Pharmacology Flashcards
1
Q
What is Pharmacokinetics?
A
The action of drugs in the body including ABSORPTION DISTRIBUTION METABOLISM EXCRETION
2
Q
What is absorption?
A
The process of transfer from the site of administration into the general or systemic circulation
3
Q
What are the different routes of administration for drugs?
A
Oral Intra venous Intra arterial – much rarer Intramuscular Subcutaneous Inhalational Topical Sublingual – e.g. GTN spray Rectal Intrathecal
4
Q
How many membranes must a drug cross to get to its target?
A
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
5
Q
What are the different ways a drug can pass through a membrane?
A
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)
6
Q
How do drugs use passive diffusion?
A
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
7
Q
How do drugs use pores or ion channels?
A
Movement through channels occurs down concentration gradient
Restricted to very small water soluble molecules e.g. Lithium, used in bipolar disorder
8
Q
How do drugs use carrier mediated transport actively?
A
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.
9
Q
How do drugs use carrier mediated transport passively?
A
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.
10
Q
How do drugs use Pinocytosis?
A
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
11
Q
What is drug ionisation?
A
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
12
Q
What is the Ionisation constant?
A
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
13
Q
How are drugs absorbed orally?
A
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
14
Q
How does drug structure affect drug absorption?
A
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.
15
Q
How does drug formulation affect drug absorption?
A
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)
16
Q
How does gastric emptying affect drug absorption?
A
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)
17
Q
What are the four major metabolic barriers to reach circulation that drugs need to pass through?
A
Intestinal lumen
Intestinal wall
Liver
Lungs
18
Q
What effects could the intestinal lumen have on drugs?
A
Contains digestive enzymes that can split peptides, esters & glycosidic bonds
Peptide drugs broken down by proteases (Insulin)
Colonic bacteria hydrolysis & reduction of drugs
19
Q
What effects could the intestinal wall have on drugs?
A
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
20
Q
What effects could the liver have on drugs?
A
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)
21
Q
How can drugs be administered transcutaneously?
A
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
22
Q
How can drugs be administered intradermally & subcutaneously?
A
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)
23
Q
How can drugs be administered intramuscularly?
A
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
24
Q
How can drugs be administered internasally?
A
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!)
25
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.
26
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.
27
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
28
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.
29
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.
30
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!)
31
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”
32
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
33
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
34
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
35
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
36
What happens in Phase 2 of metabolism?
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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
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37
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
38
How are drugs excreted in the urine?
Three processes in renal drug processing
| Total excretion = glomerular filtration+ tubular secretion-reabsorption
39
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”
40
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
41
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
42
What is the half-life?
The time taken for a concentration to reduce by one half.
43
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.
44
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
45
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
46
What is the Clearance of a drug?
The volume of blood or plasma cleared of drug per unit time
47
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
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48
How is Css achieved?
For iv infusion, Css is achieved when the rate of elimination equals the rate of infusion
49
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
50
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
51
What is the difference between pharmcodynamics and pharmacokinetics?
Pharmacodynamics - the drug's effect on the body
| Pharmacokinetics - the body's effect on the drug
52
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
53
What are the fours processes involved in pharmcokinetics?
Absorption
Distribution
Metabolism - usually through the liver, some in kidney, lung
Excretion - usually through the kidney
54
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.
55
What is bio-availability?
The proportion of a drug or other substance that reaches the systemic circulation.
56
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.
57
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
58
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.
59
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.
60
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.
61
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.
62
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.
63
What are four key potential drug targets?
Receptors
Enzymes
Transporters
Ion channels
64
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.
65
What are the two types of ligands?
Exogenous (drugs)
| Endogenous (hormones, neurotransmitters etc)
66
Which 'chemicals' communicate using receptors?
Neurotransmitters (acetylcholine, serotonin etc)
Autacoids (local hormones e.g. cytokines, histamine)
Hormones (testosterone, hydrocortisone)
67
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
68
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.
