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Adrenergic agonists: drugs acting on sympathetic system and drugs

acting on parasympathetic system


Drugs that mimick sympathetic system are called sympathomimetic
drugs, also known as adrenergic drugs or agonists
Drugs which decrease the activity of sympathetic systemsympatholytic, anti-adrenergic, adrenergic antagonists
Neurophysiology of sympathetic system- prepares you to fight with the
stress
Parasympathetic system is there when its relaxes
All the pre-ganglionic fibers that come out of the spinal cord are
cholinergic
Neuotransmitters are synthesized in the nerve endings
Tyrosine is pumped into nerve endings and tyrosine hydroxylase works
on the tyrosine to create DOPA- which is converted to dopamine by
bringing the carbon dioxide out, so the enzyme is DOPA decarboxylase
Dopamine is pumped into a membrane bound vesicle so that it is not
destroyed by an enzyme expressed on mitochondria- MAO, this
enzyme breaks down monoamines- molecules derived from single
amino acids
Within the wall of the membrane there is an enzyme called dopamine
beta hydroxylase- dopamine converted to NE
Reuptake one mechanismCOMT- attacks the methyl group and transfers methyl group
Methyl tyrosine- it will enter at the same site as tyrosine and inhibits
tyrosine hydroxylase
Reserpine (blocks storage of neurotransmitter) block vesicular
transport mechanism, Dopamine is destroyed and not transported
across nerve endings
A drug that prevents the vesicle binding to membrane, GUANADRIL,
BRETYLIUM
Drugs that block alpha 1 and alpha 2 are phenoxybenzamine and
phentolamine
Phenoxybenzamie- binds irreversibly receptor blocker
Phentolamine- reversible receptor blocker
Only alpha blockers specifically alpha 1- prazosin and terazosin
Prazosin has short half-life and terazosin has longer half-life
B1 b2 blockers propranol
B1- metoprolol and atenolol only in short doses, if give more it
becomes non-selective
Mainly alpha1 stimulant- Phenylephrine
Mainly alpha2 stimulant Clonidine (central sympatholytic)
Alpha 1 and Beta 1 stimulant- NE
Alpha 1 B1 and B2- Epinephrine
B1 and B2- Isoproterenol

B1 action- dopamine, in high concentrations- alpha1 receptors and


dopamine receptors
B1- Dobutamine
B2- salbutamol
Cocaine blocks the uptake transporter
TCAS also block reuptake 1, bind it mildly and inhibit the uptake (nonselective)
Prozac and SSRI- fluoxetine
MAO inhibitors- pargyline, tranylciprime
Amphetamine and tyramine- help vesicle fuse and release more nts
All the tissues to be sitmulated should have alpha one receptors and
beta 1 receptors.alpha 1 +b1 receptors are present in heart, kidney
(JGA) and adipocytes (B3)
Alpha 2- presynaptic, platelet and pancrease (insulin cell)
In the dilator pupilae there is alpha 1 stimulatory receptor when
stimulated the pupil dilate
Sympathetic vision- lens should be able to see far vision, flatten lens
This is the function of ciliaris muscle
When the ciliaris muscle contract- the suspensory muscles loose and
lens become globular near vision
When the ciliaris muscle relaxes it stretches the suspensory muscles
lens become flatten far vision
Ciliaris muscle has B2 receptor
Circular muscles should relax in sympathetic activation and the
sphincters should contract
Alpha 1 on sphincters
B2 is inhibitor receptors
Bronchioles in the sympathetic activation inhibited so more gases can
come B2 adrenergic stimulated
When B1 receptors on the heart are stimulated on the SA and AV node
there is positive chronotropic effect (increase firing , pacemaker
activity) and dromotropic effect which both combined increases HR
B1 ar- increase contractility- ionotropic
Blood flow should be decreased- people become pale
Cerebral blood flow controlled by autoregulation
Take the glucose and convert it to glycogen- in the liver, but B2 give
inhibitory signals and cause glycogenolysis

