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 مراجعة فارماكولوجي للخريجين

استعرض الموضوع السابق استعرض الموضوع التالي اذهب الى الأسفل 
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الدولة : اليمن
الكلية : كلية العلوم الطبية
المدينة : صنعاء
الجنس : ذكر عدد المساهمات : 151
عدد النقاط : 244
تاريخ التسجيل : 28/10/2010
العمر : 29

مُساهمةموضوع: مراجعة فارماكولوجي للخريجين    الخميس أكتوبر 28, 2010 11:59 pm

اخواني واخواتي..


مرحبا بكم في هذا الموضوع..


والذي يعد احد الموضوعات العلمية لمشروع :


صيدلي المستقبل


سنتناول هنا وبعون من الله..


مراجعة لاهم موضوعات...


علم الفارماكولوجي بطريقة ملخصة..


تذكرنا بما كنا قد درسناه في كلياتنا..


بحيث يمكن لنا ان نعيد الربط بين ما درسناه في السابق ..


وواقع عملنا الحالي.


طريقة العرض


1- سيراعى طرح النقاط الهامة ذات الارتباط المباشر بطبيعة عملنا ..


دون ذكر معلومات اخرى اضافية ..


غير ذات ضرورة للطرح


2- المرجع الاساسي لهذه الموضوعات هو :


Lippincotts Illustrated Reviews in Pharmacology
Second edition


اللهم تقبل منا هذا العمل خالصا لوجهك الكريم





Introduction to pharmacology

Drugs affecting the cardiovascular system


Treatment of congestive heart failure CHF

Antianginal drugs

Antihypertensive drugs

Drugs affecting the respiratory system

The autonomic nervous sysyem

Diuretic drugs

Insulin and oral hypoglycemic drugs

Anti-inflammatory drugs

Anti-inflammatory drugs2

Principles of antimicrobial activity

Principles of antimicrobial activity2

Principles of antimicrobial activity3



Introduction to pharmacology

I- Routes of drug administration : 2 major routes

A- Enteral
Oral
the most common route
the most variable mode in amount of drugs reach the target tissues
some drugs are absorbed from the stomach
most drugs are absorbed from the duodenum
most drugs absorbed from GIT enter the portal circulation and encounter the liver before they are distributed in the general circulation
first pass metabolism by intestine or liver limits the efficacy of many drugs when taken orally

Sublingual
the drug diffuses to the systemic circulation directly

Rectal
fifty percntage of the drug bypass the portal circulation
Useful if the drug
destructed by the intestinal enzymes
destructed by the low pH of the stomach
induce vomitting or the patient himself is vomitting

B- Parenteral
I.V
the most common parenteral route
drugs avoid first pass metabolism
permit a rapid effect
permit the maximal degree of control over the circulating levels of drug
the rate of infusion must be carefully controlled

I.M
main route used for depot preparations which dissolves slowly providing a sustained dose over an extended period of time
used also for many aquous solutions of drugs

S.C
as I.M it requires absorbtion
slower than I.V
minimizes the risks associated with I.V injections

Others
Inhalation
provides rapid delivery of drug producing rapid effect almost as that of I.V
Intranasal e.g salmon calcitonin used in osteoporosis
Intrathecal e.g methotrexate in leukemia
Intraventricular
Topical when local effect of the drug is required
Transdermal e.g nitroglycerine when used as antianginal




II- Absorbtion of drugs

the transfer of a drug from its site of administration to
blood streem
the rate and the efficiency of absorbtion depend on the route of administration so in

I.V : Complete absorbtion
Other routes : partial absorbtion which lowers the bioavailability

A- Transport of drugs from GIT

depending on their chemical properities drugs may be absorbed from GIT by


Passive diffusion
Active transport


B- physical factors influencing absorbtion

blood flow to the absorbtion site
total surface area available for absorbtion
contact time at the absorbtion surface


III-Bioavailability

the fraction of administerd drug that reaches the systemic circulation in a chemically unchanged form

ex : if 100 mg of the drug is administrated orally and 70 mg of this drug is absorbed unchanged ..the bioavailability is 70%

Factors that influence bioavailability

first pass hepatic metabolism
solubility of the drug
chemical instability
the nature of the drug formulation


IV-Drug distribution

the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of tissues

Factors affect drug distribution

A- blood flow

B- capillary permeability which determined by

Capillary structure
ex : blood brain barrier : lipid soluble drugs readily penetrate to the CNS since they can dissolve in the membrane of its endothelial cells but ionized or polar drugs generally fail to enter the CNS

Drug structure

Binding of drugs to proteins

reversible binding to plasma proteins sequesters drugs in a non diffusible form and slows their transfer out of the vascular compartment



V-Binding of drugs to plasma proteins


Usually albumin


bound drugs are pharmacologically inactive ...only the free unbound drug can act on target sites in the tissues and elicit a biological response
so hypoalbunemia may alter the level of free drug

A- Binding capacity of albumin

binding of drugs to albumin is reversible
albumin may show

Low capacity : one drug molecule per albumin molecule
High capacity : a number of drug molecules per single albumin molecule

albumin has the strongest affinity for anionic drugs(weak acids) and hydrophobic drugs

most hydrophilic drugs and neutral drugs do not bind to albumin

many of drugs are hydrophobic by design since this property permits absorbtion after oral administration

B- Competition for binding between drugs & clinical imprtance of drug displacement

ex : Tolbutamide is normally 95% bound and only 5% free so 95% is inert in its pharmacological action

sulfonamid with higher affinity for albumin if adminiserd it displaces tolbutamide and now 100% of tolbutamide become free in plasma

but note that.... the tolbutamide concentration does not remain elevated since the drug moves out of the plasma into the interstitial fluid and avhievs new equilibrium


VI- Drug metabolism

drugs are most often eleminated by biotransformation and/or excretion into the urine or bile

The liver is the major site for drug metabolism

Specific drugs may undergo biotransformation in other tissues

some agents are initially administerd as inactive compounds(prodrugs) and must be metabolized to thir active forms


thanks

Drugs affecting the cardiovascular system
Treatment of congestive heart failure CHF

