: Basic definition. Has to include some changes of drug
How can you increase bioavailability? Give an example.
Prompt: Apart from ....what can also increase its bioavailability.
1 Different route of administration
IM / SC
PR — low
Still may have some first pass
metabolism — only 50% bypasses
2 Depending on properties of drug
- Actively pumped into gut
Pass: Must talk about alternative routes
Define drug clearance.
Prompt: Units of measurement of clearance.
1. Volume of plasma/blood cleared per unit time, or
Rate of elimination
2. CL = concentration
CL systemic = CL renal + CL liver + CL other
Pass: Need to know either of the two
What is the relationship between clearance and the dosing frequency of a drug?
- 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 Crate in’) must equal the rate of elimination Crate out’)
- Maintenance dose needs to be adjusted for disease state which affect clearance eg renal failure.
- Dosing rates (mg/h)
= Rate of elimination (steady state) = CL x target conc.
Pass: Need to know 2 out of 3
Please give an example of dosage adjustment for impaired clearance.
Gentamicin, digoxin in renal failure.
Loading dose not affected, maintenance dose reduced or dosage interval increased.
Pass: Need to give one example
With respect to the biotransformation of drugs, please distinguish between Phase I and Phase II reactions.
- Phase I convert the parent drug to a more polar metabolite by introducing or unmasking functional groups such as —OH, -NH2, -SH.
- Phase I examples: Oxidations including cytochrome p450 dependent and independent, deaminations, desulfurations, dealkylations, dehydrogenations, Reductions, Hydrolysis.
- Phase 11 involves conjugation in an endogenous substrate to form a highly polar conjugate.
- Phase II reactions include glucuronidation, acetylation, sulfation, methylation, glutathione conjugation.
- Both types of reactions result in more polar compounds that are more amenable to urinary excretion.
Pass if definitions correct
Does Biotransformation generally result in more or less active metabolites?
Prompt: Please give some examples
Usually less active (detoxification) may frequently result in metabolites with residual pharmacological activity or even enhanced activity (activation).
Pass: Must know this and give at least one example
What variables influence the extent & rate which a drug is absorbed?
1. Route of administration- PO; SC; SL; PR
2. Nature of the absorbing surface
(a) Cell membrane – single layer of intestinal epi cells compare to several layers of skin cells.
(b) Surface area – lung, small intestine, stomach
3. Blood Flow –blood flow enhances absorption SL v SC
4. Drug Solubility – lipid soluble drugs –
5. Drug Formulation – i.e. enteric coatings
Pass: Need 3 of main concepts
Explain why aspirin absorption is enhanced by the low pH in the stomach?
Aspirin is an acidic drug (pKa 2.98) relatively un-ionised in the stomach & more ionised in the small intestine (i.e. absorbed more readily from stomach)
Pass: Aspirin is more lipid soluble in stomach & absorption is greater here
Prompt: How does ionisation of a drug affect it’s solubility?
Drugs exist as weak acids or weak bases & in the body they are either ionised or un-ionised; Ionised(charged polar) water soluble; Un-ionised (non-polar) lipid soluble
Pass: Need to correctly state un-ionised drugs lipid soluble
Describe Phase 1 and Phase 2 reactions in drug metabolism.
Prompt 1: What are some of the biochemical reactions that characterize phase 1 reactions? (Oxidation, reduction, hydrolysis)
Prompt 2: How does phase 2 reactions enhance the excretion of a drug?
Process of chemical modification of a drug leading to more hydrophilic, more polar, readily excreted compound.
Phase 1 (Functionalization) reactions: converts parent drug to more polar often inactive metabolite – process of oxidation, reduction, hydrolysis where polar functional group (OH, N H2,SH) is introduced- majority reaction via cytochrome P450 enzymes.
Phase 2 (Conjugation) reactions: metabolites combine with endogenous glucuronic a, sulphate, acetylcoenzyme A or glutathione to form more polar metabolite– reactions catalysed by different transferase enzymes.
Note: Phase 1&2 can occur alone, sequentially or simultaneously. Metabolites can be more active or toxic than the parent drugs.
Pass: Need basic understanding of ingeneral “metabolise to more polar and excretable compounds”
1 example: (oxidation, reduction, hydrolysis) CYP450
1 example: Conjugation to form more polar compound+ one example of the
Fraction of unchanged drug reaching systemic circulation following administration by any route. AUC (conc-time) is a common measure of the extent of bioavailability.
What factors affect bioavailability?
a) Extent of Absorption
i) Too Hydrophilic or too lipophilic
ii) Reverse transporter associated with P-glycoprotein – pumps drug back to gut lumen
iii) Gut wall metabolism
b) First Pass Elimination
i) Metabolism by liver before it reaches systemic circulation
ii) Small additional affect if drug has biliary excretion
c) Rate of Absorption
i) Determined by site of administration and drug formulation
How can you overcome the effects of high first pass metabolism?
Change route of admin to: Sublingual, transdermal, rectal, inhalation, IV, IM ; increase dose
Pass: need two routes of admin
How does Hartmann's differ from normal saline?
- Addition of Sodium Lactate, Potassium Chloride, Calcium Chloride (+pH adjustment)
- Na 131, K 5, Cl 112, Ca 2, Lactate/Bicarb 28 mmoL
- Compare normal saline – Na 150, Cl 150
- Bold to pass
What are the potential advantages of Hartmann's solution in resuscitation?
- Closer to physiologic – potassium, calcium
- Less hyperchloraemia
- Effective bicarbonate – some (slow) good effect on acidosis (proof of superiority lacking)
- Bold to pass
What are the potential complications of IV fluid therapy?
- Overload/under resuscitation
- Electrolyte abnormalities
- Osmo changes
- Air embolism
- Cerebral oedema
What is drug clearance?
- Measure of the ability of the body to eliminate a drug
- Rate of elimination in relation to drug concentration
- CL = rate of elimination/concentration
- Reasonable definition to pass
What factors affect drug clearance?
- Concentration – Dose & Bioavailability
- Elimination – specific organ function / blood flow & protein binding
- Major sites of elimination are kidneys and liver – therefore factors that affect these organs’ function and blood flow will have most effect
- One for each element
What is the difference between capacity-limited and flow-dependent drug elimination?
- Capacity-limited is saturable (zero order)
- Examples: aspirin, phenytoin, ethanol
- Flow-dependent is non-saturable (1st order)
- (organ blood flow, protein binding)
- Examples: alprenolol, amitriptyline, imipramine, isoniazid, labetalol, lignocaine, morphine, propoxyphene, propanolol , verapamil
- Bold to pass