69
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.
70
How can mutations affect GPCRs?
Polymorphisms can change the way the receptor responds. May mean that it has a greater response.
71
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.
72
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.
73
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.
74
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
75
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
76
What is a agonist?
A compound that bind to a receptor and activates it
77
What is an antagonist?
A compound that reduces the effect of an agonist.
78
What is the EC50 of a drug?
Half maximal effective concentration
| The concentration that gives half the maximal response
79
What is a full agonist?
A drug that is able to reach a saturation of activity.
80
What is a partial agonist?
A drug that is not able to give 100% response.
81
What is the Emax of a drug?
The maximal effect at high drug concentrations when all the receptors are occupied by the drug.
82
What is the intrinsic activity of a drug?
The ability of a drug-receptor complex to produce the maximum functional response.
83
What is a competitive antagonist?
Drug which binds to the same site as the agonist but does not activate it, thus blocking the agonist's action.
84
What is a non-competitive antagonist?
Drug which binds to an allosteric (non-agonist) site on the receptor to prevent the activation of the receptor.
85
What are the two types of cholinergic receptors?
Nicotinic (nAChR) - agonist is nicotine, antagonist is curare
Muscarinic (mAChR) - agonist is muscarine, antagonist is atropine
86
What type of receptor does histamine act on?
All histamine receptors are GPCRs
87
What is the affinity of a drug?
Describes how well a ligand binds to the receptor.
| Shown by both agonist and antagonists.
88
What is the efficacy of a drug?
Describes how well a ligand activates the receptor.
Can have low or high efficacy agonists.
Antagonists have zero efficacy.
89
Why does the number of receptors present make a difference to the effect of the drug?
Depending on how many receptors are present on the surface of the cell will have an impact on the magnitude of the drug's response.
90
What is an irreversible antagonist?
An antagonist that won't come off the receptor. The only way to remove it is to recycle the receptor back into the cell.
e.g. Bromoacetyl alprenolol menthane (BAAM) on the B-adrenoreceptor
91
What is the receptor reserve?
Where agonists need to activate only a small fraction of the existing receptors to produce the maximal response.
The reserve can be large or small, depending on the the tissue.
There is no receptor reserve for a partial agonist.
92
What is signal transduction?
Signal transduction pathways amplify the incoming signal by a signaling cascade using a network of enzymes that act on one another in specific ways to ultimately generate a precise and appropriate physiological response by the cell.
93
What is allosteric modulation?
A modulator binds to a site other than the one an endogenous activator of the receptor would bind to, to cause a response.
94
What is inverse agonism?
When a drug binds to the same receptors as an agonist but induces a pharmacological response opposite to that of the agonist.
95
What is tolerance?
Reduction in agonist effect over time.
| Occurs when the drug has been continuously present at high concentrations.
96
What is desensitisation?
Occurs when a receptor decreases its response to an agonist at high concentration. It is a process through which, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade, internalised and degraded and thus the cellular effect of receptor activation is attenuated.
97
What is specificity?
Specificity is the measure of a receptors ability to respond to a single ligand.
No compound is ever truly specific so selectivity is a better term.
e.g. Isoprenaline is a B2-adrenoreceptor agonist (non-selective)
Whereas Salbutamol is selective for B2-adrenoreceptors
98
What is an enzyme inhibitor?
A molecule that binds to an enzyme and normally decreases its activity.
Prevents the substrate from entering the enzyme's active site and prevents it from catalyzing its reaction.
99
What are the two types of enzyme inhibitor?
Irreversible inhibitors - usually react with the enzyme and change it chemically (e.g. covalent bond formation)
Reversible inhibitors - bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme substrate complex or both.
100
What is the action of statins?
Statins are HMG-CoA reductase inhibitors
They block the rate limiting step in the cholesterol pathway.
They are a class of lipid-lowering medications that reduce the levels of 'bad cholesterol'.
