④

collagen synthesis
not drawn to actual shape )
Disclaimer organelles size (
:
or
.

② Rottgufudnlasmic ③ Apparatus
GIG

"

⑦ Nucleus
s

'm
:b
:*
':t:*
:L
Yang
:

" "

are
't .ec ,

chromosome 17 :
count .

ME
chromosome 7
:
COLIAZ TH dibsunfdsdl
ribosome
gu

.is?....Quoe*ri*oro...ainc.o...f.f:?m:nsion
pH meet
→
moon

Ntr
→

::"""⇒
!

:e÷÷÷
fibrils
assn
:{:
%9e.mm.mg

?f÷:÷x
* .

xrmjfmex
Of
' "

minimis
'

I
'

35¥ >

w¥m q¥÷f
ppp
*
.
-
- AAAAA →

CH
3

pro
-

tzchaintt )
\

.eu#tnexaEx*x-
m÷÷÷÷i÷÷÷n÷÷
:ddPmI¥dYYFIfI)
Pro collagen →
solute

.tn#drexHase,nnteIaIcna.m :*

reexamine
fermium
,

Ntr Ntm
'a%dmby
nth lysis oxidase
ex
stiff lemme
Hoppers . "
agen
.

↳
insoluble twpocollagen
↳ deaminate lysine collagen
.

oxidase t
hydroxy lysine residues to form
lysyl
respectively ft product of )
ayysinethydroxyallysine ammonia as rxn
.

Wo ends of molecules
modified peptides @ collagen
↳ forms covalent bonds w/ other
lysine or
lysine
residues .

( cross-linking )
anyone allow
stdassembly
.

↳ how
collagen fiber .

( non -

spiral part @ end of collagen)

 elastin
synthesis

÷÷÷÷÷:.i÷
)
Cytosol

===-÷÷÷÷:÷÷÷"÷÷""
[
highly soluble

topoelastin

④ There's only one

for elastin but ,

twpo
gene

j
attractive
.sn#i::siiaa
:

ya
*,

:c
on
÷i
- I
'

I I

chat

÷i
! c f twotwpoelastih no
,

mwftEYesfnefahysinema.io
c

⇒
t
y
÷÷÷:÷÷
,

: :*:
write i
*
-

[ Stretched elastin
(B)

fiber

-
- crosslinks
~

fiber
XI
→
←

t.mn .am . .sn .

scaffold for
that act as a

tropoelastin
#
a

a
Y
?
-

relaxed elastic
Proteoglycans Description Found in Proteoglycans: Contain mainly GAGs (95%) and are a part of the ECM.
Chondroitin Sulfates Most abundant GAGs in the body Cartilage, Bone, Ligaments, Aorta Glycosaminoglycans (GAGs): long, unbranched chains of negatively charged sugars, and are
sulfated. Do not have a protein.
Keratan Sulfates "Special" because they contain a sulfated Cartilage, Cornea (where it's -They're composed of repeating disaccharide units. In position 1, it contains an acidic sugar (such as
galactose in position 1 and the most needed for transparency) glucuronic acid/Iduronic acid), and in position 2, it contains an amino sugar (such as glucosamine,
heterogenous regarding their sugars galactosamine), which can be acetylated.
Dermatan Sulfates contains iduronic acid as main uronic acid Skin, Blood Vessel, Heart valve -GAGs have strong negative charge from carboxyl and sulfate groups. They bind large amounts of water,
producing a gel-like matrix part of the ECM, and react to compression with squeezing water out and to
relaxation by absorbing water.
Heparan Sulfates contains sulfated glucuronic acid and basement membranes or on cell- -Functions of GAGs: Flexible support of the ECM, molecular sieve, lubricant, shock absorber
iduronic acid cell surfaces used for cell-cell
recognition
Heparin contains mainly iduronyl sulfates and is contained in mast cells that line
the GAG with largest amount of sulfates artieries of the lung, liver, and
and negative charges spleen. It's released from
intracellular granules and acts as
an anticoagulant by ending blood
clotthing via. facilitating inhibition
of thrombin
Hyaluronic Acid not sulfated, not covalently attached to a vitreous humor of the eye,
protein, contains glucuronic acid, synovial fluid of joints, cartilage,
synthesized in the extracellular space, loose connective tissues
provides extracellularly the central strand
in proteoglycan aggregates, connected to
core proteins via. link proteins, facilitates
embryogenesis (neural tube closure,
morphogenesis, and wound repair
Transcription Factor Cis Element it Binds Inactive state Active state Coactivators/Repressors?
Hypoxia Inducible Hypoxia Response Element (HRE) Oxygen is present and binds to No/low oxygen, N/A
Factor the PEST amino acid sequence on HIFa stabilized,
the HIF1a, proline residue gets moves to nucleus
hydroxylated by prolyl and dimerizes with
hydroylase, HIF1a gets HIF1b to activate
polyubiquinated and is quickly genes that increase
degraded by proteasome. HIF1a oxygen delivery to
therefore not able to dimerize tissues / energy
with HIF1b --> NO EXPRESSION supply via
OF GENES glycoylsis
Glucocorticoid Receptor Hormone Response Element (HRE) No cortisol, GR hangs out in the Cortisol present, Coactivator - help
(Zinc finger) cytoplasm bound to a multi- binds to GR, GR upregulate expression of
protein complex dissociates from genes Repressors -
protein complex, repress transcription
forms a dimer,
moves to the
nucleus, binds to
HRE, induces
expression of target
genes
Myc/Max regulates transcription of genes In the absence of Myc, Max forms In the presence of Nah But MYC
involved in cell cycle progression . a homodimer and represses gene Myc, Max and Myx Overexpression: impairs
transcription. In non-proliferating form a heterodimer, differentiation and
cells, Myc is not expressed. binds to enhancer promotes cell proliferation
site, and allows - which is a step in the
transcription + cell progression of cancer.
proliferation. (Myx regulates about
~15% of genes)
 purine synthesis
① Purine Nucleotide
-
denar
synthesis -

