Pharmacology 1+2 - Drug Kinetics and Toxicity Flashcards
Pharmacology
Effects of drugs on living systems
Pharmacodynamics
Study of biochemical and psychological effects of drugs and their mechanism of action on body
Pharmacokinetics
Absorption, distribution, biotransformation and excretion of drugs - effect of the body on the drug
Toxicology
Adverse effects of drugs and chemicals
Pharmacotherapeutics
Use of drugs in the prevention and treatment of disease
Fx of drugs
Effects
Modify physiological processes not create new ones
- prevent, diagnose/treat disease
- modify actions of other drugs
- analyse mechanisms or functions of an organism
Expressed in terms of altering a known fx or process
- returns a fx to normal operation
- changes fx away from normal condition
Drug definition
Chemical substance of a known structure, which when given, produces a biological effect in a living organism
3 aspects of drugs
Describe terms
Goal of therapeutics is
- Specificity - only produces one effect
- Selectivity - one effect predominates over a particular dose conc –> THERAPEUTIC WINDOW
- Toxicity - usually occurs beyond therapeutic dose conc. Some show toxicity at higher end of therapeutic dose –> adverse effects
To achieve specificity
General mechanisms
Deficiency
Excess action
Antagonists also
Physiochemical environment
- Replacement therapy for conditions such as iron or hormone deficiency
- Chemical antagonists can block or reduce the effects of XS activity of normal processes
- block excess effects of exogenous substances e.g reversal of overdose
- Drugs can alter the environment or characteristics of a cell or tissue, changing its activity
Dose/concentration
Drug quantity in weight / volume
Response/effect
Different effects
Change occurring after administration
- Therapeutic - intended effect
- Side - effect other than therapeutic
- Toxic/adverse - harmful unexpected effects usually occurring at higher dose
- Lethal - death caused by very high drug dose
Acceptor
Substances drugs bind to without effect e.g plasma proteins
Receptor
Cell component directly involved in reaction
Receptors
Mechanisms on binding
Component of cell/organism which interacts with a drug and initiates chain reaction of events –> effect
Ligand binds to receptor
- agonist - initiates response e.g NTS and hormones
- antagonist - prevents agonist binding therefore no response
Drug receptors as molecular targets
Types of receptors
Mechanism and name of it
Molecules on or in the cell that the drug molecule first interacts with and activates/blocks?
Membrane receptors, enzymes, ion channels, DNA, cytosolic proteins
Receptors convert drug molecule signal to a biochemical signal via effectors = TRANSDUCTION
Receptor location
3 possible locations and examples
Cell membrane - transmitters/peptides
Nucleus - thyroxin and insulin sensitivity
Cytoplasm - steroids
Classes of cell surface receptors
- Ion channel linked
- G protein linked
- Enzyme protein linked
Receptor subtypes
Action
Adrenoreceptors
β1, 2 and 3
Found in heart, lungs and bladder
Beta-agonists = bronchodilation due to muscle relaxation
β agonist will down regulate β -adrenoreceptor during tolerance
β antagonist will up regulate β adrenoreceptor during withdrawal
Drug/receptor interaction terms
EC50
POTENCY
EFFICACY
AFFINITY
EC50 - drug concentration which produces 50% of the maximal effect
Potency - conc required to produce a particular effect - depends on E AND A
Efficacy - relationship between receptor occupancy and ability to initiate a response at molecular, tissue or cellular level
Affinity - ability to bind a receptor
drugs can have same affinity but different efficacy
Receptor activation
full agonist or partial
antagonist
based on maximal pharmacological response that occurs when all the receptors are occupied
binds but doesn’t activate and are used to prevent agonist from binding
Intracellular receptors
Binding sites for…
Steroids e.g hydrocortisone, betamethason, beclomethasone
Steroid - anti-inflammatory action
Inhibit prostaglandin production
glucocorticoids
Role in events
- vascular
- as inflammatory and immune mediators
- as cellular population control
Reduce vasodilaton and reduce fluid exudation
Reduces production and action of cytokines
Reduces clonal expansion of T and B cells
Decreases action of cytokine-secreting T cells
NSAIDs
Function and mechanism
Inhibit enzyme activity (COX1 COX2)
Inhibit prostaglandin release
Diclofenac
Aspirin
Ibuprofen
Paracetamol
Benzodiazepines/barbiturates
Mimic GABA
Stimulate GABA receptors at allosteric sites therefore constant hyperpolarisation –> CNS depression
Transport ion channel
Ion channels can be blocked by substances such as LA
Nervous impulse transmission is blocked
Proton pump inhibitors
Irreversibly block the H+/K+ATPase gastric pump