Reduce the risk of cardiovascular disease in those who are at high risk.
101
What is the action of ACE inhibitors?
The renin-aldosterone-angiotensin system is a major blood pressure regulating mechanism. The system increases blood pressure by increasing the amount of water and salt the body retains.
Inhibiting Angiotensin-converting enzyme reduces angiotensin II production and therefore causes a reduction in blood pressure.
102
Give 5 ways in which you can increase the levels of dopamine pharmacologically?
Used to treat Parkinson's disease. Can target different aspects of the pathway...
L-Dopa substrate is produced from the amino acid L-tyrosine as a precursor for neurotransmitter biosynthesis. L-Dopa can be given directly.
Peripheral DDC inhibitor blocks DCC in the periphery meaning that there is more conversion of L-Dopa to Dopamine in the CNS pathway.
Peripheral COMT inhibitor prevents breakdown of L-Dopa generating more for CNS.
Monoamine oxidase B inhibitor prevents dopamine breakdown and increases availability.
Central dopamine receptor agonists
103
What is cell transport?
Molecules move across a cell membrane.
Active transport moves ions from a lower concentration to a higher concentration. Allows cells to get what they need such as ions, glucose and amino acids.
104
What are the different types of protein ports?
Uniporters - use energy from ATP to pull molecules in
Symporters - uses the movement of one molecule to pull in another molecule against the concentration gradient
Antiporters - one substance moves against its gradient using energy from the second substance moving down its gradient
105
What is the action of Furosemide?
The Na-K-Cl (NKCC) is a protein that transports Na, K, Cl into cells and it moves the ions in the same direction.
Furosemide is a loop diuretic.
It inhibits the luminal NKCC co-transporter in the thick ascending limb of the loop of Henle. It causes Na, Cl, and K to be lost in the urine.
106
What is the epithelial sodium channel?
An apical membrane-bound heterotrimeric ion channel selectively permeable to Na ions. It causes reabsorption of Na ions at the collecting ducts of the kidney's nephrons (also acts in the colon, lung and sweat glands).
Can be blooked by the high affinity diuretic amiloride. This is an anti-hypertensive usually used with thiazide diuretic to also target the Na-Cl cotransporter.
107
What are voltage-gated calcium channels?
Voltage-gated calcium channels are found in the membrane of excitable cells e.g. muscle, glial cells, neurons etc.
At resting membrane potential they are normally closed. They are activated at depolarized membrane potentials. When Ca enters the cell, there is activation of Ca-sensitive K channels, muscle contractiion and excitation of neurons etc.
108
What is the action of Amlodipine?
Amlodipine is a angioselective Ca channel blocker that inhibits the movement of Ca ions into vascular smooth muscles cells and cardiac muscle cells, inhibiting their contraction.
Causes vasodilation and a reduction in peripheral vascular resistance, thus lowering blood pressure. Prevents excessive contriction in coronary arteries.
109
What are voltage-gated sodium channels?
Voltage-gated sodium channels conduct Na through the plasma membrane.
They are classified according to the trigger than opens them.
3 main conformational states: closed, open and inactivated.
AP allows the gates to open, allowing Na in, increasing voltage.
Lidocaine - blocks the transmission of AP, blocks signalling in the heart.
110
What are voltage-gated potassium channels?
Selective for K over other cations.
>40 known voltage-gated potassium channel a subunits.
Present in many excitable tissues.
3 conformational states: closed, open and inactivated.
AP allows activation gates to open.
111
What do voltage-gated potassium channels do in the pancreas?
Increased glucose leads to the blockage of ATP-dependent K channels. Repetitive firing of AP causes Ca influx, leading to insulin secretion from the B islets of Langerhans.
Repaglinide, natelinide, sulfonylureal all decrease glucose by blocking K channels to stimulate insulin secretion.
112
What are receptor- mediated chloride channels?
