Introduction to drug kinetics and drug toxicity

Question 1

What is pharmacology?

Answer 1

Study of the effects of drugs on living systems (in relation to therapeutics and toxicology)

Question 2

What is pharmacodynamics?

Answer 2

deals with the study of the biochemical and physiological effects of drugs and their mechanism of action. Effect of the drug on the body.

Question 3

What is pharmacokinetics?

Answer 3

absorption, distribution, biotransformation and excretion of drugs. Effect of the body on the drug

Question 4

What is toxicology?

Answer 4

Adverse effects of drugs and chemicals

Question 5

What is pharmacotherapeutics?

Answer 5

use of drugs in the prevention and treatment of disease

Question 6

Drugs modify physiological processes

Answer 6

Drugs DO NOT create new processes or effects
Drug effects are expressed in terms of alteration of a known function or process
-returns a function to normal operation
-changes a function away from the normal condition

Question 7

4 main parts of pharmacology

Answer 7

Pharmacodynamics
Pharmacokinetics
Toxicology
Pharmacotherapeutics

Question 8

Drugs are used to

Answer 8

Prevent, diagnose and/or treat disease
Modify actions of other drugs
Analyse mechanisms or functions of an organism

Question 9

What is a drug?

Answer 9

A chemical substance of known structure which, when given to a living organism, produces a biological effect

Question 10

Virtually all drugs produce more than one effect

Answer 10

Specificity
Selectivity
Toxicity

Question 11

Specificity

Answer 11

Drug produces only one effect.

Question 12

Selectivity

Answer 12

One effect predominates over a particular dose range – this is called the “therapeutic window” – within this range, the drug may be termed “selective”.
The goal of therapeutics is to achieve “specificity”.

Question 13

Toxicity

Answer 13

Normally occurs beyond the therapeutic dose range. Some drugs may show toxicity at the higher end of the therapeutic doses (i.e.; adverse effects).

Question 14

General mechanisms of drug activity

Answer 14

In deficiency
In the case of excess action
For the physiochemical environment

Question 15

Deficiency

Answer 15

Replacement therapy for conditions such as iron, vitamin or hormone deficiency

Question 16

Excess action

Answer 16

Chemical antagonists can reduce or block the effects of excess activity of normal process.
Antagonists can also block excess effects of exogenous substances (e.g.; reversal of overdose).

Question 17

Physiochemical environment

Answer 17

Drugs can alter the environment or characteristics of a cell or tissue, changing its activity - “nonspecific effects”

Question 18

Dose or concentration

Answer 18

Drug quantity in weight (mg) or volume (ml).

Question 19

Response or effect

Answer 19

The change occurring after drug administration. Effects include:
Therapeutic effect: The desired or anticipated effect
Side effect: Other than therapeutic effects occurring at therapeutic doses
Toxic or adverse effect: Deleterious effects usually occurring at higher doses
Lethal effect: Death caused by very high drug dose

Question 20

Acceptor

Answer 20

Substances drugs bind to without causing any effect (e.g.; plasma proteins)

Question 21

Receptor

Answer 21

Component of a cell or organism that interacts with a drug and initiate the chain events leading to the drug’s observed effect
Ligand - agonist and antagonist

Question 22

Ligand

Answer 22

Bind to a receptor

• agonist - initiates a response, many endogenous agonist (e.g. neurotransmitters and hormones)
• antagonist - does not initiate a response, prevent agonist binding

Question 23

Drug receptors: molecular targets for drugs

Answer 23

Receptors are the molecules on or in the cell that the drug molecule first interacts with and activates (agonist) or blocks (antagonist)
-Membrane receptors, enzymes, DNA, cytosolic proteins, ion channel
-7-TMS receptors (800-1000); 650 genes, activated by 70 ligands. Target for half of all prescription drugs.
Receptors convert the drug molecule signal (3D shape) to a biochemical signal (‘transduction’) via ‘effectors’
The effect is ‘hard-wired’: drugs modify ongoing physiological processes

