Pharmacology Flashcards
What is Pharmacokinetics?
The action of drugs in the body including ABSORPTION DISTRIBUTION METABOLISM EXCRETION
What is absorption?
The process of transfer from the site of administration into the general or systemic circulation
What are the different routes of administration for drugs?
Oral Intra venous Intra arterial – much rarer Intramuscular Subcutaneous Inhalational Topical Sublingual – e.g. GTN spray Rectal Intrathecal
How many membranes must a drug cross to get to its target?
Most drugs with the exception or IV or IA injections must cross at least one membrane in its passage from the site of administration to the general circulation
Drugs acting at intracellular sites must also cross the cell membrane
What are the different ways a drug can pass through a membrane?
Passive diffusion through the lipid layer
Diffusion through pores or ion channels
Carrier mediated processes
Pinocytosis (the ingestion of liquid into a cell by the budding of small vesicles from the cell membrane)
How do drugs use passive diffusion?
Drugs can move passively down concentration gradient
Need to have degree of lipid solubility to cross phospholipid bilayer directly e.g. steroids
Rate of diffusion proportional to concentration gradient, the area & permeability of the membrane and inversely proportional to thickness
How do drugs use pores or ion channels?
Movement through channels occurs down concentration gradient
Restricted to very small water soluble molecules e.g. Lithium, used in bipolar disorder
How do drugs use carrier mediated transport actively?
Active transport uses ATP as energy.
Transports drugs in or out of cells against the concentration gradient
Family of carriers called ATP- Binding Cassette (ABC).
Humans have 49 ABCs
An ABC called P-gp is also known as Multi Drug Resistance (MDR1) as it removes a wide range of drugs from cytoplasm to the extracellular side.
How do drugs use carrier mediated transport passively?
Facilitated transport of a molecule by a carrier aids passive movement down concentration gradient or uses the electrochemical gradient of a co-transported solute to transport the molecule against the concentration gradient
Neither of these needs ATP ( energy)
There are over 300 members of the SLC ( solute carrier) superfamily
One example is OAT1 ( organic anion transporter) which is found in kidney and secretes Penicillin & uric acid. Probenicid blocks it, leading to uric acid being excreted. Uric acid levels drop.
How do drugs use Pinocytosis?
A form of carrier mediated entry into the cytoplasm
Usually involved in uptake of endogenous macro molecules, can be involved in uptake of recombinant therapeutic proteins
Drugs such as Amphotericin can be taken up into liposome for pinocytosis
What is drug ionisation?
Ionisation is a basic property of most drugs that are either weak acids (e.g. Aspirin) or weak bases (e.g. Propranolol) ((strong would lead to stomach ulcers))
Ionisable groups are essential for the mechanism of action of most drugs as ionic forces are part of the ligand receptor interaction
Drugs with ionisable groups exist in equilibrium between charged (ionised) and uncharged forms.
The extent of ionisation depends on the strength of the ionisable group and the pH of the solution
Ionised form regarded as most water soluble & un-ionised as lipid soluble
What is the Ionisation constant?
Ionisation/dissociation constant
The pH at which half are in the ionised form and half are in the unionised form
Weak acids best absorbed in the stomach
Weak bases best absorbed in the intestines
How are drugs absorbed orally?
Oral route is easiest & most convenient for many drugs
Large surface area & high blood flow of small intestine can give rapid and complete absorption of oral drugs
There are a number of obstacles for the drug to overcome before it reaches the systemic circulation
How does drug structure affect drug absorption?
A major determinant of absorption
Drug needs to be lipid soluble to be absorbed from gut
Highly polarised drugs tend to be only partially absorbed with much being passed in faeces (Use this property with Olsalazine for colonic-specific IBD)
Some drugs unstable at low pH (e.g. Benzyl penicillin) or in presence of digestive enzymes (e.g. insulin) so have to give by alternative route.
How does drug formulation affect drug absorption?
The capsule or tablet must disintegrate & dissolve to be absorbed.
Most do so rapidly
Some formulated to dissolve slowly (modified release MR) or have a coating that is resistant to the acidity of the stomach (enteric coating- EC)
How does gastric emptying affect drug absorption?
Rate of gastric emptying determines how soon a drug taken orally is delivered to small intestine
Can be slowed by food or drugs (e.g antimuscarinics such as Oxybutinin) or trauma (e.g. head injuries – all the blood redirected to area of trauma)
Can be faster if had gastric surgery e.g gastrectomy or pyloroplasty (surgically widened pylorus)
What are the four major metabolic barriers to reach circulation that drugs need to pass through?
Intestinal lumen
Intestinal wall
Liver
Lungs
What effects could the intestinal lumen have on drugs?