Ligand-gated ion channels (iontrophic receptors) that open to allow ions to pass through the membrane in response to the binding of a chenmical messenger (i.e. a ligand) such as a neurotransmitter.
e.g. Many drugs like barbituates can block the GABA-A complic post-synaptically, opening the Cl- channels, leading to hyperpolarisation.
113
What does the Na/K ATPase do?
Pumps out 3Na for every 3K in and creates an electrochemical gradient.
Antiporter activity.
Pumping is active - using ATP.
Reverse process is spontaneous.
114
What is the action of Digoxin?
First isolated from the fox glove plant.
Digitalis lanata inhibits the Na/K ATPase, mainly in the myocardium.
Digoxin used for AF, atrial flutter and heart failure.
Inihibition causes an increase in intracellular Na, resulting in decreased activity of Na-Ca and increased intracellular Ca.
Lengthens cardiac AP which leads to a decrease in HR.
115
What does the proton pump (H/K ATPase) do?
The gastric H/K ATPase is the proton pump of the stomach. It is heterodynamic protein.
Exchanges potassium from the interstinal lumen with cytoplasmic hydrogen.
Responsible for the acidification of the stomach and the activation of pepsin (digestive enzyme).
116
What are proton pump inhibitors?
Block the proton pump (H/K ATPase).
Used as potent inhibitors of acid secretion.
Omeprazole irreversibly inhibits H/K ATPase.
Has a half-life of 1 hour but works for 2-3 days.
117
How can irreversible enzyme inhibitors be dangerous?
Organophosphates, insecticides and nerve gases.
Block nicotinic and muscarinic receptors.
Nicotinic - salivation, defeacation, urination, bradycardia, hypotension
Muscarinic - twitching, severe weakness, paralysis of the diaphragm
118
What determines the duration and intensity of a drug's action?
The rate of metabolism of a drug determines the duration and intensity of a drug's pharmacologic action.
Metabolic breakdown of drugs occurs through specialized enzymatic systems and generates compounds that are more readily excreted.
119
Why is Cytochrome P450 so important in drug metabolism?
Located in inner membrane of mitocondria or ER.
Metabolise thousands of endogenous and exogenous chemicals.
Most drugs e.g. parcetamol undergo deactivation by Cytochrome Ps either directly or by facilitated excretion from the body.
Many substances are bioactivated by CYPs to form their active compounds.
120
What are the major types of opoids?
Morphine and Codeine are naturally occuring opoids that come from the resin of the opium poppy.
Simple chemical modifications brought about diamorphine, oxycodone and dihydrocodeine.
Synthetic opoids include pethidine, fentanyl, alfentanil, remifentanil.
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Why was dimorphine produced?
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Morphine brought with it serious problems with addiction and so the drug companies looked to make a non-addictive and non-respiratory depressant version of morphine.
Unfortunately diamorphine (heroin) was produced, which is actually more potent and fasting acting and still causes problems with addiction.
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Why were synthetic opioids produced?
Developed to try to reduce dependence and side-effects.
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How do opioids work?
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Use the existing pain modulation system.
Natural endorphins (endogenous morphine) and enkephalins inhibit the release of pain transmitters at the spinal cord and midbrain and modulate pain perception in high centres - changing the emotional perception of pain.
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Why do opioids cause addiction?
Opioids inhibit pain perception but this pathways were not designed for sustained activation.
This leads to desensitisation and more drug is required to get the same effect - addiction.
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What are opioid receptors?
There are three classical receptors (DOP, KOP and MOP). The novel NOP receptor is considered to be a non-opioid branch of the opioid receptor family.
At the moment all the opioid drugs we use are u agonists.
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What is potency?
Whether a drug is strong or weak relates to how well a drug binds to the receptor, the binding affinity.
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What is efficacy?
The maximum effect that a given drug will produce, irregardless of the dose.
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What is tolerance?
Down regulation of the receptors with prolonged use. Need higher doses to achieve the same effect.
