Pharmacology Flashcards
Pharmacokinetics
What the body does to the drug
I.e. metabolism, absorption
Pharmacodynamics
What the drug does to the body
I.e. Binding, drug-receptor interaction
Drug
A chemical substance of known structure
When administered to a living organism produces a biological effect
Medicine
Usually, but not necessarily, contains one or more drugs which is administered with the intention of producing a therapeutic effect
Therapeutics
Use of drugs to diagnose, prevent or treat illness or pregnancy
I.e. medical use of drugs
Formulations
How the drug is ‘packed’
E.g. different chemical substances (excipients)
Combined to produce a medicine
Akko’s the drugs to survive in the gut
Make it suitable
Excipients
Substances ‘formulated’ along side the drug
Nomenclature of drugs and medicines
Drugs have at least three different names
Chemical name
Generic name
Proprietary name
Nomenclature of drugs and medicines: chemical name
Describes the chemical structure
Specifically describes exactly what the drug is
Nomenclature of drugs and medicines: generic name
Class of drugs to which molecule belongs
Nomenclature of drugs and medicines: proprietary name
Manufacturer’s name for the drug
The “trade name”
Ligand
A molecule that binds to a receptor
E.g. ACh
Receptor
The molecular ‘target’ for a drug
Complex protein
E.g. ACh receptor
Agonist
A molecule that ‘activates’ a receptor
Depolarisation
Antagonist
Blocks or reduces agonist mediated responses
Affinity
How well the ligand (e.g. agonist) binds to receptor
I.e. the strength of agonist-receptor interaction
High affinity may activate the receptor in a more significant way
Ligands: exogenous
From and made outside the body
E.g. morphine
Ligands: endogenous
From and made within the body
E.g. acetylcholine
Ligands might be a
Drug - e.g. morphine
Neurotransmitter - e.g. 5HT, ACh
Hormone - e.g. corticosteroid
Ligands: receptor
Acts on different receptors
Different effects from the same ligand
E.g. ACh acts on beta receptors in the heart and nicotinic AChRs in skeletal muscle
What do we want from a drug/medicine
Desirable pharmacological action
Acceptable side effects (or none)
Reach it target in the right concentration at the right time
Remain at the site of action for sufficient time
Rapidly and completely removed from the body when not longer needed
How do drugs produce effect
Interact in a ‘structurally specific’ way its target
Steric interaction - based on spatial 3D relationship
Lock and key mechanism
Local electrostatic charges
Properties that affect drug-receptors binding
Physico-chemical properties
Steric properties
Properties that affect drug-receptors binding: physico-chemical properties
Charges are compatible allowing the ligand to bind to the receptor
Large complex molecule have positive and negative charges
E.g. electrostatic charges
Properties that affect drug-receptors binding: steric properties
Physical shape of the ligand and the receptor
Molecular structure of a drug and the binding site
Pharmacogenomics
Drug targets are proteins
Proteins encoded in genome
Genetic variation in drug receptor
Genetic variation in proteins involved in cellular processes
Genetic variation in enzymes that process/inactivated drugs
Lead to differences in the way people respond to any given drug
Oxytocin
Endogenous ligand mainly released in childbirth
Syntocinon - synthetic version, delivered to speed up aspects of childbirth
Multiple receptors - mammary gland myoepithelial cells (milk release), uterus myometrium (contraction), mesolimbic pathway (emotional attachment and bonding to baby)
Targets for drug action
Binding to a protein
Proteins sub-serve important roles - physiological regulation
Receptors
Ion channels
Carrier molecules
Enzymes
Receptors: agonist ligand
Endogenous - ACh activates
Exogenous - nicotine activates
Change the shape of the receptor so positive ions can enter the cell
Causing excitation and depolarisation.