Precursors amino acids :

glutamate aspartate glycine donates the specific Corn atom

}
:O , ,

of-ormy.tl#ydrofo-ate(THF)deriredfromfolicacid
-
FB
form the
sequentially to
purine ring
.

Pentose phosphate pathway

Lqg

:
datwimostehemyenpto.sepn.ie
bolismfnaninbditors
Eoemyltetrahy )
shunt or HMP shunt )

D
synthetase Sguufffoanadmmigdll
pppp " " ② PRPP.ca/alyzedriaPRPP

synthetase
Ipf ③
fhhtamjnngpndoiigkjitsm.YY.am
" "

t 't

#
,÷¥÷¥ .

\
can

ATPIGTP ibosylamine transferase

f
phosphor
.

sigh
'
'

④⑤
prep
ftp.T.E.saddemdtoomgmusmga.anaa .
A NADPH t Ht
regulator }
respectively .

Dihydro folate
purine synthesis
.

↳ ensures
that cellular C ATP ] -
Corp ] ①
reductase

Phosphfyainbgsetaasmeidofqfwtam.nl
⑥
pnosaphmpmegtiagnpvgakjnaseimgone ;ffp⇒ .
t
Methotrexate :

Dihyd%f
hoprim

m.ms#@ I
ji;ia!;,cn÷¥÷
AMPIGMP

Fdkh¥¥¥Iati
fkinase
pro asNo-formylTHF@txomusemd9nmFxaIt9npsoYYasis.r

Jvkinase
ADiphohae*l
name
.

*
transferase '
folate
.

Dihydro
i

)
, cand N atoms are -0

.fm#ign:bitosajam.d.PhosPhoYbosYtam
reductase
.FI#YrIntdesf:.rwa.tOPh;sghnoprn:bsgsna4eD
Ribosephosphaleftokphkspenapheosfhaathwisg.de
sequentially i added

Guanosiyg⇒Dpighosph*
,

hot "

parent purine tnosine÷ITpoenosp :&!

-07Mt
ftp.Yffg/imcpAcid
:

nucleotide IEhopr.im ( antibiotic )

inhibits bacterial dihydro folate

.int
dehydrogenase

%
.

reductase
IMP dehydrogenase Ayp
←
.

f
→

↳p*
A -7 Methotrexate Cant

a¥tfo¥a
III
:!#
-

,
.
used urine synthesis tweets

Pr
'
I

Ajmal
GuanosineMmophosph
r hematoid
( AMP ) I arthritic
( Gmp )
.

I AI
sicdeef effects rapidly

%
④ :
on

I
cells which affects
dividing
kinase " "
inairmioiiftmdmlnmbaaeneiieidg
.
, .

I I
I

( ADP ) I I
I
I

I
i
I
kinase ,

! '
i

Atoms fuanosgiypgTriphosph

conversionoftonuceotikstodoxyribonucleotides-lhioreodf.la?eYd
"
" " )
Thioredoxin
'

'
i%fi¥ieI¥:÷÷÷
"

:¥:
fitting →
NADH Htt
→
uieiiiinatonnnisma .
NADPT

Ribonucleotide during all division

reductase
①
② XDATP ,dGTP

t
minus.in#aiihwar

Hydroxy
:
urea

inhibits synthesis of deoxyribonuclease de

 of
2
Salvage -
/ Recycling pathway
- =
purines

Guanine
FrelpurihlBAL-Aden.me .
Hypoxanthine : prpp

PRPP .

Hypoxanthine

:(
. .

:•
immanent

IIHF
↳ |qy

lnosimamopnopt.at#
'
' " µ
r 's ' tom
:
✓
1-yurimnudotttdenos.me
> pp ,

mp
Guanine
Monophosphate
Monophosphak ( • )

.tn?oKIYaomd:(at*esn.yenosn(Ywaan#nIEEym
) CAMP

be recycled reused Lesch Syndrome

+
•
purinebases can
Nyhan -

by the salvage pathway •

x. linked recessive disorder
,
.
: Per preponderance in men .

•
bases are converted to the Purim Absent HGPRT activity
Free purinl
•

↳
of to form
reused : increased degradation purines
bases ¢
nucleotides by this pathway
.
,
purine
•

UR "AaD '

of cellular DNA
↳
freebases derived from hydrolysis •
f levels of PRPP stimulate amidotrahslerdse ( feed .

forward ) and increases

s/p
all death and RNA ( all turnover ) .

biosynthesis of
purines
nucleotides

↳ n
80% of bases = reused !
•

symptoms
: •
hyperuriamia ( uric acid crystals in
urine
disturbances ( self mutilation →
iebitingoflips fingers
Salvage pathway behavioral +
the
-
•

HGPRT and APRT are of

enzymes
.

