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Introduction

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Nifedipine is a yellow crystalline powder considered as dihydro pyridine calcium channel blockers which cause vasodilation of blood vessels and relaxation of smooth muscle so it used to treat hypertension,Glaucoma and angina.

Calcium channels blockers
According to Kes S, Caglar N.(2003).
They act by alter regulation of calcium ion across cell membrane.Recent researches show that calcium channels blockers are more effective than Beta blockers in case of hypertension patients there are 3 class of it Dihydropyridine,non-dihydropyridine and Benzothiazepine.

1-Non-dihydropyridine
their structure derived from phenylalkylamine.they act manily on heart decreasing cardiac out put and cardiac work so decrease oxygen demand also prevent vasospasm of coronary so they used in case of angina and myocardium infarction.Example: verapamil 

2-Benzothiazepine
their structure obtain from dihydropyridine and  phenylalkylamine so they act by two mechanism on blood vessels and arteries causing vasodilation by reduce total vascular resistant and on heart by reduce cardiac work and oxygen demand.Example: Diltiazem 

3-Other Calcium channel blockers: they act by block alpha-2/delta-1 calcium channel which used to treat epilepsy Example: Gabapentinoids and pregablin

4-Dihydropyridine
Their structure synthesized from dihydropyridine and the main action of this class is to decreases total vascular resistance and reduce arterial blood pressure by the cause of vasodilation effect,So they used mainly to treat hypertension patients.Example:Nifedipine

IUPAC Name: ( 3,5-pyridinedicarboxylic acid,2,6-dimethyl,2-nitrophenyl-dimethyl ester)
 
Brand Name:  Adalat CC, Procardia XL, and Afeditab CR

Pharmacokinetics

According to Sorkin,E.(1985)

1-Solubility 
Nifedipine is insoluble in water less than 1 mg/mL.Also it soluble in methanol and ethanol.

2-Bioavailability 
Nifedipine has a bioavailability about 55% due to first pass metabolism (presystemic).So it has a poor bioavailability when it taken orally so we try to make eye’s dosage form nifedipine to over come first pass metabolism to enhance it’s bioavailability and absorption 

3-plasma proteins binding
Nifedipine is highly bound to plasma protein about (92—95%) of dose.

 4-Half life (t12)
Nifedipine has a short half life about 2-5 hours 

5-Metabolism
Nifedipine metabolized in liver by cyt-P450 3A4.So any drug which induce or inhibit cyt-P450 3A4 will change concentration of NifedipineIn addition to
it is extensively undergo biotransformation to inactive metabolites which excreted in urine and feces.

Mechanism of action 
According to Held,P, Furberg,C.(2009).
Nifedipine Blocks L-type calcium channels so it inhibits influx of calcium ion by physically plugging it.calcium channels bind to calmodulin and form calmodulin bound-Calcium that act on myosin light chain kinase causing activation to it then enhance phosphorylation of light chain subunit of myosin which is the the most important step in muscle contraction across membrane of vascular smooth muscle and blood vessels causing depolarizations of the membrane causing peripheral arterial vasodilatation,Reducing peripheral vascular resistance, and reduce cardiac out put as a result it cause vasodilation to blood vessels so decreases blood pressure.Also it increases oxygen supply to the myocardial parts by reduce myocardial wall tension of  the heart.Nifedipine has potent peripheral vasodilation effect as we mention so it decrease after load in addition to it can change systemic balance between oxygen supply and demand so has anti-ischemic activity.another mechanism of action is that Nifedipine inhibit phosphodiesterase which may lead to relaxation of vascular smooth muscle. 

Side effects 
some side effect of nifedipine occur in all patient taking it and it’s not a serious side effects for example pain under breastbone, Belching, mood changes, diarrhea, dizziness, headache , insomnia , muscle cramps , abdominal pain , polyuria and 
on the other hand it has a serious side effects like chest congestion, heart block, bloody stools, syncope, pain in genitals parts, bradycardia , Stevens-Johnson syndrome, hemolytic anemia and ulcers. Charles,S, Buysschaert,M.(2002)

Hemodynamics
Nifedipine cause negative inotropic effect due to reflex mechanism of body because of vasodilating effect resulting from decreases after load and total peripheral vascular resistance.Also it cause increase in ejection fraction and reduce ejection fraction in left ventricular filling.In addition to it affect sinoatrial node function causing depression to it.

