Pharma Flashcards
First pass metabolism
Any metabolism before the blood i.e. gut lumen (acid), gut wall (P glycoprotein efflux), liver
Bioavailability =
the fraction of a drug reaching a particular body compartment
Vd=
How much volume we’d need to keep the total body conc equal to the plasma conc. Vd is low for drugs that stay in the blood and high for drugs that go to muscle/fat/etc
Vd = dose of drug given/ plasma conc
Factors affecting distribution
Volume of distribution Protein binding (if bound then it can't have an effect)
Give examples of drugs with volumes of distributions from low to high
Ibuprofen, warfarin (lowest Vd i.e. stay in blood) Alcohol, insulin, dextrose Paracetamol, caffeine Cocaine, diazepam Haloperidol, TCAs
Describe drug route from mouth to liver
Mouth, gut lumen, gut wall, portal vein, liver
Potency =
amount needed to produce a given effect (depends on efficacy and affinity)
Vd relates to our body fluid volumes- explain
Our plasma is 5%, about equal to heparin’s Vd so it stays in blood
ECV is 20%, about equal to gentamicin which stays outside cells and can’t enter very well
Total water is 55%, about equal to drugs that cross cells easily such as ethanol
Drugs with a Vd greater than our body volume go everywhere and are hard to remove by harm-dialysis e.g. TCAs, haloperidol
Vd is proportional to…
half life (higher Vd, longer half life)
Outline our fluid compartment numbers
42L total, 2/3 ICF 1/3 ECF
Why do drugs get conjugated
So they become water soluble to be eliminated
What is phase I and II metabolism
Both in liver
Phase I is oxidation, reduction, dealkylation and hydrolysis reactions. CYP450s carry out redox reactions (e.g. 2D6, absent in 7% white, hyperactive in 30% East African, metabolises codeine and inhibited by haloperidol)
Phase II is conjugation
What are first order and zero order kinetics
First order- elimination is proportional to amount of drug. Called linear
Zero order- elimination is at the same rate and does not vary with drug concentration. More likely to cause toxicity.
Some drugs have both e.g. paracetamol is linear and then non-linear when saturated
How many half lives to reach CpSS (concentration plasma steady state) and how many half lives to eliminate
4-5 half lives
What’s the point of loading doses
Allow us to get to CpSS without waiting for 4-5 half lives if the half lives are long
Loading dose = Vd / target CpSS
What is k?
Elimination constant
K = Clearance / Vd
T1/2 = Vd / Clearance
EC50 and Emax
EC50 is concentration at 50% effect
Emax is max effect
What is Km
Concentration at half the Vmax (max velocity)
Is the Vmax and Km different to the enzyme with:
a competitive inhibitor
a non-competitive inhibitor
Comp: same Vmax, different Km
Non-comp: different Vmax (lower), same Km
Define affinity
How well it binds to receptor
Efficacy
How much drug achieves its effect
Potency
How much of a drug is needed to produce desired response
Therapeutic index
EC50 of adverse effect / EC50 of desired effect
TD50 : ED50 (toxic to effective dose)
Used to quantify the therapeutic window (minimum toxic concentration - minimum effective concentration)
What is P-glycoprotein
Efflux transporter, found in GI (moves back into gut lumen), kidneys (moves into urine), liver (moves into bile)
Grapefruit juice inhibits
St Johns wort induces
What could affect metabolism
Genetics of CYP450s e.g. 2D6 (7% white absent 30% East African hyperactive for codeine)
Portal blood flow
Inducers (St Johns wort) or inhibitors (ethanol) of CYP450s
Give a pharmacokinetic drug interaction example
I.e. affecting ADME.
Alginates (gaviscon) reduce absorption of other drugs
Or aspirin displaces warfarin from albumin –> excessive bleeding
Give a pharmacodynamic drug interaction example
Agonism/antagonism at same receptor e.g. salbutamol is a beta agonist and stall is a beta blocker
Describe disease-drug interactions
Renal disease: e.g. CKD impaired clearance so longer half life of renally excreted drugs e.g. digoxin
Hepatic disease: impaired clearance of hepatic cleared drugs e.g. opiates in cirrhosis can lead to coma
CVS disease: impaired hepatic and renal perfusion so impaired clearance
What’s a normal QT interval and what can happen if its prolonged
350-450ms. If prolonged can cause torsades de pointes, a form of VT that can become VF. Sotalol, cocaine, TCAs can prolong QT
Give examples of off target and on target ADRs
Beta blockers on-target ADR of bradycardia, off target bronchospasm
Antagonists have affinity but no efficacy. Agonists have…
affinity and efficacy
Grapefruit juice…
is a CYP450 inhibitor
Obesity ____ Vd so need ___ dose
Increases Vd, need higher dose
Kd
affinity between site and ligand
Why is LDL bad for vessels
Enters arterial wall, becomes oxidised, oxidised LDL enters macrophages to become foam cells, activates T cells, mitogenic for SM cells, inhibits macrophages, increases platelet aggregation, toxic to endothelial cells.
How do statins work? name one
Simvastatin. Inhibit cholesterol synthesis in hepatocytes via inhibiting HMG-CoA reductase
When should you prescribe statins and name ADRs
When 20% 10yr risk of CVD or familial hypercholesterolemia.
ADRs myopathy, arthralgia
What are fibric acid derivatives/ fibrates
PPAR agonists, treatment for hypertriglyceridemia by increasing LPL production to decrease TGs. As an adjunct to diet
ADRs cholelithiasis and abnormal LFTs (contraindicated in hepatic or renal or gallbladder disease)
What does nicotinic acid do
Increase HDL-C
Decrease VLDL and coronary events
ADRs peptic ulcer activation, hepatotoxic, pruritus
Contraindicated in peptic ulcer disease, acute liver disease
What does ezetimibe do
Inhibits GI LDL absorption and increases hepatic LDL Rs, circulating enterohepatically
ADRs abdo pain, diarrhoea
Adjunct to diet and statins in hypercholesterolemia