Triglycerides- breakdown of fatty acids, break down of lipids


Gluconeogenesis happens!!! So pancreas have the B1 modified and
so stimulates the production of gluconeogenesis
Skeletal muscle have to breakdown glycogen to glucose- so B2 helps
do that!
When a drug is changing the TPR its changing the diastolic pressure,
diastolic pressure reduced means that there is arteriole dilation and if
there is an increase in diastolic pressure it means that there is
arteriolar constriction
Now when the drug is changing the cardiac output then its changing
the systolic pressure, when the drug increases the systolic pressure, it
increases CO and when it decreases CO it decreases systolic pressure
When the systolic and diastolic pressure is increased that means the
cardiac output is increased and the tpr is increased, arteriolar
constriction!
When both diastolic and systolic pressure are reduced that means that
arteriolar dilation and cardiac output is reduced
BPH- alpha 1 antagonist- so relaxes the prostate
When male given alpha 1 blockers to relax the prostate
Alpha 2 actions- alpha2 present in presynaptic neurons, alpha 2 inhibit
nerve ending function.reduce NE release
Insulin producing cells in the pancreas has alpha 2 receptors , reduce
release of insulin
Adipocytes- modified B3 receptors increases lipolysis
Alpha 2 adipocytes- inhibit lipolysis
Alpha 2 are present in the platelets, activated platelets undergo
aggregation
Dobutatmine CARDIOSELECTIVE stimulant and dopamine is
cardiostimulant and dilate renal vessels (reno-dilator)
Hypokinetic heart but renal flow okay? Dobutamine
AV node stimulated- positive dromotrophy
SA node stimulated- chronotrophy
Excitability- positive bathmotrophy increase excitability of specialized
conduction system
Increase the risk of tachyarrythmias
Degree myocardial contractility increase- positive ionotrophy
Increase in velocity shorter time to reach its peak contraction so that
effect is called positive clinotrophy
JGA in the kidney have beta 1 receptors- renin produced
Adipocytes have modified beta 1 receptors known as b3- produce
lipolysis

Tocolysis- relaxes the myometrium, stimulate B2 receptor on uterus


Liver has b2 RECEPTORS and it stimulates gl
Alpha 1 stimulates Gq receptor which activates IP2 and DAG, increases
intracellular Calcium
Alpha 2 receptor- decrease cAMP, increase K+ efflux and and decrease
calcium influx
B1 AR- Gs- increase intracellular cAMP and increase Ca influx
Desentization- specific agonist is continuously stimulating- it becomes
less efficient and the response to the same amount decreases

The stroke volume can be measured by stroke volume and cardiac


output
EDV- 140 mL
About 50% blood ejected, SV = 70 mL
The difference between a healthy and failing heart is that in the
healthy heart when the EDV is more then the contractility is more
however in the failing heart the EDV is more then the contractility is
not more
In a failing heart, when the contractility is reduced and cardiac output
is reduced the vasomotor center detects the drop in pressure and
activates the sympathetic system and sympathetic outflow is
increased, B1 receptors on SA node is increased so heart rate is
increasedstroke volume is increased and cardiac out put is increased.
The increase in sympathetic outflow for an extended period of time is
bad for the failing heart because with sympathetic outflow there is also
arteriole constriction so there is more resistance towards which the
heart has to pump blood and there is venoconstriction so there is more
venous return t
o the heart and so more EDV which means the heart has to work more
to pump this blood.
Laplace law: Pressure= tension/radius
Tension results in pressure so that cardiac output should be maintained
If you increase raidus the pressure is decreased
***For a failing heart the ability to produce tension is less so it cant
maintain the pressure to maintain the cardiac output
when heart starts failing, the renal perfusion is decreased so kidney
produce more renin
GFR is less and amount of sodium reaching Na is less

Sympathetic system stimulate the renal arteriole and stimulate the


production of renin
Preload- is the load in the ventricle (in the diastolic phase) before it has
to contract, it is also known as the EDV
Afterload- resistance against which the heart has to perform!
ACE inhibitors reduce mortality and morbidity
So first they reduce preload, afterload and cardiac remodeling, they
also decrease the risk of MI, arrhythmias and stroke
They are super important in CHF! Or when E.F. is < 35%
The lower the ejection fraction the more beneficial the drugs
Captopril is the active drug, the other drugs are prodrugs and have to
pass through the liver to become active!
Analapril, lisinopril, ramipril, fosinopril
ACE inhibitors are prodrugs, need to get hydroxylzed and become
active
All drugs except for fosinopril they get excreted via kidney
All these drugs are taken orally so taken on empty stomach
They are used in CHF, hypertension or recent MI, diabetic nephropathy
Diabetic patients- develop the thickening of efferent and afferent
arteriole and blood flow to glomeruli is reduced
Angiotensin II act on efferent arteriole and keep that constricted and
leads to further leak of proteins
ACE inhibitors- will reduce systemic BP, overall damage to glomerulus
is reduced
Efferent arteriole dilate- there is reduced glomerular hypertension and
leaky proteins reduced and so damage to mesengium is reduced
Angiotensin II act as a growth factor for mesengium cells
Side effecst of captopril- C stands for cough, many patients who take
ACE inhibitor they develop dry cough as a result of accumulation of
bradykinin since its not being broken down
ARBs angiotensin receptor blockers they do not produce the cough
A stands for angioedema- patient develop swelling of nasal, throat, lips
and buucal mucosa and produce life threatening situation
Accumulated bradykinin leads to angioedema
C1-esterase inhibitor complement activation- vasodilators increased
resulting in angioedema
Stop the drug immediately
P- proteinuria
T- taste changes
O- hypotension, it is very important side effect of ACE inhibitors , as a
result of increase plasma renin activity (CHF, or salt depeleted they
develop increase renin activity)