•
monosodium
important for the
Brain !
-
salvage pathway

u@Aad•@-(Xahthimf
uses and treatment
,
.
-
Nucleic Acid Nucleic Acid

ttyperuamatg
G@ Got

Symptoms
:
actively swollen small
joints ,
accompanying pain } warmth ,

crystals
5. nudeotidase unable to bear weight on joint
'

nudeotidase 5
.

omutationsofPRppsynthetasegenl.resuHingin4levelsofPRPP.HyPoxanth@ynine0.aeaaoepnrgpPoafsIatpurfaeasrYharndynaangtiratorofamidotmnsarase.0chemothempy-9Hofalldeatht9DNAtRNAbreaKdown.X

↳
A@--@p
uratedepositsinjointstsofttissue@Puri_mDegred_atonPathwayftErrmationofuricacidlHyperuriamiqdiseases.ca

bimkmnasmo.H@uanbeamotsideorienatnttgupdreaspniaraottonmdaemYnoayeoapnmoenxogomdinuamntoa.e
Purine -lHyperuric_a
Caused
in the
synovial fluid .

fmospnmiase
urine

Nucleoside nucleoside
nospnomiase
oafeimatiyrsotmuar.IT#jeYndjopathid

anthinetx
×an+mm*
M

2 Underexcretimof Uric Acid

b. oxidase -

" " as e

isauannma
.tk?!curraYeYod.mspeeaesew/iaaaiearexoretion .

oxidase *

Treatment
:

and anti ( )
ttcueepisode dchicine inflammatory agents Nsaibhcortisd
.

f
:c
ctxonxfhfntshinmldgxbidhffuem

chronittyperuriumia :

allopurioloxahthiheoxidase inhibitor
; defamation of

acid
:

Atopurihol uric
.

ostmctuml analogue of
hypoxanthine
Irreversibly hibits
.

Xahthine oxidase .
oconvertstooxypurinolcalloxahtinejandisa
irreversible competitive inhibitor
xahthineinurine
.

non
hypoxanthine
.

+
→ increases
acid formation Febnxiatixanthineoxidaeinhibitr
.

decreases uric
.

Plrobenecid
:
P excretion ofuricacidfisedinnnderexcretors )

Diary of meat
( of
purines ) and
:

dinlake rich source

alcohol .
Inherited Disorders of Purim
-
Degradation
Adenosine Deaminase Deficiency ( ADA SCID )
Purine Nucleoside Phosphatase Deficiency .

autosomal recessive disorder o

inherited deficiency of PNP ( enzyme of purine degradation )
have less

=
°
children severe
OADA
deficiency mainly affects
lymphocytes immunodeficiency involving T cells
.

symptoms
:
recurrent infections
0 accumulation results in increased DATP

levels that inhibit Adenosine

ribo nucleotide reductase .
lab tests →
Fall
deficiency .

°
inhibition of ribo nucleotide reductase leads to

reduced rates of all division in lymphocytes .

and B all
of T immunity .

symptoms
:

o persistent infections
levels of
remarkably low serum
°

immuno globins .

Treatment
:
o bone marrow replacement or
enzyme
replacement
where
gene therapy
successful
first disorder was
0 .
 pyrimidine synthesis
amino-acid and Cozlinthelormof bicarbonate
aspartate , glutamate )
:

Precursory :
,

hydiofoate
methylene
④ unlike synthesis the assembled
purine , pyrimidine ring
is first and the ribose phosphate is added later .

t
Glutamine phosphate
:bpYnma-e£%%f→BDihydqr
Synthetase I

teach
① to

:K÷
I
\

acarbe
pg

Grotty
I
ATP
,

I
L activators ) biosynthesis
.

'

i :*:
PRPP.ypur.me/pyrimidine
ai
:* :*
it:
Feedback
I ptoYypesfffdecha.in ( OPRT ) ↳ .
Inhibition I
( ump synthase)
I
(orotak°mMoPophosph
I

-④p←ump@
OMP
I

!
:
CFP
DVDP
synthetics Thymidine Synthesis
:
T
via
- -
.

! might methotrexate

:p

lA¥,c⑨ My¥
cytidine triphosphate
.

Dihydwf
! to
:* .

I
.
1

:
✓
yqdVMP.in#yaoesynthtasedTggMPO
.
.

:
.

: I .
.
.
.
.

yd.ro#aause-o-'
. I
.

. .
.

,
④ 5 Fluorouracil :

area

aµp,aµp,a,,,p,dqj#
✓ Hydroxy canonariiiedeiiibiytiuiousmaoldmr

| µ thsmiisdlcafuhn.ae

gig
Ribonucleotide
Dna ,ynµ , ,,µµ , ,a+ , ,

thioredoxin
Thinoraedpoxincreduad

④ SFUTMTX anti cancer

drugs
-
-
.
-
 Folale requirement +
deficiency .

ka . folic acid ÷/ vitamin 139 -

essential in diet

°
formyl THF / methylene THF needed in
Purim +
pyrimidine synthesis .

leads normal and

deficiency to
ofolateanemia
maarocytic ( larger than RBCS )

decreased rates of cell division .

flat Per incidence of neural tube defects

pre
perinatal deficiency
° →
+
.

