Pharmocology Flashcards
WHAT IS PHARMOKINETICS?
The action of drugs in the body including/What the body does to a drug
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION
What is absorption?
The process of transfer from the site of administration into the general or systemic circulation
What are some routes of administration of drugs?
Enteral (oral)
Enteric-coated (intestinal absorption, e.g. aspirin)
Extended-release (slower absorption, e.g. metformin)
Sublingual/Buccal (rapid absorption + avoids 1stpass metabolism)
Parenteral (systemic circulation)
Intravenous
Intramuscular (anti-psychotics)
Subcutaneous (insulin)
Other
Inhalation(oral, nasal)
Topical
Rectal
How many membranes must most drugs cross? What is the exception to this?
One. IV and IA.
How can transfer through a membrane occur?
Passive diffusion
Facilitated diffusion
Active transport
Endocytosis
What do drugs need to be to pass directly through the cell membrane?
Lipid soluble.
What is the rate of diffusion proportional to?
Rate of diffusion proportional to concentration gradient, the area & permeability of the membrane and inversely proportional to thickness.
What is drug ionisation?
Basic property of weak acids or weak bases.
Why are ionisable groups important for drugs?
The ionic forces are part of the ligand receptor interaction.
What is the PKa of a drug?
pH of which half the substance is ionised and half not.
Where are weak acids absorbed?
Stomach.
Where are weak bases absorbed?
Intestine.
What determines absorption of drugs?
pH
Vascularity (e.g. shock reduces SC absorption)
Surface area
Contact time (e.g. with food = slower gastric emptying)
What are four factors that determine the rate of absorption of an oral drug?
Drug Structure.
Drug formulation.
Gastric emptying.
First pass metabolism.
What do drugs need to be to be absorbed from gut?
Drug needs to be lipid soluble to be absorbed from the gut.
What happens with highly polarised drugs in the gut?
Highly polarised drugs tend to be only partially absorbed with much passed into the faeces.
Some drugs are unstable at low pH or in the presence of digestive enzymes.
What must a tablet be to be absorbed?
The capsule or tablet must disintegrate & dissolve to be absorbed.
Most do so rapidly. Some having coating e.g. Enteric.
What is first pass metabolism?
Concentration of a drug is greatly reduced before it reaches the systemic circulation
What major metabolic barriers do drugs have to cross to reach the circulation?
Intestinal lumen
Intestinal wall
Liver
Lungs
What is contained within the intestinal lumen which limits absorption?
Contains digestive enzymes that can split peptide ,ester & glycosidic bonds.
Peptide drugs broken down by proteases (Insulin).
Colonic bacteria hydrolysis & reduction of drugs.
What is contained within the intestinal wall which limits absorption?
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.
How is the liver a metabolic barrier? How can you avoid this barrier?
Blood form gut delivered by splanchnic circulation directly to liver.
Liver is major site of drug metabolism
Avoid hepatic first pass metabolism by giving drug to region of gut not drained by splanchnic e.g mouth or rectum ( GTN )
WHAT IS DISTRUBITION?
Rate & extent of movement of a drug into (and out)of tissues from blood.
What factors control distrubition?
Blood flow (e.g. brain > muscles)
Capillary permeability
Plasma protein binding (e.g. albumin)
Tissue protein binding (e.g. cyclophosphamide accumulating in bladder leading to cystitis)
Lipophilicity(ability to cross cell membranes)
What can some drugs bind to? And what do these act as?
Plasma proteins.
Act as a depot as they release the drug when the blood concentration becomes lower giving a slow release.
What is the half life?
Time taken for a concentration to reduce by half.
In practice the half life is normally for the elimination rate from the plasma as this is easy to measure.
What is bioavailability?
This is the fraction of the administered drug that reaches the systemic circulation unaltered. (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
What are the factors that control bioavailability?
First Pass Hepatic Metabolism (hepatic transformation of drug to inactive metabolites)
Solubility
Chemical instability (e.g. GI enzyme destruction of insulin)
Why is bioavailability important?
If an oral drug has a score of 0.1 it will need to be 10x the IV dose to be as effective.
Why can’t you measure oral and iv bioavailability at a single point in time?
Different concentration/time profiles.
WHAT IS METABOLISM?
