Hp-Chazot: Adme - Essay

Front 1

What is pharmacokinetics?

Back 1

the study of the movement of drugs into, within and out of the body.

Front 2

What is absorption?

Back 2

Passage of drug from its site of admin into plasma

Front 3

Name some absorption routes

Back 3

• Enteral (GI tract), oral, sublingual, rectal (diazepam)

Cutaneous - poor absorption.

Front 4

What is the fastest route?

Back 4

inhalation - used for volatile and gaseous anaesthetics.

Large Sa and blood flow.

Bronchodilators

Front 5

What is the advantage of IV?

Back 5

100% absorption and no loss of drug

Front 6

What does ionisation affect?

Back 6

• Ionisation will affect ability to cross plasma membrane for absorption through epithelial cells into the circulatory system

Front 7

What is Bioavailability?

Back 7

proportion of drug dose which appears in the systemic circulation following admin.

Oral admin – determined by stability in gut (gastric acid, flora), extent of absorption and extent of first-pass metabolism – fraction of drug lost to liver/gut.

F = AUCoral/AUCIV.

Does not account for rate of absorption - a drug completely absorbed in 30 min reach a much higher peak plasma conc. than if slowly

Front 8

Factors that affect bioavailability

Back 8

Variations in enzyme activity of gut wall or liver

Gastric pH or intestinal motility.

Front 9

Graph for absorption of drugs from intestine, as a function of Pka for acids and bases

Back 9

Front 10

• Absorption in intestine affected by?

Back 10

GI motility Splanchnic blood flow - increased by meal, reduced by hypovolaemia or heart failure particle size Physicochemical factors -

Front 11

What is Distribution?

Back 11

movement of drug around the body through membrane barriers

Front 12

What are compartments?

Back 12

ECF – blood plasma and interstitial fluid and lymph, ICF and TCF

Heparin is confined to plasma - too molecular to cross capillary wall.

Front 13

What is • BBB?

Back 13

Continuous layer of endothelial cells joined by tight junctions and surrounded by pericytes.

Inaccessible to many drugs with low lipid solubility. However, inflammation can disrupt integrity of BBB- pencillin given IV for bacterial meningitis.

Active uptake system transport nutrients and metabolites. Lipophilic molecules pass through. Bypassed by injection into spinal canal.

Bradykinin and enkephalins increase BBB permeability - treatment in brain tumours.

Front 14

What is • Volume of distribution (Vd?

Back 14

the volume of fluid required to contain the total amount, Q, of drug in the body at the same concentration as that present in the plasma V, Cp. Vd = Q/Cp.

High value - extensive distribution to other compartments in the body (tissue binding)

Must avoid IDing a given range of Vd too closely with a particular anatomical compartment.

Front 15

What does ionisation affect?

Back 15

distribution steady state distribution of drugs between aqueous compartments. pKa governs and pH of compartment governs the ration of ionised to unionised drug.

Front 16

Examples of drugs bound to plasma

Back 16

Albumin binds many acidic (warfarin) and some basic drugs (chlorpromazine)

Front 17

What does distribution depend on?

Back 17

• vascular permeability• regional blood flow• cardiac output and perfusion rate of tissue • ability of drug to bind tissue and plasma proteins• lipid solubility

Front 18

What is Metabolism?

Back 18

Enzyme- catalysed chemical modifications of drug molecules to inactivate and facilitate excretion

Front 19

Where does first pass metabolism occur?

Back 19

• Liver

Front 20

What is first pass metabolism?

Back 20

concentration of a drug is greatly reduced before it reaches the systemic circulation

It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall.

Issues: marked individual variation occur in extent of FPM

Front 21

How do phases affect lipid solubility?

Back 21

decrease it - increasing renal elimination

Front 22

What is phase I?

Back 22

catabolic (oxidation, reduction and hydrolysis). Oxidation mediated by cytochrome P450 enzymes (haem proteins) in liver carry out small-molecule drug metabolism.

Paradoxically: sometimes more toxic or carcinogenic than parent drug

Introduce a reactive group (-OH) – functionalisation. Serves as point of attack for conjugating system to attach a substituent e.g. glucuronide.

Many hepatic enzymes embedded in SEM. Drug must cross plasma membrane - lipid-solbule so less so for polar.

Often involve a monooxygenase system in which cytochrome P450 plays a key role.

Front 23

What is phase II?`

Back 23

Anabolic.

