Introduction to drug kinetics and drug toxicity Flashcards
What is pharmacology?
Study of the effects of drugs on living systems (in relation to therapeutics and toxicology)
What is pharmacodynamics?
deals with the study of the biochemical and physiological effects of drugs and their mechanism of action. Effect of the drug on the body.
What is pharmacokinetics?
absorption, distribution, biotransformation and excretion of drugs. Effect of the body on the drug
What is toxicology?
Adverse effects of drugs and chemicals
What is pharmacotherapeutics?
use of drugs in the prevention and treatment of disease
Drugs modify physiological processes
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
4 main parts of pharmacology
Pharmacodynamics
Pharmacokinetics
Toxicology
Pharmacotherapeutics
Drugs are used to
Prevent, diagnose and/or treat disease
Modify actions of other drugs
Analyse mechanisms or functions of an organism
What is a drug?
A chemical substance of known structure which, when given to a living organism, produces a biological effect
Virtually all drugs produce more than one effect
Specificity
Selectivity
Toxicity
Specificity
Drug produces only one effect.
Selectivity
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”.
Toxicity
Normally occurs beyond the therapeutic dose range. Some drugs may show toxicity at the higher end of the therapeutic doses (i.e.; adverse effects).
General mechanisms of drug activity
In deficiency
In the case of excess action
For the physiochemical environment
Deficiency
Replacement therapy for conditions such as iron, vitamin or hormone deficiency
Excess action
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).
Physiochemical environment
Drugs can alter the environment or characteristics of a cell or tissue, changing its activity - “nonspecific effects”
Dose or concentration
Drug quantity in weight (mg) or volume (ml).
Response or effect
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
Acceptor
Substances drugs bind to without causing any effect (e.g.; plasma proteins)
Receptor
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
Ligand
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
Drug receptors: molecular targets for drugs
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
Receptor Location
- Cell membrane (transmitters/ peptides)
- Cytoplasm (steroids)
- Nucleus (thyrosin/ insulin sensitivity)
Biological targets of drugs **
Receptors -agonist -antagonist Ion channels -blockers -modulators Enzymes -inhibitor -false substrate -pro-drug Transporters -normal transport -inhibitor -false substrate
Classes of cell-surface receptors (DIAGRAM AND ENCORE)
Ion-channel-linked receptor
G-protein-linked receptor
-a lot of types
Enzyme-linked receptor
Receptor subtypes - example of adrenoreceptors
Alpha and beta adrenoreceptors
Beta-adrenoceptors
Tolerance
-Β agonist down regulate β-adrenoceptor
Withdrawal
-β antagonist upregulate β-adrenoceptor
Drug/ receptor interaction (GRAPH)
EC50
Potency
Efficacy
Affinity
EC50
[drug] that produces 50% of the maximal effect
Potency
how much drug is required to produce a particular effect. Depend on both affinity and efficacy
Most important
Efficacy and affinity
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
Receptor activation
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
Intracellular receptors
Steroids:
Hydrocortisone
Betamethasone
Beclomethasone
Steroids: anti-inflammatory
Block production of phospholipase
-beginning of chain
Glucocorticoids: inflammatory and immune mediators
Reduces generation of eicosanoids and PAF
-lipocortin inhibits phospholipase A2
Reduces production and action of cytokines
-IL-2, IL-6, TNFα
Glucocorticoids: cellular population
Reduces clonal expansion of T and B cells
Decreases action of cytokine-secreting T cells
NSAIDs
Inhibit ezymatic activity Aspirin Diclofenac Ibuprofen Paracetamol
NSAIDs
Inhibit enzymatic activity - COX1 and COX-2 Aspirin Diclofenac Ibuprofen Paracetamol
Benzodiazepines/ Barbiturates
Block chloride ion channels -bind to GABA site -increase duration of Cl- channel opening -increase transmission of opening Benzodiazepines change *** Diazepam Temazepam
Proton pump inhibitors
Act by irreversibly blocking H+/ K+ ATPase (gastric proton pump)
Used for prolonged and long lasting inhibition of gastric acid
-Omeprazole
-Lansoprazole
Early therapeutic monoclonal antibodies
Successful antibiotic therapy depends on the host defense mechanisms, location of infection, pharmacokinetics and dynamic properties of the anctibacterial
- Basiliximab
- Daclizumab
Anti-infective agents adverse effects
Diarrhoea
Fever
Allergy
Anti-infective agents
