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 system- sympatholytic, 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 mechanism- COMT- 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
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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 system- sympatholytic, anti-adrenergic, adrenergic antagonists Neurophysiology of sympathetic system- prepares you to fight with the stressParasympathetic 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 endingsTyrosine 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 acidsWithin the wall of the membrane there is an enzyme called dopamine beta hydroxylase- dopamine converted to NEReuptake one mechanism-COMT- attacks the methyl group and transfers methyl group Methyl tyrosine- it will enter at the same site as tyrosine and inhibits tyrosine hydroxylaseReserpine (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, BRETYLIUMDrugs 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 terazosinPrazosin 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-selectiveMainly alpha1 stimulant- PhenylephrineMainly alpha2 stimulant – Clonidine (central sympatholytic) Alpha 1 and Beta 1 stimulant- NE Alpha 1 B1 and B2- EpinephrineB1 and B2- Isoproterenol B1 action- dopamine, in high concentrations- alpha1 receptors and dopamine receptors B1- DobutamineB2- salbutamol
Cocaine blocks the uptake transporter
TCAS also block reuptake 1, bind it mildly and inhibit the uptake (non-selective)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 visionWhen the ciliaris muscle relaxes it stretches the suspensory muscles – lens become flatten – far visionCiliaris muscle has B2 receptor
Circular muscles should relax in sympathetic activation and the sphincters should contractAlpha 1 on sphinctersB2 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 HRB1 ar- increase contractility- ionotropicBlood 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 glycogenolysisTriglycerides- breakdown of fatty acids, break down of lipidsGluconeogenesis – 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 constrictionNow 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 pressureWhen 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 insulinAdipocytes- 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? DobutamineAV node stimulated- positive dromotrophySA node stimulated- chronotrophy Excitability- positive bathmotrophy – increase excitability of specialized conduction system Increase the risk of tachyarrythmiasDegree 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 lipolysisTocolysis- relaxes the myometrium, stimulate B2 receptor on uterus Liver has b2 RECEPTORS and it stimulates glAlpha 1 stimulates Gq receptor which activates IP2 and DAG, increases intracellular CalciumAlpha 2 receptor- decrease cAMP, increase K+ efflux and and decrease calcium influxB1 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 increased…stroke 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 to the heart and so more EDV which means the heart has to work more to pump this blood….
Laplace law: Pressure= tension/radiusTension 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 lessSympathetic 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 EDVAfterload- 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 strokeThey are super important in CHF! Or when E.F. is < 35%The lower the ejection fraction the more beneficial the drugsCaptopril 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 activeAll drugs except for fosinopril they get excreted via kidneyAll 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 proteinsACE inhibitors- will reduce systemic BP, overall damage to glomerulus is reducedEfferent 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 downARBs angiotensin receptor blockers they do not produce the coughA stands for angioedema- patient develop swelling of nasal, throat, lips and buucal mucosa and produce life threatening situation Accumulated bradykinin leads to angioedemaC1-esterase inhibitor – complement activation- vasodilators increased resulting in angioedemaStop the drug immediatelyP- proteinuriaT- 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 activityP- not given in PregnancyR- they produce rashesThe 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 doesn’t 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 blockersBlockage 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 failureLow output heart failure is present as a result of ischemic heart not being able to produce the normal cardiac output 5L/minThe 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 BVFWhen 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 edemaRVF- generalized or systemic edemaBVF- 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 edemaForward failure features- fatigueness, exercise tolerance is reduced Backward failure- pulmonary edema – cough, dyspnea, orthopnea and paraxymal dyspneaPulse is weak – forward failure Cant breathe- backward failure
Systolic failure and diastolic failure- the difference is during diastole- left ventricle relaxes for ventricular filling and accumulate proper EDVSystolic function is it has to contract and so that cardiac output has to be maintained, related to SV and EFIf 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 bloodVery sever LV hypertrophy- stiff and cant relax in diastole, and accommodate not a lot of EDVDiastolic function failure and backward failureIf 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 nodeClinotrophic effectDromotropic 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 fibrinProphylaxis of pulmonary embolism, preventing clotting in arterial and cardiac surderyProtamine sulfate if poisoning by heparin Measure PTTWarfarin- 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 it’s 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 anti-thrombotic,
