Pharmacology Flashcards
How do ion channels ensure only the target ion passes through
Molecular selectivity filter – specific substrates
Define antagonist
Antagonist: blocks or reduces agonist mediated responses
Define placebo
Any intentionally ineffective medical treatment, such as a sugar pill, used to replace medication.
Still gives a physiological as well as psychological response
Describe the effect of ‘induction’ i.e. brussel sprouts
Induction = shortens action of drugs
Define therapeutics
use of drugs to diagnose, prevent and treat illness (and/or pregnancy) i.e. the medical use of drugs
Define drug
a chemical substance of known structure, which when administered to a living organism produces a biological effect.
What is the relationship between the systemic circulation and the tissue called?
i.e.
Circulation – high conc = Greater movement to tissue
As tissue concentration increased = Movement back to blood
dynamic equilibrium
What are the 4 common protein target types
Enzymes Carrier molecules (transporters / pumps) Ion channels Receptors
Describe orthosteric binding
A different substance to the intended ligand competes for the target binding site by binding orthosterically via the same binding site. This blocks access for the intended ligand.
Described how a Ca2+ channel blocker would work (and overall effect)
Physically blocks the channel to prevent the ions from passing through e.g. Vasodilator – smooth muscle Reduced myocardial contraction force Slows SA node Slows AV node conduction
Describe phase 2 of metabolism
- Adding of endogenous substance- (covalent bonding)
- Making it water soluble
- Inactivates pharmacologically
- Converting the drug/toxin by covalently joining to other molecules
Finish the sentence:
Basic drugs e.g. propranolol
———- ionised in basic solutions (high pH)
———- ionised in acidic solutions (low pH)
Basic drugs e.g. propranolol
Less ionised in basic solutions (high pH)
Become ionised in acidic solutions (low pH)
What are the 4 basic principles of pharmokinetics
- Absorption
- Distribution
- Metabolism
- Excretion
In the duodenum (pH 8.5) could an acidic drug pass into the blood plasma?
Acidic drug = ionised so NO
define enzyme
A protein (or protein-based molecule) that acts as a catalyst to speed up a chemical reaction. Acts on specific substances known as substrates
Does this illustrate well, or poorly perfused tissues?
Well perfused tissues
Which one of the 3 injection site types is generally the best, and why?
Intravenous (I.V.)
–most direct, bypasses absorption barriers
–rapid, high concentrations
–bioavailability ~100%
–avoids 1st pass metabolism
Intramuscular (I.M) –dependant on blood flow
Subcutaneous (S.C.) –more slowly absorbed, again dependant on blood flow
In the duodenum (pH 8.5) could a basic drug pass into the blood plasma?
Yes, as unionised
Basic drug becomes unionised –> Less lipophilic –> Becomes partitioned (trapped)
State 4 Transepithelial routes: AKA enteral routes of drug absorption
- Oral
- Buccal
- Inhalation
- Rectal Suppository
How does drug ionisation affect their permeability?
Affects drug permeation i.e. their solubility by changing lipophillicity, as Ionised molecules cant diffuse across membranes
True or False: Drugs have complete specificity for their actions
No drug acts with complete specificity
What does this graph infer
The Atenolol is a ‘selective’ β1 receptor antagonist
As reduced potency
Define pharmacokinetics
The way the body effects the drug- How the drug is handled.
What are the 3 major types of membrane protein
transporter enzyme receptor
Define affinity
the relative attraction of a drug molecule to the target receptor
(which may or may not produce a response i.e. antagonist)
What is an EC50
The effective concentration of the drug in question- Concentration needed to give 50% maximal response
State 3 factors that can affect distribution
- Protein binding
- Blood flow
- Membrane permeation \ Tissue solubility
describe the Quaternary protein structure
2 or more polypeptides combine to form functional protein
Why can protein binding be dangerous in terms of pharmacology?
Drugs can compete at plasma protein binding site
may displace each other →drug-drug interaction
e.g. warfarin & aspirin have same binding site of serum albumin and could lead to uncontrollable bleeding if both taken together
Broadly, how does a drug produce an effect
the drug molecule binds to a target molecule, changing the properties to either activate, deactivate or modulate the target molecule to produce an effect
Why is drug ionisation an issue?
And how does this occur?
Affects the way the drug behaves i.e. its actions
Due to pH changes in the body
i.e. propanolol in +ve state, and aspirin in -ve state
What are the beneficial affects of having poorly perfused tissues?
- Slower increase
- But- acts as a ‘sink’, effectively removing drug for circulation
- Until equilibrium point is reached
What is important to consider in biliary excretion?
