Pharmacology Flashcards
What is Pharmacodynamics?
How the drug affects the body
What is pharmacokinetics?
How body affects the drug
Describe the 4 aspects of Pharmacokinetics
ADME
Administration - route
Distribution - systemic spread
Metabolism - 1st pass metabolism, IV skips this!
Excretion - hepatically or renally
Drug Receptor types
Ligand-gated ion channels - nicotinic ACh receptors
G Protein Coupled receptors (GPCR’s) - beta-adrenoceptors
Kinase-linked receptors - for growth factors
Cytosolic/nuclear receptors - steroid
What questions should you ask when prescribing a drug, with pharmacokinetics in mind?
How quickly will drug reach its site of action? How quickly will I see a response?
Drug interactions likely?
Is a dose adjustment needed in certain disease states?
What monitoring is required?
What mechanisms do drugs use to permeate membranes?
- Passive diffusion through hydrophobic membranes - lipid soluble molecules
- Passive diffusion through aqueous pores - only v small soluble drugs, e.g. lithium
- Carrier mediated drugs - quite unusual, basically when proteins that usually transport sugars, amino acids etc transport drugs
How does drug ionisation affect drug absorption?
Ionised drugs have poor lipid solubility
∴ only unionised drugs can pass
Why are the majority of medications PO?
Convenient
Cost-effective
Where are medications that are weak bases best absorbed? Why?
In the small intestine
bc small intestine has a pH of ~ 6.5 ∴ more likely to be similar pH to pKa of medication (the pH at which ionised & unionised drug is 50/50)
Where are medications that are weak acids best absorbed? Why?
In stomach
bc stomach has a pH of ~ 3 ∴ more likely to be similar pH to pKa of medication (the pH at which ionised & unionised drug is 50/50)
What factors affect the oral drug absorption in the stomach?
Gastric enzymes - digest the drug, esp large protein drugs e.g. insulin (∴ never given orally)
Low pH - can degrade
Full stomach = slower absorption
Gastric motility - can be altered by drugs/disease
Prev. surgery
What factors affect the oral drug absorption in the small intestine?
Drug structure - large/hydrophillic molecules are poorly absorbed
Medicine formulation - i.e. capsule has a coating to control release
Modified release slows rate of absorption (bc less freq dosing)
P-glycoprotein - will remove substrates from endothelial cells back into lumen lol
What is first pass metabolism?
Metabolism of drugs which prevents them from reaching systemic circulation
(The fraction of drug lost at absorption)
What happens during first-pass metabolism?
Degradation by enzymes in intestinal wall
&
Absorption from intestine into hepatic portal vein and metabolism via liver enzymes
What is bioavailability?
Proportion of administered dose which reaches the systemic circulation
What is bioavailability (F) dependent on?
Extent of absorption and first pass metabolism
NOT on rate of absorption
Varies w/ route of administration and between Px
e.g. tablet has lower bioavailability (F) than IV
What is bioavailability expressed as?
% or fraction
Pros of PR route
Local administration
Avoids first pass metabolism
Helps if patients has severe N/V ∴ can’t take meds orally
Cons of PR route
Absorption is variable
Patient preference
Example of PR medication
Diazepam suppositories for epileptic seizures
Pros of INH route
Well perfused large SA
Local administration
Cons of INH route
Inhaler technique might be ineffective
Example of INH route meds
Gaseous anaesthetic
Salbutamol inhaler
Pros of SC route
Faster onset than PO
Formulation can be changed to control absorption rate
Cons of SC route
Not as rapid as IV
Examples of SC route meds
Long acting insulin for T1DM and T2DM
Pros of TD route
Provides continuous drug release
Avoids first pass metabolism
Cons of TD route
Only suitable for lipid soluble drugs
Slow onset of action
Examples of TD route medication
Fentanyl patches for severe chronic pain
What factors influence distribution?
- Molecule size (small, ↑ distribution)
- Lipid solubility (if lipophillic, ↑ distribution)
- Protein binding (if NOT protein bound, ↑ distribution)
What is the volume of distribution (Vd)?
Also sometimes known as apparent volume of distribution
Theoretical vol a drug will be distributed in the body
Vol of plasma required to contain the total administered dose
If well distributed, high Vd
If poorly distributed, low Vd
What is the blood brain barrier?
Membrane that separates foreign substances in blood from CNS
Describe the physical aspect of the BBB
Continuous layer of endothelial cells with tight junctions
Has high number of efflux pumps that remove water soluble molecules
How can drugs reach the CNS?