First dose very low in patients with increased plasma renin activity
P- not given in Pregnancy
R- they produce rashes
The I IS FOR increased potassium level and increased renin levels
L is for low aldosterone and angiotensin II levels
ARBS- LOSARTAN, valsartan and candesartan- they directly block
angiotensin II receptors so these receptors do no work on arteriole or
venule receptors
Typically the angiotensin II binds to angiotensin 2 receptor on zona
glomerulosa and this allows the zona glomerulosa to release
aldosterone so when this receptor is inhibited this doesnt happen
Metoprolol and carvidolol are beta blockers used in CHF, carvidilol
blocks alpha and beta receptors (Beta 1 and beta 2)
Carvidilol is a alpha receptor blocker and non selective beta blockers
Blockage of alpha 1 receptor it produces the arteriole and venodilation
At the same time B1 receptor blockage reduces heart rate and B2
blockage reduces renin production
There are two types of cardiac heart failure- high output and low
output heart failure
Low output heart failure is present as a result of ischemic heart not
being able to produce the normal cardiac output 5L/min
The heart is failing to reach the demands of the peripheral tissue but
the main cause is reduced cardiac output
Hyperthyroidism- increases the metabolism of body, so oxygen
demand of tissues is increased so the heart to produce more CO to
meet the demands of these tissues
There is RVF, LVF and BVF
When there is LVF there is an increase in heart pressure on the left side
that backs up to the pulmonary capillary causing them to leak and
produce pulmonary edema
Clinically patients come with dyspnea, orthopnea or paraoxysmal
dyspnea
RVF- back pressure increase in right increase in atrium, so systemic
capillaries leak and patient develop generalized edema
LVF- pulmonary edema
RVF- generalized or systemic edema
BVF- congestion of pulmonary and systemic failure- Congestive heart
failure

Forward failure and backward failure also- when there is left ventricular
failure the heart cant pump well so there will be reduced cardiac
output and there is backward pressure increase leading to pulmonary
edema
Forward failure features- fatigueness, exercise tolerance is reduced
Backward failure- pulmonary edema cough, dyspnea, orthopnea and
paraxymal dyspnea
Pulse is weak forward failure
Cant breathe- backward failure
Systolic failure and diastolic failure- the difference is during diastoleleft ventricle relaxes for ventricular filling and accumulate proper EDV
Systolic function is it has to contract and so that cardiac output has to
be maintained, related to SV and EF
If the heart has infiltrative disease, suppose amyloid proteins deposited
into the myocardium and the ventricle thickens the thick wall cant
relax well- during the diastole it cant accommodate much blood
Very sever LV hypertrophy- stiff and cant relax in diastole, and
accommodate not a lot of EDV
Diastolic function failure and backward failure
If the heart is very much dilated and there is lack of systole- systolic
dysfunction and forward failure pronounced
Positive inotropic
Chronotrophic effect- HR, epine increases HR,
Chronotropic drugs are working on SA node
Clinotrophic effect
Dromotropic effect- conduction velocity- fast conduction from sa TO av
node we say positive dromotropic
Epinephrine has positive dromotropic action but ca channel blockers
slows it down

Bathmotrophy- some tissue in the heart has developed automaticity


abnormal automaticity
Clinotrophy- is increase the velocity of contraction

Heparin sodium is an anticoagulant and works to inhibit the conversion


of prothrombin to thrombin and also, inhibits the conversion of
fibrinogen to fibrin
Prophylaxis of pulmonary embolism, preventing clotting in arterial and
cardiac surdery
Protamine sulfate if poisoning by heparin
Measure PTT
Warfarin- anticoagulant and depresses hepatic synthesis of vitamin K
coagulation factors

Coagulation pathway

Coagulation is a process in which soluble fibrinogen transforms


into insoluble fibrin strands. In a healthy cardiovascular system
the blood is in the liquid form but as soon as there is injury the
constituents of the blood go to the site of injury and form a plug
(semi-solid) at the injury point
The endothelial cells in the blood vessel have the capability to
release nitric oxide, prostacyclin (PGI2), and ADP
dephosphatases (products are anti-platelet aggregation agents
In order for the platelet to stick to the endothelium, the platelet
receptor needs to be in its active state, but when NO, PGI2 and
ADP dephosphatases bind to the platelet receptor they inactivate
them and the platelets are not able to bind to healthy
endothelium. They also relax the smooth muscle
Healthy endothelium does not favor the attachment of platelet to
endothelium lining
Platelet love to bind to the ECM under the endothelium but
endothelium and its products release prevents this!
Healthy endothelium not only keep platelet inactivated but they
also keep the coagulation system in check! Activated coagulation
factors near the healthy endothelium are killed
Healthy endothelium cells express proteins called heparan
sulfate and its a molecule on which a special platform can sit
known as anti-thrombin III, present by the liver
When anti-thrombin III becomes active it will cut down the
thrombin molecules and it can also inactivate activated factor Xa
and IXa

