ICS - PHARMACOLOGY Flashcards
What is pharmacology?
The study of the effects of drugs
What is pharmacodynamics?
How the drug affects the body
Pharmacokinetics: How are the majority of drugs broken down and gotten rid of?
Hepatically Metabolised and Renal Excreted
What is summation?
When 2 drugs used at the same time both have the expected effect (1+1=2)
What is synergism?
When using two drugs together makes both of the drugs more effective
For example, paracetamol and morphine
(1+1>2)
What is blockage
When one drug blocks the action of another
For example, salbutamol and non-selective beta blockers (1+1=0)
What is potentiation?
When one drug makes the other more potent, but its potency stays the same (1+1 = 2.5)
What is bioavailability?
How much of a drug taken is used. IV is always 100% but orally, this figure can change
Describe the difference between tolerance and desensitisation
- Tolerance - reduction in drug effect over time (continuously repeated high conc)
- Desensitisation - receptors become degraded / uncoupled / internalised
What is pharmokinetics?
What are the 4 things?
What the body does to the drug. There are 4 things
Absorbtion,
Distribution,
Metabolism
Excretion
ADME
Pharmokinetics: Outline what is meant by administration
Administration refers to the route/entry to the body.
What are the two main rotes of drug administration. What can the first be subdivided into?
Systemic and local
Systemic can be split into enteral and par-enteral (GI tract or not GI tract)
Give an example of
a) Enteral administration
b) Par-enteral Administration
a) Oral, Rectal , Sublingual
b) Intravenous, Intramuscular, Subcutaneous, and at times inhalation and transdermal
Give examples types of drug be administered locally
Topical
Intranasal
Eye drops
Inhalation (Inh)*
Transdermal*
Inhalation and transderaml can be local of systemic, depending on the drug
What are the four main things drugs target?
Cellular receptors - main one
Enzymes (ACE inhibitors)
Membrane ion channels (Lidocaine)
Membrane transporters (PPIs)
Pharmokinetics: What things does distribution depend on?
Blood flow to the area – drug will get to the brain (if can pass through BBB) faster than the skin
Permeability of capillaries – Slits (like in liver) or not (like in brain)
Whether bound to albumin in the blood or not (faster if free from albumin)
Lipophilicity – lipophilic drugs can penetrate the cell membrane easily
How does the body metabolise lipid soluable drugs?
Liver converts lipid soluble drugs into water soluble drugs so they can be excreted by the kidney
phase 1= make drug hydrophilic (cytochrome p450 catalyses);
phase 2 = if still too lipophilic, add something else to make it polar so the drug can’t be absorbed - e.g. acetylation/adding glutathione)
What can happen when drugs influence Cytochrome P450 enzymes?
Some drugs induce Cytochrome P450 enzymes ===> so other drugs are metabolised faster - can lead to sub-therapeutic dose
some inhibit CYP450, so other drugs are metabolised more slowly ====>and may reach toxic levels
You can see alcohol abuse, both chronic and acute, can mess up the P450 system
- (chronic alcohol can induce the P450 system, and acute alcohol can inhibit the P450 system)
name some drugs that induce the CY P450 enzymes
name some that inhibit it
Induce -
Chronic alcoholism
Anti-epileptics: phenytoin, carbamazepine
Smoking
Inhibit
Amiodoarone
Abx: ciproflaxacin, erythromycin
Allopurinol (gout)
SSRIs - fluoxetine, sertraline
Rate of elimination - What is meant by
First order elimination?
What is the most common way, first order or zero order?
First order = curve
a)
RATE OF METABOLISM DIRECTLY PROPORTIONAL TO THE DRUG CONCENTRATION
so starts off slow as all enzymes are full, when the amount of drug left goes down, the rate can speed up –> Curve )
First order is more common
Rate of elimination - what is meant by zero order elimination?
Give examples of some drugs that are eliminated by zero order.
b) enzymes saturated by high drug doses, rate of metabolism is constant, e.g. ethanol, phenytoin
Less common than first order
How is Paracetamol processed in the liver normally?
95% Converted into nom toxic compounds, conjugated with either sulphate or glucuronide (Phase II metabolism)
5% is converted into N-acetyl-p-benzoquinone imine (NAPQI) by Cytochrome p450 enzymes into highly reactive and toxic which would then be conjugated with glutathione so it can be excreted in the urine
What happens in a paracetamol overdose?
Too much NAPQI and not enough glutathione, so it accumulates and damages the liver.
How do you treat an paracetamol OD?
