Pharm Flashcards
5 core drugs for depression?
sertraline citalopram mirtazapine venlafaxine fluoxetine
3 SSRIs? primary mechnaimis?
citalopram, sertraline, fluoxetine
act on serotonin reuptake transporter on presynaptic neuron to inhibit serotonin reuptake → ↑ serotonin in synapse
side effects of SSRIs?
nausea, diarrhoea
sexual dysfunction
anxiety
insomnia
what other transporter does sertraline inhibit?
dopamine transporter (mildly)
citalopram is a mild antagonist of which receptors?
muscarinic and histamine
fluoxetine is a mild antagonist of which receptors?
5HT2A
5HT2C
when taking fluoxetine caution needs to be taken with which drug?
warfarin - could inhibit it’s anticoagulant effect
what are the drug targets of venlafaxine?
serotonin and noradrenaline transporters
venlafaxine mechanism of action?
inhibits serotonin and noradrenaline reuptake by acting on reuptake transporters (serotonin≥NA) SNRI
side effects of venlafaxine?
nausea, diarrhoea sexual dysfunction insomnia anxiety hypertension at high doses
what are the drug targets of mirtazapine?
alpha 2 receptor
5-HT2 & 3 receptor
H1 receptor
mechanisms of action of mirtazapine?
antagonises central presynaptic a2 adrenergic receptors → ↑ serotonin and NA release
antagonises central 5HT2&3 receptors → 5HT1 receptors unopposed → anti-depressant effects
side effects of mirtazipine?
weight gain
sedation
may exacerbate REM sleep behaviour disorder
(±sexual dysfunction)
with what drug is citalopram contraindicated? why? (ecg)
erythromycin
both associated with prolonging QT interval
why do antidepressants need to be gradually discontinued?
risk of drug interactions
serotonin syndrome
withdrawal symptoms
relapse
what receptor is mirtazapine most selective for? what is the side effect of this and how is it offset?
histamine H1 receptor
sedation
however at increased doses this is offset by increased NA transmission
4 core drugs for diabetes?
metformin
DDP4 (dipeptidyl-peptidase4) inhibitors eg.sitagliptin
sulphonylurea eg. gilclazide
SGLT2 inhibitors eg. dapaglifozin
metformin mechanism of action?
activates AMPK in hepatocyte mitochondria → inhibits ATP production → blocks gluconeogenesis → ↓ HGO → restore insulin sensitivity
blocks adenylate cyclase → ↑ fat oxidation → restore insulin sensitivity
side effects of metformin?
abdo pain diarrhoea ↓appetite vomitting (especially at high doses, slow increase in dose better)
what transporter does metformin require to enter tissues?
OCT-1
what makes metformin more effective?
presence of endogenous insulin (some residual functioning pancreatic islet cells)
give an example of a DDP-4 inhibitor?
sitagliptin
mechanism of action of DDP-4 inhibitors?
inhibit DPP-4 action in the vascular endothelium → ↓ metabolism of incretins like GLP1 → more incretins → ↑ insulin secretion & ↓ glucagon production
slow down digestion and ↓ appetite
side effects of DPP-4 inhibitors?
upper respiratory tract infections w flu-like symptoms
allergic reactions
DDP-4 inhibitors should be avoided in patients with what?
pancreatitis
what do DDP-4 inhibitors require to be effective?
residual functioning pancreatic beta cell activity
example of a sulphonylurea?
gliclazide
mechanism of action of sulphonureas?
inhibit ATP-sensitive potassium channel on pancreatic beta cells → ↑ depolarisation → Ca2+ influx → insulin vesicle exocytosis
side effects of sulphonylureas?
weight gain
hypoglycaemia
how is weight gain mitigated with sulphonylureas?
taken with metformin
example of SGLT-2 inhibitor?
dapaglifozin
mechanism of action of SGLT-2 inhibitors?
reversibly inhibits SGLT-2 in renal proximal convoluted tubule → ↓ glucose reabsorption → ↑ urinary glucose excretion
side effects of SGLT-2 inhibitors?
uro-genital infections (increased glucose load) slight decrease in bone formation can worsen DKA hypotension weight loss
what would cause SGLT-2 inhibitors to be less effective?
renal impairment
where is OCT-1 expressed?why is this important?
