pharmacokinetics (intro+ quan)

Question 1

Pharmacokinetics vs pharmacodynamics

Answer 1

Question 2

WHta is pharmacokinetics

Answer 2

• To be effecvtive, a drug must act at a specific site within the body. As soon as a drug enters the body, it starts leaving again. Drug action must either be sustained or turned off as required.
• Absorption = from outside to inside. Routes, bioavailability, drug properties, biological properties
• Ddistribution = From one place to another. Volume of distribution, blood flow, durg properties, bioloigcal properties
• Metabolism = From one thing to another. Biotransformation, transforming enzymes (eg, liver), drug properties, bioloigcal properties
• Excretion/ ELimination = From inside to outside. Clearance, rmeoval mechanisms )eg, kidney), drug properties, biological properties.

Question 3

Absoprtion of drugs

Answer 3

• Routes of administration:
  
  • Parenteral (avoid GIT) = IV (Blood), IM (highly vascularised tissue), Subcutaeous (Poorly vasculrised space), epidural (epidural space), trans-dermal (across skin), sublingual/buccal (under tongye/oral mucosa - avoids gut cf oral), inhalation (through breathing/lungs), intranasal (spray into nose).
  • Enteral (via GIT) = oral (Mouth>stomach>intestines), rectum (suppositries), sublingual/buccal (avoids GIT-cf.oral)
  • Systemic vs topical/ effect vs administration
• Oral bioavailability = fractional availability (F)- fraction of a drug that gets into systemic circulation. 100% (all drug gets in), 0% (none of drug gets in). Higher the bioavailability, the more useful the drig will be as an oral, systemic medicine. The factors affecting this: Stability within the gut, absorptiona cross gut wall into blood and metabolism in the liver (first pass effect)

Question 4

Factors affecting oral bioavailibility of a drug

Answer 4

1. Stability within the gut:

• Chemical stability - eg, acidic in stomach ph2.5, pH varies in small intestine
• Biological stability - enzyme action in gut, intestinal bacteria
• Drug properties - chemical, pharamceutical (different formualtions - tablets coated, capsules, liquids, syrups), biological (digestive enzymes - proteins/peptides, antibiotics, lipids)

1. Absorption across gut wall into blood:

• Gut is adapted for absorption (nutrition)
• Gut lumen -> blood vessel lumen: Gut epithelium, ECM, capillary endothelium
• Absorption depends on: Drug properties (solubility, size, change, pKa), pharmaceutical, gut properties (anatomy & physiology, pathology)
• IMAGE

1. Metabolism in the liver (firts pass effect):

• Liver is principal organ of drug metabolism - ‘screens’ xenobiotics
• Firts pass effect - durgs absorbed in(most of) the gut pass ENTIRELY to the liver. Hepatic portal vein runs from gut to liver
• Drugs with substantial hepatic metaboism may have poor ral bioavailability.

Quantification of Bioavailability:

• COmparison of iV vs oral doses. Bioavailability is expressed as % (maximum f is 100% (all gets into plasma) and minimum F is 0% (none gets in to plasma).
• Clinically used drugs can still have very low F eg, saquinavir (F is about 4%)

Question 5

weak acid and base between aqueosus comaprtments

Answer 5

Question 6

Distribution of a drug

Answer 6

• How much drug is needed - voluem of distribution?
• Where does the drug go - differential blood flow.
• Volume (ml) = amount (mg)/ concentration (mg/ml-1). Volume is constant
• Volume of distribution (Vd) = drug TOT-/ Conc p.
• Vd defiens the relationship between two real, important values:
  
  • Concentration in the plasma (Cp) - something measureable, directly related to clinicl effects
  • Amount in body (DrugTOT) - something we need to know, how much?
• Effects of blood flow:
  
  • High blood flow - brain, propofol (iv general anaesthetic). IV -> rapid delievry to brain -> asleep ‘instantly’.
  • Low blood flow - bone/cartilage/joints, antibiotics, difficult to achieve adequate concentrations of drug -> infections difficult to treat.
• Vd tells us the relative distribution of drug in the body comapred to the plasma. Therefore Vd tells us how much drug is required in the body to achieve a certain concentration in the plasma.
• Once a drug is in the blood it goes everywhere the blood goes. Differential blood flow affects deliveyr of drug to different parts of the body.