Either Within an hour of OD, or over an hour since OD
If it has been less than 1 hour since OD give activated charcoal
If longer than this give intravenous N-acetylcysteine
What is a receptor?
A component of a cell that interacts with a specific ligand and initiates a change of biochemical events
They are the principle means by which chemicals communicate
What are 3 things that naturally target receptors?
Neurotransmitters e.g., acetylcholine, serotonin
Autoacids (local hormones) e.g., cytokines, histamine
Hormones e.g., testosterone hydrocortisone
What are the 4 main different types of receptors?
Ligand-gated ion channels
G protein coupled receptors (most common)
Kinase-linked receptors
All on the cell surface membrane^^^^^
Cytosolic/nuclear receptors
Intracellular^^^
What kind of ligands to intracellular receptors recognise?
Hydrophobic ligands eg Steroids, which can diffuse across PL membrane
What kind of ligands to cell surface receptors recognise?
Larger ligands that can’t pass through the plasma membrane, or Hydrophyllic ligands
Cell surface receptors: What receptors do ligand-gated ion channels have? What happens when this substance binds to them?
nicotinic ACh receptor:
* Binding of ACh opens pore and allows an influx of any kind of cation(+ve) or efflux of any kind of anion (-ve).
Typically, cations (Ca2+, Na+, K+) ions passively diffuse into the cell, triggering reactions
Cell surface receptors: What is the shape of G-protein coupled receptor, and what is a G protein?
Starts out of the cell, and then wiggles in and out of the cell 7 times (like a snake before ending up inside the cell
G proteins, (guanine nucleotide-binding proteins,) are a family of proteins (35 in humans) involved in transmitting signals from G protien recpetor channels
What happens when a ligand binds to a G-protein receptor?
The G protein changes shape, causing GDP to be released, allowing for GTP to bind
…
Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate(GTP) toguanosine diphosphate(GDP)
What are the two main types of G protein?
Gq and Gs
G protein types: What receptor couples Gq protein? What two molecules does this produce as secondary messengers?
M3R (muscarinic receptor) couples with Gq protein =
Leads to IP3 and DAG formation, which are its secondary messengers
G protein types - what do the secondary messengers of Gq protein coupling go onto do within the cell?
IP3 = opens calcium channels, causing a Ca2+ efflux into the cytoplasm
DAG = activates protein kinase C (PKC),
*Protein Kinase C can go on phosphorylate target proteins
(The majority of GPCR’s interact with Phospholipase C or adenylyl cyclase)
G protein types: What enzyme does Gs protein activate, via what receptor? What two molecules does this produce as secondary messengers?
Binds to Beta 2 adrenoreceptor
Increases amounts of Cyclic AMP, which is its secondary messenger
leads to activation of PKA enzyme (PROTEIN KINASE A)
PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism
Cell surface receptors: What happens when ligand binds to a kinase-linked receptor?
Main one is tyrosine kinase
It triggers phosphorylation of the tyrosine molecules on the intracellular domain of the receptor.
Phosphorylated tyrosine molecules are involved in many different signalling cascades which are crucial for various processes such as cell division and wound healing.
Pharmalogically speaking, why do all medicines cause side effects?
Because in reality no drug is 100% specific. Ligands will not only bind to their target receptors, but also other very similar receptors on/in cells, causing unintended reactions.
What are the two types of ion channel, and what do they rely on?
Voltage gated and Ligand Gated
Voltage open or close in response to changes in membrane potential.
Ligand-gated ion channels, open or close in response to the binding of a specific ligand (for example a neurotransmitter) to their extracellular domain.
When they open, they provide a channel through which ions can passively enter the cell.
What happens when relevant ligands bind to intracelluar nuclear receptor?
Forms a ligand-receptor complex, which will then bind to DNA in the nucleus and directly affect gene transcription and protein synthesis.
Name diseases that are due to an imbalance of chemicals/ligands in signalling.
allergy; increased histamine
Parkinson’s; reduced dopamine
Name diseases that are due to an imbalance of receptors in signalling.
myasthenia gravis; loss of ACh receptors
mastocytosis; increased c-kit receptor
Define ligand
a molecule that binds to another (usually larger) molecule.
Define Agonist
a compound that binds to a receptor and activates it
Define antagonist
a compound that reduces the effect of an agonist
Define Efficacy
Describes how well a ligand activates the receptor
Does antagonists have efficacy?
No they Have affinity but zero efficacy
What receptors do G protein coupled receptors have?
M3R (muscarinic receptor)
Beta-2-adrenoreceptor. Produces second messenger cyclic-AMP
What are kinase-linked receptors targets for?