I- Overview of congestive heart failure CHF

it is a condition in which the heart is unable to pump sufficient blood to meet the needs of the body
it can be caused by
impaired ability of the cardiac muscle to contract
an increesed work load imposed on the heart

CHF is accompanied by abnormal increase in blood volume and interstitial fluid
the heart,veins,and capillaries therefore generally dilated with blood.Hence,the term (Congestive) heart failure

Underlying causes of CHF

arteriosclerotic heart disease
dilated cardiomyopathy
congential heart disease
valvular heart disease
left systolic dysfunction secondary to coronary artery disease is the most common cause of CHF

The therapeutic goal for CHF is to increase cardiac output

Three classes of drugs have been shown to be clinically effective in reducing symptoms and prolonging life
Vasodilators: reduce the load on the myocardium
Diuretic agents : decease extracellular fluid volume
Inotropic agents : increase the strength of contraction of
cardiac muscle

these agents
relieve the symptomps of cardiac insufficiency
do not reverse the underlying pathologic condition

Drugs that may preciptate or exacerbate CHF so should be
avoided as possble

non steroidal antiinflammatory drugs
alcohol
B blockers
calcium ghannel blockers
some antiarrythmic drugs


II- Vasodilators
In CHF,the impaired contractile function of the heart is exacerbated by compensatory increase in preload and afterload

Preload
the volume of blood that fills the ventricle during diastole
elevated preload causes overfilling of the heart which increases the work load
Afterload
the pressure that must overcome for the heart to pump blood into the arterial system
elevated afterload cause the heart to work harder to pump
blood into the arterial system

Vasodilators are useful in reducing excessive preload and afterload as follow
dilation of veinous blood vessels increases the venous capacitance by which a decrease in preload occurs
arterial dilators reduce systemic arteriolar resistance by which a decrease in afterload occurs

Classes of vasodilators

A- Angiotensin convertizing enzyme (ACE) inhibitors
ex : captopril - lisinopril - enalapril

Adverse effects

postural hypotension
renal insuffeciency
persistant dry cough
should not be used in pregnant women

B - Direct smooth muscle relaxants
ex: hydrazaline - isosorbide - sodium nitroprusside

III - Diuretics
ex : bumetanide - furosemide - hydrochlorothiazide

relieve pulmonary congestion and peripheral edema
useful in reducing the symptoms of volume overload
Thiazide diuretics are relatively mild diuretics and lose efficacy if patient creatinine clearance is less than 50 ml/min
Loop diuretics are used in patients with renal insuffiency
Overdoses of loop diuretics can lead to profound hypovolemia

IV- Inotropic agents

positive inotropic agents enhance cardiac muscle contractility
and increase cardiac output

although these drugs act by different mechanisms ,in each case the inotropic action is the result of an increased cytoplasmic calcium concentration that enhances the contractility of the cardiac muscle

A-Cardiac glycosides(Digitalis)=digoxin &digitoxin

digoxin(lanoxin) is the most widely used agent

Therapeutic uses

digoxin is indicated in patients with severe left ventricular systolic dysfunction after initiation of diuretic and vasodilation therapy
not indicated in patient with diastolic or right sided heart failure
patients with mild to moderate heart failure will often respond to treatment with ACE inhibitors and diuretics and do not require digoxin

N.B. The digitalis glycosides show only a small difference between a therapeutically effective dose and doses that are toxic or even fatal i.e. have low therapeutic index

Factors predisposing to digitalis toxicity

a) Electrolytic disturbances

hypokalemia can preciptate serious arrythmia
reduction of serum K levels is most frequently observed in patients receiving thiazide or loop diuretics
hypokalemia can be usually prevented by use of a K sparing diuretics or supplementation with potassium chloride
hypercalcemia and hypomagnesemia also predispose to digitalis toxicity

b)Drugs

Quinidine : can cause digitalis toxicity by
displacing digitalis from plasma protein binding sites
competing with digitalis for renal excretion
Verpamil(isoptin) : displace digitalis from( PPBS) and can increase digoxin levels by 50 to 75% which may require a reduction in the dose of digoxin

c)Others

potassium depleting diuretics
corticosteroids
hypothyrodism
hypoxia
renal failure
myocarditis

B- B adrenergic agonists
ex : dobutamine

improves cardiac performance by both
positive inotropic effects

vasodilation
must be given by I.V. infusion and is primarily used in the
treatment of acute heart failure in hospital setting

C- Phosphodiesterase inhibitors : not used clinically

thanks


Antianginal drugs


I- Overview


Angina pectoris : a characteristic chest pain causd by coronary blood flow that is insuffecient to meet the oxygen demands of the myocardium


The impalance between oxygen delivery and utilization may result from
a) a spasm of the vascular smooth muscle
b) obstruction of blood vessels caused by atherosclerotic lesions


Characters of angina :sudden severe pressing substernal pain radiating to the left arm


Three classes of drugs are effective either alone or in combination,in treating patients with stable angina


Nitrates : decrease coronary vasoconstriction or spasm and increase perfusion of the myocardium by relaxing coronary arteries


B blockers : decrease the oxygen demands of the heart


Calcium channel blockers


Prinizimetals angina :a variant angina caused by spontaneous coronary spasm either at work or at rest ...rather than by increases in myocardial oxygen requirements


It is controlled by organic nitrates or calcium channel blockers but B blockers are contraindicated


II- Organic nitrates & nitrites
these compounds cause a rabid reduction in myocardial oxygen demand followed by rapid relief of symptoms


A- Nitroglycerin
its sublingual or spray forms are the drug of choice used for prompt relief of ongoing attagk of angina precipitated by excercise or emotional stress


Effects on cardiovascular system


at therapeutic doses :has 2 major effects


a) Dilation of the large veins resulting in pooling of blood in the veins which diminish the preload(discussed before) and reduces the work of the heart


b) Dilates the coronary vasculature providing increased blood supply to the heart muscle


The total effect is a decrease in myocardial oxygen cosumption because of decreased cardiac work


