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Pharmacology (Den 303) > Introduction to drug kinetics and drug toxicity > Flashcards

Introduction to drug kinetics and drug toxicity Flashcards

1
Q

What is pharmacology?

A

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

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2
Q

What is pharmacodynamics?

A

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

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3
Q

What is pharmacokinetics?

A

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

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4
Q

What is toxicology?

A

Adverse effects of drugs and chemicals

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5
Q

What is pharmacotherapeutics?

A

use of drugs in the prevention and treatment of disease

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6
Q

Drugs modify physiological processes

A

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

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7
Q

4 main parts of pharmacology

A

Pharmacodynamics
Pharmacokinetics
Toxicology
Pharmacotherapeutics

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8
Q

Drugs are used to

A

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

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9
Q

What is a drug?

A

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

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10
Q

Virtually all drugs produce more than one effect

A

Specificity
Selectivity
Toxicity

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11
Q

Specificity

A

Drug produces only one effect.

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12
Q

Selectivity

A

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”.

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13
Q

Toxicity

A

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

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14
Q

General mechanisms of drug activity

A

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

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15
Q

Deficiency

A

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

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16
Q

Excess action

A

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).

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17
Q

Physiochemical environment

A

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

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18
Q

Dose or concentration

A

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

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19
Q

Response or effect

A

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

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20
Q

Acceptor

A

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

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21
Q

Receptor

A

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

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22
Q

Ligand

A

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
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23
Q

Drug receptors: molecular targets for drugs

A

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

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24
Q

Receptor Location

A
  1. Cell membrane (transmitters/ peptides)
  2. Cytoplasm (steroids)
  3. Nucleus (thyrosin/ insulin sensitivity)
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25
Q

Biological targets of drugs **

A 
Receptors
-agonist
-antagonist
Ion channels
-blockers
-modulators
Enzymes
-inhibitor
-false substrate
-pro-drug
Transporters
-normal transport
-inhibitor
-false substrate
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26
Q

Classes of cell-surface receptors (DIAGRAM AND ENCORE)

A

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

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27
Q

Receptor subtypes - example of adrenoreceptors

A

Alpha and beta adrenoreceptors

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28
Q

Beta-adrenoceptors

A

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

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29
Q

Drug/ receptor interaction (GRAPH)

A

EC50
Potency
Efficacy
Affinity

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30
Q

EC50

A

[drug] that produces 50% of the maximal effect

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31
Q

Potency

A

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

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32
Q

Efficacy and affinity

A

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

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33
Q

Receptor activation

A

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

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34
Q

Intracellular receptors

A

Steroids:
Hydrocortisone
Betamethasone
Beclomethasone

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35
Q

Steroids: anti-inflammatory

A

Block production of phospholipase

-beginning of chain

36
Q

Glucocorticoids: inflammatory and immune mediators

A

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

37
Q

Glucocorticoids: cellular population

A

Reduces clonal expansion of T and B cells

Decreases action of cytokine-secreting T cells

38
Q

NSAIDs

A 
Inhibit ezymatic activity
Aspirin
Diclofenac
Ibuprofen
Paracetamol
39
Q

NSAIDs

A 
Inhibit enzymatic activity - COX1 and COX-2
Aspirin
Diclofenac
Ibuprofen
Paracetamol
40
Q

Benzodiazepines/ Barbiturates

A 
Block chloride ion channels
-bind to GABA site
-increase duration of Cl- channel opening
-increase transmission of opening
Benzodiazepines change ***
Diazepam
Temazepam
41
Q

Proton pump inhibitors

A

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

42
Q

Early therapeutic monoclonal antibodies

A

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

  • Basiliximab
  • Daclizumab
43
Q

Anti-infective agents adverse effects

A

Diarrhoea
Fever
Allergy

44
Q

Anti-infective agents

A 
acylovir
amoxicillin
azithromycin
cefalaxin
cefradine
clarithyromycin
co-moxilav
doxycline
erthyromycin
fluconazone
metronidazole
miconazole
nystatin
oxytetracycline
penciclovir
Phenoxymethylpenicillin
tetracyclin
45
Q

B-lactam antibiotics

A

Disrupt the synthesis of the peptidoglycan layer of bacterial cell walls

46
Q

B-lactam antibiotics - cephalosporine

A
  • Cefalaxin

- Cefradine

47
Q

B-lactam antibiotixs - Penicillins

A

Amoxicillin
Co-moxiclav
Phenoxynethylpenicillin

48
Q

Anti-fungal agents

A

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

49
Q

Anti-viral drugs

A

Inhibit DNA polymerase

  • Acyclovit
  • Penciclovir
50
Q

Pharmacokinetics - drug administration

A 
Oral
IV
IM
SC
Topical
Inhalation
Transdermal
Intrathecal
Sublingual
Rectal
51
Q

ADME properties

A 
Absorption
Distribution
-plasma protein
Metabolism
-cytochrome P450
Excretion
52
Q

Drug absorption

A

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

53
Q

Gastric emptying and surface area

A

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

54
Q

Gastric emptying and surface area

A

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

55
Q

Bioavailability

A

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

56
Q

Bioavailability depends on

A

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)

57
Q

Bioavailability is different between drugs

A 
Lidocaine 15%
Propanolol 20%
Morphine 30%
Paracetamol 57%
Theophilline 81%
Diazepam 97%
58
Q

Distribution

A

Physiochemical properties of drug

Physiological factors

59
Q

Transport ion channel

A

Transport neural information

Drugs can block by binding and closing ion channels e.g. LA blocks sodium ion channels

60
Q

Distribution: Physiochemical properties of drug

A

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

61
Q

Distribution: physiological factors

A 
Organ or tissue size
Blood flow rate
Physiological barriers
-blood capillary membrane
-cell membrane
-specialized barriers
62
Q

Plasma protein

A

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

63
Q

Rate of drug distribution

A

Perfusion-limited tissue distribution

Permeability rate limitations or membrane barriers

64
Q

Rate of drug distribution: Perfusion-limited tissue distribution

A

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

65
Q

Rate of drug distribution: Permeability rate limitations or membrane barriers

A

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

66
Q

Placenta barrier

A

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.

67
Q

Drug elimination

A

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

68
Q

Drug metabolism

A 
De-Activation
-decrease of pharmacological effect
Decrease of toxicity
Activation
-increase pharmacological effect
-increase toxicity (i.e. chemical carcinogenesis)
Phase I and Phase II
69
Q

Phase I reactions

A

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

70
Q

Phase II reactions

A

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

71
Q

Enzymes of drug metabolism

A

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-

72
Q

Cytochrome 3A4

A

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

73
Q

Genetic polymorphism

A

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

74
Q

CYP2D6 polymorphism

A

8% of Caucasian lack CYP2D6

Are POOR METABOLISER for cardiovascular, psychiatric and opiate drugs

75
Q

Biliary excretion

A

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

76
Q

Factors influencing secretion in bile

A

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

77
Q

Drug elimination

A 
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
78
Q

Nephron - glomerular filtration

A 
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
79
Q

Nephron: Passive reabsorption

A

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

80
Q

Active secretion - nephron

A

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

81
Q

Renal clearance

A

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

82
Q

Therapeutic index

A

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

83
Q

Factors affecting metabolism

A 
High or low blood level
Environmental
Disease
Genetic
Age 
Drug interaction
84
Q

Factors affecting metabolism - high blood level

A 
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
85
Q

Factors affecting metabolism - low blood level

A

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

Pharmacology (Den 303) (3 decks)

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