Conjugation reactions – methyl/acetyl/sulphate. (acetyl CoA) Aspirin – attachment of glycine/glucuronic acid.

Conjugate is pharmacologically inactive (usually), more water-soluble, and easily excreted.

Front 24

How does detoxification of paracetamol occur?

Back 24

• The tripeptide glutathione can conjugate drugs or their phase 1 metabolites via its sulfhydryl group

Front 25

Can metabolites be active?

Back 25

Yes,. pharmacologically active – sometimes more than parent drug

Front 26

How is aspirin metabolised?

Back 26

metabolised by the attachment of glycine or glucuronic acid

Front 27

Which enzyme metabolises ethanol?

Back 27

By a soluble cytoplasmic enzyme - alcohol dehydrogenase

Not involved in P450 system

Front 28

What is Excretion?

Back 28

excretion of drug and/or metabolites

Front 29

Where does it occur?

Back 29

• Kidney, hepatobiliary system, lungs (volatile anaesthetics) and glandular secretions. Waste products of metabolism and other non-useful materials are eliminated from an organism.

• Some drugs secreted into bile via the liver, but most are reabsorbed from intestine.

Front 30

Renal excretion: Filtration

Back 30

20k Da. If drug binds plasma albumin, only free drug is filtered. Warafin, 98% bound to albumin, conc. in filtrate is 2% of that in plasma – reduced clearance

Heparin too large to cross.

Front 31

• Tubular secretion

Back 31

20% filtered, 80% pass to peritubular capillaries of pt. OAT transports acidic drugs while OCT handles organic bases.

OAT carrier – against electrochemical gradient - can reduce plasma conc. to almost zero OCT – transport down ec gradient.

Unlike filtration, carrier-mediated transport can achieve maximal drug clearance even when most of drug is bound to plasma.

Penicillin – 80% protein bound – is almost completely removed by pt secretion.Diazepam - cleared extremely slowly

Drugs compete for same transport system - drug interactions

Front 32

• Passive diffusion across tubular epithelium

Back 32

Volume of urine only 1% of filtrate. Lipid-soluble drugs are excreted poorly (as reabsorbed) whereas polar drugs of low tubular permeability remain in lumen.

The ion-trapping effect –a basic drug is more rapidly excreted in an acid urine which favours the charged form and thus inhibits reabsorption (and vice versa).

Front 33

• Excretory products

Back 33

carbon dioxide, ammonia, urea, uric acid, guanine and creatine

Front 34

What is pH trapping?

Back 34

build-up of a higher concentration of a chemical across a cell membrane due to the pKa value of the chemical and difference of pH across the cell membrane.

• Results in basic chemicals accumulating in acidic bodily fluids (cytosol) and acidic chemicals accumulating in basic fluids.

Front 35

pH trapping - energy requirement?

Back 35

• No energy required.

Front 36

Explain pH trapping further?

Back 36

• Cells are more acidic inside than outside so basic drugs are more charged inside cells.

• Once non-changed molecule of basic chemical crosses membrane, ionised due to gaining H+ ion – unable to cross back. To maintain tm equilibrium, another unionised molecule enters cell.

• Explains by basic drugs are secreted in acidic stomach (morphine) and acidic drugs excreted in urine (alkaline).

Front 37

What is half life?

Back 37

time taken for plasma concentration to fall to half its initial value. After single IV dose - Cp = C0e-Kelt, where C0 = initial plasma concentration and Kel = elimination rate constant; Kel = clearance / volume of distribution

Front 38

What causes variation between individuals?

Back 38

absorption, first-pass metabolism, Vd, clearance, effects of disease on pharmacokinetics, drug interactions

Front 39

Main routes by which drugs and their metabolites leave the body

Back 39

Kidneys - most drugs leave in urine, uncharged or as polar metabolites
Hepatobiliary system - some drugs are secreted in bile via liver. Most are reabsorbed from intestine.
Lungs - occurs only with highly volatile or gaseous agents.

Front 40

Relevance of stereoselectivity

Back 40

Warfarin

mixture of stereoisomers

Differ in pharmacological effects and metabolism

Front 41

Clearance

Back 41

Volume of plasma containing the amount of substance that is removed from the body by kidneys in unit time

Urine conc x urine flow rate/ plasma conc.

Varies greatly - less than 1 ml/min to 700 ml/min - (renal plasma flow)

Front 42

Graph for effect of clearance of weak acid in alkaline and acidic urine

Back 42