The transformation of the drug molecule into a different molecule.
What happens in metabolism?
Lipid soluble drugs are converted into water soluble ones.
Two phases.
What is first order kinetics?
Catalysed by enzymes, rate of metabolism directly proportional to drug concentration
An exponential fall in the plasma drug concentration
What happens when you plot the log of the concentration in first order kinetics?
Gives a straight line with -k gradient and gives you the concentration at time 0.
What is zero order kinetics?
Enzymes saturated by high drug doses, rate of metabolism is constant, e.g. ethanol, phenytoin
Linear fall in concentration.
What are the steps in metabolism?
What is involved 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 found?
Smooth endoplasmic reticulum.
Largely in liver tissue.
What increases and decreases P450 metabolism?
Smoking and alcohol increase.
Grapefruit and Cimetidine decrease.
What happens in a phase 2 reaction?
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.
Where are some other drugs metabolised?
Plasma, lungs gut.
WHAT IS ELIMINATION?
The removal of a drugs activity from the body.
What is excretion?
The molecule is expelled in liquid, solid or gaseous “waste”.
What does total excretion equal?
Total excretion = glomerular filtration+ tubular secretion-reabsorption.
What does water soluble drugs rate depend on?
Water soluble drugs rate of distribution depends on rate of passage across membranes.
What does lipid soluble drugs rate depend on?
Lipid soluble drugs rate of distribution depends on blood flow to tissues that accumulate drug.
What does Vd stand for?
Vd = total amount of drug in body (dose)/plasma concentration.
The extent of distribution of drug more clinically important as this determines the total amount of drug that has to be administered to produce a particular plasma concentration
This measure is the apparent volume of distribution Vd
What does a low or high apperent volume show?
Low confined to circulatory volume.
High distributed in total body water.
What is clearance?
Clearance ( CL ) is the volume of blood or plasma cleared of drug per unit time.
Eg if 10% of a drug carried to the liver is cleared at flow rate of 1000ml/min the clearance is 100ml/min
If a drug has a high Vd what is the rate proportional to?
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 k? What is it equal to?
k is the rate constant of elimination
K= CL/Vd
Previously k =0.693/t1/2
Therefore t1/2 =0.693 Vd/CL
What is the AUC?
Area under the plasma drug concentration versus time curve; a measure of drug exposure.
How is clearance determined?
Clearance is usually determined using the AUC after an iv dose.
CL= Dose/AUC for iv drug
CL= Dose x F/AUC for oral drug with bioavailabilty of less than 1.
What is meant by steady state?
The rate of elimination is the same as drug input.
What does the rate of elimination equal?
Clearance x steady state.
How can an IV steady state be reached?
- With iv infusion it takes approx. 4-5 half lives to reach 95% of Css
- a drug with slow elimination will take a long time to reach steady state and it will accumulate high plasma concentrations before elimination rate rises to match drug infusion
- A high Vd can also lead to a delay in reaching Css as t1/2 is also dependent on Vd ( t1/2 = 0.693Vd/CL )
When is steady state achieved for IV?
For iv infusion, Css is achieved when the rate of elimination equals the rate of infusion
Rate of elimination equals CL x Css so at steady state the rate of infusion also equals this.
So Css = rate of infusion/ CL
or can calculate plasma clearance CL =rate of infusion/Css
What are the properties of oral administration?
- Most long term drug administration is by oral route
- Doses are intermittent so will have peaks and troughs
- Rate of absorption will affect the profile- rapid= exaggerated peaks, slow= flatter peaks
- Correct for bioavailability
D x F/t (t is time interval between doses)
What is the steady state equal to with oral?
- When steady state is reached , the rate of administration is equal to the rate of elimination which is CL x drug concentration between peaks and troughs
- D x F/t = CL x Css
- So Css = D x F/ t x CL
- This means can alter plasma Css by changing either dose ( D) or interval (t )
What is the loading dose and what is it needed for?
- 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 PERIPHERAL NERVOUS SYSTEM DIVIDED INTO?
Sympathetic and Parasympathetic
What information does the autonomic nervous system convey?
All CNS information except for muscles.
What happens in the somatic nervous system?
One neurone comes from the CNS to innervate one muscle.
What happens in the autonomic nervous system?