Inherited -Defects in
pyrimidine -
nucleotide synthesis -

OroticA=da
Moddlficiehcy
:
9 levels of orotic acid excretion { of OPRT OMP decarboxylase ( synthase)
or
UMP

normal blood ammonia levels o accumulation of ontic acid .

tianya.sn?YaTroiaItIamimIaiohbYaosYnlInYmIafdimoEYIaacebaYkYmImllbimaIIYardonma:mnoasmaai:taonnttetyaeaa

ontkaciduria synthesis in this well

diagnosis way
as
: .

treatment UMP diet

:
in
giving
.
Cholinergic Drugs Target Main function Mechanism of Action Therapeutic Uses Contraindications/Side effects Notes
Receptor/Enzyme
Methacholine (choline M2 receptors mainly Bronchoconstriction Muscarinic Agonist Used in diagnosis of 3x as resistance to
ester) asthma. Inhalation of hydrolysis by AChE, little
methacoline results in affinity for nicotinic
bronchoconstriction. receptors
Patients with asthma
are more sensitive to
bronchoconstriction via
methacholine and will
respond at a small dose
than someone who
does not have asthma.
Bethanechol (choline ester) M3 receptors mainly Smooth muscle Muscarinic Agonist, Used in post-operative rapidly hydrolyzed; short
relaxation + vasodilation Increases vasodilation, urinary retention, atony half life
decreases in BP, HR, and of the urinary bladder
conduction velocity of
heart, miosis, increased
peristaltic activity &
relaxation of sphincters,
contraction of detrusor
muscle + relaxation of
sphinctor promoting
emptying, crying
Acetylcholine (choline Non-selective for Miosis during surg Muscarinic and Nicotinic used to obtain rapid Sweating, salivation, flushing, quaternary ammonium;
ester) Muscarinic receptors, Agonist miosis (constriction) low blood pressure, nausea, lipophobic, rapidly
Nictotinic Receptors after delivery of lens in abdominal pain, diarrhea, hydrolyzed, effects can't
cataract surgery bronchospasm be localized - not really
used clinically.
Pilocarpine (natural Muscarinic Receptors Miosis Muscarinic Agonist - glaucoma, treatment of tertiary amine, not
alkaloid) (it's a partial agonist) activates miosis on M dry mouth due to charged and lipophilic.
receptors on circular radiotherapy for cancer stable to hydroylsis of
muscles of the eye, which of head and neck, CF acetylcholinesterase
in turn causes drainage of diagnostics
aqeous humor and further
decrease in intraocular
eye pressure
Nicotine (natural alkaloid)
Edrophonium
Physostigmine (carbamate)
Neostigmine (carbamate)
Nicotinic receptors nicotinic agonist. dose smoking cessation
dependent! at low doses: therapy
ganglionic stimulation by
depolarization. (resembles
simultaneous discharge of
both parasympathetic and
sympathetic nervous
systems). at high doses,
ganglionic blockage and
neuromuscular blockade,
leading to paralysis.
Indirect-acting cholinergic
agents, inhibit
acetylcholinesterase and
increase concentration of
endogenous acetylcholine
by binding reversibly to
the active site of the
enzyme. inhibition is short
lived.
Indirect-acting cholinergic treatment of overdoses
agents, inhibit of anticholinergic drugs
acetylcholinesterase and
increase concentration of
endogenous acetylcholine
by forming covalent bond
with enzyme.
Acetylcholinesterase Increases concentration Indirect-acting cholinergic
of endogenous agents, inhibit
acetylcholine (indrect acetylcholinesterase and
agonists) increase concentration of
endogenous acetylcholine
by forming covalent bond
with enzyme.
ADDICTION OBVIOUSLY tertiary amine, not
charged and lipophilic.
used in diagnosis of short half life. quaternary
myasthenia gravis. ammonium, lipophobic
edrophonium IV leads to and does not enter CNS.
rapid increase in muscle
strength so will see
immediate, short-lived
improvement in people
with MG. also used to
revese neuromuscular
block produced by non-
depolarizing muscular
blockers in surgery (a.k.
a tubocurarine).
long half life. tertiary
amine, lipophilic and can
enter + stimulate CNS
used to treat urinary long half life. quaternary
retention. reversal of ammonium, lipophobic
effects of non- and does not enter CNS
depolarizing
neuromuscular blockers
s/p surgery. treatment
of myasthenia gravis
(because half life is
longer than
edrophonium)
Pyridostigmine (carbamate) Indirect-acting cholinergic treatment of myasthenia long half life. quaternary
agents, inhibit gravis ammonium, lipophobic
acetylcholinesterase and and does not enter CNS
increase concentration of
endogenous acetylcholine
by forming covalent bond
with enzyme.
Malathion (toxin) Indirect-acting cholinergic N/A insecticide - highly poisonous. long half life. rescue
agents, inhibit synthetic. drug for
acetylcholinesterase via organophosphate
covalent bonding. OD/exposure= atropine
Sarin (toxin) Indirect-acting cholinergic N/A synethetic toxic agents -
agents, inhibit "poison terrorist gas"
acetylcholinesterase and
increase concentration of
endogenous acetylcholine
by phosphorylating
enzyme. the covalent
bond formed is extremely
stable and hydrolyzes
very slowly.
Atropine (belladonna all M receptors myadriasis (dilation) and muscarinic antagonists. antitode for cholinergic dry mouth, blurred vision (cus tertiary amine, lipophilic.
alkaloids) cycloplegia (paralysis of reversible competitive agonist overdose, of too much dilation), sandy rescue drug for atropine