Contraindication 
1-sever hypotension
2-patient with beta blocker withdrawal 
3-patient with congestive heart failure as Nifedipine may cause edema
4-Porphyria
5-Liver and kidney problems as it may accumulate and cause toxicity
6-if patient has constipation
7-Dihydropyridine hypersensitivity
8-Breast-feeding as it excreted with milk
9-Geriatric 
10-In case of gastroesophageal reflux disease as Nifedipine  cause relax the lower esophageal sphincter

Drug Interaction
According to Zhou,Y, Zeng,S.(2014).

1-Beta blockers: The use of Nifedipine with beta blockers potentiate negative inotropic and negative chronotropic effect so it cause sever hypotension effect and can worsen cardiac arrhythmias and coronary stenosis.

2-Barbiturates: Nifedipine should not combined with Barbiturates as Nifedipine is  CYP3A4 substrate and Barbiturates are Hepatic microsomal enzyme inducers so they potentiate effect of Nifedipine and increase it’s metabolism.

3-Phenylephrine: coadministration of Nifedipine with Phenylephrine is not recommend as phenylephrine increases blood pressure and has a vasoconstriction effect so it contributes with antihypertensive effect of Nifedipine.

4-Clarithromycin: The use of Nifedipine with Clarithromycin should not be done to prevent severe hypotension and kidney damage.As Clarithromycin considered as  Hepatic microsomal enzyme inhibitor so it inhibit metabolism of Nifedipine by decreasing  the clearance which may lead to shock.

 5-Celecoxib: this drug is non-steroidal anti-inflammatory drug so it decreases renal blood flow and may cause renal insufficiency so it cause sodium water retention as a result blood pressure increses and this counter of anti-hypertension effect of nifedipine.

6-Lithium: Patients who takes Nifedipine with Lithium may developed some neurotoxic symptoms like ataxia, tinnitus and tremors 

7-Warfarin: Nifedipine as we mention above has a highly plasma protein bound effect which may lead to displacement of warfarin from plasma protein so increasing it’s concentration so it increase anti-coagulation effect of warfarin Also increases prothrombin time.

8-administration of nifedipine with grapefruit juice increases effect of Nifedipine  2 times greater than normal.

Indication of Nifedipine 
1-Hypertension
2-Stable angina
3-Un-stable angina
4-Pulmonary edema
5-Raynaud’s phenomenon
6- Esophageal spasm and achalasia
7-Glaucoma
8-preterm labor

Dosage forms
Sublingual dose of Nifedipine is better than oral as it has a rapid onset of action about 10 mins compared with oral onset of action about 1 hour.so it can be used in case of emergency hypertensive patients.McAllister,R(2008).

Glaucoma 
it is a diseases of chronic optic neuropathy which cause decrease in neurons and axons of retina.Glaucoma is due to many eyes diseases but it is usually associated with the increases in intra ocular pressure due to retention and backup of aqueous humor which excreted from ciliary gland of the eye.eye consist of  trabecular meshwork spongy tissues which act as a drain for the eye.The problem arise when this trabecular meshwork become clogged so it prevent aqueous humor from leaving eye (amount produced more than excreted).so as a result it increase intra ocular pressure which affect nerve cells of eye make it more compressed then destroy them.nerve cells responsible for occurrence of visual mechanism as they deliver  visual information to the brain so the death of this cells result in blindness.
Heiil,A, Leske,M.(2002) 

Types of Glaucoma 

According to Copt,R, Thomas,R.(2008)

1-Open-Angle Glaucoma
this type of glaucoma is a genetic chronic disease and it always affect elderly 
people intra ocular pressure increase slowly and gradually reaching  20 mmHg or much more and the normal range should be 14-16 mmHg so cornea of the eye swell without any pain so patient does’t know that their is a problem and the eye is begin to has no vision and this loss is irreversible due to formation of blind spot that become larger and developed in the area of eye vision first around outer peripheral field of vision then it develop at the center of eye vision.

2-Closed-angle glaucoma 
this type of glaucoma is the most popular type as it is an inherited disease that the anterior chamber of the eye is smaller than normal range.so the migration of aqueous humor to the lens is reduced,increasing intra ocular pressure and forced
trabecular meshwork against eye lens resulting in further angle narrowing and  blocking drainage.
 

3-Acute Glaucoma
in this type of glaucoma Intra ocular pressure increases suddenly and with fast rate unlike closed angle glaucoma it increases slowly and gradually.As a result of this sudden increase it will cause intense pain in the eye,Swelling of cornea, blurred vision also nausea and vomiting.