Two nerves, pre and post ganglionic fibres.
How long is each parasympathetic and sympathetic fibre?
Parasympathetic long pre ganglionic with short post ganglionic.
Sympathetic short pre ganglionic with long post ganglionic.
What nerves are parasympathetic?
Some cranial nerves and sacral nerves.
What neurotransmitter do post ganglionic fibres release and what receptors do they act on in the parasympathetic system?
Acetylcholine on muscarinic receptors.
What neurotransmitter do post ganglionic fibres release and what receptors do they act on in the sympathetic system?
They release noradrenaline which activates adrenergic receptors, of which there are two main types (alpha/beta) with subtypes.
What parts of the body are only sympathetic control?
Sweat glands and blood vessels.
What parts of the body are only parasympathetic control?
eye and bronchial smooth muscle.
What is the pre ganglionic neurotransmitter for both autonomic systems and what receptor do they act on?
Acetylcholine and nicotinic receptor.
What is released at sweat glands from the sympathetic system?
Acetylcholine on muscarinic receptors.
What are some NANC neurotransmitters?
NO and vasoactive intestinal polypeptide parasympathetic. ATP and neuropeptide Y.
What effect does nicotine have on receptors?
It activates both sympathetic and parasympathetic systems.
What effect does muscarine have on receptors?
Activates the muscarinic receptors on the parasympathetic system.
What are two types of muscarinic receptors?
M1-5, GPCRs.
Where are each of these receptors found? M1. M2. M3. M4/M5.
M1: mainly in the brain.
M2: mainly in the heart. Their activation slows the heart, so we can block these (atropine for life- threatening bradycardias and cardiac arrest)
M3: glandular and smooth muscle. Cause bronchoconstriction, sweating, salivary gland secretion.
M4/5: mainly in the CNS.
What effects does the muscarnic agonist pilocarpine have on the body?
Stimulates salivation.
Activating the sympathetic nervous system. Contracts iris smooth muscle (parasympathetic nervous system).
Side effects would be to slow the heart.
What are some examples of muscarinic antagonists?
Atropine. Hyoscine.
What can Hyoscine be used for?
Antagonise sympathetic driven secretions.
What drugs can you use to treat bronchoconstriction?
Short-acting: ipratropium bromide (atrovent)
Long-acting: LAMAs such as tiotropium, glycopyrrhonium
What else is ACh involved in?
Memory.
What side effects do anti-cholinergic drugs have?
In the brain, anticholinergics worsen memory and may cause confusion Peripherally, may get constipation, drying of the mouth, blurring of the vision, worsening of glaucoma Tricyclic antidepressants, some early antihistamines, some anti-emetics (prochlorperazine).
What side effects do cholinergic drugs have?
Organophosphate insecticides and nerve gases causing poisoning are irreversible acetylcholinesterase inhibitors, and cause muscle paralysis and twitching, salivation, confusion.
What are the catecholamines?
Noradrenaline: released from sympathetic nerve fibre ends, beloved in the management of shock in the intensive care unit.
Adrenaline: released from the adrenal glands (fight and flight, management of anaphylaxis).
Dopamine (the precursor of adrenaline and noradrenaline).
What do each of these receptors do? Alpha 1 Alpha 2 Beta 1 Beta 2 Beta 3
Alpha 1
Contracts smooth muscle (pupil, blood vessels)
Alpha 2
Mixed effects on smooth muscle
Beta 1
Inotropic effects on heart
Beta 2
Relaxes smooth muscle (premature labour, asthma)
Beta 3
Enhances lipolysis, relaxes bladder detrusor
What does alpha 2 receptor do?
Lower blood pressure.
What are some alpha blockers?
Doxazosin and tamsulosin.
Are there any alpha 2 blockers?
No.
What will beta 1 activation do?
Increase heart rate and chronotropic effects.
What do beta 2 agonists induce?
Muscle relaxation: beta 2 activation is life saving in asthma, and can delay onset of premature labour But beta agonists will cause tachycardia and affect glucose metabolism in the liver: beta 1/3 affect carbohydrate and lipid metabolism
What can beta 3 agonists do?
Reduce over-active bladder.
Give examples of some beta blockers?
Propanolol and atenolol.
What does propranolol do?