High lipid solubility - can permeate and diffuse across BBB
Intrathecal route
Inflammation - causes BBB to be leaky ∴ drugs can cross
In actuality, what must you think about when prescribing drugs, in relation to distribution?
Careful w dosing drugs with a small Vd - using actual body weight in obese patients
e.g. Aciclovir NOT distributed to fat ∴ should be dosed based on ideal body weight, not actual
Distribution changes in diff disease states (i.e. sepsis = leaky blood vessels = BBB penetration)
Age changes body composition, which changes Vd of water soluble drugs
Drugs that can cross BBB have CNS s/e
What is drug elimination?
The process by which the drug becomes no longer available to exert its effect on the body
Name 2 methods of drug elimination
Metabolism - modification of drug to new chemical entity
Excretion of unchanged drug
What are the 2 phases of metabolism?
- Oxidation / Reduction / Hydrolysis to introduce reactive group to chemical structure. Slightly increase hydrophilicity
By microsomal enzymes e.g. CYP450 - CONJUGATION. Adds functional group to produce hydrophilic, inert molecule.
e.g. glucuronidation
then excreted
What cytochrome is mainly responsible for Phase 1 metabolism? Where are these located?
Cytochrome P450 (CYP450)
Mostly in liver (also small intestine, lung)
When will CYP enzyme function vary?
Genetic variation
↓ Function in severe liver disease
Interactions w/ drugs/foods which can ↑ or ↓ activity
How many CYP450 enzymes are there?
57
What CYP enzyme has the substrates caffeine, paracetamol, theophylline and warfarin?
CYP 1A2
What CYP enzyme has the substrates ibuprofen and warfarin?
CYP 2C9
What CYP enzyme has the substrates codeine and warfarin?
CYP 2D6
What CYP enzyme has the substrates simvastatin, warfarin, DOACs, carbamazapine and diltiazem?
CYP 3A4
What substrates are associated with CYP1A2?
Caffeine, paracetamol, theophylline, warfarin
What substrates are associated with CYP2C9?
Ibuprofen, warfarin
What substrates are associated with CYP2C19?
Omeprazole, phenytoin
What substrates are associated with CYP2D6?
Codeine, warfarin
What substrates are associated with CYP3A4?
simvastatin, warfarin, DOACs, carbamazapine and diltiazem
Which are the most signif CYP for drug metabolism?
3A4, 2C9, 2C19, 1A2, 2D6
In actuality, what must you think about when prescribing drugs, in relation to metabolism?
If severe liver impairment, is metabolism reduced?
∴ reduced dose? additional monitoring? avoid??
Drug interactions
Saturation of metabolic pathways can lead to accumulation or toxicity (paracetamol overdose)
If normal dose of paracetamol, how is it metabolised?
Via glucuronidation and sulphation to form a non-toxic metabolite
If paracetamol overdose, how is it metabolised? What is the result? How do we treat this?
Normal pathway is saturated
∴ Oxidation by CYP2E1
Forms NAPQI (v toxic)
Causes hepatocyte necrosis ∴ liver failure
We would give IV n-acetyl cysteine (NAC)
Replenishes body’s stores of glutathione
∴ glutathione conjugation
∴ produces a non-toxic metabolite :)
When would we give a reduced paracetamol dose?
In low body weight patients
Or if severe hepatic impairment
In what forms can drugs/metabolites be excreted?
Liquids - small polar molecules e.g. urine, bile, sweat, tears, breast milk
Solids - large molecules e.g. faeces (thru biliary excretion)
Gases - volatiles e.g. expired air
What is the first process that accounts for renal excretion?
-
Glomerular filtration
Free/unbound drug molecules will pass through
V large molecules will be excluded and will go thru efferent arteriole
What is the 2nd process of renal excretion?
-
Active tubular secretion
Drug molecules transported from blood into renal tubule thru carriers
(organic anion transporter (OAT) & organic cation transporter (OCT))
Can clear protein bound drugs
Most effective renal clearance mechanism
What is the 3rd process of renal excretion?
-
Passive reabsorption
Diffusion down conc gradient from tubule into peritubular capillaries
Hydrophobic drugs diffuse easily
Highly polar drugs will be excreted
Types of Adverse drug reactions
ABCDEFG
Augmented
Bizarre
Chronic/continuing
Delayed
End of use/withdrawal
Failure of treatment
Genetic
What should you do if a patient has a Adverse Drug reaction?
Report to MHRA using the YELLOW CARD SCHEME
What is Augmented ADR caused by?
Exaggerated effect of drugs pharmacology at therapeutic dose
Usually not fatal
What is the most common ADR?