Adverse effects


long acting preparations cause headache in about 30% - 60% of patients
high doses can cause postural hypotension,flushing &tachycardia


B- Isosorbide dinitrate'
has a lower potency than nitroglycerin in relaxing vascular smooth muscle - can be used orally


III- B adrenergic blockers


Supress the activation of the heart by blocking B1 receptors
reduce the work of the heart by decreasing cardiac output and causing a slight decrease in blood pressure
Reduce the frequency and severity of angina attacks
Particullary useful in the treatment of patient with myocardial infarction


Contraindications


in diabetes
peripheral vascular disease
chronic obstructive pulmonary disease


IV- Calcium channel blockers


Inhibit the entrance of calcium into cardiac and smooth muscle cells of the coronary and systemic arterial beds so
All of them are vasodilators and decrease smooth muscle tone and vascular resistance


A- Nifedipine


Mainly,an arteriolar vasodilator
Exerts greater effect on cardiac conduction and heart rate
Used in variant angina


B- Verpamil


Slows cardiac conduction directly which decrease the heart rate and the oxygen demand
Has negative inotropic effects greater than that of nifedipine but weaker as a vasodilator


Contraindications


in preexisting depressed cardiac function
in atrioventricular conduction abnormalities


Adverse effects


Used with caution in digitalis patients...discussed before
Constipation


C-Deltiazem


Its cardiovascular effects similar to verpamil
Reduce the heart rate but lesser than verpamil
Reduce blood pressure
Relieve coronary artery spasm so used in variant angina
Can be used in angina in patients with concomitant diseases



Thanks




Antihypertensive drugs

I-Hypertension
a sustained diastolic blood pressure greater than 90 mm Hg accompanied by an elevated systolic blood pressure > 140 mm Hg

Chronic hypertension if not controlled can lead to

Congestive heart failure
Myocardial infarction
Renal damage
Cerebrovascular accidents

II- Etiology of hypertension

Secondary to other disease
Ninty percentage of patients from disorder of unknown origin affecting the blood pressure regulating mechanism
Family history of hypertension increases the liklihood of the disease

It occurs in blacks four times more than in whites
in middle aged males more than middle aged females

Predisposed factors
Stressful life style
High dietary intake of sodium
Obesity
Smooking

N.B NSAIDS interfere with the hypotensive action of many antihypertensives

III-Mechanisms for controlling blood pressure

Reducing the cardiac output
Deceasing the peripheral resistance

IV- Treatment sterategies

Mild hypertension can often be controlled with a single drug
More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen
Treatment is initiated with (a diuretic ,B blocker,ACE inhibitor or a Ca channel blocker ) depending on the individual patient

If not adequately controlled
B blocker is added if the initial was a diuretic or
a diuretic is added if the initial was a B blocker

A vasodilator can be added as a third step for those patients who still fail to response

A- Individual care

Black patients respond well to diuretics and Ca channel blockers
In elderly Ca channel .ACE inhibitors and diuretics are favored

N.B Hypertension may coexist with other disease that can be aggrevated by some of the antihypertensive drugs
ex
Diuretics and B blockers avoided in insulin dependant diabetes and in hyperlipidimia
B blockers avoided in asthma or chronic pulmonary disease

B-Patient compliance in antihypertensive therapy

ex B blockers can decrease libido and induce impotence in males particullary middle aged and elderly men
This this drug induced ***ual dysfunction may prompt the patient to discontinue therapy
Thus it is important to enhance compliance by carefully selecting a drug regimen that both

a) reduces advers effects
b) minimizes the number of doses required daily

V- Diuretics
Diuretics and/or B blockers are currently recommended as the first line drug therapy for hypertension
Recent data suggest that diuretics are superior to B blockers in older ******

A- Thiazide diuretics
ex: hydrochlorothiazide

the most widespread used diuretics

Therapeutic uses
Particularry useful in treatment of black or elderly patients
Can be used in those with chronic renal disease
Not effective in patients with inadequate kidney function i.e creatinine clearance less than 50 mls/min
N.B loop diuretics may be required in these patients

Adverse effects
Induce hypokalemia so serum ptassium level should be monitored closely in patients predisposed to cardiac arrythmia
Should be avoided in diabetes or hyperlipidemia

B-Loop diuretics

ex : bumetanide -furosemide
Act promptly even in patients who have poor renal function or have not respond to other diuretics

VI- B blockers
ex : atenolol - propranolol

Recommended as a first-line drug therapy for hypertension
Efficacious but have some contraindications

Propranolol : is the protoyype B blocker
acts on both B1 and B2 receptors so contraindicated in asthmatic patients

Atenolol : newer agents
selective for B1 receptors so commonly used in asthmatic patients

Therapeutic uses
Effective in white than in black
Effective in young than in elderly

Advers effects ... discussed

VII- ACE inhibitors
ex captopril - ramipril

Recommended when first- line agents are contraindicated or ineffective

Therapeutic uses
Most effective in white and young patients as B blockers
If used in combination with a diuretic the effectiveness will be similar in both white and black
Effective in patients with CHF ...unlike B blockers
A standard in care of patient following a myocardial infarction

Adverse effects
the most important are
Dry cough
Alterd taste
Hypokalemia :so K supplements and spironolactone are contraindicated
Fetotoxic : so must be avoided in pregnancy

VIII- Angiotensin
ex : losartan

Its phamacologic effects are similar to ACE inhibitors
Its adverse effects profile is improved over ACE inhibitors
Also fetotoxic

IX- Ca channel blockers
ex :Amlodipine - deltiazem - nifedipine - verpamil

Recommended when first line agents are contraindicated or ineffective
One study suggests that the use of short acting ones especially in high doses increase the risk of myocardial infarction

Deltiazem and Verpamil : discussed before

Amlodipine :a newer agent have the advantage that show little interaction with other cardiovascular drugs e.g : digoxin - warfarin

Therapeutic uses
Not usually require the addition of a diuretic
Can be used in asthmatic,diabetes,angina and/or peripheral vascular diseases

