مراجعة فارماكولوجي

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

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

Thanks

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