Thrombomodulin expressed on healthy endothelium it binds to


the healthy thrombin and thrombin will activate protein C and
the activated protein C will eat/destroy factor V activated and
VIIIa
Healthy endothelium produces a product called tissue
plasminogen activator and this product can convert another
protein coming from the liver plasminogen and it activates it to
plasmin- plasmin it will take the fibrin strands and break the
fibrin
Plasmin is an enzyme that cuts fibrin.
These are all mechanism that keep the blood circulating
Healthy endothelium is a tissue that is anti-coagulant and antithrombotic, anti-platelet
First thing that happens when a vessel is injured isvasospasticity (constriction).surrouding nerve ending
vasoconstrictors are released (neurogenic reflex vasoconstrictor)
Myogenic constriction- injured smooth muscle wall
Endothelin is produced by injured endothelial cells and it acts on
smooth muscle and makes them contract
Injured endothelial cells produce and these molecules allow the
platelets to stick! These molecules are called von Willenbrand
factor
Platelets have these receptors that allow it to stick to vWF, this
receptor is called GpIb
Platelet activation- phospholipase activated- arachanoidic acidthromboxane a2 (VASOCONSTRICTOR +PLATELET AGGREGATOR)
Aspirin (salicylic acid) inhibit COX enzymes in the platelets and
then platelets loose the capability to produce TXA2, so platelet
does not have ability to aggregation
There are granules in platelets- alpha granules and dense/delta
granules
Delta granules (sac)serotonin, adp and calcium
Serotonin- vasoconstriction
ADP- platelet aggregating and sticky, there is drug ticlopidine
and it antagonizes it
There is calcium released and calcium is imp for gamma
carboxylation that allows platelet to stick!
Alpha granules have fibrinogen, platelet derived growth factor,
and coagulation factors
When platelets stick to another surface not platelet its adhesion
and when they stick to one another its aggregation
Platelet aggregation- primary platelet plug
Intrinsic and extrinsic pathway- whats the difference??

Within the blood there is an intrinsic factor ((hagemann or factor


XII) when it touches a non-endothelial surface it activates the
coagulation
Extrinsic pathway- tissue factor activates this pathway
Whether its the intrinsic or extrinsic pathway it should have the
same ending conversion of fibrinogen to insoluble fibrin strands
Intrinsic pathways- 12 a- 11 a- 9a- in the presence of
phospholipids, calcium and in VIII it activates factor X
Xa acts on prothrombin in the presence of phospholipids, ca,
factor V and converts it to thrombin and thrombin break down
fibrinogen to fibrin monomers (they are deposited on platelets)
Thrombin stabilizing factor (13) produce cross linking
TF from endothelial convert VIIa and it does two functions it
activates IXa and Xa (fast system)

Cancer and Chemotherapy Out of control of growth of abnormal cells


Cytotoxic agents include tissues with renewal cell populations
such as lymphoid tissues, bone marrow, and epithelium of the GI
and the skin
Acute toxicities- nausea, vomiting, hypersensitivity reactions
Severe toxicities associated with paclitaxel and carboplatin is
MYELOSUPPRESION
This chemotherapy regimen can significantly affect any cell line,
including RBCs, neutrophils and platelets and the
cytopenias can cause significant morbidity and mortality
Decreased RBCs cause anemia and this presents as fatigue and
decreased exercise tolerance
Low neutrophil counts increases risk of bacterial infections
Reduced plateelts can cause thrombocytopenia which can cause
bleeding from GI and genitourinary tracts
With most myelosuppressive agents the patients white blood cell
and platelet counts begin to fall within 5-7 days of cytotoxic
therapy administration
Phase specific cytotoxic chemotherapy agents such as vinca
alkaloids and antimetabolites cause a fairly rapid onset of
cytopenia that recovers faster than those occurring after
treatment with phase nonspecific agents such as alkylating
agents and anthracyclines
Nitrosoureas produce sever, delayed neutropenia and
thrombocytopenia