Growth factors
Give the pharmalogical definition of Affinity.
How strongly a medication binds to its receptor (determined by the strength of the chemical bond between the two)
What are cytosolic receptors targets for?
Steroids
Where would you find intracellular (nuclear) receptors? What tends to bind to them?
In the cell cytoplasm and nucleus,
Small, hydrophobic (i.e. lipid-soluble) molecules, which can diffuse across the plasma membrane by themselves tend to bind to them.
Give the pharmalogical definition of Potency
Amount of medication need to elicit an effect. (higher the affinity of a drug, the higher the potency)
What is intrinsic activity?
Emax of partial agonist/Emax of full agonist
Basically, how well a drug works against something that fully works
eg Emax of partial agonist (substance X) gives a 68% response
We know that a full agonist would give 100% response, so 68/100= 0.68
Therefore substance X has an intrinsic activity of 0.68
How do competitive antagonism work? What will it do to the drug sigmoidal curve?
The reverse the effects of agonists by competing with them to bind with receptors.
This therefore prevents agonists from having as strong of an effect
They shift the curve to the right meaning more agonist is required for the same response
DECREASE POTENCY. AS MORE OF THE FURG IS THEREFORE NEEDED TO ILLICT THE SAME RESPONSE - BUT EFFICACY STAYS THE SAME
(Like competitive inhibitor?)
How does non-competitive antagonism work? What will it do to the drug sigmoidal curve?
It shifts the curve right and down meaning even more agonist is required to illicit the same response
This is because an non-
competitive antagonist binds near the receptor and prevents activation of it but does not bind directly to it so the agonist is still
able to bind but just not activate the receptor
(like allosteric site inhibitors)
done up to 19
What do competitive antagonists do to a drug? What effect does this have on the sigmoid curve?
- reverses the effects of agonists, by competing with them to bind to the receptors
- So stops the agonists from having as strong an effect
- SHIFTS CURVE TO THE RIGHT
DECREASE THE POTENCY OF THE DRUG, AS MORE IS NEEDED TO ILLICIT THE SAME RESPONSE
What do non-competitive antagonists do to a drug? What effect does this have on the sigmoid curve?
Decrease potency - as more drug is needed to elicit the same response - curve goes the the right
competitive antagonists bind away from the ligand that the receptor would bind to - so the ligand will still bind to this receptor still but no response will be elicited (decrease efficacy, as no activation) - curve goes down
In the sympathetic nervous system, what do preganglionic neurons release? What does this bind to on the cell body of the postganglionic neuron cell bodies?
neurotransmitter Ach, which binds to nicotinic receptors on the cell membrane of postganglionic neuron cell bodies
Preganglionic - always nicotinic !!!!!
In the sympathetic nervous system, what do postganglionic neurons release? What does this bind to on the cell body of the postganglionic neuron cell bodies?
adrenaline (epinephrine) and noradrenaline (norepinephrine), collectively called catecholamines. These catecholamines bind to adrenergic receptors on the plasma membrane of the target organ cells.
In the parasympathetic nervous system, what do preganglionic neurons release? What does this bind to on the cell body of the postganglionic neuron cell bodies?
Ach, which binds to nictotinic receptors on the postganglionic cell bodies
Same as sympathetic preganglion!
In the parasympathetic nervous system, what do postganglionic neurons release? What does this bind to on the cell body of the postganglionic neuron cell bodies?
postganglionic neurons release ACh, but in this case it binds to the muscarinic receptors on the target organ cells.
Remember - Muscarinic receptors - a type of Cholinergic receptor
Autonomic nervous system - How many neurons?
Unlike the somatic system, the ANS has two neurons separated by the autonomic ganglion - pre and post ganglionic neurones
How are the two neurons arranged in
a) Sympathetic Nervous system
b) Parasympathetic nervous system
In the sympathetic system, the ganglion is within a chain adjacent to the spinal cord
In the parasympathetic system, the ganglion is within or very close to the effector organ
The sympathetic and parasympathetic systems are also different in their use of neurotransmitters
Exception - what do
a) sweat glands
b) blood vessels
release at postganglionic termini within the sympathetic nervous system?
At both these places, what does sympathetic action lead to?
a) acetylcholine (sweat)
b) Dopamine (Vasodilation)
Where would you find M1 receptors?
Where would you find M2?
M1 Brain
M2 - Heart (found in the SA node)
Where would you find M3 receptors?
Where would you find M4 and M5?