Question 7

Metabolism of a drug

How do the drugs change/ what do they change into?

Answer 7

• Metabolism alters the chemical structure of drugs - biochemical (enzymes- biotransformation), metabolism acts on other substances too. We eat many diverse chemicals, body detoxifies
• Where are drugs metabolised - liver (msotly), gut wall, kidney, lung, plasma, any tissues with metabolic activites. What?-> cytochrome P450 (CYP)
• Phase I reaction: Synthetic - oxidation (hydroxylation, dealkylation, deamination), reduction, hydrolysis. Usually makes drug more polar and soluble
• Phase II reaction: Conjugation - glucuronidation, methylation, sulphation, acetylation, glutathione. Makes drug larger and more polar. Often follows from phase I.
• Increased size, polarity and solubility -> increased renal excretion.
• WHta do drugs change into?
  
  • Phase I reaction = synthetic. Cna convert drug to active, inactive, or toxic metabolites
  • Phase II reactions = conjugation. Typically converts drug to inactive form. Exceptions are morphine.
• Actve drug -> Toxic metabolite/ inactive metabolite/ active metabolite/ inactive drug (-> prodrug eg, aciclovir)

Question 8

Paracetamol metabolism

Answer 8

Question 9

Excretion/ Elimination of a drug

Answer 9

• Elimination = disappearance of drug from plasma: Excretion (parent drug physically gone from body) and metabolism ( parent drug changed into something else- metabolites stil present).
• Exretion = physical rmeoval of durg/metabolite from body: Kidney-urine, lungs-breath, skin-sweat, gut/liver- faeces/bile, other.
• Renal Elimination = Promoted by increased prolarity & charge, aqeous solubility and size (upper cut off 50kDa/6-8nm ish). metabolites produced by phase I&II metbaolism will usually be more rapidly eliminated by kidney than parent drug.
• Quantifying elimination:
  
  • Rate of elimination - drug is eliminated form plasma over time. Unit mg.min-1
  • Clearance - plasma ml is cleared of drug over time. Ml.min-1
  • Rate o constant of elimination (ke)- proprotion of drug eliminated in 1 unit of time, min-1
  • Half-life (t1/2) - tiem taken for plasma concentraiton to fall by half. Units eg, min.
• Increasing clearance shortens half life
• Reducing clearance lengthens half life

Question 10

How long do drugs remain?

Answer 10

Question 11

Half life

Answer 11

• Most drug is gone after abour 6 half lives.
  
  • t1/2 s = 0>1>2>3>4>5>6
  • % = 100%>50$,35%, 12.5%, 6.25%> 3,1%> 6.1
• For an oral drug, ideal dosing is once per day. T1.2 is about 4-12hours roughly
• Short half life (seocndary/minutes) - onset/offset rapid, uses lot od drug
• Long hal ife (hours/days)- onsetoffset slow, uses les drug.

Question 12

Quantitiative pharmacokinetics basics

Answer 12

Question 13

1st order vs 3rd order elimination

Answer 13

Question 14

Rate of change in Single iV bolus dose - 1 compartment model

Answer 14

Question 15

Rate of elimination - single iV blus dose 1 compartment model

Answer 15

Question 16

Area under the curve calculation for single IV bolus dose - 1 comaprtment model

Answer 16

Question 17

Howoften and how much of a single IV bolus dose?

Answer 17

Question 18

How long does it take for 95% of drug to be eliminated?

Answer 18

34?

A. when Ct = 0.05 x C0

0.05co = coe ^-ket95% -> ln (.0.05) = -ket95%

t95% = ln(0.05)/-ke = 2.996/ke = 32hr=4.3 half lives

Question 19

Summary of a singlr IV bolus dose

Answer 19

Question 20

Single iV bous dose -d ata handling

Answer 20

Question 21

Single IV vs oral dose bioavailability

Answer 21

Question 22

Calculating Bioavailability single vs different doses

Answer 22

Question 23

Summary - single IV dose

Answer 23