Question 24

Receptor Location

Answer 24

1. Cell membrane (transmitters/ peptides)
2. Cytoplasm (steroids)
3. Nucleus (thyrosin/ insulin sensitivity)

Question 25

Biological targets of drugs ****

Answer 25

``` Receptors -agonist -antagonist Ion channels -blockers -modulators Enzymes -inhibitor -false substrate -pro-drug Transporters -normal transport -inhibitor -false substrate ```

Question 26

Classes of cell-surface receptors (DIAGRAM AND ENCORE)

Answer 26

Ion-channel-linked receptor G-protein-linked receptor -a lot of types Enzyme-linked receptor

Question 27

Receptor subtypes - example of adrenoreceptors

Answer 27

Alpha and beta adrenoreceptors

Question 28

Beta-adrenoceptors

Answer 28

Tolerance -Β agonist down regulate β-adrenoceptor Withdrawal -β antagonist upregulate β-adrenoceptor

Question 29

Drug/ receptor interaction (GRAPH)

Answer 29

EC50 Potency Efficacy Affinity

Question 30

EC50

Answer 30

[drug] that produces 50% of the maximal effect

Question 31

Potency

Answer 31

how much drug is required to produce a particular effect. Depend on both affinity and efficacy Most important

Question 32

Efficacy and affinity

Answer 32

Efficacy: relationship between receptor occupancy and ability to initiate a response at molecular, tissue or cellular level. Affinity: ability to bind a receptor. -adrenalin similar affinity than propanolol but very different efficacy

Question 33

Receptor activation

Answer 33

Full agonist or Partial agonist: based on the maximal pharmacological response that occurs when all the receptor are occupied. Antagonist: binds but does not activate and are used to prevent agonist from binding

Question 34

Intracellular receptors

Answer 34

Steroids: Hydrocortisone Betamethasone Beclomethasone

Question 35

Steroids: anti-inflammatory

Answer 35

Block production of phospholipase | -beginning of chain

Question 36

Glucocorticoids: inflammatory and immune mediators

Answer 36

Reduces generation of eicosanoids and PAF -lipocortin inhibits phospholipase A2 Reduces production and action of cytokines -IL-2, IL-6, TNFα

Question 37

Glucocorticoids: cellular population

Answer 37

Reduces clonal expansion of T and B cells | Decreases action of cytokine-secreting T cells

Question 38

NSAIDs

Answer 38

``` Inhibit ezymatic activity Aspirin Diclofenac Ibuprofen Paracetamol ```

Question 39

NSAIDs

Answer 39

``` Inhibit enzymatic activity - COX1 and COX-2 Aspirin Diclofenac Ibuprofen Paracetamol ```

Question 40

Benzodiazepines/ Barbiturates

Answer 40

``` Block chloride ion channels -bind to GABA site -increase duration of Cl- channel opening -increase transmission of opening Benzodiazepines change *** Diazepam Temazepam ```

Question 41

Proton pump inhibitors

Answer 41

Act by irreversibly blocking H+/ K+ ATPase (gastric proton pump) Used for prolonged and long lasting inhibition of gastric acid -Omeprazole -Lansoprazole

Question 42

Early therapeutic monoclonal antibodies

Answer 42

Successful antibiotic therapy depends on the host defense mechanisms, location of infection, pharmacokinetics and dynamic properties of the anctibacterial - Basiliximab - Daclizumab

Question 43

Anti-infective agents adverse effects

Answer 43

Diarrhoea Fever Allergy

Question 44

Anti-infective agents

Answer 44

``` acylovir amoxicillin azithromycin cefalaxin cefradine clarithyromycin co-moxilav doxycline erthyromycin fluconazone metronidazole miconazole nystatin oxytetracycline penciclovir Phenoxymethylpenicillin tetracyclin ```

Question 45

B-lactam antibiotics

Answer 45

Disrupt the synthesis of the peptidoglycan layer of bacterial cell walls

Question 46

B-lactam antibiotics - cephalosporine

Answer 46

- Cefalaxin | - Cefradine

Question 47

B-lactam antibiotixs - Penicillins

Answer 47

Amoxicillin Co-moxiclav Phenoxynethylpenicillin

Question 48

Anti-fungal agents

Answer 48

Fluconazole,Miconazole (inhibit CYP3A lanosine 14A) Metronidazole (inhibit DNA synthesis) Nystatin (cell membrane pores increases K+ efflux)

Question 49

Anti-viral drugs

Answer 49

Inhibit DNA polymerase - Acyclovit - Penciclovir

Question 50

Pharmacokinetics - drug administration

Answer 50

``` Oral IV IM SC Topical Inhalation Transdermal Intrathecal Sublingual Rectal ```