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What is dependence?
Psychological effects without the drugs - physical effects, craving
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Why do opioids cause side-effects?
There are other systems that also use the opioid receptors, which means they are also activated.
Including respiratory depression, sedation, nausea and vomiting, constipation, itching, immune suppression, endocrine effects.
Different patients have different sensitivity to opioids.
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How should you treat opioid induced respiratory depression?
Call for help
Give them IV Naloxone
Titrate to effect
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Why do different people have different responses to codeine?
Codeine is a prodrug and needs to be metabolised by cytochrome CYP2D6 to morphine to work.
CYP2D6 activity is decreased in 10-15% of the Caucasian population.
CYP2D6 is absent in a further 10% of this population
But CYP2D6 is overactive in 5% of this population, so they may be at risk of respiratory depression with codeine.
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Why is morphine dangerous in patients with reduced renal function?
Morphine is metabolised to morphine-6-glucoronide which is more potent than morphine and is renally excreted. With normal renal function this is cleared quickly.
In renal failure it will build up and may cause respiratory depression.
Be careful with patients who have <30% renal function (creatinine clearance at <30) - reduce their dose and timing intervals.
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Why can tramadol be dangerous?
Weak opioid agonist, slightly stronger than codeine.
Needs to be metabolised by CYP2D6 to o-desmethyl tramodol.
Can be dangerous because it has a secondary effect in analgesia as a serotonin and nor-epinephrine reuptake inhibitor so it interacts with SSRIs, tricyclic antidepressants and MAOis, sometimes fatally.
Can be used as a substance of misuse, now a controlled drug.
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What is the role of the ANS?
Conveys all the outputs from the CNS to the body, except for skeletal muscular control.
Regulatory roles in vascular, airway and visceral smooth muscle, exocrine secretions (sweat), control of heart rate, energy metabolism in the liver and links to the immune system.
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How does the set up of the symp and para differ?
The parasympathetic ganglia are near their targets with short post-ganglionic nerves, whereas the sympathetic ganglia are near the spinal cord with post-ganglionic fibres.
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What are the major parts of the parasympathetic nervous system?
Cranial nerves III, VII, IX and X carry signals to the body.
A further sacral outflow innervates the pelvis.
Short post-synaptic fibres reach the targets and release ACh to act on muscarinic receptors.
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What are the major parts of the sympathetic nervous system?
Regulates the fight and flight response.
Nerve fibres originating in the spinal cord terminate in ganglia near the cord, then send out long nerve fibres to blood vessels and muscles.
Release noradrenaline which activates adrenergic receptors, of which there are two main types (a/B) with subtypes.
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How is ACh involved in both para and symp NS?
Para and symp fibres coming out of the CNS both release ACh which act on specific receptors called nicotinic receptors.
The post-ganglionic parasympathetic fibres release more ACh, this time acting on muscarinic receptors.
The post-ganglionic sympathetic fibres release noradrenaline acting on a and B adrenoreceptors.
(Except when they innervate sweat glands - ACh on muscarinic).
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What are NANC?
Non-adrenergic, non-cholinergic autonomic transmitters
Used by enteric NS, parasympathetic system, sympathetic system.
Multiple transmitters can be released at any one time, exerting mixed effects with different time courses.
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What are muscarinic receptors?
M1-M5
G-protein coupled receptors
M1: mainly in the brain
M2: mainly in the heart - activation slows the heart so we can block these in bradycardia and cardiac arrest
M3: glandular anad smooth muscle. Causes bronchoconstriction, swearing, salivary gland secretion
M4/5: mainly in the CNS
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What are muscarinic agonists?
Mimick muscarine
Activate the parasympathetic NS
e.g. Pilocarpine
Stimulates salivation by activating para NS. Useful after radiotherapy or in Sjogren's syndrome.
Contracts iris smooth muscle so may be used to treat glaucoma by facilitating drainage of the aqueous humor.