Contains digestive enzymes that can split peptides, esters & glycosidic bonds
Peptide drugs broken down by proteases (Insulin)
Colonic bacteria hydrolysis & reduction of drugs
What effects could the intestinal wall have on drugs?
Walls of upper intestine rich in cellular enzymes e.g. Mono amine oxidases (MAO)
Luminal membrane of enterocytes contains efflux transporters such as P-gp which may limit absorption by transporting drug back into the gut lumen
Extensive bowel surgery “short gut syndrome” – poor oral absorption as little surface left and rapid transit time
What effects could the liver have on drugs?
Blood from gut delivered by splanchnic circulation directly to liver.
Liver is major site of drug metabolism
To avoid hepatic first pass metabolism by giving drug to region of gut not drained by splanchnic e.g mouth or rectum (GTN)
How can drugs be administered transcutaneously?
Human epidermis effective barrier to water soluble compounds. Limited rate & extent of absorption of lipid soluble drugs. Need potent, non irritant drugs.
Slow and continued absorption useful with transdermal patches e.g. Fentanyl patch 72 hourly in chronic pain/palliative care
How can drugs be administered intradermally & subcutaneously?
Avoids barrier of stratum corneum
Mainly limited by blood flow
Small volume can be given
Use for local effect (e.g. local anaesthetic) or to deliberately limit rate of absorption (e.g. long term contraceptive implants)
How can drugs be administered intramuscularly?
Depends on blood flow and water solubility
Increase in either enhances removal of drug from injection site
Can make a Depot injection by incorporating drug into lipophilic formulation which releases drug over days or weeks (e.g Flupenthixol )
Injected into the buttock
How can drugs be administered internasally?
Low level of proteases and drug metabolising enzymes
Good surface area
Can be used for local (e.g. decongestants) or systemic (e.g. desmopressin) effects (cocaine can provide both!)
How can drugs be administered through inhalation?
Large surface area & blood flow BUT limited by risks of toxicity to alveoli and delivery of non volatile drugs - mostly anaesthetically drugs
Largely restricted to volatiles such as general anaesthetics and locally acting drugs such as bronchodilators in asthma
Asthma drugs non volatile so given as aerosol or dry powder.
What is distribution?
The process by which the drug is transferred reversibly from the general circulation to the tissues as the blood concentration increases and then returns from the tissues to the blood when the blood concentration falls.
How does distribution occur?
Occurs by passive diffusion across cell membranes for most lipid soluble drugs
Once equilibrium is reached any process that removes the drug from one side of the membrane results in movement to restore that equilibrium
How does protein binding affect drug concentration?
Many drugs can bind to plasma or tissue proteins
This may be reversible or irreversible
The commonest reversible binding occurs with the plasma protein albumin
Binding lowers the free concentration of drug and can act as a depot releasing the bound drug when the plasma concentration drops through redistribution or elimination
Some drugs bind irreversibly (e.g cytotoxic chemo with DNA) and cannot re enter the circulation and is equivalent to elimination.
How are drugs distributed to the brain?
Lipid soluble drugs easily pass from blood to brain
Water soluble drugs enter slowly despite the good blood supply
The BBB is due to tight junctions , smaller number & size of pores in the endothelium.
Efflux transporters “protect” the brain by returning drug molecules to the circulation.
Some drugs do use the SLC transporters that supply the brain with carbohydrate & amino acids (e.g L- Dopa for Parkinsons)
The brain does little metabolising and drugs are removed by diffusion into plasma, active transport in the choroid plexus or elimination in CSF.
What do you need to be aware of when giving drugs to a pregnant woman?
Have to consider both when prescribing in pregnancy.
Lipid soluble drugs readily cross placenta
Placental blood flow relatively low, so slow equilibration with foetus
Large molecules do not cross placenta (e.g Heparin)
Foetal liver has low levels of drug metabolising enzymes, so relies on maternal elimination
Opiates given during labour may persist in newborn who has to then eliminate them (e.g. Pethidine 7 sleepy baby!)
What is elimination?
The removal of a drugs activity from the body
May involve METABOLISM – the transformation of the drug molecule into a different molecule
And/or EXCRETION – the molecule is expelled in liquid, solid or gaseous “waste”
What is metabolism?
Metabolism is necessary for the elimination of lipid soluble drugs
They are converted to water soluble products that are readily removed in the urine( if they remained lipid soluble they would be reabsorbed)
Metabolism produces one or more new compounds which may show differences from the parent drug (eg less biological activity)
Drug metabolism may be divided into two phases
What happens in Phase 1 of metabolism?
These reactions involve the transformation of the drug to a more polar metabolite
This is done by unmasking or adding a functional group (e.g – OH, -NH2, -SH)
Oxidations are the commonest reactions catalysed by important enzymes called Cytochrome P450
What is Cytochrome P450?
Superfamily of membrane bound isoenzymes
Present in smooth endoplasmic reticulum
Largely in liver tissue.