OCT-1 allows the polar metformin to enter tissues
found in hepatocytes - allows for distribution
enterocytes of small bowel - for absorption
proximal renal tubules - excretion
pharmacodynamics vs pharmacokinetics?
pd = drug actions on body pk = body actions on drug
4 types of drug targets?
enzymes
ion channels
transporter protein
receptors
types of drug-receptor interactions?
electorstatic - eg vdws, h bonds
hydrophobic - lipid soluble drugs
covalent - least common, irreversible
stereospecific
affinity and efficacy?
a = strength ability of a drug to bind a receptor, ↑ affinity = ↑ receptor occupancy e = ability of a drug to produce an effect once bound
agonists vs antagonists?
no efficacy = antagonist = prevents activation of receptor
partial agonist = affinity for receptor but sub maximal efficacy = partial response
agonist = has affinity for receptor and maximal efficacy
what is potency?
concentration/dose of a drug required to produce a 50% tissue response (EC50 and ED50)
major pharmacokinetic factors?
absorption
distribution
metabolism
excretion
what is bioavailability?
the fraction of initial drug dose that gains access to systemic circulation
what is the bioavailability of IV administration?
100%
forms of drug administration?
oral inhlaed dermal/percutaneous intranasal IV
how are drugs normally transported into tissues?
diffusion across lipid membranes
carrier mediated transport
what form of drug is more lipid soluble?
unionised = more likely to diffuse across plasma membrane
pKa and pH are equal , what does this mean?
the drug will be 50/50 ionised/unionised
weak acids have what pKa range?
3-5
as pH decreases what happens to weak acids?
unionised form dominates
weak bases have what pKa range?
8-10
as pH decreases what happens to weak bases?
ionised form dominates
what pHs are best for weak acids and bases to be absorbed?
weak acid - low pH → more unionised → more lipid soluble
weak base - high pH → more unionised → more lipid soluble
what factors determine how much drug a tissue is exposed to?
regional blood flow
plasma protein binding
capillary permeability
tissue localisation
regional blood flow of tissues?
what factors affect regional blood flow?
liver, kidneys, muscle, brain, heart
exercise = more to muscle
large meal = more to GI tract
which plasma protein is good at binding acidic drugs?
albumin
what determines how much of a drug is bound to plasma proteins?
free drug concentration
affinity for protein binding sites**
plasma protein concentration
what kind of capillary structure does the liver have?
discontinuous = allows for easy diffusion of drugs out of blood into liver tissue
what kind of capillary structure does the kidney glomerulus have?
fenestrated = allows for passage of some small drugs to pass from blood into kidney tubules = better excretion
explain tissue localisation
depends on tissue fat and water content compared to plasma
eg. brain has a higher fat content and plasma has higher water content
for fat soluble drugs the equilibrium is more weighted towards retention in tissue with higher fat content
same for water soluble drugs
what liver enzymes are mainly responsible for drug metabolism?
P450 enzymes (phase 1) transferases (phase 2)
what are the 2 phases to drug metabolism?noverall effect?
phase 1 - add reactive polar group to drug
phase 2 - add conjugate to reactive group
=↓ lipid solubility = ↑ excretion elimination
how can phase 1 metabolism occur?
oxidation **
reduction
hydrolysis
what are pro-drugs?
drugs that require metabolism in order to become pharmacologically active (parent drugs has no activity)
what happens in phase 2 metabolism?
attachment of substituent group to functional group from phase 1 → inactive , ↓ lipid soluble metabolite → facilitates excretion via urine/bile
what is first pass metabolism?
orally administered drugs are absorbed in small intestine and enter hepatic portal circulation → first pass through liver → heavily metabolised → ↓ drug reaching systemic circulation
solution to first pass metabolism? associated problems?
give a larger dose of drug to ensure enough reaches systemic circulation
however, amount of first pass metabolism varies between people → drug effects and side effects difficult to predict