Side effects: slow the heart
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What are some examples of muscarinic antagonists?
Deadly nightshade gave us atropine, useful for bradycardia induced by excessive doses of B blockers or cardiac arrest.
Thorn apple gave us hyosine which is useful in palliative care.
Solifenacin used to treat overactive bladder.
Short acting anticholinergics open up pupil in eye examination.
Receptor selectivity or local delivery can give specificity.
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How can muscarinic antagonists be used in bronchoconstriction?
Drugs that block M3 receptor in the airway, known as anti-cholinergic or anti-muscarinics.
Short-acting: ipratropium bromide (atrovent)
Long-acting: LAMAs such as tiotropium, glycopyrrhium selectivity by drug delivery mechanisms and receptor selectivity.
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How can ACh be manipulated outside the autonomic system?
ACh is involved in memory - anticholinesterase inhibitors may be useful for treatment of dementia
Anti-emetics actions - hyosine for travel sickness
Botulinum toxin prevents ACh release - cosmetic and anti-spasmodic uses.
Nicotinic blockers such as pancuronium and suxamethorium can be used to inhibit ACh and block muscle activity in surgery.
Give anti-acetylcholinesterases to increase the amounts of ACh in myasthenia gravis.
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What are the side effects of anti-cholinergics?
Brain: worsens memory and may cause confusion
Peripherally: constipation, drying of the mouth, blurring of the vision, worsening of glaucoma
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What are the effects of acetylcholinesterase inhibitors?
Organophosphate insectides and nerve gases are irreversible acetylcholinesterase inhibitors and cause muscle paralysis, twitching, salivation and confusion.
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What are the 3 main adrenergic neurotransmitters?
3 main catecholamines
Nordadrenaline: released from sympathetic nerve fibre ends, used in management of shock
Adrenaline: release from adrenal glands (fight and flight), used in management of anaphylaxis
Dopamine: precursor of noradrenaline and adrenaline
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Which nicotinic recepotors will adrenaline and noradrenaline bind to?
a1 - Noradrenaline > Adrenaline (contracts smooth muscle)
a2 - Noradrenaline = Adrenaline (mixed effects on smooth muscle)
B1 - Noradrenaline = Adrenaline (chronotropic and ionotropic effect on heart)
B2 - Adrenaline >> Noradrenaline (relaxes smooth muscle)
B3 - Noradrenaline > Adrenaline (enhances lipolysis, relaxes bladder detrusor muscle)
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What are alpha blockers?
Block a1 to lower blood pressure
E.g. Doxazosin
Block a1 a in the prostate to treat prostatic hypertrophy
E.g. Tansulosin
No useful a2 blockers
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What are B agonists?
B1 activation will increase heart rate and chrontropic effects. May increase the risk of arrhythmias.
B2 activation is life saving in asthma.
B3 agonists can reduce over active bladder symptoms.
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What are B blockers?
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Propanolol : blocks B1 and B2. Will slow heart rate, reduce tremor, but may cause wheeze.
Atenolol, Bisoprolol, Metoprolol: B1 selective B blockers, main effects on the heart.
Lower BP (by reduction in cardiac output and gradual reduction in central sympathetic outflow activity), reduce cardiac work, treat arrhythmias.
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What are B blockers used to treat?
Angina, MI prevention, high BP, anxiety, arrhythmias, heart failure.
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What are the side effects of B blockers?
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Tiredness
Cold extremities
Bronchconstriction
Bradycardia
Hypoglycaemia
Cardiac depression
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Why are adverse drug reactions important?
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Account for 5% of hospital admissions
Can cause harm and even death
May mimic disease
Reduce quality of life
Increase cost
Reduce trust in healthcare professionals
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What is an adverse drug reaction?
Unwanted or harmful reaction following administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug.
Has to be noxious and unintended.
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What is a side effect?
Unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment.
Often minor and predictable.
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What are the 3 different types of effects caused by adverse drug reactions?