Adverse effects
The main ,is constipation in 10% of patients

X- Alpha adrenergic blocking agents
ex : prazosin - terazosin -oxazosin

May cause postural hypotension
Prazosin :Treat mild to moderate hypertension
prescribed in combination with propranolol or a diuretic for additive effect

XI- Centrally acting adrenergic drugs

A-Clonidine
Used for mild or moderate hypertension that has not responded adequately to diuretics alone
Useful in the treatment of hypertension complicated by renal diseases
As it causes sodium and water retention , it is usually administerd in combination with a diuretic

B- Alpha methyl dopa
Valuable in treating hypertensive patients with renal insufficiency
Can be used during pregnancy

XII- Vasodilators
ex :hydrazaline - minoxidil

Direct acting smooth muscle relaxants
Not used as hypotensives nowadays due to their serious adverse effects

Minoxidil : Nowadays used topically to treat male pattern baldness


Thanks




Drugs affecting the respiratory system

I- Overview
Drugs can be deliverd to the lung by
inhalation : preferred as
The drug is deliverd directly to the target tissues
Effective in doses do not cause significant systemic side effects
oral route
parenteral route

Main mechanisms of action
Relaxing bronchial smooth muscles
Modulating the inflammatory response

II- Drugs used to treat asthma
Asthma is a chronic disease characterised by episodes of acute bronchoconstriction causing
Shortness of breath
Cough
Chest tightness
Wheezing
Rapid respirations

The goal of the therapy is to
Relieve symptoms
Prevent recurrence of asthmatic attacks if possible

Role of inflammation in asthma
Airflow obstruction in asthma is due to bronchconstriction resulting from
contraction of bronchial smooth muscle
inflammation of the bronchial wall
increased mucous secretions

Asthmatic attacks may be related to
Recent exposure to allergans
Inhaled irritants
leading to bronchial hyperactivity and inflammation of the airway mucosa

The symptoms of asthma may be effectively treated by several drugs but none of them provide a cure for this obsructive lung disease

A-Adrenergic agonists

Inhaled B2 agonists(as direct bronchodilators) ..are drug of choice for mild asthma (occurs occasionaly with intermittent symptoms)
Have no anti-inflammatory effects
Should not be used as the sole therapeutic agents for patient with chronic asthma

Short acting : used as a rescue agents to combat acute bronchoconstriction
ex :terbutaline - albuterol - pirbuterol
Onset : rapid (15-30)minutes
Duration : (4-6)hours

Long acting drugs
ex:salmetrol
Onset :slow so should not be used in acute asthmatic attack
Duration : at least 12 hours

Prescriped only for administration at regular intervals and not to relieve symptoms

B- Corticosteroids
ex : beclomethazone - triamcinolone
Drug of first choice in patients with moderate to severe asthma who require inhalation of B2 agonists more than once daily
To be effective in controlling inflammation ,glucocorticoid must be taken continuously

Actions on the lung
Inhaled glucocorticoids decrease the number and activity of cells involved in airway inflammation
Prolonged(several months)inhalation of steroids reduces the hyperresponsiveness of the airway smooth muscle to a variety of bronchoconstriction stimuli such as
allergans - irritants - cold air - exercise

The most common adverse effect associated with the use of inhaled glucocorticoids is oropharyngeal candidiasis = oral thrush

C- Cromolyn & nedcromil - inhalations
Effective prophylactic anti-inflammatory agents
Not useful in management of acute ashmatic attack because they are not direct bronchodilators
Pretreatment with cromolyn blocks bronchoconsriction induced from allergans and exercise
Useful in reducing symptoms of allergic rhinitis

D- Cholinergic antagonists
ex: ipratropium
Has slow onset and nearly free of side effects
Less effective than B agonists but useful in patients unable to tolerate them

E- Theophylline
Relieves airflow obstruction in chronic asthma
Previously,it was the main stay of asthma therapy but now it is largely replaced with B agonists and corticoids
Has a narrow therapeutic window so overdose of it may cause seizures or potentially fatal arrythmias

III- Drugs used to treat allergic rhinitis

Rhinitis : an inflammation of the mucous membranes of the nose and is characterized by
Sneezing -nasal itching - watery rhinorrhea - congestion

A- Antihistamines = H1 receptor blockers
ex : diphenhydramine - chlorpheniramine - loratadine - terfenadine - astemizole
Useful in treating the symptoms of allergic rhinitis
When congestion is a feature of rhinitis , combination with decongestants is effective

B- Alpha adrenergic agonists = nasal decongestants
ex: phenylephrine - oxymetazoline
Constrict dilated arterioles in nasal mucosa and reduce airway resistance
Should not be used no longer than several days because rebound nasal congestion often occurs upon discontinuence of these drugs

C- corticosteroids
Topical steroids may be more effective than antihistamines in relieving the nasal symptoms of both allergic and non allergic rhinitis
Treatment of chronic rhinitis may not result in improvement until 1 to 2 weeks after starting therapy

D- Cromolyn
Intanasal cromolyn may be useful particularly when administerd before contact with an allergan

IV- Drugs used to treat chronic obstructive pulmonary disease COPD



It is a chronic irreversible obstruction of airflow
Smoking is the greatest risk factor for COPD
This disease may respond to
Anticholinergic agents
B adrenergic agents e.g : impratropium
Theophylline
These three classes does not cure the disease or even significantly slow its progress
Glucocorticoids : may be helpful in the treatment of acute exacerbations in some patients

V- Drugs used to treat cough
ex : codeine -hydrocodone -hydromorphone
at doses lower than required for analgesia they can
decrease the sensitivity of the CNS cough centers to peripheral stimuli
decrease mucosal secretion

Dextromethorphane : synthetic derivative of morphine

Supress the response of the cough center
Has no analgesic or addictive potential
Less constipating than codeine