Cancer drugs
Side effects:
NeurotoxicitySIADH vincristine
Coma- Ifosfamide
Cerebral toxicity
Cytosobine
Ototoxic + Kidney + N/V : cisplastin
To prevent cisplastin- water with saline and give a diuretic such as
mannitol
Alkylating agents- attach alkyl groups to DNA, allows cross linking of
base pairs and non specific
Typical alkylating agents- cyclophosphamide, ifosfamide, melphalan,
busulfan, mechlorethamine, chlorambucil, thiotepa
Side effects- myelosuppression, N/V, secondary malignancies,
hemorrhagic cystitis
Atypical alkylating agents- platinum compounds covalently bind purine
bases- cisplastin- nephrotoxicity and N/V
Carboplatin thrombocytopenia
Oxaliplatin cold sensitivity
All cause peripheral neuropathies, paresthesia
Nitrosureas- carmustine pulmonary toxicity, phlebitis, CNS
Antimetabolites
Inhibit DNA replication
Specific to S phase
Inhibit DNA replication or repair by mimicking cell compounds
S phase specific
Folate inhibitor: methotrexate inhibits DHF prevents regeneration of
THF
Adjuvant leucovorin and protects the healthy cells
Side effects- mucositis, myelosuppresion
Pyrimidine inhibitors- 5-FU
It inhits thymidylate synthetase
Bolus dose causes myelosuppression
GI prblems- mucositis, diarrhea
Leucovorin potentiate the action
Capecitabine- oral prodrug for 5-FU
Hand and foot syndrome palms and hand and feet become red and
blistering

Cytarabine- AraC is DNA chain terminator


Conjunctivitis and cerebral neural defects
Purine analog- 6-mercaptopurine
Microtubule targeting agents
These drugs inhibit mitosis, specifically M phase
Vinca alkaloids destroy microtubules
SE- peripheral neuropathy, myelosuppressive
Fatal if give intrathecally
Taxanes- stabilize microtubules, preventing their function
Paclitaxel, docetaxol
SE peripheral neuropathy, myelosuppresion
Hypersensitivity
Abrazane- protein bound paclitaxel avoid hypersensitivity
Less sensitivity but more neuropathy
Topoisomerase inhibitors
Topoisomerase I inhibitors prevent relaxation of supercoiled DNAtopotecan irinotecan
Both have side effect of myelosuppresion
Diarrhea
TOPO II inhibitors- etoposide, teniposide
myelosuppresion, mucositis secondary malignancies (AML)
AnthracyclinesIntercalate DNA, inhibit topo II, generate ROS, perhaps alkylation
Rubicins: doxorubicin,
Se: biventricular heart failure
Monoclonal antibodies- -ximab, -mumab
Rituximab- CD20 and treat lymphoma
Trastuzumab- Her-2 AND TREAT BREAST cancer
Cetuximab- EGFR solid tumors (initially for colorectal cancer)
---acneiform rash
Bevacizumab- VEGF- solid tumors (colorectal and lung cancers) GI
perforation
Bleomycin- causes lung toxicity

Cholinergic Drugs
Direct acting and indirect acting cholinergic drugs
The peripheral nervous system is subdivided into the efferent and
afferent divisions
The efferent neurons signals away from the brain and spinal cord to the
peripheral tissues
Afferent neurons bring info from the periphery to the CNS
Afferent neurons provide input to modulate the function of the efferent
division through reflex arcs
CN III, VII, IX, X -> S2 to S4 of the spinal cord and synapse in ganglia
near or on the effector organs
The vagus nerve accounts for 90% of preganglionic parasympathetic
fibers in the body, postganglionic neurons from the nerve innervate
most of the organs in the thoracic and abdominal cavity
Effects of stimulation output is to increase the heart rate and BP,
mobilize energy stores of the body and to increase blood flow to
skeletal muscles and the heart while diverting flow from the skin and
internal organs
Dilation of pupils and bronchioles
Contraction of iris radial muscle pupil dilates
Contraction of iris sphincter muscle- pupil contracts
Contraction of ciliary muscle- lens accommodates for near vision
Kidney- secretion of renin (Beta 1 increases, alpa 1 decreases)
Uterus- relaxation of detrusor; contraction of trigone and sphincter
Parasympathetic stimulation- contraction of detrusor, relaxation of
trigone and sphincter
Gentalia stimulation of ejaculation
Stiumulation of erection
Stimulation of tears
Thick viscous secretion
Copious watery secretion
Increased rate; increased contractility
Decreased rate; decreased contractility