Fr prolonged inhibition of gastric acid
Omeprazole
Lansoprazole
Early therapeutic monoclonal antibodies
Depends on
host defence mechanisms
location of infection
pharmacokinetics and dynamic properties of the antibacterial agent
Anti-infective agents
Mechanism
Protein synthesis inhibitor in bacteria
B-lactam antibiotics
Function
Disrupt synthesis of peptidoglycan layer of bacterial cell walls
Destroy bacterium
Anti fungal
Anti viral
e.g metronidazole inhibits DNA synthesis
Inhibit DNA polymerase
Drug absorption mainly via MEMBRANE PENETRATION
G.I mucosa
Capillary endothelium
Blood-brain barrier
Cell membrane
Passes through via passive diffusion
IV drugs will actt quicker
Gastric emptying
Essential for drug absorption
Most drugs absorbed from intestine due to greater SA
Bioavailability
Definition
Depends on
Fraction of unchanged drug reaching the system circulation following any route of admin
Absorption
First pass metabolism
Food
Differs between drugs
Distribution
Physiochemical properties
Physiological factors
molecular size
oil/water miscibility
protein binding
degree of ionisation
organ/tissue size blood flow rate physiological barriers - blood cap membrane - cell membrane - specialised barriers
Plasma proteins… are involved in …
Drug binding in blood
Acid drugs –> albumin
Basic drugs –> α1-acid glycoprotein
Displacement of one acid drug by another ==> free drug concentration increase
Free drugs will be eliminated faster
Guidelines for rate of drug distribution
perfusion limited tissue distribution
permeability rate limitations or membrane barriers
- immediate equilibrium of drug in blood and in tissue
- only limited by blood
flow i.e PERFUSION - poor perfusion - skin, fat, bone, muscle
- high perfusion - lungs, liver, kidneys, brain
blood-brain barrier - extra layer
blood-testis barrier
placenta
Placenta barrier
Mother’s blood –> foetus
- sugars, fats and oxygen
- passive immunity antibodies
Foetus –> mother
- Urea and CO2
Viruses can pass
Toxins e.g drugs and alcohol can pass
Lipid soluble toxic substances can pass to foetus
Drug metabolism
De-activation
Activation
Excretion
Decrease of pharmacological effect
Decrease of toxicity
Increase pharmacological effect
Increase toxicity
Drug undergoes phase I –> primary metabolite –> excretion
Phase II –> conjugate –> excretion
Phase I reactions
Drug –> primary metabolite
Exposure of a polar group
Metabolites may be excreted if sufficiently polar
Phase II reactions
Primary metabolite –> conjugation
Drug –> conjugation
Attachment of an endogenous molecule to a drug
Produces less active compounds than phase I
Drug metabolism enzymes
Phase 1
Phase II
Oxydation
- cytochrome P450
- found in liver
- varying substrate specificity
Conjugation
- transferases
Polymorphism
Occurrence of variant form of an enzyme/receptor through inheritance of drug metabolising enzymes
e. g lack CYP2D6
- poor metaboliser for CV, psychiatric and opiate drugs
Biliary excretion
- secreted by
- important in
- fate
- composition of bile
factors influencing secretion of drugs in bile
where else can products end up
Hepatic cells of liver
Digestion and absorption of fats
90% reabsorbed from intestine and transported back into liver
Metabolites more excreted than parent drugs –> increased polarity
- m.w
- polarity
- nature of biochange
- gender, diseases, drug interactions
Some pass into intestine
Reabsorption from gut during process of enterohepatic recycling may prolong pharmacological effect of a drug
Drug elimination
Two types
Renal
- water soluble
- ionised
Hepatic
- lipid soluble
- unionised e.g propanolol, cyclosporin
Drugs high in water/ionised excreted renally
Drugs lipid soluble or unionised will be hepatic ally processed
role of nephron
- glomerular filtration - not much for protein bound drugs
- active secretion - adds to tubular fluid - free and bound drug
- passive reabsorption - only unionised drugs transfers back to blood
renal clearance
formula
what may affect it
excretion = (filtration + secretion) - reabsorption
if > GFR = net secretion
efficiency of renal excretion
renal diseases
Therapeutic index
Greater = greater safety of drug
Minimum toxic concentration is margin between therapeutic effects and toxic effects
Factors affecting metabolism when
HIGH blood level - XS dose - decreased clearance
Normal variation Saturable metabolism genetic enzyme deficiency Renal/liver failure Age Enzyme inhibition
Factors affecting metabolism when
LOW blood level - too low a dose - no effect - increased clearance
Normal variation Poor absorption High first pass metabolism Non-compliance Enzyme induction
Factors affecting drug metabolism
Environmental
Disease
Genetic
Age
Drug interaction
Saturable metabolism
Increase in the dose would result in a decrease in hepatic clearance and a more proportionate increase in the drug levels