CYP1 to CYP4 involved in drug metabolism
Smoking and alcohol can induce P450 enzymes- more rapid drug metabolism
Drugs & foods can induce or inhibit P45O (Cimetidine & Grapefruit)
There are genetic variations in Cytochrome P450 - different metabolising rates
Do all oxidations of drugs require Cytochrome P450?
No!
Some drugs are metabolised in plasma (e.g. Suxamethonium & plasma cholinesterase breaks it down), lung or gut
Ethanol is metabolised by alcohol dehydrogenase
Monoamine oxidase inactivates noradrenaline
Xanthine oxidase inactivates 6-mercaptopurine
Reductions and hydrolysis also occur
What happens in Phase 2 of metabolism?
Phase 2 (conjugation) involves the formation of a covalent bond between the drug or its phase 1 metabolite and an endogenous substrate The resulting products are usually less active and readily excreted by the kidneys
How are drugs excreted?
Drugs and metabolites excreted in;
FLUIDS; important for low molecular weight polar compounds ( urine , bile , sweat , tears , breast milk )
SOLIDS ; faecal elimination, important for high MWT compounds excreted in bile. Hair analysis!
GASES ; expired air important for volatiles
How are drugs excreted in the urine?
Three processes in renal drug processing
Total excretion = glomerular filtration+ tubular secretion-reabsorption
How are drugs excreted in the faeces?
High molecular weight molecules taken up into hepatocytes and eliminated into bile.
Bile passes down gut, some drug may be reabsorbed and re- enter the hepatic portal vein “enterohepatic circulation”
What is First Order Kinetics?
A drug given iv is rapidly distributed to the tissues.
By taking repeat plasma samples the fall in the plasma concentration with time can be measured.
Often the decline is exponential – a constant fraction of the drug is eliminated per unit of time
Change in concentration (dC/dt)at any time is proportional to the concentration
What is Zero Order Kinetics?
If an enzyme system that removes a drug is saturated (all available space is being used up) the rate of removal of the drug is constant and unaffected by an increase in concentration
The change in concentration per time(dC/dt) is a fixed amount of drug per time, independent of concentration
What is the half-life?
The time taken for a concentration to reduce by one half.
What is bioavailability?
This is the fraction of the administered drug that reaches the systemic circulation un –altered (known as F)
IV drugs have F=1 as 100% of drug reaches circulation
Oral drugs may have F< 1 if they are incompletely absorbed or undergo first pass metabolism
Determined by measuring plasma concentration after oral and iv doses.
What does the rate of distribution of a drug depend on?
Water soluble drugs rate of distribution depends on rate of passage across membranes
Lipid soluble drugs rate of distribution depends on blood flow to tissues that accumulate drug
What is the apparent volume of distribution Vd?
The total amount of drug that has to be administered to produce a particular plasma concentration
If drug has a high Vd it will have a low plasma concentration so the rate of elimination is inversely proportional to Vd
What is the Clearance of a drug?
The volume of blood or plasma cleared of drug per unit time
What are repeated drug doses used for?
Repeated drug doses are used to maintain a constant drug concentration in the blood and at the site of action for therapeutic effect Steady state (Css)is a balance between drug input and elimination Oral and iv administration will give different profiles
How is Css achieved?
For iv infusion, Css is achieved when the rate of elimination equals the rate of infusion
What are the pros and cons of oral administration?
Most long term drug administration is by oral route – cheap, easy to do at home
Doses are intermittent so will have peaks and troughs – compliance can be poor
Rate of absorption will affect the profile- rapid= exaggerated peaks, slow= flatter peaks
How to decrease the time it takes for a drug to reach steady state in the body?
If drug has long t1/2 it will take a long time to reach steady state ( 4-5 half lives) e.g. t1/2 of 24 hours will mean 4-5 days to reach Css
If give a high initial dose this “loads” the system and shortens the time to steady state
Loading dose = Css x Vd
After the loading dose the steady state can be maintained by the maintenance dose given by the equation Css = D x F/ t x CL
What is the difference between pharmcodynamics and pharmacokinetics?
Pharmacodynamics - the drug’s effect on the body
Pharmacokinetics - the body’s effect on the drug
What are the four different outcomes of pharmacodynamics?
Additive effect - summation
Synergistic effect - synergism
Anatognist effect - antagonism
Potentiontiation e.g. two drugs give, drug A acts as usual but also causes drug B to have a larger effect than usual
What are the fours processes involved in pharmcokinetics?
Absorption
Distribution
Metabolism - usually through the liver, some in kidney, lung
Excretion - usually through the kidney
How is drug absorption different when a drug is given by injection vs. by mouth?
By injection - high blood concentration is achieved almost immediately
By mouth - takes a bit longer to get a high blood concentration, takes longer to get out too
Oral dose will typically be higher than the IV dose.