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Toxic effects (beyond therapeutic range) - too much
Collateral effects (therapeutic range) - normal amounts
Hyper-susceptibility effects (below therapeutic range) - too little
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What are toxic effects?
Some drugs have a therapeutic range which is very close to a dose that can cause effects.
Can occur if dose is too high or drug excretion is reduced by impaired renal or hepatic function or by interaction with other drugs.
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What are collateral effects?
The effects of a given action or inaction that are unintended, unknown, or at least not explicit.
Standard therapeutic doses.
B blockers causing bronchoconstriction
Broad spectrum antibiotics causing c.difficile and pseudomembranous collitis.
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What are hypersensitivity reactions?
Subtherapeutic doses
| Tiny dose of penicillin can cause anaphylaxis
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What are the different types of severity of ADRs?
Can be mild: nausea, drowsiness, itching, rash
| Can be severe: respiratory depression, neutropenia, catastrophic haemorrhage, anaphylaxis
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What are the 2 timelines for ADRs?
Time-independent reactions: occur at any time during treatment
Time-dependent reactions:
Rapid reactions e.g. histamine release after administration of vancomycin
First close reactions e.g. hypotension and ACE inhibitors
Early reactions e.g. GTN spray and nitrate-induced headache
Intermediate reactions e.g. delayed immunological reactions such as Stevens-Johnson syndrome with carbamazepine
Late reactions e.g. adverse effects of corticosteroids
Delayed reactions e.g. thalidomide and phocomelia
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How would you classify ADRs?
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Type A (Augmented pharmacological) - predictable, dose dependent, common e.g. morphine and constipation
Type B (Bizarre or idiosyncratic) - not predictable and not dose dependent e.g. anaphylaxis and penicillin
Type C (Chronic) e.g. osteoporosis and steroids
Type D (Delayed) e.g. malignancies after immunosuppression
Type E (End of treatment) - after abrupt drug withdrawal e.g. opiate withdrawal syndrome
Type F (Failure of therapy) - failure of oral contraceptive pill
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What factors affect the risk of ADRs?
Dose relatedness (toxic, collateral or hypersensitivity)
Timing (e.g. fast infusion)
Patient suseptibility
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What are the risk factors for ADRs?
Patient risk: more females, elderly and neonates, polypharmacy, genetic predisposition, hypersensitivity/allergies, hepatic/renal impairment, adherence problems
Drug risk: steep dose-response curve, low therapeutic index, commonly cause ADRs
Prescriber errors
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What are the causes for ADRs?
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Pharmaceutical variation
Receptor abnormality
Abnormal biological system unmasked by drug
Abnormalities in drug metabolism
Immunological
Drug-drug interactions
Multifactorial
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What are the effects of thalidomide?
Used for mild sedative effects and morning sickness.
Animals tests did not include effects on pregnancy.
Major effects in day 35-50 of pregnancy.
Most commonly limb defects.
Led to tougher testing and drug approval.
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When should we suspect an ADR?
Symptoms soon after a new drug is started
Symptoms after a dosage increase
Symptoms disappear when a drug is stopped
Symptoms reappear when drug is restarted
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What are the most common drugs to give ADRs?
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Antibiotics
Anti-neoplastics
Cardiovascular drugs
Hypoglycaemics
NSAIDs
CNS drugs
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What are some common systems that will be affected by drugs?
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GI
Renal
Haemorrhagic
Metabolic
Endocrine
Dermatologic
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What are some common ADRs?
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Confusion
Nausea
Balance problems
Diarrhoea
Constipation
Hypotension
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What is the yellow card scheme?
First ADR reporting scheme (voluntary)
| Collects spontaneous reports of suspected adverse drug reactions.
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What are the strengths of the yellow card scheme?
Acts as 'early warning system' for identification of previously unrecognised reactions.
Provides information about factors which predispose patients to ADRs.
Allows comparisons of ADR 'profiles' between products.