Gut bacteria can convert drug to original form via metabolising enzymes.
Drug can be resorbed across intestinal wall and re- circulate in blood.
Then can be metabolised in liver again and re-secreted into bile
Define pharmacodynamics
Effect(s) of a drug on the body- How it works!
Define allosteric
Allosteric: binds to different region but still affects the binding site
Define ligand
Ligand: a molecule that binds to the receptor e.g. ACh
describe the tertiary protein structure
α-helices and β-sheets re-folded to form a globular molecule.
Would ions move up or down the electrochemical gradient preferentially
Down
Give an example of an instrinsic situation of poor perfusion
The blood brain barrier
L-DOPA can’t cross BBB due to its charge, so transported with L Amino Acid Transporter instead
What does the rate of absorption of drugs depend on?
- Route of administration
- Permeation ability
What are the three different names for a drug
The chemical name The generic name The proprietary name
Which organ is the principle site of drug metabolism?
The liver
Define efficacy
The ability to produce maximal response
Describe the principle excretory route of billary excretion
- hepatocyte uptake
- bile
- duodenum
- excreted in faeces
State 2 causes of tachyphylaxis
- Change in receptors
- e.g. GPCRs - phosphorylation by kinases
- Known as desensitisation – loss of affinity for ligand
- Loss of receptors
- e.g. internalisation
- Exhaustion of mediators
- e.g. loss of downstream transmitters
- Physiological adaptation
- e.g. other systems adjust / homeostasis
- Increased metabolic degradation
- e. g. Enzyme upregulation
What is the difference between full and partial agonists
Full agonists give an increase in response with increase in concentration until maximum tissue response is reached
Partial agonists give an increase in response with increased concentration but cannot produce maximal possible response
What is an EMax
maximum response a drug can produce point at which receptors are saturated
Describe the principle of lipophillicity in relation to membrane permeation
oCharged molecules, ions, ionised molecule diffuse less efficiently
oUncharged, non-ionised drugs have better access to membrane bound compartments
What is first pass metabolism
the rapid uptake and metabolism of an agent into inactive compounds by the liver, immediately after enteric absorption and before it reaches the systemic circulation.
Nutrient rich blood from the gut passes directly to the liver
Describe the effect of ‘inhibition’ i.e. grapefruit
What is the key function of metabolism
Conversion from lipid-soluble compound to more water-soluble one
Lipid soluble drugs can freely return to plasma from filtered urine and / or faeces
Define medicine
‘usually, but not necessarily, contains one or more drugs which is administered with the intention of producing a therapeutic effect.’
State one enzyme type which is involved first pass metabolism in each of the:
Liver, intestine, and lungs
- Liver- cytochrome p450
- Intestine- proteases or amino acid converting enzymes
- Lungs- oxidising enzymes
Define bioavaliability
proportion of active drug that reaches the systemic circulation
What organs display the most first pass metabolism
Liver, intestine, skin and lungs
Define orthosteric
Orthosteric: ‘competes’ for the same binding site
what is a false substrate analogue
Similar molecular shape to normal substrate Drug behaves like normal substrate Target enzyme produce an abnormal product Disruption the normal pathway i.e. signalling or metabolic i.e. methyldopa reducing production of norepinephrine by binding to dopamine hydroxylase
Define agonist
Agonist: a molecule that ‘activates’ a receptor
State 3 factors affecting oral absorption
- Disintegration of dosage form
- Chemical stability of drug
- Stability of drug to enzymes
- Presence and type of food
- Passage across GI tract wall
What is an excipient
substances ‘formulated’ along side a drug
In the gut lumen, could a basic drug pass into the blood plasma?
Basic drug (ionised) so NO
Ionised = more lipophillic
State 3 methods of transporting things in the body (via carrier proteins)
Active transport Facilitated diffusion Osmosis Passive transport
What are the benefits of having well perfused tissues?
- Rapid increase in bioavailable drug
- Rapid decrease –drug partitions to poorly perfused tissues
- Plasma concentration falls so- Drug re-partitions back to plasma
(Well perfused tissue ‘feeds’ uptake in poor)
Which drug is more potent? Red or Green?
Green as it has a higher EC50 at a lower concentration
Define potency
Concentration of a drug necessary to produce a given response
Define tachyphylaxis
- rapidly decreasing response to drug
- repeated or continuous administration
What are the 3 injection site types of drugs?