ciliary muscle)., reduces antagonist at muscarinic blocks respiratory tract eyes, tachycardia, constipation, OD = physostigmine
gastric motility, receptors. (M blockade); secretions prior to urinary retention, restlessness,
decreases hypermotility blocking allows surgery confusion, hallucinations,
of urinary bladder, sympathetic innervation delirium, stop sweating all
moderate to high to take precedence together and body temp
therapeutic doses cause skyrockets
tachycardia (atrial M2
blockade), secretions are
blocked (salivary, sweat,
lachrymal glands)
Scopolamine (belladonna muscarinic antagonist, by prevention of motion contraindicated in patients with
alkaloids) blocking allows sickness angle-closure glaucoma, should
sympathetic innervation be used with caution in
to take precedence patients with prostatic
hypertrophy and in the elderly
Ipratropium muscarinic antagonist, used in the treatment of contraindicated in patients with quaternary ammonium,
blocking allows chronic obstructive angle-closure glaucoma, should lipophobic and does not
sympathetic innervation pulmonary disease be used with caution in enter CNS
to take precedence (COPD) and asthma patients with prostatic
hypertrophy and in the elderly
tropicamide produces mydriasis with muscarinic antagonist, by used as mydriatic for contraindicated in patients with tertiary amine -
cycloplegia blocking allows fundoscopy angle-closure glaucoma, should lipophilic! (so that it can
sympathetic innervation be used with caution in penetrate through eye)
to take precedence patients with prostatic
hypertrophy and in the elderly
Hexamethonium Nn receptors ganglion blocker ganglion blocker obolete + no longer if we block a ganglion,
used in therapy due to the sympathetic nervous
adverse effects of system will take over (ie.
ganglion blockers turn of parasympathetic
- causes tachycaria)
Tubocurarine Nm receptors neuromuscular blocker, non-depolarizing used as adjuant drugs in
anesthetic in surgery blockers, competitive anasethesia during
neuromuscular nicotinic surgery to relax skeletal
antagonists at muscle
neuromuscular junction
Succinylcholine Nm receptors neuromuscular blocker, neuromuscular nicotonic rapid endotracheal short half life
anesthetic in short agonist. binds to the intubation, ECT (tx of
procedures nicotinic receptor and severe depression)
depolarizes the junction.
Persists in the synaptic
cleft, stimulating the
receptor. receptor
desensitizes, leading to
flaccid paralysis.
Botulinum toxin inhibits ACh release prevents release of ACh injected locally into
(colloquially known as and acts pre-synaptically muscles for treatment of
botox) several diseases
involving muscle
spasms. approved for
cosmetic treatment of
facial wrinkles and also
to treat hyperhidrosis.
Adrenergic Drugs Target Main function
Receptor/Enzyme
Epinephrine α and β receptors increases heart rate and
contractile force (β1 effect),
cardiac output increases:
oxygen demand of myocardium
increases, increases renin
release (β1 effect), constricts
arterioles in skin and viscera (α1
effect), dilates blood vessels of
skeletal muscle (β2 effect),
relaxes bronchial smooth
muscle (β2 effect), increases
liver glycogenolysis (β2 effect),
increases lipolysis (β1 and β2
effect)
Norepinephrine α1, α2, and β1 causes peripheral
receptors (little action vasoconstriction (α1 effect),
on β2 receptors) increases cardiac contractility
(β1 effect), and increases
peripheral vascular resistance,
systolic blood pressure, and
diastolic blood pressure.
Isoproterenol β1 and β2 increases heart rate, force of
contraction, and cardiac output.
dilates arterioles of skeletal
muscle resulting in a decrease in
peripheral vascular resistance.
mean arterial pressure typically
falls, causes bronchdilation.
Dobutamine β1 produces less increase in HR
and less decrease in PVR than
isoproterenol. causes mild
vasodilation. increases
myocardial O2 consumption -
this is the basis of the
dobutamine stress
echocardiogram.
Albuterol β2 causes bronchodilation
Phenylephrine α1
Mechanism of Action Therapeutic Uses Contraindications/Side effects/other
notes
agonist. at low anaphylactic shock, acute
concentrations, asthmatic attacks, cardiac
epiephrine activates arrest
mainly β1 and β2
receptors (increased
broncodilation, etc). at
higher concentrations,
α1 effects take
precedence
(vasoconstriction, and
increased BP)
endogenous agonist of treats shock because it (β2 is more sensitive to epinephrine so it
α1, α2, and β1 increases vascular resistance would act on the other adrenergic
receptors and therefore increases blood receptors more)
pressure
agonist used in emergencies to
stimulate heart rate in patients
with bradycardia or heart
block
β1 agonist management of acute heart
failure, management of
cardiogenic shock. good for
use in patients who are elderly
or with co-morbidities, used
for dobutamine stress
echocardiogram.
β2 agonist treats asthma, drug of choice
for acute asthma attacks
α1 selective agonist nasal decongestant, given
orally or topically. mydriatic
Clonidine α2 reduces symapthetic outflow α2 selective agonist. centrally-acting does the opposite of what adrenergic