GI- decreased muscle motility and tone


The adrenergic neuron- release NE as the primary neurotransmitter
These neurons are found in the CNS and also in the sympathetic
nervous system -> links between ganglia and the effector organs
Adrenergic drugs act on the adrenergic receptors located either
presynaptically on the neuron or postsynaptically on the effector organ
Neurotransmission involves- synthesis, storage, release and receptor
binding to NE, followed by removal of the NT in the synaptic gap
Tyrosine is transported by a carrier into the adrenergic neuron, where it
is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine
hydroxylase
This is rate limiting step in the formation of norepinephrine.
DOPA is then decarboxylated by the enzyme aromatic l-amino acid
decarboxylase to form dopamine in the presynaptic neuron
Storage of norepinephrine in vesicles- Dopamine is then transported
into synaptic vesicles by an amine transporter system
****blocked by reserpine
release of norepinephrine- an action potential arriving at the nerve
junction triggers an influx of calcium ions from the extracellular fluid
into the cytoplasm of the neuron
GUANETHIDINE block this release
Norepinephrine released from the synaptic vesicles diffuses into the
synaptic space and binds to postsynaptic receptors on the effector
organ or to presynaptic receptors on the nerve ending
NE- diffuse out of the synaptic space and enter the systemic
circulation, be metabolized to inactive metabolites by catechol-omethyltransferase in synaptic space
Undergo reuptake back into the neuron
TCAs inhibit the reuptake of NE via sodium/chloride dependent NE
transporter
Imipramine by serotonin-NE reuptake inhibitor such as duloxetine
For alpha receptors the rank of order of potency and affinity is
epinephrine > NE > isoproterenol

Phenylephrine has higher affinity for alpha 1 receptors


Clonidine has greater affinity to alpha 2 receptors
Alpha 1 activation -> G protein activation of phospholipase C- IP3 and
DAG
IP3 initiates the release of calcium from ER into the cytosol
DAG turns on the other proteins within the cell
Alpha 2 receptors- stimulation of alpha 2, inhibits NE from the
stimulated adrenergic neuron
NE released from presynaptic sympathetic neuron can diffuse to and
interact with these receptors inhibiting acetylcholine release
Tamsulosin is a selective alpha antagonist, TX benign prostatic
hyperplasia
B1 has equal affinity towards E + NE
B2 has greater affinity for E than for NE
Catecholamines are metabolized by COMT postsynaptically and by
MAO intraneuronally as well as by COMT and MAO in the gut wall, and
by MAO in the liver
Compounds lacking the catechol hydroxyl groups have longer half-lives
because they cant be inactivated by COMT
These include- phenylephrine, ephedrine, amphetamine- cant be
degraded soon
And lipid solubility of it allows access to the CNS
Direct acting agonists are- NE, E, isoproterenol, phenylephrine
Indirect-acting agonists- block the reuptake of norepinephrine or cause
the release of norepinephrine from the cytoplasmic pools or vesicles of
the adrenergic neuron
The norepinephrine then traverses the synapse and binds to alpha or
beta receptors
Examples of reuptake inhibitors and agents that cause norepinephrine
release- Cocaine and amphetamines
Mixed action agonists- ephedrine and its stereoisomer, pseudoepherine
both stimulate adrenoreceptors directly and release of norepinephrine
Epinephrine- low doses beta effects cause vasodilation on vascular
system and high doses alpha effects vasoconstriction are the strongest

Rate of contraction and contractilityp positive iontrophe and


chronotrope
Epinephrine causes a slight decrease in diastolic pressure and systolic
pressure
Epinephrine causes a powerful bronchodilation by acting directly on
bronchial smooth muscle (B2 action) , it inhibits the release of allergy
mediators as histamines from mast cells
Epinephrine has significant hyperglycemic effect due to increased
glycogenolysis in the liver, increased release of glucagon and
decreased release of insulin
Epinephrine initiates lipolysis
Epinephrine is used in acute asthma and anaphylactic shock
Beta 2 agonist- albuterol are favored in chronic treatment of asthma
for longer duration of action
Anaphylactic shock- type 1 hypersensitive reactions (anaphylaxis) in
response to allergens
Epinephrine can produce anxiety, fear, tension, headache and tremor
Cardiac arrhythmias particularly if patient receives digoxin
Induce pulmonary edema
Norepinephrine is used to treat shock as it increases vascular
resistance and therefore increases blood pressure
Norepinephrine is used to treat shock because it increases vascular
resistance and therefore increases blood pressure
Impaired circulation from norepinephrine may be treated with an alpha
receptor antagonist phentolamine
Norepinephrine constricts all blood vessels causing increased
peripheral resistance
Norepinephrine induces reflex bradycardia
Norepinephrine causes increased systolic and diastolic pressure
Isoproterenol is a direct acting synthetic catecholamine that stimulates
both beta and beta2 receptors
Its nonselectivity is one of its drawbacks and the reason why it is rarely
used therapeutically
It produces intense stimulation of the heart increasing heart rate,
contractility, cardiac output
Active as epinephrine in this action
Isoproterenol also dilates the arterioles of the skeletal muscle resulting
in decreased peripheral resistance
It increases systolic blood pressure
Reduces MAP and diastolic pressures