What is bio-availability?
The proportion of a drug or other substance that reaches the systemic circulation.
How can acidity levels in the body affect drug absorption?
Drug is split into an ionised and unionised portion.
The ionised portion cannot cross the phospholipid bilayer, whereas the unionised portion can cross.
The acidity will change the proportion of unionised drug present, therefore changing the amount absorbed into the cell.
Abcessses are very acidic which means local anasthetics (and other drugs) aren’t very effective.
What occurs during the distribution of the drug?
Drug will attach to proteins in the blood, spread to other tissues and to the effect site.
Low volume of distribution - present in blood and at effect site
High volume of distribution - lots of redistribution to other sites
What happens if a drug is highly protein bound?
Drugs that are highly protein bound will replace other similar kinds of drugs that would otherwise be bound to proteins. This may increase the therapeutic effect to potentially risky levels.
Give an example of enzyme induction related to morphine?
Morphine is metabolised by the CYP450 pathway. One of the products is morphine-6-glucaronide which is 10x more potent than morphine.
In healthy patients it is excreted before it can have an effect. But if phenytoin (anti-epileptic drug) is given at the same time, it increases the CYP450 pathway, giving increased levels of morphine-6-glucaronide.
Give an example of enzyme inhibition related to morphine?
Morphine is metabolised by the CYP450 pathway. One of the products is morphine-6-glucaronide which is 10x more potent than morphine.
If you give metronidazole (antibiotic) at the same time, the CYP450 pathway is decreases, meaning that the conversion of morphine to morphine-6-glucuronide happens more slowly. This means that it is less effective.
What happens during drug excretion?
Most drugs are renally excreted. If the drugs have an effect on the kidney, preventing excretion it may mean that the drug is more potent than it otherwise would be.
What is druggability?
The ability of a protein target to bind small molecules with high affinity.
AKA ligandability
Estimates suggest around 10-15% of the human genome may be druggable.
What are four key potential drug targets?
Receptors
Enzymes
Transporters
Ion channels
What is a receptor?
A compontent of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligand’s observed effects.
Can be present on a target or non-target cell.
What are the two types of ligands?
Exogenous (drugs)
Endogenous (hormones, neurotransmitters etc)
Which ‘chemicals’ communicate using receptors?
Neurotransmitters (acetylcholine, serotonin etc)
Autacoids (local hormones e.g. cytokines, histamine)
Hormones (testosterone, hydrocortisone)
What are main types of receptor?
Ligand-gated ion channels e.g. nicotinic ACh receptor
G-protein coupled receptor e.g. B-adrenoreceptors
Kinase-linked receptors e.g. receptors for growth factors
Cytosolic/nuclear receptor e.g. steroid receptors
What is a ligand-gated receptor?
Majority transduce signals from the outside, to the inside
When the ligand is bound it induces a transformational change to the receptor’s association protein/channel opening it up.
What are GPCRs?
Largest and most diverse group of membrane receptors
7 transmembrane regions
Targeted by >30% of drugs
G proteins (GTPases) act as molecular switches.
They are ON when bound to GDP. They are OFF when bound to GTP. The activity of GPCRs is regulated by factors that control their ability to bind to and hydrolyse GTP to GDP.
How can mutations affect GPCRs?
Polymorphisms can change the way the receptor responds. May mean that it has a greater response.
Give two examples of POSTIVE impact GPCRs?
Muscarinic acetylcholine receptor M3 uses the G-protein Gq, coupled to PLC which initiates a 2nd messenger response using IP3 and DAG.
B2-adrenoreceptor uses the G-protein Gs, coupled to adenylyl cyclase which initiates a 2nd messenger response using cAMP.
What are kinase-linked receptors?
Transmembrane receptors activated when the binding of an extracellular ligand causes enzymatic activity on the intracellular side.
e.g. phosphorylation and then the recruitment of molecules that will only bind to phosphorylated components.
What are nuclear receptors?
Ligand binding domain interacts with the ligand, this causes a conformation and translocation to the nucleus. Zinc fingers then bind to DNA and work to modify gene expression.
e.g. Tamoxifen acts as a selective oestrogen receptor modulator (SERM) or as a partial agonist of the oestrogen receptors.
Give examples of pathology that occurs when there is increased/decreased chemicals/receptors?
Chemicals
Increased: allergies due to increased histamine
Decreaed: Parkinson’s due to reduced dopamine
Receptors
Increased: Mastocytosis due to increased c-kit receptors
Decreased: Myasthenia gravis due to loss of ACh receptors
How are drugs for specific receptors designed?
Identify the receptor involved in a pathophysiological response
Develop drugs that act at that receptor
Quantify drug action at that receptor
What is a agonist?
A compound that bind to a receptor and activates it
