Pharmacokinetics 1 Flashcards

Question

PKa values of acidic and basic drugs

Answer 1

PKa is a measure of the tendency of an acid to give up a H+: AH ⇌ A- + H+ PKa of a base= tendency of the conjugate acid form of the base (BH+) togive up a H+ BH+ ⇌ B + H+ Low pKa = readily gives up a H+ - Acid with low pKa = strong acid - Base with a low pKa = weak base High pKa = does not readily give up a proton - Acid with a high pKa = weak acid - Base with a high pKa = strong base Many drugs are acids or bases

Answer 2

Acids with pKa below 3 and weak base with a pKa above 10= poorly absorbed from the intestine

Answer 3

-greater the number of hydrogen bonds= less likely absorption -rate of permeation also depends upon molecular weight -large molecules = have problems diffusing across membrane -molecular weight greater than 500= most likely to be incompletely absorbed -good absorption= need low molecular weight <500 + some lipophilicity

Answer 4

“Rule of 5”= • From review of 2245 compounds with superior physicochemical profile (dataset of >50,000) concluded poor absorption more likely if: • Molecular weight > 500 • logP > 5 • Number of H-bond donors > 5 • Number of H-bond acceptors > 10

Answer 5

-to be transcellulary absorbed = a drug must permeate membranes Membrane permeation depends upon: -area of absorptive surface -lipophilicity -pKa -hydrogen bonding -molecular size

Answer 6

Drug passes through the gaps between cells (tight junction) -no membrane permeation -requirement for low molecular weight (<300) + water solubility -poor paracellular absorption from the colon -pores between cells larger in dog than in rat and man

Answer 7

-drugs carried through the membrane by a transporter; energy dependant, not passive -many transporters exist for nutrient molecules -unlike passive absorption- can be saturated by high concentrations

Answer 8

P-glycoprotein (P-gp) initially discovered in cancer patients displaying MDR (Multi-Drug Resistance) P-gp is found in high levels at the apical surface of cells associated with transport: biliary canalicular membrane brush border of the renal proximal tubules apical surface of the intestinal epithelial cells endothelial cells of brain and testis P-gp can effectively act as a barrier to oral absorption

Answer 9

Once absorbed a drug molecule is subject to distribution throughout the body via the circulatory system

Answer 10

hypothetical volume into which drug is dissolved or distributed, V for a drug is constant Defined as the volume that would contain the total body content of the drug at a concentration equal to that of plasma Used to define dose required to achieve a particular drug [plasma] A drug that partitions (distributes) into tissues readily has a low [plasma] is likely to have large Vd and vice versa

Answer 11

Major compartments for drugs to distribute into are: Plasma (5% of body weight) Interstitial fluid (16%) Intracellular fluid (35%) Transcellular fluid (2%) Fat (20%)

Answer 12

70kg healthy male subject Extracellular fluid (ECF) 20% weight -plasma 3L (4% of body weight) -interstitial fluid 11L (16% of body weight) Total body water 42L (60% weight) -intracellular fluid 28L (40% of body weight)

Answer 13

Vd = amount of drug in body (A) / [plasma drug] (C) Where: A = mg (mass of drug) C = mg/L (drug concentration) Often further divided by patient’s body weight to give L/kg Vd is used clinically to determine the loading dose needed for a particular blood concentration The interactive website: https://www.icp.org.nz/volume-of-distribution/vd-and-loading-dose

Answer 14

Values for Vd are determined experimentally and are constant in healthy humans This means, given known values of Vd and the therapeutic range of a drug we can calculate an appropriate ‘loading’ dose. e.g. If drug X has a volume of distribution of 15L and is effective once it reaches a plasma concentration of 8mg/L what i.v dose should we administer? First: Plasma concentration = mass in body (A)/ volume of distribution Mass in body (A)(i.v. dose ) = plasma concentration (C0) x volume of distribution (Vd) i.v dose = 8mg/L x 15L = 120mg

Answer 15

Drug X is going to be an OTC drug so needs to be taken orally. It has a bioavailability F= 0.6. What oral dose should be given? Plasma concentration (C 0)= mass in body/ volume of distribution (Vd) Mass in body (A)= C 0 x Vd Mass in body for an oral dose (A)= F x oral dose= 0.6 x oral dose So 0.6 (F) x oral dose = c0 x V d Then = oral dose= c0 x Vd/ 0.6 (F) = 8mg/Lx 15L / 0.6 (F) = 200mg