Augmented (80%)
When is Augumented ADR dependent on?
Dose dependent
Reversible when drug is withdrawn
Give some examples of Augmented ADR
AKI w/ ACE-i
Bradycardia w/ beta blockers
Hypoglycaemia w/ gliclazide, insulin
Resp depression w/ opiates
Bleedings w/ anticoag
Describe Bizarre ADRs
Not related to pharm
Not dose related
Can cause serious illness/death
Symptoms don’t always resolve when stopping drug
Give examples of a Bizarre ADR
Anaphylaxis w/ penicillin
Tendon rupture w/ quinolone abx
Steven Johnson Syndrome w/ IV vancomycin
What is a Chronic/Continuous ADR?
An ADR that continues after drug has been stopped
Give examples of Chronic/Continuing ADR
Osteonecrosis of the jaw w/ bisphosphonates
HF w/ pioglitazone
What is a delayed ADR?
ADRs that become apparent some time after stopping drug
Give an example of a delayed ADR
Leucopenia w/ chemo
What is an End of Use/Withdrawal ADR?
ADR that develops after drug has been stopped
Give examples of End of Use/Withdrawal ADR
Insomnia after stopping benzodiazepine
Rebound tachycardia after stopping BB
What could cause a Failure of treatment ADR?
Drug-drug or drug-food interaction
Poor compliance with administration instructions
Give examples of a Type F ADR
Failure of bisphosphonates due to taking w/ food
Failure of DOAC due to enzyme inducer (e.g. carbamazepine)
What is a Genetic ADR?
When drug causes irreversible damage to genome
Give an example of a Genetic ADR
Phocomelia in children of women taking thalidomide
Other than the ABCDEFG classification, what is another way of classifying ADRs?
DoTS
Dose-relatedness
Timing
Susceptibility
Describe the Do in DoTS
Dose relatedness
Looks at the dose you might get a ADR
//
Hypersusceptibility reaction
When you get an ADR at a subtherapeutic dose
e.g. anaphylaxis w/ penicillin
Collateral effect
ADR at a therapeutic dose
e.g. hypokalaemia w/ loop diuretic
Toxic effects
ADR at subpratherapeutic dose
e.g. liver damage w/ paracetamol
Describe the T in DoTS
Timing
When does ADR develop in relation to the drug taken
TYPES :
Rapid
First dose
Early
Intermediate
Late
Delayed
Describe the S in DoTS
Susceptibility
Certain patients/groups have specific susceptibility to ADRs
Could be due to :
Age
Gender
Disease states
Physiological states
Define Agonist
Have full affinity and FULL efficacy
∴ ↑ Activation of the receptor
Define Antagonist
Full affinity and ZERO efficacy
∴ ↓ Activation of the receptor
Define affinity
How well a ligand binds to its receptors
Define efficacy
How well a ligand successfully activates its receptors
Define Potency
Relative strength of the drug
i.e. lower dose needed for response
Define a Competitive inhibitor
Binds AT active site
↓ Efficacy reversibly
Affinity is unchanged
Define a Non-Competitive inhibitor
Binds AWAY from active site, changes its shape
↓ Efficacy irreversibly
↓ Affinity
In terms of the Dose/Response curve, describe competitive inhibitors
Curve shifts to the RIGHT
Drug has less affinity but same efficacy
Same EC50
DRUG IS LESS POTENT
What is Ec50?
The conc required for a 50% effect
In terms of the Dose/Response curve, describe non-competitive inhibitors
Curve shifts RIGHT & DOWN
Drug has less affinity and less efficacy
EC50 decreases
DRUG IS LESS POTENT
Define Bioavailability
How much drug is uptaken systemically for effect
e.g. IV = always 100%
What is the therapeutic range?
Upper and lower bounds of safe dose of a drug
(if narrower range, needs more care in dispensing)
Drug Targets for drugs
Examples of each
Receptor action (MC!!) - Beta blockers
Enzymes - ACEi
Ion channels - CCB
Transporters - PPI
Where does metabolism of drugs occur?
GIT - mechanical & chemical digestion, for majority of food
Renal - simple, already soluble molecules.
Hepatic - more complex, hydrophobic molecules. Undergoes Phase 1 +/- Phase 2 reactions
Autonomic vs Somatic?
What transmission falls under what?
Autonomic - automatically, no conscious effort
Parasympathetic and Sympathetic
Somatic - voluntary
Skeletal muscle motor
Parasympathetic pre and post synpatic?
ACH - pre
ACH - post
Sympathetic pre and post synaptic?
AcH - pre
Noradrenaline - post
Skeletal muscle motor what neurotransmitter?