It is a potent bronchodilator
It is useful in av block
Dopamine it occurs naturally in the norepinephrine
Dopamine dilates renal and splanchnic arterioles by activating
dopaminergic receptors
It is the drug of choice for cardiogenic and septic shock and is given in
continuous infusion
Dopamine is the drug of choice for cardiogenic and septic shock--- it
raises BP by stimulating the beta receptors on the heart to increase
cardiac output and alpha receptors on blood vessels to increase total
peripheral resistance
It enhances perfusion to the kidney and splanchnic areas
Phenylephrine is direct acting synthetic adrenergic drug that binds
primarily to alpha 1 receptors
It has both systolic and diastolic blood pressures
It has no effect on the heart itself but rather induces reflex bradycardia
when given parenterally
Phenylephrine has replaced pseudoephedrine in many oral
decongestants
Beta 2 receptor mediated inhibition of degranulation of mast cells,
which prevents the release of histamine and other inflammatory
agents
Epinephrine is often used together with local anesthetics to prolong the
action of the anesthetic
This increased duration is due to the epinephrine induced
vasoconstriction (mediated by alpha 1 receptor activation) which
localizes the anesthetic at the desired site, slowing its systemic
distribution
The most appropriate management of cardiac arrest induced by
ventricular fibrillation is 200 J defibrillation
Additional shocks at higher energy should be given in case of initial
failure
If ventricular fibrillation persists the aha indicates that epinephrine
should be given
Norepinephrine causes an increase in systolic and diastolic pressure
and a concomitant decrease in heart rate
This pattern suggests that the decrease in heart rate is reflex vagal
discharge

Apraclonidine is a selective alpha 2 agonist that can decrease the


production of aqueous humor by the ciliary epithelium
The aqueous humor of the eye is produced by the cells of the ciliary
body and is control of alpha 2 and beta 2 located on theses cells
Activation of alpha 2 receptors decreases the production of b receptors
increases the production
Clonidine is often used to decrease the symptoms of sympathetic
activation which are prominent during withdrawal from many sedative
drugs
Epinephrine is sometimes used to treat open angle glaucoma because
it decreases aqueous humor production by activating alpha 2 receptors
on the ciliary epithelium and it aslo increases aqueous humor outflow
Drugs alpha 1 adrenergic activity such as norepinephrine,
phenylephrine and dopamine to restore the arteriolar tone thus
conteracting the decreased BP
Norepinephrine, phenylephrine and dopamine restore arteriolar tone
Isoproterenol is often used in the operating room after heart
transplant, because contractility and sinus node function of the new
heart rate temporarily impaired to varying degrees based on the
condition of the donor heart
Activation of beta 2 receptors in the pancreas actually increase insulin
release
Activation of beta 2 causes vasodilation
Alpha2 stimulation of platelet aggregation
The signs and symptoms of the patient strongly suggest the diagnosis
of septic shock
High fever, high WBC , hypotension, tachycardia, elevated cardiac
output and low systemic vascular resistance
Septic shock is a vasodilatory shcok and is partly due to vasodilatory
effects
M2 is less effective than M3
Beta 2 agonists administered by inhalation are first-line drugs for
asthma
Tremors is the most frequent adverse effect of beta 2 agonists
It is likely occur because of beta2 agonist receptor activation
accelerates sequestration of cytosolic calcium by opening calcium

channels in the SR of the skeletal muscle and increases discharge of


skeletal muscle
Activation of D1 receptors in the kidney causes vasodilation and
inhibition of Na+ reabsorption by the proximal tubules
Both actions contribute to the increased diuresis that can occyr with
low doses of dopamine
Inhibition of sodium from the proximal tubules
Increased diuresis that can occur with low doses of dopamine
Dopamine decreases total peripheral resistance at low doses by
selectively activating D1 receptors (mainly in mesenteric and renal
beds) at higher doses dopamine can also activate alpha receptors and
increase norepinephrine release from adrenergic terminals
Dopamine decreases total peripheral resistance at low doses by
selectively activating D1 receptor
Tyramine is a normal by-product of tyrosine metabolism in the body
and is found in high concentration in fermented food it is normally
inactive when ingested
Pilocarpine is a muscarinic agonist, the drug induced activation of M3
receptors causes contraction of the sphincter muscle of the iris
(decreasing pupillary diameter) and contraction of the ciliary muscles
(increasing lens curvature)
Ocular pressure is decreased because of contraction of the ciliary
muscle opens the pores of the trabecular meshwork, facilitating the
outflow of the aqueous humor into the schlemm canal
This actiation causes contraction of the detrusor muscle of the bladder,
therefore the amount of bladder space that can be filled (distensibility
of the bladder or its compliance is decreased)
Ecothiophate is an irreversible cholinesterase inhibitor when given
locally in the subconjunctival sac it increases the availability of
acetylcholine at the cholinergic synapses
By activating M3 receptors acetylcholine contracts the ciliary muscle,
which in turn opens the trabecular meshwork and the schlemm canal
and increasing the outflow of aqueous humr
Being an irreversible inhibitor the drug has a long duration of action
that affords good control of glaucoma

