ICPP (12-17) Flashcards
How many types of GPCR do we need to know about
7
- alpha-1,2
- Beta- 1,2
- muscarinic-1,2,3
When ligand attaches to the outside of the receptor
GaBYGTP turns into aGTP and BY
How many forms of aGTP
3
- asGTP
- aiGTP
- aqGTP
Outline QISS QIQ
Q- a1
I- a2
S- B1
S- B2
Q- M1
I- M2
Q- M3
asGTP
Stimualtes adenylyl cyclase- increasing cAMP
aiGTP
Inhibits adenylyl cyclase- decreasing cAMP
aqGTP
Stimulates phospholipase C, increasing IP3 and DAG
cAMP
Second message which stimulus PKA to phosphorylates proteins
IP3 stimulates
Calciumr elease from the ER through calcium channels to
DAG
Stimulates PKC to phosphorylates proteins e.g. VOCC
CGMP
Stimulates PKG to phosphorylates proteins
Signal amplification
1 GPC x multiple G- proteins x multiple effectors x multiple second messenger x calcium induced calcium release
E.g. M2 cholinrecepts with GI in the heart cause
Negative chronotoropy when ligands bind
B1 adrenoreceptors with Gs in the heart cause
Positive chronotropy when ligand bind
B1- adrenoreceptors wit gq cause
Arteriolar vasoconstriction
U- opioid receptors with GI cause
Less NT release
Relatively high calcium in
Extracellular space
High (ca2+)e created by
Sodium calcium exchanger (NCX)
Plasma membrane calcium ATPase (PMCA)
Where else is calcium high
In the SER/SR
How is high conc of calcium maintained in SR
Smooth endoplasmic reticulum calcium ATPase (SERCA)
What releases calcium into the cytoskeleton false
Voltage gated calcium channels and ligand gated Calcium channels
What releases calcium intot he cytoplasms slowly
Store operated calcium channels (SOC)
Explain calcium induced calcium release
- IP3 from phospholipase C binds to ligand gated calcium channel not he SR
- calcium leased
- calcium binds to different ligand gated calcium channels;s
- more calcium is released
All fibres in the ANS are
Efferent
the ANS is not
Under conscious contro
Main devious for he ANS
Sympathetic and aradymapthetic
Sympathetic
Fight or flight
Parasympathetic
Rest and die gets
Preganglionic neuron release
ACH into nicotinic acetyl choline receptor in post ganglionic neuron
Sympathetic (fight or flight)
- thoracolumbar emergence
- ganglaite in peruses paravertebrally or elsewhere
- medium pre
- Long post
- Release NA into a1, a2, B2 adrenoreceptors
Parasympathetic (rests and digest)
Cranial sacral (top and bottom) eme3rgence
- ganglia at the target organ
- long pre
- short post
- release ACH into M1 and m2 and M3 mACHr
What breaks ACetyl choline down
Acetylcholineesterase
What makes ACH
Actetycholinetransferase
How is adrenaline male
Catecholamine synthesis
- tyrosine -> DOPA —> dopamaine —> NA —> A
What breaks down cytoplasmic NA
Monoamine oxidase (MAO)
adrenoceptor agonists
increase sympathetic stimulation
adrenoceptor antagonists
decrease sympathetic stimulation
muscarinic cholinoceptor agonists increase
parasympathetic stimulation
muscarinic cholinoceptors antagonists
decrease parasympathetic stimulation
name 9 ways drug can be administed
oral intravenous intramusuclar transdermal intranasal subcutaneous sublingual inhalation rectal
transdermal
administered onto the skin
intramuscular
administered by injecting into a muscle
intravenous
administer by injecting into a vein
sublingual
under the tongue
subcutaneous
administered by injecting under the skin
two main ways drugs are delivered
enteral
parenteral
enteral
via GI
pareteral
not via GI
ways drugs are absorbed via enteral delivery
passive diffusion
facilitated diffusion
active transport
pinocytosis
passive diffusion
small non-ionic or unionised lipophilic drugs
facilitated diffusion
using solute carrier proteins (SLC)
- organic nation transports (OAT)
- organic cation transporters (OCT)
OAT
organic nation transports
OCT
organic cation transporters
what may affect drug action
first pass metabolism in the stomach and liver via enzymes such as cytochrome p450
active transport
primary with SLC or secondary with pre-eastibliashed conc gradient using co-transport
pinocytosis
large molecules like B12
what may affect enteral absorption
metabolism and contents of the gut
bioavailability
fraction of drug entering circulation after first pass hepatic metabolism
what is the most common reference compartment used in bioavailability
CVS compartment bioavailability reference – IV bolus= 100% (no physical/metabolic barriers to overcome)
Foral =
amount reaching systemic circulation oral/ Amount reach systemic circulation IV
= AUCoral/AUCIV
volume of distribution =
vd= urgence dose/ [plasma drug]
Kd
concentration at which 50% of drug binds tor eceptor
Bmax
concentration at which 100% binding is achieved
when there are extra receptors
fulll effect may be at 30% bidnding
EC50
dose at which 50% of the effect is achieved
phase 1 of drug metabolism
oxidation, reduction and hydrolysis (adds COOOh,- OH and NH2)
–> cytochrome P450 enzyme (CYP450)
CYP450 en zyme
can be induced or inhibited by various drugs
phase 2 of drug metabolism
conjugation (adds extra molecules to drug, usually glucoronate)
drug excretion
permanent removal of drug from body
drug excretion is usually
renal
- glomerular filtration
- proximal tubular secretion
- distal tubular reabsorption
drug excretion may also occur through
GI tract, sweat, tears, skin
clearance is the
rate of elimination
total clearance is
real clearance e+ hectic clearance
linear or first order kinetics means that
clearance psi dependent on conc (has a half life)
non linear or zero order or saturated kinetics means
clearance is independent of concentration (no half life)
some drug shave …… at low conc and …… at high conc
first order kinetics at low cocnentrations
zero order kinetics at high cocnentrations
(enzymes relevant to clearance become saturated at higher concentrations)
ligand
molecule that binds to a receptor
affinity
likelihood of ligand binding to receptor
efficacy
producing an effect when ligand is bound
potency
the product of affinity and efficacy
intrinsic activity
ability of the agonist to activate the receptor
agonists
ligand with affinity and efficacy
partial agonist
ligand with affinity and particle effaces
antagonist
ligand with affinity but no efficacy
reversible competitive antagonist
affinity to natural ligand binding site (orthosteric)
- reversible
- no efficacy
irreversible competitive antagonist
affinity to natural ligand binding site (orthosteric)
- non reversible
- no efficacy
non competitive antagonist
affinity to allosteric site
- no efficacy
- can be reversible and non reversible
non reversible
due to to covalent bonds
reversible
due to non-covalent bonds
what is salbutamol used to treat
bronchospasm in asthma
- administered via inhalation
salbutamol has affinity to
B2 adrenergic receptors in bronchi
- Has efficacy
- B2 agonists
which GPC does salbutamol effect
Gs
outline Gs stimulation via salbutamol
1) Salbutamol binds to Gs GPCR
2) GTP for GDP exchange
3) Separation of a and BY subunits
4) a-GTP subunit activates adenlyly cyclase
4) increase in cAMP
5) activation of PKA
6) causes inhabitation of myosin phosphorylation
7) smooth muscle relax
8) easier to rbeath
adrenaline autoinjector (EpiPen)
treatment of anaphylaxis and anaphylactic shock
how is EpiPen administered
intramuscular injection to lateral middle thigh
EpiPen has an affinity to
adrenergic receptor (agonists) - reversible