anti-platelet First thing that happens when a vessel is injured is- vasospasticity
(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 acid- thromboxane
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 it’s 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: Neurotoxicity- SIADH vincristine Coma- IfosfamideCerebral toxicityCytosobine Ototoxic + Kidney + N/V : cisplastinTo 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 specificTypical alkylating agents- cyclophosphamide, ifosfamide, melphalan, busulfan, mechlorethamine, chlorambucil, thiotepaSide effects- myelosuppression, N/V, secondary malignancies, hemorrhagic cystitisAtypical alkylating agents- platinum compounds covalently bind purine bases- cisplastin- nephrotoxicity and N/V Carboplatin – thrombocytopeniaOxaliplatin – cold sensitivityAll cause peripheral neuropathies, paresthesia
AntimetabolitesInhibit DNA replication Specific to S phaseInhibit DNA replication or repair by mimicking cell compoundsS phase specific Folate inhibitor: methotrexate inhibits DHF prevents regeneration of THF Adjuvant leucovorin and protects the healthy cellsSide effects- mucositis, myelosuppresion
Pyrimidine inhibitors- 5-FU It inhits thymidylate synthetaseBolus dose causes myelosuppressionGI prblems- mucositis, diarrheaLeucovorin potentiate the action
Capecitabine- oral prodrug for 5-FUHand and foot syndrome palms and hand and feet become red and blistering
Cytarabine- AraC is DNA chain terminatorConjunctivitis and cerebral neural defects
Purine analog- 6-mercaptopurine
Microtubule targeting agents These drugs inhibit mitosis, specifically M phase Vinca alkaloids destroy microtubulesSE- peripheral neuropathy, myelosuppressive
Fatal if give intrathecally
Taxanes- stabilize microtubules, preventing their function Paclitaxel, docetaxolSE” peripheral neuropathy, myelosuppresion Hypersensitivity
Abrazane- protein bound paclitaxel avoid hypersensitivityLess sensitivity but more neuropathy
Topoisomerase inhibitorsTopoisomerase I inhibitors prevent relaxation of supercoiled DNA- topotecan irinotecan
Both have side effect of myelosuppresion Diarrhea TOPO II inhibitors- etoposide, teniposidemyelosuppresion, mucositis secondary malignancies (AML)
The peripheral nervous system is subdivided into the efferent and afferent divisionsThe 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 dilatesContraction of iris sphincter muscle- pupil contractsContraction 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 ejaculationStiumulation of erection Stimulation of tears
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-o-methyltransferase in synaptic space
Undergo reuptake back into the neuron
TCAs inhibit the reuptake of NE via sodium/chloride dependent NE transporterImipramine 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 hyperplasiaB1 has equal affinity towards E + NEB2 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 neuronThe 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 cellsEpinephrine 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 tremorCardiac arrhythmias – particularly if patient receives digoxinInduce 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 resistanceNorepinephrine induces reflex bradycardiaNorepinephrine 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 outputActive 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 pressuresIt is a potent bronchodilatorIt 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 resistanceIt 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 pressuresIt 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 rateThis 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 cellsActivation 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 vasodilationAlpha2 – 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 resistanceSeptic 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 tubulesIncreased 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 receptorTyramine 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 difficultWho already of micturition due to prostate induced narrowing of the urethraAntimuscarinic 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
Basophils- s-shaped and basophilic granules- IgE receptors Basophil granules secrete heparin- anticoagulant, heparin sulfate HistamineLT4 are all secreted 0-2% is the amount of basophils foundstippled 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 IgEbasophils- has granules that secrete heparin, heparan sulfate, histamine, LT4
kupfer cells – liver phagocytosis are what macrophages dothey are very important antigen presenting cellsall 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 cellAnd also determined the compatibility between the grafted and the recipient- in organ transplantHLA- 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 dadMHC 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 areasThis molecules is like a human being Alpha1 and alpha2 – captures a molecule , so variation allows different types of antigens to fit in this complexMHC CLASS 1 gene- hypervariable region- so every area is capable of binding different antigen than the other oneEvery cell has molecular ID and these are MHC I and MHC II moleculesClass 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,