By blocking M3 receptors the drug relaxes the smooth muscle of the


bladder so the compliance (a measure of the ease with which a hollow
internal organ may be distended) of the bladder is increased

Ipratropium is a quaternary ammonium antimuscarinic drug, by


blocking M3 receptors in the ciliary muscle it causes cycloplegia with
loss of accommodation for near vision
Urge incontinence is due to contraction of the detrusor muscle
By blocking M3 receptors antimuscarinic drugs would cause relaxation
not contraction of the detrusor muscle
Antimuscarinic drugs are sometime used to prepare the eye for
measurement of refractive errors
Even if atropine is administered topically it can pass into the
nasolacrimal duct and be absorbed from the nasal mucosa
Atrial fibrillation this increase can cause tachycardia (more impulses
originating in the atrium can reach the ventricle) which in turn
stimulates the release of ANP
Most frequent symptoms of antimuscarinic poisoning are tachycardia,
mild hypertension, dilated pupils, dry and hot skin and diminished or
absent bowel sounds
Antimuscarinic drugs relax the detrusor muscle so voiding of the
bladder becomes more difficult
Who already of micturition due to prostate induced narrowing of the
urethra
Antimuscarinic drugs can precipitate acute urinary retention
Acetazolamide is a carbonic anhyrdrase inhibitor, carbonic anhydrase
is an enzyme located in the brush border and cytoplasm of renal
proximal convoluted tubule epithelial cells.the proximal tubule a
large amount of H+ is secreted into lumen via Na/H exchanger
Most of this H+ combines with bicarbonate on in the tubular fluid to
form carbonic anhydrase
Acetazolamide a carbonic anhydrase inhibitor is the only diuretic used
to prevent mountain sickness in people who are at risk for this disorder
ha

Fluoroquinolones and Quinolones

IgM and IgG these activate complement system

Macrophages take antigen and present


Eisonophils go up- neopplasia, allergy, asthma, parasites, collagen
vascular condition , allergy, neoplasia
Bilobed nucleus , eosinophilic
Neutrophils- multi-lobed nucleus,
Kidney shaped nucleus
Bi-lobed nucleus
Non-specific granules are produced in all of them, but the specific
granules are present in granulocytes
Myeloblast- promyleocyst- myleocyst- metamyelocyst- stab cells
Basophils- s-shaped and basophilic granules- IgE receptors
Basophil granules secrete heparin- anticoagulant, heparin sulfate
Histamine
LT4 are all secreted
0-2% is the amount of basophils found
stippled basophils- many dots, there is TAIL- thalassemias, anemias of
chronic diseases, Iron deficiency L is for lead poisoning
lead poisoning- paint in lead

basophils- bi-lobed and it is s-shaped and granules are basophilic


circulating the blood, and coated with IgE
basophils- has granules that secrete heparin, heparan sulfate,
histamine, LT4
kupfer cells liver
phagocytosis are what macrophages do
they are very important antigen presenting cells
all the antigen presenting cells- dendritic cells, all the classes of
macrophages, b-lymphocytes
macrophages have non-specific (azuphilic granules)
the adaptive
MHC AND Transplantation
What are MHC- they were also called HLA molecules and they are
called MHC molecules

They were discovered on leukocytes and so called Human leukocyte


antigen and they finally found that they are found in every nucleated
cell
And also determined the compatibility between the grafted and the
recipient- in organ transplant
HLA- MHC molecules
Class I presented in all nucleated cells except RBCs and even platelets
present these molecules
Chromosome 6 there are two chromosome 6 and one is coming from
mom and the other is dad
MHC molecules on short arms- MHC CLASS I molecule the class one
alpha chains synthesized varies from molecules to molecules due to
recombination
Varying from molecule to molecule- hyper-variable areas
This molecules is like a human being
Alpha1 and alpha2 captures a molecule , so variation allows different
types of antigens to fit in this complex
MHC CLASS 1 gene- hypervariable region- so every area is capable of
binding different antigen than the other one
Every cell has molecular ID and these are MHC I and MHC II molecules
Class I molecules- THEY are coming
Class II are only expressed in antigen presenting cells
They are selective and so expressed only on APCs
Those are macrophages, B lymphocytes,