Blocks beta 1 and beta 2. Will slow heart rate, reduce tremor, but may cause wheeze.
What does atenolol do?
Beta 1 selective, main effects on heart.
What is Methyldopa useful for?
Useful in preeclampsia and clampsia.
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.
What are some different adverse drug reactions?
One in 20 hospital admissions caused by ADR’s
Side effects (therapeutic range)
Toxic effects (beyond therapeutic range)
Hypersusceptibility effects (below therapeutic range)
What is the Rawlins Thompson classification? Different types?
Type A (Augmented pharmacological)– predictable, dose dependent, common (morphine and constipation, hypotension and antihypertensive)
Type B (Bizarre or idiosyncratic)– not predictable and not dose dependent (anaphylaxis and penicillin)
Type C (Chronic) – osteoporosis and steroids
Type D (Delayed) – malignancies after immunosuppression
Type E – (End of treatment) – occur after abrupt drug withdrawal.
What are some causes of adverse drug reactions?
Pharmaceutical variation.
Receptor abnormality.
Abnormal biological system unmasked by drug.
Abnormalities in drug metabolism.
Immunological.
Drug-drug interactions.
Multifactorial.
What are the effects of type A adverse drug reactions (augmented)?
Extension of primary effect (bradycardia and propranolol, hypoglycaemia and insulin, haemorrhage due to anticoagulants).
Secondary effect (bronchospasm with propranolol B2 blocking effect).
What are the properties of type B adverse drug reactions?
Not predictable
Not dose dependant
Cant be readily reversed
Less common but often serious
Life threatening
Can be idiosyncrasy
Can be allergy or hypersensitivity
What is idiosyncrasy?
Inherent abnormal response to a drug
Genetic abnormality, enzyme deficiency
May be due to abnormal receptor activity
Rare but serious
What is an example of enzyme abnormality?
Haemolysis with primaquine
Glucose 6 phosphate dehydrogenase (G6PD) enzyme deficiency + primaquine
Haemolysis and haemolytic anaemia
What is an example of receptor abnormality?
Malignant hyperpyrexia with general anaesthetics
Sudden huge rise in calcium concentration
Increase in muscle contraction
Increase in metabolic activity
Rise in body temperature
What is allergy/hypersensitivity?
Antigen/antibody reaction
First dose acts as antigen
Antibody produced
Second dose causes antibody-antigen reaction
What are the different types of allergic reaction?
Type 1 immediate anaphylactic IgE eg penicillin allergy
Type 2 cytotoxic antibody IgG, IgM eg methyl dopa and haemolytic anaemia
Type 3 eg procainamide induced lupus
Type 4 delayed hypersensitivity T cell eg contact dermatitis
What are examples of type C adverse reactions?
Steroids and osteoporosis
Analgesic nephropathy
Steroids and iatrogenic Cushing’s syndrome
Colonic dysfunction due to laxatives
What are examples of type D adverse reactions?
Teratogenesis – drugs taken in the first trimester e.g. thalidomide.
Carcinogenesis eg cyclophosphamide and bladder cancer.
What are some examples of type E adverse reactions?
Glucocorticoid abruptly withdrawn leads to adrenocortical insufficiency.
Withdrawal seizures when anti-convulsants are stopped.
What are the patient risks for adverse drug reactions?
Gender
Elderly
Neonates
Polypharmacy
Genetic predisposition
Hypersensitivity/allergies
Hepatic/renal impairment
Adherence problems
What are the drug risks for adverse drug reactions?
Steep dose-response curve.
Low therapeutic index.
Commonly causes ADR’s.
WHAT ARE THE DIFFERENT TYPES OF DRUG INTERACTIONS?
Synergy.
Antagonism.
Other.
What are the risks for drug interactions for the patient?
Polypharmacy
Old age
Genetics
Hepatic disease
Renal Disease
What are the risks for drug interactions for the drug?
Narrow therapeutic index
Steep Dose/Response Curve
Saturable Metabolism
What are the mechanisms of pharmacodynamics?
Receptor based.
Signal transduction.
Physiological systems.
What affects absorption of a drug?
Motility
Acidity
Solubility
Complex formation
Direct action on enterocytes
What affects distribution of a drug?
Protein binding.
What affects metabolism of a drug?