Receptors: antagonist ligands
E.g. curare inactivates receptors, it blocks ACh receptors so ACh can’t bind
Mecamylamine; allosteric - doesn’t block the binding site but changes it so ACh can’t bind
Receptors: G-protein
Linked trans-membrane receptors
Ligand binds e.g. opiate drug
Alters receptor conformation
Activation of intracellular second messenger cascade
Diverse intracellular effect - cellular excitability
Modulation of other ion channels - e.g. Ca2+, cell excitability
Down-regulation of G-protein linked receptors
Ion channels
Selective pore in the membrane
Allows movement of ion across membrane
Complex membrane proteins
Molecular selectivity filter
Blockers
Modulators
Ion channels: blockers
Ligand is blocking the channels so no charged ions through the channel
Ion channels: modulators
Changes how the channel behaves
Different regulations
E.g. increases or decreases amount of ions through the channel
Carrier proteins
Facilitators for transport - e.g. ligands or cellular products across the membrane
Active transport
Facilitated diffusion
E.g. digitalis blocks sodium potassium ATPase
Enzymes: enzyme inhibitor
Blocking the binding site on the enzyme
The ligand can’t bind
Reaction to be inhibited
Substrate analogues
E.g. aspirin blocks cyclooxygenase which is involved in production of thromboxane and prostaglandins
Enzymes: false substrate
Take the place of the endogenous ligan
Enzyme produces an abnormal metabolite or inappropriate product
Enzymes: pro-drug
Ligand is processed by the enzyme and converted into an active drug
E.g. codeine converted to morphine in the liver
Drug specificity
Non-specific interactions
Drug may bind to the something other than the target
More likely with larger doses
Pharmacokinetics: ADME
Absorption
Distribution
Metabolism
Excretion
Absorption
Process by which the drug reaches the systemic (blood) circulation
Drug must be in a solution that can be absorbed
Soluble
Affected by - route of administration, permeation
Routes of administration: enteral administration
Via the gut
Oral ingestion and gut absorption
E.g. oral, buccal, rectal
Positives - low infection risk, very simple (self administration)
Negatives - harsh environment (drug meets to be protected), first pass metabolism
First pass metabolism
Through the gut then the liver then circulatory system
Can be lost through excretion and metabolism
Reduces bioavailability
Routes of administration: parenteral administration -
Not via the gut
E.g. injection or topical
Routes of administration: parenteral administration - topical
Positives - local effects, low systemic effects, limited first pass metabolism, suited to slow continuous long periods of administration, systemic absorption, low infection risk
Negatives - process of lipid permeation (lipid soluble), small molecular size, carrier molecules, irritant to increase absorption
Routes of administration: parenteral administration - injections
Intravascular (IV, IA) - drug enters directly into the blood stream
Intramuscular (IM) - drug injected into skeletal muscle
Subcutaneous (SC) - drug absorbed from subcutaneous tissue
Dermal (ID) - dermal vascular layer
Depot injection - slow release formulations
Positives - rapid bioavailability for IV, avoids first pass metabolism
Negatives - infection risk, targeting risk
Bioavailability
Proportion of active drug that reaches the systemic circulation and is free to bind to its target
Affected by - route of administration, formulation
Not a measure of how effective a drug is
Factors affecting distribution
Protein binding
Blood flow
Membrane permeation/tissue solubility
Protein binding
Partly bound to plasma protein and in plasma water
Reversible
Bound to not the target so become inactive
Protein binding can reduce availability of drug
Only unbound drug can bind to target
Blood flow
Primarily through circulatory system
Tissue perfusion rate per tissue
The VRG (e.g. lungs and gut) absorb the drug readily as it has good blood supply
Membrane permeability
Lipophilicity
Charged molecules diffuse less efficiently
Uncharged molecular have better access to membrane bound compartments
Balance - need to cross membrane but also soluble to be absorbed
Fick’s law - thickness, surface area and characteristics of layer
Metabolism
Inactivated drugs
Liver, kidney, intestine, lungs, plasma, skin and placenta
Metabolic rate determine duration of drug action
Make drug soluble
Excretory form - inactive and hydrophilic
Phase I of metabolism
Produces toxic metabolites
Processing the drug
Doesn’t inactivate the drug
Oxidation, reduction, hydrolysis reactions
Change polarisation, increase water solubility, reduce pharmacological activity
May activate prodrugs
Phase II of metabolism
Converts toxins to soluble metabolites for excretion
Inactive drug for excretion
Conjugation - adding endogenous substance
Water soluble and biologically inactive
Converting the drug by covalently joining to other molecules - methylation; CH3, acetylation; COCH3, glutathione conjugation
Excretion
Kidney/renal main route
Filtration
Unbound metabolites can be processed via glomerular filtration
Proximal convoluted tubule cells actively secrete into nephron
Reabsorption of Lipophilicity drugs, unionised at urine pH
Other routes - biliary, saliva, breast milk, sweat and tears
Excretion: biliary excretion
Large metabolites and fatty substances are absorbed by hepatocytes and converted into bile
Excreted into the duodenum that is excreted in the faeces
Excretion: enterohepatic circulation
Reactivated the drug
Sent round the circulatory system again
Gut bacteria convert drug to original form
Resorbed across intestinal wall
Be metabolised in the liver again and re-secreted into bile
Drug elimination half-life
T1/2
Time taken to decrease plasma concentration to 50%
Estimates the time taken to void/excrete drug
Bioavailability of drug in the blood decreases with each half-life
Elimination is normally around 4 or 5 half-lives