- Intravenous
- Intramuscular
- Subcutaneous
What is this schematic indicating?
first pass metabolism occuring
What is the major benefit of topical administration of drugs (absorption)
virtually insignificant first pass metabolism
define pro-drug
inactive/ partially active drug metabolically transformed in the body to an active form
What is a drug formulation
how the drug is ‘packaged’
Finish the sentence:
Acidic drugs e.g. Aspirin
———- ionised in acidic solutions (low pH)
———- ionised in basic solutions (high pH)
Acidic drugs e.g. Aspirin
Less ionised in acidic solutions (low pH)
Become/more ionised in basic solutions (high pH)
What are the two phases of metabolism
Phase 1- oxidation, reduction and hydrolysis etc
Phase 2- covalently joining of metabolite to other molecule
- Phase 1 may produce toxic metabolites
- Phase 2 converts to soluble metabolites for excretion
In urine, can acidic drugs pass into the blood plasma
Acid drug > tend to become non-ionised –> Looses it’s net charge = Become lipophilic
SO freely diffuses
****Acid drug –> mostly ionised –> remains in plasma
Describe the primary protein structure
Amino acids in a polypeptide chain Polar side groups
what are the three key drug/enzyme interactions
- Substrate analogues 2. False substrates 3. Conversion of pro-drugs
State 2 types of ion channels
Ligand-gated Voltage-gated Leak Background
what is an enzymatic substrate analogue
Similar molecular shape to normal substrate Usually work via ‘competitive’ inhibition of enzyme i.e. neostigmine (ACh inhibitor) for myasthenia gravis which binds to AChE resulting in more ACh at the NMJ
Describe protein binding in the context of drug distribution
- Partly bound to plasma protein and partly in plasma water
- Binding is reversible
- Only the UNBOUND fraction becomes avaliable and can cross membranes or bind to receptors
State 2 characteristics on an ideal drug
have a desirable pharmacological action with acceptable side effects (or none) reach it target in the right concentration at the right time remain at the site of action for sufficient time (in sufficient concentration) be rapidly and completely removed from the body when no longer needed
In the gut lumen (pH 1-2), could an acidic drug pass into the blood plasma?
Acid drug (unionised), so YES
Acid drug becomes ionised –> Less lipophilic –> Becomes partitioned (trapped)
Broadly, what is EC50 used to measure
The drugs potency
describe the secondary protein structure
Chains ‘fold’ or ‘coil’ α-helix: linkage within polypeptide chain β-sheet: linkage within or between chains
Describe why a pro-drug might be useful
If the drug isn’t metabolically activated until a specific target area it would minimise side effects, and increase the drug efficacy by having a stronger dose at the intended site.
Give an example of an endogenous ligand
Acetylcholine GABA Glutamate
Fick’s law states the rate of permeation depends on what 3 things?
- Surface area
- Concentration gradients
- Thickness of barrier
In the kidney, what are the 3 main mechanisms of excretion
- Glomerular Filtration
Only unbound drugs
- Secretion
Proximal convoluted tubule cells
- Reabsorption
Lipophilic drugs resorbed throughout nephron
Describe phase 1 of metabolism
Phase I – oxidation, reduction, hydrolysis
- oxidation (losing electrons)
- reduction (gaining electrons)
- hydrolysis (adding H2O)
- Polarization of the substance
- Increase water solubility
- Reduce pharmacological activity
- BUT may activate prodrugs
- Other enzymes often involved- (oxidases, hydrolases, reductase)
What is the implication of first pass metabolism
Reduced bioavaliabilty of the drug where it is needed in the body
Where are these protein targets found in the cell
in the cell membrane
Give an example of an exogenous ligand
Neostigmine Aspirin Methyldopa Acetylcholine etc. (manufactured)
Does this illustrate well, or poorly perfused tissues?
Poorly perfused tissues
What can our metabolic rate determine
•Metabolic rate can determine the duration of drug action and affects the rate of repeat dosing (Related to half-life)
Give 3 way drugs can be excreted
- Fluids- Urine / Sweat / Tears / Breast milk
- Solids- Faeces / hair
- Gases- Expelled air
State 4 main receptor superfamilies
Ionotropic (ligand-gated channels) Metabotropic (G-protein coupled) Kinase-linked Nuclear
True or False-
the two phases of metabolism are mutally dependent
Not mutually dependent-
One or other or both
May be required…
phase II can precede phase I
phase II can occur in the absence of phase I
What are the 4 major transportational processes of drug absorption?
oAqueous diffusion
oPassive diffusion
oCarrier-mediated diffusion
oActive transport
(pinocytosis with high molecular weight drugs)
Define drug distribution
Drugs transferred from circulation into tissue
State 3 sources of individual variation in drug response
Genetic variables Physiological variables Drug interactions Age Sex Weight Kidney & liver functions - elimination of drug