4-Normal Tension Glaucoma
this type of glaucoma has normal intra ocular pressure so it also called  low-tension glaucoma.But progressive optic nerve cell destruction and visual loss occur due to insufficient blood flow to the optic nerve which lead to death of this nerve that responsible for carrying visual information impulses to the brain. so decreases intra ocular pressure is dangerous also.Foster,P, Buhrmann,R.(2002)

5-Pigmentary Glaucoma
Foster,P, Buhrmann,R.(2002) stated that.Pigmentary glaucoma is a type of open angle glaucoma but it affect teenage.it is due rubbing of eye’s pigment layer to the lens causing shedding with aqueous humor leading to blockage of pores of  trabecular meshwork tissues so intra ocular pressure increased.

Drugs used in glaucoma

According to Japan Glaucoma Society(2003).
there are many classes of drugs that used to treat glaucoma.But the main action of this drugs is decreases pressure in the eye.Eye drops are the first choice for treatment of glaucoma.

Examples of drugs used in glaucoma

Prostaglandin Analogues: This class of drugs decreases IOP by enhance the flow of aqueous humor out of the eye, it taken once a day preferred at night.But it cause  redness of the eye also can cause eyelash growth which may lead darken the lids and in some patient it gradually change eye color make it more darker. examples bimatoprost, travoprost and latanoprost

Beta Blockers: It decreasing production of aqueous humor so decreases IOP. it used twice daily Beta blockers have some side effects like hypotension and tachycardia.The most used beta blocker used is timolol

Carbonic Anhydrase Inhibitors: It decrease production of aqueous humor so lower IOP.This class of drug may cause burning sensation in the eye and stinging e.g dorzolamide  (eye drop ) or acetazolamide (oral formulation) which act as a diuretic so it decreases the amount of fluid that can accumulate in the eye.But it not recommended to use it for a long time as it’s effect is reduced by time also it cause decreases in potassium levels 

4. Colinergic drugs: this class of drug increasing ability of aqueous humor to flow out from the eye as a result it decreases I.O.P.Example: pilocarpine which is may cause blurred vision in some patient as it has a constriction effect on eye’s muscle.
 
5. Alpha agonist drugs: This class of drugs act by decreasing synthesize of aqueous humor also it has a drying effect on it make it dry fast  example: Brimonidine which may cause some side effects like stinging and burning eye sensation.  

Nifedipine mechanism of action in glaucoma 
According to Sung,Y(2012).
Due to side effects of previous drugs we use Nifedipine to treat glaucoma to over come this side effect.Nifedipine decreases Intra ocular pressure and ophthalmodynamometric force of the eye as a result it decreases retinal venous pressure.

Abstract 
Nifedipine is Dihydro-pyridine calcium channel blockers which block L-type
calcium channels.It Has a poor bioavailability due to first pass metabolism when it taken orally so we try to make eye’s dosage form nifedipine to over come poor bioavailability and enhance absorption. 
References 
Kes S, Caglar N, Canberk A.(2003).Treatment of mild-to-moderate hypertension with calcium channel blockers.

Sorkin EM, Clissold SP, Brogden RN.(1985) Nifedipine: a review of its pharmacodynamic and pharmacokinetic properties,; 30: 182-274.

Held P, Furberg C.(2009). Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol.

Charles S, Ketelslegers JM, Buysschaert M, Lambert AE.(2002); adverse side effect of nifedipine.Br J Med 283: 19-20

Zhou YT, Yu LS, Zeng S et al.(2014) Pharmacokinetic drug-drug interactions. 1,4-dihydropyridine calcium channel blockers.Therapeutics and Clinical Risk Management ;10: 17

McAllister RG.(2008) Kinetics and dynamics of nifedipine after oral and sublingual doses.Am
JMed; 81 (Suppl6A): 2-5.

Heijl A, Leske MC, Bengtsson B, et al.(2002) Reduction of intraocular pressure and glaucoma progression: result from the earryl Manifest glaucoma Trial.

Copt RP, Thomas R, Mermoud A.(2008).Corneal thickness in ocular hypertension, primary open-angle glaucoma, and normal tension glaucoma. Arch Ophthalmol:17:14–16.

Foster PJ, Buhrmann R, Quigley HA, Johnson GJ.(2002): The definition and classification of glaucoma in prevalence surveys Br J Ophthalmol 86: 238-242,

Japan Glaucoma Society: Glaucoma Diagnosis and Treatment Guideline. Acta Soc Ophthalmol Jpn 107:126-157, 2003.

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