CYP450
Inhibition
Induction
What is CYP450?
Haemoprotein,.
How does inhibition work?
Drug A blocks metabolism of Drug B, leaving more free Drug B in the plasma -> increased effects.
How does induction work?
Drug C induces CYP540 isoenzyme, leading to increased metabolism of Drug D -> decreased therapeutic effects.
What is renal excretion dependent on?
pH.
How do weak acids and bases differ in urine excretion?
Weak bases - cleared faster if urine acidic
Weak acids - cleared faster if urine alkali
What are some examples of weak acids and bases?
What are the types of pharmacodynamics mechanisms?
Receptor based
Signal transduction
Physiological systems
What are the properties of receptor based mechanism?
Agonists
Partial Agonists
Antagonists
Competitive
Non-competitive
What are the properties of physiological systems?
Different drugs that effect different receptors, but in the same physiological system.
Ca Channel antagonist + B-Blocker.
ACE-I + NSAID.
WHAT DOES A ALLERGIC REACTION TO A DRUG INVOLVE?
Interaction of drug/metabolite with patient and disease.
Subsequent re-exposure.
What are the different types of hypersensitivity?
Type 1 – IgE mediated drug hypersensitivity.
Type 2 – IgG mediated cytotoxicity.
Type 3 – Immune complex deposition.
Type 4 – T cell mediated.
What is involved in type 1 hypersensitivity reactions? Acute Anaphylaxis?
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 sustances.
What is involved with acute anaphylaxis?
Occurs within minutes and lasts 1-2 hours.
Vasodilation.
Increased vascular permeability.
Bronchoconstriction.
Urticaria.
Angio-oedema.
What is involved with type 2 hypersensitivity reactions?
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 e.g. methyl-dopa-induced haemolytic anaemia.
What is involved with type 3 hypersensitivity reactions?
Antigen and antibody form large complexes and activate complement.
Small blood vessels are damaged or blocked.
Leucocytes attracted to the site of reaction release pharmacologically active substances leading to an inflammatory process.
Includes glomerulonephritis, vasculitis.
What is involved with type 4 hypersensitivity reactions?
Antigen specific receptors develop on T-lymphocytes
Subsequent administration leads to local or tissue allergic reaction.
E.g. contact dermatitis.
What is non immune anaphylaxis?
Due to direct mast cell degranulation.
Previously called Anaphylactoid reactions
Some drugs recognised to cause this
No prior exposure
Clinically identical
What are some risk factors for hypersensitivity?
Medicine factors:
Protein or polysacharide based macro molecules
Host factors:
Females > Males
Immunosuppression
Genetic factors:
Certain HLA groups
WHAT HAPPENS IF MORPHINE IS TAKEN ORALLY?
First pass metabolism by the liver
50% of oral (enteral) morphine is metabolised by first pass metabolism
Halve the dose if giving it s/c, IM, IV (parenterally) etc.
What does opium contain?
morphine and codeine.
What is heroin?
Diamorphine
How do opioids work?
Review of pain pathways - opioid drugs simply use the existing pain modulation system
Natural endorphins (endogenous morphine) and enkephalins
G protein coupled receptors - act via second messengers
Inhibit the release of pain transmitters at spinal cord and midbrain - and modulate pain perception in higher centres - euphoria - changes the emotional perception of pain.
What is the problem with inhibiting the pain pathway like opioid do?
Descending inhibition of pain
Part of the fight or flight response
Never designed for sustained activation
Sustained activation leads to tolerance and addiction
What are some examples of opioid receptors?
mew, delta and kappa. nociceptin opioid-like receptor
What happens if you activate the kappa receptor?
Depression.
What does potency mean?
Whether a drug is ‘strong’ or ‘weak’ relates to how well the drug binds to the receptor, the binding affinity.
What is the efficiency of a drug?
Is it possible to get a maximal response with the drug or not?
Or even if all the receptor sites are occupied do you get a ceiling response?
The concept of full or partial agonists.
Which opioid has the most potency?
Diamorphine.
What does tolerance mean?
Down regulation of the receptors with prolonged use Need higher doses to achieve the same effect
What does craving mean?
Psychological - craving, euphoria Physical.
How long does opioid withdrawal last?