which reduces blood pressure activates central antihypertensive output would look like because it acts on
presynaptic α2 an inhibitory receptor (Gi)
adrenoreceptors
Amphetamine causes NE release from causes norepinephrine release has centrally ADHD, narcolepsy
presynaptic vesicles. from presynaptic terminals. stimulatory action and
potentiates effects of can increase BP by α-
norepinephrine produced agonist action on
endogenously. vasculature as well as β
stimulatory effects on
the heart.
Tyramine causes NE release from causes norepinephrine release normally oxidized by - In a patient who is taking MAO inhibitors
presynaptic vesicles. from presynaptic terminals. MAO (anti-depressant), it can precipitate serious
potentiates effects of vasopressor episodes
norepinephrine produced
endogenously
Cocaine blocks monoamine monoamines accumulate in increased endogenous -
uptake synaptic space and results in monoamine
potentiation and prolongation of
their action
Ephedrine mixed acting NOT A CATECHOLAMINE! this adrenergic agonist used as a pressor agent
adrenergic agonist is a poor substrate for COMT during spinal anesthesia
and MAO -> long duration.
penetrates the CNS
Pseudoephedrine mixed acting this is an ephedrine enantiomer adrenergic agonist decongestant
adrenergic agonist (one of four),
Phenoxybenzamine α1 and α2 (non- reduces sympathetic ftone of α1 and α2 irreversible used in pheochromocytomas -
selective) blood vessels and decreases antagonist prior to excision surgeries of
PVR the tumor
Phenytolamine α1 and α2 (non- reduces sympathetic ftone of α1 and α2 reversible pheochromocytoma: control of
selective) blood vessels and decreases antagonist hypertension during
PVR preoperative preparation and
surgical excision, hypertensive
crisis due to stimulant drug
overdose
Prazosin α1 selective lowers blood pressure by
relaxing both arterial and
venous smooth muscle
Propanolol β non-selective slow heart rate and decrease
myocardial contractility (β1
effect), decreased
glycogenolysis (β2 effect),
decreased glucagon secretion
(β2 effect)
Atenolol β1 selective slow heart rate and decrease
myocardial contractility
Pindolol β non-selective slow heart rate and decrease
myocardial contractility (β1
effect), decreased
glycogenolysis (β2 effect),
decreased glucagon secretion
(β2 effect)
α1 selective antagonist used in treatment of
hypertension, however not
drug of choice for
hypertension. drug of choice
for symptom relief for benign
prostatic hyperplasia - relaxes
smooth muscle in the bladder
neck, prostate capsule and
prostatic urethra improving
urinary flow.
β non-selective used to treat hypertension, potentially lethal adverse effect in
antagonist stable angina pectoris, asthmatics due to blockade of β2
myocardial infarction, atrial receptors in the bronchi. nonselective β
firbrillation, hyperthyroidism, blockers may impair recovery from
glaucoma, migraine hypoglycemia in insulin-dependent
prophylaxis, performance diabetics due to blockade of β2 receptors
anxiety in the liver. β-blockers also mask the
tachycardia that is typically seen with
hypoglycemia, denying the patient an
important warning sign. therefore in
patients with diabetes, β1 selective blocker
is preferable,
other CNS side effects: sedation, dizziness,
lethargy, fatigue
β1 selective antagonist hypertensive patients with selectivity of β blockers for β1 is modest;
impaired pulmonary function therefore they should be avoided entirely
and in patients who are (if possible) in patients with asthma
diabetic and hypertensive
partial β agonist (so preffered in individuals with
acts as competitve diminished cardiac reserve or
reversible antagonist) a propensity to bradycardia
Disease
Down Syndrome (Trisomy 21)
Patau Syndrome (Trisomy 13)
Edward's Syndrom (Trisomy 18)
Turner Syndrome
Kleinfelter Syndrome
Karyotype Genetic Causes Characteristics/Symptoms DIagnosis Notes
47, X(X/Y), +21 Nondisjunction during Intellectual disability, Rapid FISH probe (3 probe Some can be mosaics
meiosis, robertsonian cognitive delay, short stature, signals for chromosome for trisomy 21. Risk
translocation depressed nasal bridge, 21), Standard G-band increases with maternal
upslanting palebral fissues, Karyotyping age
epicanthal folds, congenital
heart defects, develop
changes similar to alzheimers
at a young age (because one
of the genetic factors
responsible for Alzheimers
localized to chromosome 21)
47, X(X/Y), +13 Nondisjunction during Polydactyly, cleft lip + palate, Rapid FISH (3 signals for
oogenesis intellectual disability, cardiac chromosome 13), Standard
abnormalities G-band karyotyping
47, X(X/Y), +18 Nondisjunction during Microcephaly, intellectual Rapid FISH probe (3 probe Can vary in severity
oogenesis disability, clenched fist, signals for chromosome
overlapping fingers, rocker 18), standard G-band
bottom feet, congenital heart karyotyping
defects, lower set ears, small
lower jaw (micrognathia)
45, X Monosomy x due to Most = normal intelligence, FISH, G-Band, cells with Mosacism can be seen,
nondisjunction during short stature, webbed neck, 45x have no barr body most girls aren't
spermatogenesis cystic hygroma (neck diagnosed until puberty
swelling), primary
amenorrhea, no development
of sexual characteristics,