Thanks



The autonomic nervous sysyem
Anatomy
I-Efferent neurons
Carries nerve impulses from the CNS to the effector organs by way
of 2 types of efferent neurons

a) a preganglionic neuron
Its cell body located within the CNS
Emerge from the brain stem or the spinal cord
Make a synaptic connection in ganglia which act as arelay station between the preganglionic neuron and the postganglonic neuron

b) a postganglionic neuron
Its cell body originating in the ganglia
Terminates on effector organ such as
Smooth muscle of the viscera
Cardiac muscle
Exocrine glands

II- Afferent neurons
are important in the reflex regulation of this system
ex: sensing pressure in the carotid sinus and aortic arch and signaling the CNS to influence the efferent branch of the system to respond
Sympathetuc neurons

The preganglionic neurons of sympathetic system
Come from thoracic and lumber regions of the spinal cord
Synapse in 2 cord-like chains of ganglia that run parallel on each side of the spinal cord
Axons of the postganglionic neurons extend from these ganglia to glands & viscera

Special case : (The adrenal medulla) : acts like the sympathetic ganglia
a)receives preganglionic fibers
b)lacking axons
c) if stimulated,it secretes the hormone(epinephrine= adrenaline) + less amount of norepinephrine which influence other organs

Parasympathetic neurons

The preganglionic fibers
arise from the cranial and sacral areas of the spinal cord
synapse in ganglia near the effector organs

In both : postganglionic fibers extend from the ganglia to the effector organs

Function of the sympathetic system
Not essential for life
Has the property of adjusting in response to stressful situations such as
trauma - fear - hypoglycemia - cold - exercise

Effects of stimulation of the sympathetic devision
increase heart rate
increase blood pressure
mobilize energy stores in the body
increase blood flow from the skin to skeletal muscles and heart
diverting flow from the skin and internal organs
stimulation of the pupils and bronchioles
i.e : Fight &Flight response due to
Direct sympathetic response
Stimulation of adrenal medulla to release epinephrine and norepinephrine

Functions of the parasympathetic system
Essential for life
Maintain essential body functions
Usually acts to oppose or balance the actions of the sympathetic division
It is a dominant over the sympathetic division in rest & digest stimulation
Affect specific organs such as stomach and eye


Innervation by the autonomic nervous system

I- dual innervation

Most organs in the body are innervated by both divisions
'ex : the heart has
a) vagal parasympathetic innervation which slows the rate of contraction
b) sympathetic innervation speeds contraction
c)the vagus is the predominant controlling factor for rate

II- Organs receiving only sympathetic
examples
Adrena medulla
Kidney
Pilomotor muscle
Sweat glands

N.B :the control of blood pressure is also mainly a sympathetic activity
Neurotransmitters

Cholinergic and adrenergic neurotransmitters are the primarily chemical signals in the autonomic nervous system
The autonomic nerve fibers can be classified into 2 groups based on the chemical nature of the neurotransmitter released

Acetyl choline
Released from the preganglionic neurons in
both parasympathetic and sympathetic
in adrenal medulla
in neuromuscular junction

Norepinephrine & epinephrine
In sympathetic.it is released from the postganglionic neurons to the
effector organs


Thanks


Diuretic drugs

I-Overview
They are drugs inducing a state of increased urine flow
They are ion transport inhibitors that decrease the reabsorbtion of Na at different sites in the nephron

As a result,Na and other ions such as cl enter the urine in greater amounts than normal along with water which is carried passively to maintain osmotic equilibrium

II-Kidney function in disease
in many diseases,the amount of Nacl reabsorbed by the kidney tubules is abnormally high

this leads to the retention of water,an increase in blood volume,and expansion of the extravascular fluid compartment resulting in edema of the tissues

Several commonly encounterd causes of edema include

a- Congestive heart failure

the decreased ability of the failing heart to sustain adequate cardiac output,causes the kidney to respond as if there were a decrease in blood volume
The kidney as a part of normal compensatory mechanism retains more salt and water as a means of raising blood volume and increasing the amount of blood that it is returned to the heart
However,the diseased heart can not ingrease its cardiac output,and the increased vascular volume results in edema

b-Hepatic ascitis

Ascitis: the accumulation of fluid in abdominal cavity,is a common complication of cirrhosis of the liver
that is due to
The increased portal blood pressure
the secondary hyperaldosteronism

c-Nephrotic syndrome
d-Premenstural edema
is a result of imbalances in hormones such as estrogen exess which facilitates the loss of fluid into the extracellular space

A-Carbonic anhydrase inhibitors
e.g acetazolamide

Therapeutic uses

Treatment of glaucoma :by decreasing the production of aquous humor ,probably by blocking the carbonic anhydrase in the cilliary body of the eye
it is useful in the chronic treatment of glaucoma but should not be used for an acute attack

N.B. Pilocarpine is preferred in acute attack because of its immediate action

Epilepsy : it reduces the severity and magnitude of the seizures
often it is used chronically in conjunction with antiepileptic medication to enhance the action of these other drugs
Mountain sickness:less commonly it can be used in the prophylaxis of acute mountain sickness among healthy physically active individuals who rapidly ascend above 10000 feet

B-Loop diuretics
e.g bumetanide-furosemide

These drugs have the highest efficacy in mobilizing Na & cl from the body
Furosemide shows the greater side effects than those seen with the other loop diuretics
Bumetanide is much more potent and its use is increasing

Therapeutic uses
Drugs of choice for reducing the acute pulmonary edema of C.H.F because of their rapid onset of action
Useful in treatment hypercalcemia

Adverse effects

a-Ototoxicity :particullary when used in conjunction with aminoglucosides antibiotics

N.B. Permanent damage may result with continued treatment

b- hyperuricemia :especially furosemide causing or exacerbating gouty attacks

c- Acute hypovolemia:with possibility of hypotension,shock and cardiac arrythmias

d- Potassium depletion : which can be averted by use of potassium sparing diuretic or dietary supplementation with K

C-Thiazides and related agents
e.g: chlorthiazide - hydroghlorothiazide-indapamide

The most widely used of diuretic drugs
Chlorthiazide

Therapeutic uses

Hypertension =discussed
C.H.F = discussed
Renal impairment :if loop diuretics alone fail in treatment
Idiopathic hypercalciuria
Diabetes inspidus