Answer 16

1.)The drug may remain largely within the vascular system. For example, plasma substitutes such as dextran are an example of this type, but drugs which are strongly bound to plasma protein may also follow this pattern. 2. ) Some low molecular weight water soluble compounds such as ethanol become uniformly distributed throughout the body water. 3.) A few drugs are concentrated specifically in one or more tissues that may or may not be the site of action. For example, iodine is concentrated by the thyroid gland. The antimalarial drug, chloroquine may be present in the liver at concentrations 1000 times those present in plasma. Tetracycline is almost irreversibly bound to bone and developing teeth. Consequently, tetracyclines should only be given to young children or infants in extreme conditions as it can cause discoloration and mottling of the developing second set of teeth. Another type of specific concentration may occur with high lipid soluble compounds which distribute into fat tissues. 4. Most drugs exhibit a non-uniform distribution in the body with variations that are largely determined by the ability to pass through membranes and their lipid/water solubility. The highest concentrations are often present in the kidney, liver, and intestine usually reflecting the amount of drug being excreted.

Answer 17

Binding of drugs to proteins in blood is a major determinant of PK and source of drug-drug-interactions Drug-drug interactions can involve competition for protein binding – i.e. dislodging a bound drug from a protein increases its unbound (active) concentration Particularly dangerous for drugs with a narrow therapeutic index – i.e. digoxin (95% bound)

Answer 18

Drugs can bind to macromolecules in the blood – known as plasma protein binding (PPB) – restricted to plasma Only unbound compound is available for distribution into tissues, “Active” drug = unbound – can bind to target so it is pharmacologically active Acids bind to basic binding sites on albumin, bases bind to alpha-1 acid glycoprotein 0-50% bound = negligible 50-90% = moderate 90-99% = high >99% = very high

Answer 19

Acidic drugs tend to have higher PPB than neutral/basic drugs. The more lipophilic a compound the higher the degree of PPB

Answer 20

Free drug pharmacological effect Elimination Protein-bound drug not available to exert pharmacologic effects or distribute to tissues or unavailable for elimination

Answer 21

The fraction of drug that is free in aqueous solution can be less than 1%, Small differences in protein binding (e.g. 99.5 versus 99.0%) can have large effects on free drug concentration and drug effect. Differences are common between human plasma and plasma from species used in preclinical drug testing

Answer 22

Blood brain barrier (BBB) Only lipid soluble drugs can enter brain and CSF ‘Leaky’ in disease – eg penicillin in meningitis Within the penicillins, penetration is as low as 1% with intact (non-inflamed) BBB and may rich above 30% in the presence of inflammation. Penicillin G has approx. two-thirds of its CSF elimination via an efflux pump. Placenta Allows passage of lipid and some water soluble drugs - eg opioids, antiepileptics, sodium valproates took by pregnant women affected their babies development! Enzymes in placenta inactivate some drugs

Answer 23

Rate of Distribution: Membrane permeability Blood perfusion Extent of Distribution: Lipophilicity (logP) pKa Extent of protein binding Size Only unionised unbound drug in the plasma can distribute into tissues and therefore is pharmacologically active Go on slide 66 for calls

Answer 24

100 mg of drug A, B, and C is administered IV in a subject, the plasma concentration at time zero (Co) was estimated as follows: Drug A = 10 mg/L Drug B = 2 mg/L Drug C= 1 mg/L What is the volume of distribution of drug A, B, and C? Drug A = 10 L Drug B = 50 L Drug C = 100 L 𝐶_𝑜=𝐷𝑜𝑠𝑒/𝑉. 𝑽=𝑫𝒐𝒔𝒆/𝑪_𝟎

Answer 25

Considering the dose of all three drug was same, i.e., 100 mg They were all administered through the same route, i.e., IV They were given to the same subject and assuming no changes in subject physiology

Answer 26

Drugs may be administered as salts to increase solubility - but doses are defined in terms of mass of parent drug Therefore, need to adjust dose given to take account of “salt factor” Dose of salt form of drug = (Dose of Drug Required)/(Salt Factor) e.g. theophylline is generally administered as aminophylline – aminophylline contains 80% w/w theophylline - So, the salt factor = 0.8 If we want to administer 400mg of theophylline we would require: Dose of salt form (aminophylline) = (400 mg)/0.8=𝟓𝟎𝟎𝐦𝐠 aminophylline

Answer 27

1. A patient requires a dose of 250mg of Drug X; Drug X is only available as a salt (75% w/w). How much of the salt form of the drug do we need to administer? 3. Why do we need to ensure the correct concentration of drug in the blood? 6. For a given dose of drug which patient-related factors may affect the concentration observed in blood?

Pharmacokinetics 1 Flashcards

(51 cards)