Question 51

ADME properties

Answer 51

``` Absorption Distribution -plasma protein Metabolism -cytochrome P450 Excretion ```

Question 52

Drug absorption

Answer 52

Membrane penetration Gut --(gi. mucosa)-> blood --(capillary endothelium + blood-brain barrier)--> ECF -- (cell membrane)-> ICF For a drug to rich its site of action it has to penetrate various biological membranes. Passive diffusion

Question 53

Gastric emptying and surface area

Answer 53

Gastric Emptying critical for drug absorption Surface Area Intestine > stomach Most drugs are absorbed from intestine

Question 54

Gastric emptying and surface area

Answer 54

Gastric Emptying critical for drug absorption Surface Area Intestine > stomach Most drugs are absorbed from intestine

Question 55

Bioavailability

Answer 55

Fraction of unchanged drug reaching the system circulation following any route of administration

Question 56

Bioavailability depends on

Answer 56

Absorption First pass metabolism Food: can decrease the oral availability of sparingly lipid soluble drugs (i.e. atenolol oral availability decreased by 50% by food)

Question 57

Bioavailability is different between drugs

Answer 57

``` Lidocaine 15% Propanolol 20% Morphine 30% Paracetamol 57% Theophilline 81% Diazepam 97% ```

Question 58

Distribution

Answer 58

Physiochemical properties of drug | Physiological factors

Question 59

Transport ion channel

Answer 59

Transport neural information | Drugs can block by binding and closing ion channels e.g. LA blocks sodium ion channels

Question 60

Distribution: Physiochemical properties of drug

Answer 60

Molecular size Oil/water partition coefficient Degree of ionization that depends on pKa Protein binding

Question 61

Distribution: physiological factors

Answer 61

``` Organ or tissue size Blood flow rate Physiological barriers -blood capillary membrane -cell membrane -specialized barriers ```

Question 62

Plasma protein

Answer 62

Drug binding in blood Acid drugs mainly bind to albumin Basic drugs mainly bind to α1-acid glycoprotein Displacement of one acid drug by another acid drug results in transient increase of “free” drug conc > in free drug conc results in > in clearance of free drug from circulation Drug/drug protein interaction rarely clinically significant

Question 63

Rate of drug distribution

Answer 63

Perfusion-limited tissue distribution | Permeability rate limitations or membrane barriers

Question 64

Rate of drug distribution: Perfusion-limited tissue distribution

Answer 64

Immediate equilibrium of drug in blood and in tissue Only limited by blood flow Highly perfused: liver, kidneys, lung, brain Poorly perfused: skin, fat, bone, muscle

Question 65

Rate of drug distribution: Permeability rate limitations or membrane barriers

Answer 65

Blood-brain barrier (BBB) -acidic brain cell “traps” ionised weak base (i.e. Morphine) -in brain tight junctions, no pore passages - this creates barrier -gilial brain cells support barrier -lipid soluble substances can cross barrier -carrier-mediated transport Blood-testis barrier (BTB) Placenta

Question 66

Placenta barrier

Answer 66

Sugars, fats and oxygen diffuse from mother’s blood to fetus Urea and CO2 diffuse from fetus to mother Maternal antibodies actively transported across placenta Some resistance to disease (passive immunity) Most bacteria are blocked Many viruses can pass including rubella, chickenpox, mono, sometimes HIV Many drugs are toxins and can pass including alcohol, heroin, mercury Drugs that are lipid soluble and mostly un-ionised can easily pass the barrier to the fetus compared to the more polar and ionised ones.

Question 67

Drug elimination

Answer 67

Oxidation (cytochrome P450s) --> metabolite --> renal elimination Conjugation (glucorination etc.) --> stable adducts --> non-polar species --> biliary elimination Metabolite --conjugation--> stable adducts

Question 68

Drug metabolism

Answer 68

``` De-Activation -decrease of pharmacological effect Decrease of toxicity Activation -increase pharmacological effect -increase toxicity (i.e. chemical carcinogenesis) Phase I and Phase II ```

Question 69

Phase I reactions

Answer 69

Introduction, or exposure, of a polar group by oxydation, reduction or hydrolysis (catalysed by CYP450) At this point if the metabolites are sufficiently polar can be excreted A C-H group can be turned into a C-OH converting non pharmacological active compound into active. DANGER:Toxic compound can be created as well

Question 70

Phase II reactions

Answer 70

Attachment of an endogenous molecule to a drug or Phase I metabolite, glucoronide, sulphate, acetyl The outcome products are heavier in m.w. so tend to be less effective Major difference between Phase I and Phase II reaction is that Phase I predominantly produces more active compounds while Phase II produces less active