Adverse effects
as loop diuretics plus
In hyperglycemia :patients with diabetes mellitus who are taking thiazides for hypertension may become hyperglycemic and have difficulty in maintaining appropiate blood sugar levels

Hydrochlorothiazide

is a thiazide derivative has proven to be more popular than the parent drug as it is more potent so less dose is required to provide the same efficacy of the parent drug

Indapamide = thiazide analoge
at low doses it

Shows significant antihypertensive action with minimal diuretic effects
Often used in advanced renal failure to stimulate additional diuresis on top of that achieved by loop diuretics

Less likely to accumulate in patients with renal failure and may be useful in their treatment

D-Potassium-sparing diuretics
e.g spironolactone

act in the collecting tubule to inhibit Na reabsorbtion,K secretion and H secretion

The major use of it is in the treatment of hypertension most often in combination with a thiazide

it is often used in conjunction with a thiazide or loop diuretic to prevent potassium excretion that would otherwise occur with these drugs

Adverse effects

as it is chemically resembles some of the *** steroids, it does have minimal hormonal activity and may induce gynecomastia in males and menstural irregularities in females

E-Osmotic diuretics
e.g:mannitol

They are used to maintain renal flow following acute toxic ingestion of substances capable of producing acute renal failure

A mainstay of treatment for patients with

a- increased intracranial pressure
b-drug toxicity
c- trauma

thanks



Insulin and oral hypoglycemic drugs

Diabetes mellitus : it is a heterogenous group of syndromes all chracterised by an elevation of blood glucose caused by a relative or absolute deficiency of insulin

Diabetics can be divided into 2 groups based on their requirements for insulin
A- Insulin-dependent diabetes mellitus=IDDM or type I
most commonly affects juveniles but can also occur among ******
characterised by an absolute deficiency of insulin caused by massive B cell lesion or necrosis

Loss of B cells function may be due to
a)invasion by viruses
b) the action of chemical toxins
c)usually through the actions of auto immune antibodies directed against the B cell

as a result of the destruction of B cells the pancreas fails to respond to ingestion of glucose

Type I diabetic shows classic symptoms of isulin deficiency
polydipsia
polyphagia
polyuria

they require exogenous insulin to avoid hyperglycemia and life threating ketoacidosis

B-Non insulin-dependent diabetes mellitus =NIDDM or type II

Genetic factors are apparently causal
The metabolic alteration observed are milder than those of IDDM
ex: NIDDM patients typically are not ketotic

but long-term clinical consequences can be just as devastating
ex: vascular complications and subsequent infection can lead to amputation of lower limbs

Notes
a)in trype II the pancreas retains some B cell function resulting in variable insulin levels that are insufficent to maintain glucose homeostasis

b) patient with type II are often obese
c) it is usually accompanied by target organ insulin resistance that limits responsiveness to both endogenous and exogenous insulin

Treatment of type II diabetes
The goal is to
Maintain blood glucose concentrations within normal limits
prevent the development of long-term complications of the disease

It is noted that
weight reduction
exercise
dietary modification

decrease insulin resistance and correct hyperglucemia in some patients
However.most are dependent on pharmacologic intervention with oral hypoglycemic agents

Insulin therapy may be required to achieve satisfactory serum glucose levels

Insulin
insulin secretion is regulated by
Blood glucose level i.e triggerd by high blood glucose
Other hormones and autonomic mediators

N.B Glucose given by injection has a lower effect on insulin secretion than does glucose taken orally because orally taken glucose stimulates production of digestive hormones by the gut,which inturn stimulate insulin secretion by the gut

Human insulin is produced by a special strain of Esherichia coli that has been genetically alterd to contain the gene for human insulin

Insulin is isolated from beef and pork pancreas

Pork insulin is closest in structure to human insulin differing by only one amino acid

Insulin administration

insulin preparations vary primarily in their times of onset and duration
of activity this is due in large part to


a)the size and composition of the insulin crystals in the preparations
the less soluble an insulin crystals in the preparations is the longer it acts
b)site of injection
c)blood supply
d)temprature
e)physical activity

Human insulin is absorbed more quickly from its site of injection than are the beef or pork hormones
Thus,the duration of action of human insulin is shorter and doses must be adjusted accordingly

Insulin preparations

A- Rapid action insulin preparations = regular insulin
it is short acting soluble crystalline zinc insulin

it is the only preparation suitable for intravenous administration
lowers blood sugar within minutes

B- Intermediate action insulin preparations

i-Semilente insulin suspesion
amorphous precipitate of insulin with zinc ion in acetate buffer

its onset of actions and peak effect are rapid but somewhat slower than for regular insulin

ii- Isophane insulin suspension= neutral protamine hagedorn=NPH
Suspension of crystalline zinc insulin cobined at neutral pH with the positively charged polypeptide protamine forming less soluble complex

Its duration of action is intermediate
Useful in treating all forms of diabetes except diabetic ketoacidosis or emergency hyperglycemia

iii- Lente insulin = the most widely used
it is amixture of
30% semilente insulin for prompt acting
70% ultralente insulin for prolonged acting

This combination provides
a)a relatively rapid absorbtion
b) sustained action

iv-Insulin combinations
combinations of human insulin such as 70% isophane +30% regular or 50% of each of these are also available

C- Prolonged action insulin preparations = ultralente
Suspension zinc insulin(porcine or human) crystals in acetate buffer that is composed of large particles which are slow to dissolve producing a slow onset of action and a long lasting hypoglycemic effect

Oral hypoglycemic agents

Useful in NIDDM which can not be managed by diet alone
The patient most likely to respond well to oral hypoglycemic agents is one who
develops diabetes after age 40
has had diabetes less than 5 years

Patient with long standing disease may require a combination of a hypoglycemic drug and insulin to control their hyperglycemia

Oral hypoglycemics should not be given to patients with type I

A- Sulfonylureas

Mechanisms of actions
Stimulation of insulin releasefrom the B cells of pancreas
Reduction of serum glucagon levels
Increased binding of insulin to target tissues and receptors