Starts within 24 hours, lasts about 72 hours.
What are the side effects of opioids?
Respiratory Depression.
Sedation.
Nausea and Vomiting.
Constipation.
Itching.
Immune Suppression.
Endocrine Effects.
What is the response to opioid induced respiratory depression?
Call for help ABC Naloxone IV is fastest route Titrate to effect - don’t have to give it all once - once you’ve injected a drug you can’t get it back! Short half-life of naloxone - beware drug addict overdoses in A&E
What is codeine? and what does this mean?
A prodrug. It needs to be metabolised by cytochrome CYP2D6 to work.
How is morphine metabolised and into what?
Morphine is metabolised to morphine 6 glucuronide which is more potent than morphine and is renally excreted.
With normal renal function this is cleared quickly.
WHAT IS PHARMACODYNAMICS?
How the drug affects the body.
What is pharmacokinetics?
Describes the disposition of a compound within an organism.
ADME (absorption, distribution, metabolism and excretion.
What does draggability mean?
The ability of a protein target to bind small molecules with high affinity.
What are some drug targets?
receptors.
enzymes.
transporters.
ion channels.
What are some top prescribed drugs and what do they do?
What is a receptor?
A component of a cell that interacts with a specific ligand* and initiates a change of biochemical events leading to the ligands observed effects.
What are the different types of receptors? Example of each?
ligand-gated ion channels
nicotinic ACh receptor
G protein coupled receptors
beta-adrenoceptors
kinase-linked receptors
receptors for growth factors
cytosolic/nuclear receptors
steroid receptors
What are some ligands on G coupled receptors?
Ligands include light energy, peptides, lipids, sugars, and proteins.
What do the majority of G coupled receptors interact with?
The majority of GPCRs interact with PLC or adenylyl cyclase.
How do kinase-linked receptors work?
Signal dimer binds.
Kinase activity stimulated.
Tyrosine are phosphorylated.
Intracellular proteins bind to phosphorus-tyrosine doing sites.
What do nuclear receptors do?
Modify transcription.
What do zinc fingers do?
Bind DNA.
What are some imbalances in chemicals which lead to disease?
Chemicals allergy; increased histamine Parkinson’s; reduced dopamine
What are some imbalances in receptors which lead to disease?
myasthenia gravis; loss of ACh receptors mastocytosis; increased c-kit receptor
What is an agonist?
a compound that binds to a receptor and activates it.
What is an antagonist?
a compound that reduces the effect of an agonist.
What does an agonist response curve look like?
Steep rise with little increase in concentration.
What does a log concentration response curve look like?
Sigmoidal.
What is EC50?
Concentration that gives half the maximal response.
What is a partial agonist?
Agonist which never gives the full maximal response.
What is Efficacy?
The maximum response achievable from a dose.
What does intrinsic activity mean?
Intrinsic activity (IA) or efficacy refers to the ability of a drug-receptor complex to produce a maximum functional response.
What are the different agonism and antagonisms?
•Selective agonism
–potency of a range of agonists
•Selective antagonist
–competitive antagonist
What are the different types of antagonism?
Competitive and non-competitive.
What are some examples of cholinergic receptor subtypes?
muscarine atropine mAChR nicotine curare nAChR
What happens when the H2 receptor is activated and antagonised?
Histamine (agonist)
contraction of ileum
acid secretion from parietal cells
Mepyramine (antagonist)
reversed contraction of ileum
no effect on acid secretion.
What are the different Histamine receptors?
H1 - Allergic reactions. H2 - Gastric acid secretion. H3 - Mostly CNS disorders. H4 - Immune system and inflammatory disorders.
What is affinity?
Describes how well a ligand binds to the receptor. Affinity is a property shown by both agonists and antagonists.
What is efficacy?
Describes how well a ligand activates the receptor.
What is the receptor reserve about?
Holds for a full agonist in a given tissue reserve can be large or small; depends on tissue.
What does signal amplification do?
Starts at a small response but amplified to give a bigger response.
What is an allosteric modulation?
Other site on receptor for a different ligand to bind.
What is an inverse agonist?
Gives less activation the more if binds.
What is tolerance?
reduction in drug* effect over time continuously, repeatedly, high concentrations.
What is desensitisation?
uncoupled. internalized. degraded.