gonadal dysgenesis,
degeneration of ovaries,
infertile, constriction of aorta
47, XXY nondisjunction during phenotypically male, FISH probe for X Some individuals can be
meiosis gynecomastia, female chromosome, G-band mosaic, presence of barr
distribution of hair, infertility body will be observed in
and testicular atrophy due to buccal mucosal cells,
low levels of testosterone, many males aren't
feminization of features diagnosed early and get
dx when trying to
conceive
Cri-du Chat Syndrome
Di-George Syndrome (22q11.2 deletion
syndrome)
Wolf-Hirschorn Syndrome
Prader Willy Syndrome
Angelman Syndrome
microdeletion of high pitched, cat-like cry, Karyotype, rapid FISH,
chromsome 5p micrognathia, severe microarray CGH
intellectual disability,
hypertelorism (widely spaced
eyes), microcephaly
microdeletion of congenital heart defects, Microarray CGH, FISH most common
chromosome 22 absence of thymus, contiguous gene
immunological problems, cleft disorder in humans
lip + palate, learning
disability, facial abnormalities,
long midface, narrow
palpebral fissures, prominent
nasal root, bulbus nasal tip,
ear dysmorphology,
increased risk for
schizophrenia
microdeletion of seizures, skeletal microarray CGH
chromosome 4p abnormalities and congenital
heart defects, sepctrum of
intellectual and
developmental delay, facial
anomalies, widely spaced
eyes, high arched eyebrows,
broad and flat nasal bridge,
short philtrum, downturned
mouth, small chin
either microdeletion in insatiable hunger honestly should know
paternal SNRPN gene or this by now
uniparental maternal
disomy (trisomy rescue)
either microdeletion in happy-puppet honestly should know
maternal UBE3A gene or this by now
uniparental paternal
disomy (trisomy rescue)
Cancer
Retinoblastoma
Li-Fraumeni Syndrome
Familial Adenomatous Polyposis
(Colorectal Colon Cancer)
Mutation / genetic abnormality Normal Function of Protein / Gene Mutated Protein pathway
Mutation of genes that regulate Rb is a regulator of G1/S phase
phosphorylation of Rb. Can be transition. At the checkpoint, Rb is
any of the four: Rb, CDK4, Cyclin hyperphosphorylated by
D gene, CDKN2A (p16). Mutation Cyclin/CDKs and dissociates from
can occur due to either E2F. E2F then activates S-phase
spontaneous deletion or point genes and allows cell cycle
mutation. progression. In the absence of
cyclin/CDKs, Rb is
hypophosphorylated and binds to
E2F. Rb/E2F complex binds DNA
and prevents replication by
recruiting HDAC and Histone
methylase.
Inherited mutation in p53. Tumor suppressor gene that drives
expression of pro-apoptotic BLC1
family members (such as Bax) and
inhibits cell cycle progression in the
presence of DNA damage.
IMPORTANT: MOST OF THE BCL2
FAMILY IS ANTI-APOPTOTIC BUT
BECAUSE BAX IS STILL A PART
OF THE BCL-2 FAMILY, YOU
STILL HAVE TO RECOGNIZE
THAT BCL1 BEING PRO-
APOPTOTIC IS CORRECT!
Mutation in APC pathway (APC = In the presence of WNT, B-catenin
component of WNT signalling moves to the nucleus and forms a
pathway) complex with TCF-4 and activates
cell growth promoting genes. In the
absence of WNT, APC interacts to
B-catenin, phosphorylates B-
catenin, B-catenin is ubiquinated,
degraded, and B-catenin levels fall
and there is no cell growth
promoting genes being activated.
Notes
Loss of Rb function due to In Familial Rb: Autosomal Dominant
mutation Rb - nothing binds Inheritance pattern, but displays
to E2F and there is an recessiveness at the level of the
increase in transcription of S tumor. Inheritance of "one hit,"
phase genes, leading to therefore when "second hit" occurs,
increased cell cycle there is a loss of heterozygosity.
progression and unregulated Familial Rb presents with multiple
cell division. tumors, bilateral, early age of onset.
Non-Familial/Sporadic Rb: Two
incidences of somatic mutations need
to occur (two hits) in order for cancer
to occur. Usually single tumors,
unilateral, later onset of age.
loss of p52 function results
in net cell growth and
increased mutation
frequency, which drives
cancer progression
When there is a mutation in Symptoms: 100s of polyps in distal
APC, there is no APC colon
interaction with B-catenin.
So even in the absence of
WNT, B-catenin binds with
TCF-4 and activates cell-
growth genes.
Hereditary Non-polyposis colon
cancer (a.k.a. Lynch Syndrome)
Burkitt's Lymphoma
Chronic Myeloid Leukemia
Breast Cancer/Ovarian Cancer
Mutation in DNA mis-match
repair genes (MMR genes)
/caretaker genes AND/OR
microsatellite instability
Translocation between
chromosomes 8 and 14. Myc
oncogene is fused to highly active
immunoglobin promoter.
Translocation between
chromosomes 9 and 22;
formation of the philadelphia
chromosome.
BRCA1/BRCA2 genes
MSH2/MSH1 are mismatch repair
genes - there are at least 5 genes
Myc normally dimerizes with Max
(forms heterodimer) in order to
promote cell cycle progression from
G1-S. In the absence of Myc, Max
forms a homodimer with another
Max and binds to DNA and inhibits
cell cycle progression.
On Chr. 22 Breakpoint Cluster
Region (BCR), on Chromosome 9,
Abl =cytoplasmic tyrosine kinase
Normally involved in DNA repair
mutations in these genes
can cause accumulation of
mutation. these genes are
not directly involved in
control of cell division -