acylovir amoxicillin azithromycin cefalaxin cefradine clarithyromycin co-moxilav doxycline erthyromycin fluconazone metronidazole miconazole nystatin oxytetracycline penciclovir Phenoxymethylpenicillin tetracyclin
B-lactam antibiotics
Disrupt the synthesis of the peptidoglycan layer of bacterial cell walls
B-lactam antibiotics - cephalosporine
- Cefalaxin
- Cefradine
B-lactam antibiotixs - Penicillins
Amoxicillin
Co-moxiclav
Phenoxynethylpenicillin
Anti-fungal agents
Fluconazole,Miconazole (inhibit CYP3A lanosine 14A)
Metronidazole (inhibit DNA synthesis)
Nystatin (cell membrane pores increases K+ efflux)
Anti-viral drugs
Inhibit DNA polymerase
- Acyclovit
- Penciclovir
Pharmacokinetics - drug administration
Oral IV IM SC Topical Inhalation Transdermal Intrathecal Sublingual Rectal
ADME properties
Absorption Distribution -plasma protein Metabolism -cytochrome P450 Excretion
Drug absorption
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
Gastric emptying and surface area
Gastric Emptying critical for drug absorption
Surface Area Intestine > stomach
Most drugs are absorbed from intestine
Gastric emptying and surface area
Gastric Emptying critical for drug absorption
Surface Area Intestine > stomach
Most drugs are absorbed from intestine
Bioavailability
Fraction of unchanged drug reaching the system circulation following any route of administration
Bioavailability depends on
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)
Bioavailability is different between drugs
Lidocaine 15% Propanolol 20% Morphine 30% Paracetamol 57% Theophilline 81% Diazepam 97%
Distribution
Physiochemical properties of drug
Physiological factors
Transport ion channel
Transport neural information
Drugs can block by binding and closing ion channels e.g. LA blocks sodium ion channels
Distribution: Physiochemical properties of drug
Molecular size
Oil/water partition coefficient
Degree of ionization that depends on pKa
Protein binding
Distribution: physiological factors
Organ or tissue size Blood flow rate Physiological barriers -blood capillary membrane -cell membrane -specialized barriers
Plasma protein
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
Rate of drug distribution
Perfusion-limited tissue distribution
Permeability rate limitations or membrane barriers
Rate of drug distribution: Perfusion-limited tissue distribution
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
Rate of drug distribution: Permeability rate limitations or membrane barriers
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
Placenta barrier
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.
Drug elimination
Oxidation (cytochrome P450s) –> metabolite –> renal elimination
Conjugation (glucorination etc.) –> stable adducts –> non-polar species –> biliary elimination
Metabolite –conjugation–> stable adducts
Drug metabolism
De-Activation -decrease of pharmacological effect Decrease of toxicity Activation -increase pharmacological effect -increase toxicity (i.e. chemical carcinogenesis) Phase I and Phase II
Phase I reactions
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
Phase II reactions
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
Enzymes of drug metabolism
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-
Cytochrome 3A4
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
Genetic polymorphism
Occurrence of variant form of an enzyme/receptor through inheritance of drug metabolising enzymes
Most clinically studied CYP2C9, CYP2C19, CYP2D6
CYP2D6 polymorphism
8% of Caucasian lack CYP2D6
Are POOR METABOLISER for cardiovascular, psychiatric and opiate drugs
Biliary excretion
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
Factors influencing secretion in bile
Molecular weight (i.e. > 300)
Polarity (higher polarity more bile excretion)
Nature of biotransformation
Gender, diseases, drug interactions
Drug elimination
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
Nephron - glomerular filtration
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
Nephron: Passive reabsorption
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
Active secretion - nephron
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
Renal clearance
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
Therapeutic index
Margin between the therapeutic dose and the toxic dose. Higher the therapeutic index is safer the drug is.
Factors affecting metabolism
High or low blood level Environmental Disease Genetic Age Drug interaction
Factors affecting metabolism - high blood level
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
Factors affecting metabolism - low blood level
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