M3: All organs with parasympathetic innervation - eyes, lungs, gut, skin
M4: Mainly CNS
M5: Mainly CNS
What does activation of M2 do? (parasympathetic)
Activation of M2 on heart SA node
Decreases heart rate
Activation of M2 on heart AV node
Decrease conduction velocity
Induces AV node block (increases PR interval)
What does activation of M3 receptors do, in lungs, GI tract and skin?
Stimulation in the Respiratory System
Produces mucus (airways and nasopharynx)
Induces smooth muscle contraction (bronchoconstriction)
GI tract
Increase saliva production
Increases gut motility
Stimulates biliary secretion
Skin
Only place where Sympathetic system releases ACh
Stimulation of M3 causes sweating
What does activation of M3 receptors do, in urinary system and eye?
Both parasympathetic
Urinary System - Contraction of detrusor muscle, relaxation of Internal urethral sphincter
Eye - secretion of tears, MYOSIS, PUPIL CONSTRICTION -
How do nicotinic anatagonists work? When would they be used?
Compete with ACh for binding to the nicotinic receptor
eg Curare, Pancuronium (relax skeletal muscles during surgery) -
STOP SYMPATHETIC
Adrenergic Pharmacology: what
a) Alpha 1
b) Alpha 2
receptor do
Both G coupled
a1- Vasoconstriction, increased BP, Increased closure of internal sphincter of the bladder, pupil dilation
a2 - Inhibits NA release, and inhibits Ach release. Also inhibits Insulin release
Adrenergic Pharamcology: what
a) Beta 1
b) Beta 2
c) Beta 3
receptor do?
All G coupled, sympathetic (obvs)
a) Chronotropic and inotropic effects on heart (tachycardia and increased contractility)
b) Relaxes smooth muscle (seen in labour/asthma) bronchodilation, inhibits labour, causes insulin and glucagon to be secreted)
c) Enhances lipolysis relaxes bladder detrusor (urine retention)
Describe the dose-response curve for morphine.
As dose increases response increases. This association is initially rapidly and then the graph plateaus. It is not sigmoidal!
What it do you give to reverese a morphine overdose?
Naloxone - its an antagonist to morphine
What is the main opioid receptor, that all the drugs we currently use act on?
The main opioid receptor is the mμ receptors-opioid receptor (MOR).
Why can giving Buprenorophine be safer than morphine?
Because it is only a partial agonist, so only reaches up to 50% response.
Outline the potentsies of Diamorphine and pethidine, relative to morphine.
Relative potencies:
- Diamorphine (Heroin)- 5mg (twice as potent as morphine)
- Morphine - 10mg
- Pethidine - 100mg (10 times weaker than morphine)
Diamorphine - Heroin:
- More potent and faster acting (crosses blood-brain barrier quickly)
Antiplatelets: How does Aspirin work as an antiplatelet?
Aspirin works by irreversibly inhibiting the enzyme cyclo-oxygenase (COX-1) which reduces thromboxane synthesis.
Thromboxane is required to facilitate platelet aggregation and to stimulate further platelet activation.
Antiplatelets: How does Clopidogrel work as an antiplatelet?
It inhibts the binding ADP to its platelet receptor, so indirectly inhibits platelet aggregation.
By inhibiting platelet aggregation, blood flows more freely around the body.
Clopidogrel belongs to the class of medicines known as adenosine diphosphate (ADP) receptor antagonists (also called P2Y12 inhibitors). It is also a type of antiplatelet medicine
How do loop diuretics work? Give an example
act at the ascending limb of the loop of Henle
Reversibly inhibit the Na/K/Cl cotransporter, inhibiting the reabsorption of filtered sodium and chloride ions.
Ergo hypertonicity of the renal medulla, thus inhibiting water reabsorption by the collecting ducts.
eg Furosemide, Torsemide
How do thiazide diuretics work? Where do they act and give an example
Work on the distal convoluted tubule
inhibit reabsorption of sodium and chloride ions, by blocking the thiazide-sensitive Na-Cl symporter.
Inhibits the reabsorption of water, reabsorption of water is also inhibited, as water follows sodium.
Examples include clorothiazide and Bendroflumethiazide.
How do aldosterone antagonist diuretics work? Give an example
binds competitively to the aldosterone receptor (AR) at the aldosterone-dependent sodium-potassium exchange site.
This promotes sodium and water excretion and potassium retention
G protein types - what do the secondary messengers of Gq protein coupling go onto do within the cell?
IP3 = opens calcium channels, causing a Ca2+ efflux into the cytoplasm
DAG = activates protein kinase C (PKC),
*Protein Kinase C can go on phosphorylate target proteins
(The majority of GPCR’s interact with Phospholipase C or adenylyl cyclase)