What is an enzyme inhibitor?
An enzyme inhibitor is a molecule that binds to an enzyme and decreases (normally) its activity.
What are the two types of enzyme inhibitor?
Irreversible inhibitors usually react with the enzyme and change it chemically (e.g. via 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.
How do statins work?
Block the rate limiting step in the Cholesterol pathway A class of lipid-lowering medications that reduces the levels of “bad cholesterol” Reduce cardiovascular disease (CVD) and mortality in those who are at high risk. Huge cost to health care but being reduced by generics.
How does the renin-angiotensin-aldosterone system work?
Renin-angiotensin-aldosterone system is a major blood pressure regulating mechanism. The system increases blood pressure by increasing the amount of salt and water the body retains.
What does inhibiting ACE do?
Inhibiting ACE reduces ATII production and therefore causes a reduction in blood pressure.
How is L-DOPA made?
produced from the amino acid L-Tyrosine as a precursor for neurotransmitter biosynthesis.
What is Carbidopa?
Peripheral DDC Inhibitor. Blocks DDC in the periphery generating more for the CNS pathway.
What is COMT?
Peripheral COMT Inhibitorprevents breakdown of L-DOPA generating more for the CNS pathway.
What does mono amine oxidase B inhibitor do?
Mono Amine Oxidase B InhibitorPrevents Dopamine breakdown and increases availability.
What do Central Dopamine Receptor Agonists do?
Antagonise dopamine receptors (not enzyme inhibitors).
What are the three main proteins ports in a cell?
Uniporters: use energy from ATP to pull molecules in.
Symporters: use the movement in of one molecule to pull in another molecule against a concentration gradient.
Antiporters: one substance moves against its gradient, using energy from the second substance (mostly Na+, K+ or H+) moving down its gradient.
What is an example of a supporter?
NKCC.
What are some examples of ion channels.
Epithelial (Sodium) – heart failure
Voltage-gated (Calcium, Sodium) – nerve, arrhythmia
Metabolic (Potassium) – diabetes
Receptor Activated (Chloride) - epilepsy
Where are voltage gated calcium channels?
In nerves, activated upon sodium flooding into the axon.
What is Amlodipine?
Amlodipine is an angioselective (Why is that important?)
Ca channel blocker that inhibits the movement of Ca ions into vascular smooth muscle cells and cardiac muscle cells.
What do voltage gated sodium channels do?
In excitable cells Voltage-gated Na+ channels have three main conformational states: closed, open and inactivated..
What blocks voltage gated sodium channels?
Lidocane.
What is an example of voltage gated potassium channels?
Regulate insulin in Pancreas: Islets of Langerhans Increased glucose leads to block of ATP dependent K+ channels. Repetitive firing of action potentials increases Ca+ influx and triggers insulin secretion.
What blocks voltage gated potassium channels?
Repaglinide, nateglinide and sulfonylureal.
What does the GABA-A receptor do?
Endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. GABA A receptor is post-synaptic, opens Cl- channel - induces hyperpolarisation.
What increases the permeability of the GABA channel?
Barbiturates.
What inhibits the sodium potassium pump?
Digoxin.
What does digoxin do?
This inhibition causes an increase in intracellular Na, resulting in decreased activity of the Na-Ca exchanger and increases intracellular Ca. This lengthens the cardiac action potential, which leads to a decrease in heart rate.
What is the hydrogen potassium ATPase of the stomach?
The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach.
What is an inhibitor of the hydrogen potassium ATPase?
Omeprazole.
What is drug development?
Drug development is the process of bringing a new pharmaceutical drug to the market.
What are the stages of drug development?
Lead compound identification
Pre-clinical research
Filing for regulatory status
Clinical trials. on humans
Marketing the drug.
What are the different types of drug development?
Medicines from Plants
Inorganic Elements
Organic molecules
Sulphonamide Nucleus
Bacteria/fungi/moulds
Stereoisomers
Immunotherapy Antibodies
Medicines from Animals
Recombinant proteins/steroids
DNA/transcription/gene selection
Gene Therapy
High throughput assays/rational design
What are stereoisomers?
Stereoisomers have the same molecular formula and sequence of bonded atoms, but differ in the three-dimensional orientations of their atoms in space.