The primary drugs used today are tolbutamide and the second generation derivatives glyburide, glipizide(minidiab) and glimepiride amaryl

these drugs are contraindicated in patients with hepatic or renal insufficiency
They traverse the placenta and can deplete insulin from the fetal pancreas so the NIDDM pregnant women should be treated with insulin

B-Biguanides
ex:Metformin= cidophage

Differs from sulphonyl ureas in
a)not stimulating insulin secretion
b)less risk of hypoglycemia
May be used alone or in combination with them

Actions
a)primarily by decreasing hepatic glucose output by inhibiting gluconeogenesis
b)reduce hyperlipidemia
LDL & VLDL cholesterol falls and HDL cholesterol rise
so the patient often loses weight
c) long term use may interfer with B12 absorbtion
d) it is contraindicated in renal &hepatic insufficiency

C- alpha glucosidase inhibitor = Acarbose
ex:glucobay

Used in NIDDM and possibly adjunct to insulin for those with IDDM
Mechanisms of action

it inhibits alpha glucosidase in the intestinal brush border and thus decreases the absorbtion of starch and disaccharides

Consequently the postprandial rise of blood glucose is blunted
It does not cause hypoglycemia

Can be used as
a)a monotherapy in those patients being controlled by diet
b)in combination with oral hypoglycemic agent
c) with insulin

D- Repaglinide Novonorm
its actions in common with this group of drugs for NIDDM
It is taken three time daily before meals
Combined therapy with metformin is better than monotherapy
No drug interactions have been reported

E- Rosiglitazone Avandia
Used for type II particullary those whose hyperglycemia is not controlled despite insulin therapy

It acts as insulin sensitizer enhancing insulin action in the liver and skeletal muscle
The drug counteract insulin resistance

It is usually administerd with insulin and may lower the dose of this hormone required for adequate glucose control


Thanks

--------------------------------------------------------------------------------


Anti-inflammatory drugs


Inflammation: is a normal protective response to tissue injury caused by physical trauma or microbiologic agents
It is the body effort to
inactivate or invading organisms
remove irritants
set the stage for tissue repair


Non steroidal anti-inflammatory drugs = NSAIDs


are group of chemically dissimilar agents that differ in their antipyretic,analgesic and anti-inflammatory activities

They act primarily by inhibiting the cyclooxygenase
enzymes
A- salicylates


Aspirin is the protoype of this group
it is the most commonly used
it is the drug to which all other antiinflammatory agents are compared

Difluanisal: it is another salicylate drug which is 3 to 4 times more potent than aspirin as an analgesic and an antiinflammatory agent

Actions
a)reduce inflammation(anti-inflammation):in artheritis
it neither arrests the progress of the disease nor does it induce remission

b) Reduce pain(analgesia):used mainly for management of pain of low to moderate intensity arising from integumental structures rather than that arising from the viscera

NSAIDs are superior to opioids in the management of pain in which inflammation is involved

Combination of opioids and NSAIDs are effective in treating pain in malignancy
c)Reduce fever(antipyrexia): aspirin resets the thermostat toward normal

it has no effect on normal body temperature

THerapeutic uses of salicylates
a)Antipyretic and analgesic
Na salicylate in liquid form
Choline salicylate in liquid form
Choline-Mg salicylate
Aspirin

in treatment of gout
rheumatic fever
rheumatoid arthiritis :aspirin is the drug of choice
headache,arthalagia and myalagia

b)Cardiovascular application
low doses of aspirin are used prophylactically to decrease the incidence of transient ischemic attack and unstable angina in men as well as that of coronary artery thrombosis

aspirin facilitates closure of a patent ductus arteriosis

c)Colon cancer : there is evidence that chronic use of aspirin reduce the incidence of colorectal cancer

Adverse effects
G.I.T :epigastric distress,nausea and vomitting
Blood : prolonged bleeding time
Hypersensitivity : in 15% of patients

Reyes syndrome :if given during viral infections - especially encounterd in children who therefore should given acetaminophen instead of aspirin

Dosage
At low doses : aspirin exhibit analgesic activity
ex: two 300mg tablets 4 times daily produce analgesia

at high doses :show antiinflammatory activity
ex: 12 to 20 tablet perday produce both

if 160 mg every otherday
a)reduce the incidence of recurrent myocardial infarction
b)reduce mortality in post myocardial infarction

if 160-325 mg/day: prevent the first myocardial
infarction,at least in men over age of 50

B-Propionic acid derivatives

Ibuprofen :is the first drug available in this class
Naproxen
Fenoprofen
Ketoprofen
Flurbiprofen
Oxaprozin :has the longest half-life so administerd once
daily

all of them
a)possess anti-inflammatory,analgesic and antipyretic activity

b) gained wide acceptance in the chronic treatment of rheumatoid and osteoarthiritis because their G.I.T. effects are generally less intense than that that of aspirin


C-Indoacetic acids

Indomethacin
More potent than aspirin or any of the NSAIDs as an anti-inflammatory

uses
in acute gouty arthiritis

in ankylosing spondylitis

in osteoarthiritis of the hip

benefetical in the control of pain associated with uveitis and postoperative ophthalmic procedures

antipyretic in Hodgkins disease
it delay labor by suppressing uterine contraction
useful in treatment of patent ductus arteriosis

Sulindac
inactive drug closely related to indomethacin

uses
in acute gouty arthiritis

in ankylosing spondylitis

in osteoarthiritis

Etodolac
has similar effects to NSAIDs

it can raise the risk of adverse reactions caused by digoxin,lithium,methotrexate and enhance the nephrotoxicity of cyclosporine

D-Oxicam derivatives

the first is Piroxicam

its mechanism of action has not been established

its half-life of 50 hours permits administration once daily

uses
rheumatoid arthiritis

ankylosing spondylitis

osteoarthiritis

OTHERS
Fenamates
no advantages over the other NSAIDs
cases of hemolytic anemia have been reported

phenyl butazone
has powerfull anti-inflammatory effects but weak analgesic and antipyretic activities
used only for short term treatment

Diclofenac
approved for long-term use in treatment
more potent than indomethacin or naproxen