called mutator genes. Cells
can accumulate mutation at
rates of up to 1000x higher
than normal. Mutations in 5
different genes can cause
cancer - locus heterogeneity.
Once translocation occurs,
Myc becomes overexpressed
due to its translocation
downstream of the highly
active immunoglobin H
promoter.
Translocation forms hybrid
BCR-ABL fusion oncogene.
It's basically a super tyrosine
kinase that's constitutively
active (Abl stuck in its active
form) - promotes cell
growth/proliferation.
Loss of BRCA1/2 - cells can
duplicate with DNA damage
which predisposes them to
cancer
Tumors exhibit Microsatellite
Instability: Only seen in Lynch
Syndrome - short repetitive
sequences of DNA near centromeres
- tandem repeats 2-4bp in length.
TREAMENT: Imatinib: Powerful
tyrosine kinase inhibitor specific for
super tyrosine kinases such as BCR-
ABL. It binds to active site of BCR-
ABL and prevents its activity.
TREATMENT: (only in HER2 Positive
tumors): In sporadic/nonfamilial
breast cancers, there is an
amplification of HER2 (either via
double minutes of hsrs). HER2 is
human epidermal growth factor
receptor 2. When there is
overexpression of this receptor, it
binds growth factors and induces cell
growth/proliferation. Herceptin, (a.k.a.
trastazumab) are HER2 antibodies
that attack HER2 and prevent binding
of growth factors.
Disease How it Manifests / Genetic Dysfunction
Ehlers-Danlos Syndromes (classical form) defect in type V collagen
Ehlers-Danlos Syndromes (vascular form) defect in type III collagen
Osteogenesis Imperfecta Type I One allele of either COL1A1 or COL1A2 gene, leads to
displacement of clycine in bone collagen type 1 cauing
unstable collagen triple helix
Osteogenesis Imperfecta Type II (a.k.a. One allele of either COL1A1 or COL1A2 gene, leads to
osteogenesis imperfecta congenita) displacement of clycine in bone collagen type 1 cauing
unstable collagen triple helix
Marfan Syndrome defect in fibrillin 1 gene (gene for elastin is normal) -
fibrillin acts as a scaffold for tropo-elastin.
Kwashiorkor severe protein deficiency (adequate calories via carbs)
Marasmus Severe undernourishment with deficiency in almost all
nutrients: carbs, proteins, lipis, etc...
Cystic Fibrosis Lots of different mutations but most common one is delta salty skin (KNOW WHY CF PTS HAVE SALTY
F508 - deletion of phenylalanine in CFTR (3 bp deletion), SKIN), chronic respiratory infections, steatorrhea,
does not reach cell membrane, ubiquinated and degraded poor growth, etc....
via proteasomes.
Myasthenia Gravis autoimmune attack on acetylcholine receptors, leads to
imparied transmission of nerve impulses
Symptoms
hypermobility of the joints, hyperextensibility of
the skin
leads to fragility of skin and vessel walls, most
severe form because it's associated with
potentially lethal arterial rupture
early childhood long bone fractures after minor
trauma, normal/near normal height, possibility of
hearing loss in adulthood, blue sclerae
usually leads to death in utero or neonatal death
due to respiratory problems, can lead to
underdeveloped lungs and an abnormally small +
fragile rib cage
long limbs, aortic root dilation, arachnodactyly,
lens dislocation, abnormal formation of rib cage
often older than a child with marasmus, decifiency
of dietary protein and dietary essential amino
acids, decreased blood albumin (<2.8g/dL)
resulting in edema of abdomen (ascites & legs),
stunted grwoth, skin lesions, reddish hair,
anorexia, fatty liver, bilateral pitting edema
arrested grwoth, anemia, extreme tissue and
muscle wasting, loss of subcutaneous
fat/emaciation, loose skin folds hanging over
buttocks and thighs. can also result from chronic
illnesses, trauma, anorexia, and can also be found
in the elderly
increasing fatigue throughout the day, drooping
of eyelid, laziness of muscles, DX: edrophonium,
TX: pyridostigmine
Guillain-Barre Post-infectious peripheral neuropathy - damage to ascending muscle - loss of muscle coordination
schwann cells, demyelination of peripheral nerve fibers. and cutaneous sensation
accumulation of lymphocytes, macrophages, and plasma
cells
Multiple Sclerosis Autoimmune. Selective loss of myelin sheath with axon weakness, fatigue, muscle spasms, balance
preservation in the CNS. Multiple sites of demyelination problems, dizziness, vision problems. tingling and
occuring in CNS. Preferential damage to myelin - detach numbness
from axon and destroyed. Damage to oligodendricytes -
microglia cells aren't as efficient in removing myelin debris,
which reduces likelihood of regeneration
I-Cell DIsease Lysosomal storage disorder - defective Coarse facial features, skeletal abnormalities, and
phosphotransferase in the golgi-apparatus. Mannose 6 mental disability, elevated plasma lysosomal
phosphate not properly phosphorylated and cannot be enzyme concentration (because they're being
targeted to lysosomes within the cell. Proteins are secreted extracellularly instead of being directed
therefore excreted outside the cell. Lysosomes cannot to lysosomes).
function without these proteins (can't break down
oligosaccharides, lipids, and GAGs) and buildup of these
molecules occurs in lysosomes resulting in inclusion cells
(hence I-cells).