Question 71

Enzymes of drug metabolism

Answer 71

Phase I - oxydation - cytochrome P450 -major drug metabolising enzyme system found in liver -super family of several forms i.e. multiple forms of cytochrome -possess varying substrate specificity -catalytic activities show large inter-individual differences Phase II - conjugation -transferases: glycoronyl-, sulpho-, acetyl-, methyl-

Question 72

Cytochrome 3A4

Answer 72

Quetiapine uses cytochrome 3A4 to be metabolised, and then is excreted Inhibitors -reduce clearance (> blood levels) -dose reduction of quetiapine may be needed -erythromycin, ketonazole, nefazodone) Inducers -increase clearance, decreased blood levels -dose increase of quetiapine may be needed -carbamazepine, phenytoin

Question 73

Genetic polymorphism

Answer 73

Occurrence of variant form of an enzyme/receptor through inheritance of drug metabolising enzymes Most clinically studied CYP2C9, CYP2C19, CYP2D6

Question 74

CYP2D6 polymorphism

Answer 74

8% of Caucasian lack CYP2D6 | Are POOR METABOLISER for cardiovascular, psychiatric and opiate drugs

Question 75

Biliary excretion

Answer 75

Bile is secreted by hepatic cells of the liver It is important in digestion and absorption of fats 90% of bile acid is reabsorbed from intestine and transported back to the liver for resecretion Metabolites are more excreted in bile than parent drugs due to increased polarity Some drugs and metabolites excreted by the liver cells into bile, pass into the intestine. Reabsorption from the gut during the process of enterohepatic recycling may prolong the pharmacological effect of a drug

Question 76

Factors influencing secretion in bile

Answer 76

Molecular weight (i.e. > 300) Polarity (higher polarity more bile excretion) Nature of biotransformation Gender, diseases, drug interactions

Question 77

Drug elimination

Answer 77

``` The kidney and the liver are two major organs for drug elimination from the body Renal -water soluble -ionised -e.g. gentamycin, digoxin Hepatic -lipid soluble -unionised -e.g. propanolol, cyclosporin ```

Question 78

Nephron - glomerular filtration

Answer 78

``` Glomerulus 120ml/min Only unbound protein filtered Negligible for high protein Bound drugs Glomerular filtration and active secretion add drug to the tubulat fluid, while passive reabsorption transfers it back into the blood ```

Question 79

Nephron: Passive reabsorption

Answer 79

DISTAL TUBULE Lipid solubility Water soluble drugs: Urine Lipid soluble drug: Blood Only un-ionised drug Changes in urine pH important for weak acids/bases Glomerular filtration and active secretion add drug to the tubulat fluid, while passive reabsorption transfers it back into the blood

Question 80

Active secretion - nephron

Answer 80

Free and bound drug secreted Highly cleared drugs: Renal blood flow Two pump: Acids (uric) e.g. Penicillin, Thiazide diuretics Base e.g. Pancuronium PROXIMAL TUBULE Glomerular filtration and active secretion add drug to the tubulat fluid, while passive reabsorption transfers it back into the blood

Question 81

Renal clearance

Answer 81

Excretion = Filtration + Secretion -Reabsorption GFR = 120ml/min CLR = Rate of excretion / Plasma concentration >GFR – net secretion < GFR – net reabsorption = GFR – secretion = reabsorption or filtration only The net contribution of filtration, secretion and reabsorption will determine the renal clearance of a drug, an index of the efficiency of the renal excretion processes. Renal diseases may interfere with drug elimination

Question 82

Therapeutic index

Answer 82

Margin between the therapeutic dose and the toxic dose. Higher the therapeutic index is safer the drug is.

Question 83

Factors affecting metabolism

Answer 83

``` High or low blood level Environmental Disease Genetic Age Drug interaction ```

Question 84

Factors affecting metabolism - high blood level

Answer 84

``` Excessive dosing and/or decreased clearance risk of TOXICITY Decreased clearance: -normal variation -saturable metabolism -genetic enzyme deficiency -renal failure -liver failure -age (neonate or elderly) -enzyme inhibition ```

Question 85

Factors affecting metabolism - low blood level

Answer 85

Dose to low or clearance to high risk of NO EFFECT Increased clearance: -normal variation -poor absorption -high first pass metabolism -non compliance -enzyme induction