Ketorlac
used orally
used I.M. in the treatment of postoperative pain
topically for allergic conjunctivitis


thanks



Principles of antimicrobial activity

I-Overview
Antimicrobial drugs have the ability to kill an invading microorganisms without harming the cells of thehost

II-Selection of the most appropriate antimicrobial agents
requires the knowledge of
a)the organisms identity and its sensetivity to a particular agent
b)the site of infection
c)the safety of the agent
d)the patient factors
e)the cost of the therapy

N.B. some critically ill patients require empiric therapy i.e immediate adminisration of drugs covering infections by both gram positive and gram negative microorganisms
as the delay in identifieing the appropiate antimicrobial could prove fetal

A-the effect of the site of infection on therapy
adequate levels of an antibiotic must reach the site of infection in order for invading microorganisms to be effictively eradicated
natural barriers may cause inadequate penetration of the
drug into certain tissues such as

ex1:Blood brain barrier : ordinarily excludes many antibiotics .
however inflammation facilitate penetration and allows sufficient level of many (but not all) antibiotics to enter
the C.S.F. in meningitis

N.B.in meningitis bactericidal rather than a bacteriostatic
effect is important to be achieved

ex2rostate: bacterial prostatitis is difficult to cure probably because of the failure of many antibiotics to cross the prostatic epithelium
e.g penicillins can not pass so it is not efficient altuough the organisms may be susceptible to them

Trimethoprim : can diffuse throughout the prostatic epithelium so it can be used

B- the status of the patient
a)alcoholism,diabetes,infection with HIV,malnutrition or advanced age can affect a patient immunocopmpetency as can therapy with immunosupressive drugs need
higher than usual doses of bacterial agents or longer treatment

b)Renal dysfunction: in poor kidneys function (10% or less of normal)
caused accumulation of antibiotics that ordinarily eleminated by this route which may lead to serious adverse effects unless controlled by
a)adjusting the dose
b)adjusting the dosage schedule of the antibiotic

c)hepatic dysfunction : antibiotics that are concentrated or eleminated by the liver are contraindicated in patients with liver disease
e.g erythromycin - tetracycline

d)poor perfusion :decreased circulation to anatomic area as in the lower limbs of diabetic reduces the amount of the antibiotic that reaches the extremeties and makes infections notoriously difficult to treat

e)pregnancy
all antibiotics pass the placenta
adverse effects on the patients are rare except

Tetracycline : tooth dysplasia - inhibition of bone growth
Fluroquinolones : not used with young childrens as they interfer with cartilage growth

C-Safety of the agent
penicillins :from the least toxic of all drugs as they interfer with the site unique to the growth of microorganisms

Chloramephenicol : seriously toxic as it is less specific and suould be reserved for life threating infections

Chemotherapeutic spectra

a)Narrow spectrum :agents acting only on a single or a limited group of microorganisms
ex: Isoniazid is active only against mycobacteria

b) Extended spectrum : agents effective against gram positive organisms and also against a significant number of gram negative bacteria
ex:Ampicillin

c)Broad spectrum: agent effective against wide variety of microbial species
ex:tetracyclines and chloramephinicol

N.B.:The use of broad spectrum antibiotics can drastically alter the nature of the normal bacterial flora and can precipitate a superinfection of an organism

ex:Candida whose growth is normally kept in check by the presence of other microorganisms

Combination of antimicrobial activity

it is therapeutically advisable to treat with a single agent that is most specific for infecting organism

This strategy
a)reduces the possibility of superinfection
b)decrease the emergence of resistant organism
c)minimizes toxicity

However,some cases of combination is preferred
ex:tuberculosis benefits from combination

advantages
synergism e.g B lactams and aminoglycosides

disadvantages e.g interference may occurs

THanks






I- Folate antagonists

Folic acid Coenzymes are required for the synthesis of purines and pyrimidines( precursors of RNA &DNA) and other compounds required for cellular growth and replication so in the absence of folic acid cells
can not grow or divide


The sulfa drug are inhibitors of folic acid synthesis

After the advent of penicillins the sulfas were less frequently prescribed for a time untill the synergistic effect with trimethoprim was recognised

Sulphamethoxazole +Trimethoprim with the generic name Co-trimoxazole

Adverse effects
a- Crystalluria and nephrotoxicity
Newer agents as sulfisoxazole and sulfamethoxazole are more soluble at urinary pH than are older sulfonamides as sulfa diazine

b- Hypersensitivity : are fairly common as rashes,angioedema and Stevens-Johnson syndrome

c- Haemopoietic disturbance in patients with haemolytic anaemia

d- Kernicterus in newborns: because sulfas displace bilirubin from binding sites on serum albumin and the free bilirubin can pass into the central nervous system

e- Drug potentiation : also through displacement as in case of tolbutamide.warfarin and methotrexate

Contraindications

In newborns and infants less than 2 months
In pregnant women all to avoid kernicterus
Not to be used with methenamine in patient of urinary tract infection

Trimethoprim
Most often compounded with sulfamethoxazole
It is 20 to 50 times more potent than sulfonamide
Can be used alone in
a- acute urinary tract infections
b-in the treatment of bacterial prostatitis

N.B though that, flouroquinolones are preferred


Typical therapeutic applications of Co-
trimoxazole

a- Pneumocystitis carinipneumonia =PCP
the fungus responsible for a mild respiratory infections common in infants
also it is the most common opportunistic infection complicating AIDS

b- In respiratory infections with
Haemophilis influenzae
Streptococcus pneumoniae
Alternative treatment for legionella pneumophilia

c- Genital infections
in tratment of acute gonococcal uretheritis in both men and women
Effective as oral therapy of oropharyngeal gonorrhea caused by penicillinase producing organisms

d- Prostate,vaginal and urinary tract infections

e- Gastro intestinal infections
In treatment of shigellosis and non-typhoid salmonella
Management of carriers of salmonella typhi



N.B.Sulfadiazine with pyrimethamine is the only effective form of
chemotherapy for toxoplasmosis


Thanks









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