Ach at the NMJ
2 Main receptors in Cholinergic Pharm?
Where are they - in reference to synapse?
Nicotinic - Presynaptic
Muscarinic - Postsynaptic
Name the main muscarinic receptors
Where do you find them?
M1 - Brain
M2 - Heart
M3 - Lungs!
Which condition is related to disrupted Ach Transmission at the NMJ?
Myasthenia Gravis
Tx Myasthenia Gravis
Neostigmine
Pyridostigmine
S/E of XS Acetylcholine stimulation
SLUDGE
Salivation
Lacrimation
Urination
Defecation
Gastric distress
Emesis
Where do we find Alpha 1 & Alpha 2 receptors?
Vessels and sphincters e.g. bladder neck
(Distal circulation)
Where do we find Beta 1 receptors?
Heart
Where do we find Beta 2 receptors?
Lungs
What is tamsulosin?
Alpha 1 blocker
Name a Beta 1 agonist
When is it used?
Dobutamine
Cardiogenic shock!!
What does a Beta 1 AGONIST do?
INCREASES force (inotropy) and rate (chronotropy) of cardiac contractions
What does a Beta 1 ANTAGONIST do?
DECREASES force (inotropy) and rate (chronotropy) of cardiac contractions
Name a Beta 1 antagonist
Beta blocker!
When are BB CI?
Absolute asthma
What does a Beta 2 AGONIST do?
Bronchodilate airways
Example of Beta 2 agonist
SABA - salbutamol
What is a cardioselective drug?
Give an example
Only act on cardiac tissue
Beta blockers (beta 1 only)
Examples of opioids
Morphine
Diamorphine (heroin)
Codeine
Pethidine
What is the bioavailability if you take opioids PO?
50%
When do you tend to use opioids?
For chronic severe pain relief
Mostly cancer pain
5mg diamorphine =
10mg morphine = 100mg pethidine
Main S/E of opiate use?
Constipation
Opiate over can cause ?
Treatment for this and Route of administration?
Respiratory depression
IV Naloxone
Give examples of when you would use blood thinners?
DVT/PE
AF
Prosthetic valves
Bleeding disorders
Ischaemic stroke
MI
Give examples of blood thinners
DOACs - Apixaban, Rivaroxaban
Warfarin
LMWH
Alteplase IV
Antiplatelets - Clopidogrel, ticagrelor
Warfarin inhibits?
Vit K
Clotting factors 10, 9, 7, 2
LMWH inhibits?
Clotting factors 3, 10
What does COX-1 do?
Involved in Prostaglandin synthesis
which protects gastric mucosa
S/E COX-1 inhibition
Peptic ulcer
NSAID MOA?
Inhibits arachidonic acid pathyway COX-1 and COX-2
What does COX-2 do?
Involved in inflammation
Example of a selective COX-2 inhibitor?
Celecoxib
Why don’t we use COX-2 selective drugs?
Not as effective
Also expensive
Where do Loop diuretics act upon?
Ascending limb
MOA Loop diuretics
Na-K-Cl contransporter channels
Example Loop diuretic
Furosemide
Where do Thiazide Diuretics act on?
DCT
Thiazide diuretic MOA
Na-Cl co-transporter
Example of Thiazide diuretic
Bendroflumethiazide
Where do Aldosterone antagonists act upon?
Collecting duct
MOA Aldosterone antagonist
Increases Na+ excretion and retains K+ but acting on aldosterone receptors
What is an aldosterone antagonist also known as?
K+ sparing diuretic
PPI e.g.
Lansoprazole
What does PPI do?
↓ Acidity of GI lumen
Nicotinic is assoc w?
CNS
Muscurinic is assoc w?
PNS
Main S/E of ACEi
Why?
Dry cough
Bc build up of bradykinin in airways
Difference between tolerance and dependence?
Tolerance is physiological while dependence is psychological
Main S/E of CCB
What condition might this be mistaken for?
Oedema - Ankle swelling
HF
What is the first line treatment for Anaphylaxis?
IM 500 micrograms Adrenaline
Metformin S/E
GI distress
Stomach pain
S/E Sulphonylurea
Hypoglycaemic episodes
Weight gain
What is Metformin?
Biguanide
S/E Spironolactone
Hyperkalaemia
Stomach cramps
S/E Amiodarone
Clubbing
Non-productive cough
Fine crackles on ausc
Reduced chest expansion
Thyroid disease
Corneal deposits
S/E Statin
Myalgia
Liver impairment
S/E BB
Bradycardia
Bronchospasm
Cold peripheries