Continual safety monitoring of a product throughout its lifetime.
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What are the weakness of the yellow card scheme?
Cannot provide estimates of risks as true numbers of cases is underestimated.
Relies on ADRs being recognised.
Not all ADRs are reported.
May be stimulated by promotion and publicity.
Reporting is high for newly marketed drugs.
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Why are reporting rates in the yellow card scheme so low?
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Ignorance
Diffidence
Fear
Lethargy
Guilt
Ambition
Complacency
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What is a black triangle drug?
A medicine that is undergoing 'additional monitoring'
e.g.
A new active substance
A biological medicine
Conditional approval
Additional studies needed - rare side effects seen
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What is a serious reaction from a drug?
A reaction that is fatal, life threatening, is disabling or incapacitating, results in/prolongs hospitalisation.
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What is drug hypersensitivity?
Objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects and may be caused by immunologic and non-immunologic mechanisms.
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What are the different types of anaphylaxis?
Can be immunological or non-immunological.
Can be immediate (<1hr) - urtucarual, anaphylaxis
Or delayed (>1hr) - other rases, hepatitis, cytopenias
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What type of hypersenstivity reaction is anaphylaxis?
Type 1 hypersensitivity reaction
Prior exposure to the antigen/drug
IgE antibodies formed after exposure to molecule
IgE becomes attached to mast cells or leucocytes, expressed as cell surface receptors
Re-exposure causes mast cell degranulation and release of pharmacologically active substances - histamine, prostaglandins, leukotrienes, platelet activating factor
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What is antibody dependent cytotoxicity?
Type 2 hypersensitivity reaction = antibody dependent cytotoxicity
Drug or metabolite combines with a protein
Body treats it as foreign protein and forms antibodies (IgG, IgM).
Antibodies combine with the antigen and complement activation damages the cells.
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What is an immune complex mediated reaction?
Type 3 hypersensitivity reaction
Antigen and antibody form large complexes and activate complement
Small blood vessels are damaged or blocked
Leukocytes attacted to the site of reaction release pharmacologically active substances leading to an inflammatory process (includes glomerulonephritis, vasculitis).
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What is a lymphocyte mediated reaction?
Type 4 hypersensitivity reaction
Antigen specific receptors develop on T-lymphocytes
Subsequent administration leads to local or tissue allergic reaction.
e.g. contact dermatitis
Stevens Johnson syndrome
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What is non-immune anaphylaxis?
Previously called anaphylactoid reaction
Due to direct mast cell degranulation
No prior exposure
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What are the main features of anaphylaxis?
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Exposure to drug, immediate rapid onset
Rash (absent in 10-20%)
Swelling of lips, face, oedema, central cyanosis
Wheeze/shortness of breath
Hypotension
Cardiac arrest
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How would you manage anaphylaxis?
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Airway, Breathing, Circulation
Stop drug if infusion
Adrenaline IM 500mg
High flow oxygen
IV fluids
IV anti-histamines
IV hydrocortisone
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What does adrenaline do in anaphylaxis?
Vasoconstriction - increase in peripheral vascular resistance, increased BP and coronary perfusion via a1-adrenoreceptors
Stimulation of B1-adrenoreceptors positive ionotropic an chronotropic effects on the heart
Reduces oedema and bronchodilates via B2-adrenoreceptors
Increases cAMP and decreases release of inflammatory mediators
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What are the risk factors for hypersensitivty?
Medicine factors - protein or polysacharide
Host factors - F>M, immunocompromised, HIV, previous drug adverse, uncontrolled asthma
Genetic factors - certain HLA groups, acetylator status
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What might suggest that a patient has an allergy to a drug?
The response does not correlate with the pharmacological properties of the drug.
No linear relation with the dose.
Reaction similar to those produced by other allergies
Induction period of primary exposure
Disappearance on cessation
Re-appears on re-exposure
Occurs in a minority of patients
