Drug	Agent	Atropine	Glycopyrrolate	Hyoscine
	Class	Alkaloid Tertiary amine	Semisynthetic Quaternary amine	Alkaloid Tertiary amine
	Structure
	Presentation	1200mcg/1ml	400mcg/2ml	0.4mg/1ml 20mg/1ml
Admin	Use	Reversal NDMBs	Reversal NDMBs	Preop med Anti-sialogogue Sedation Motion sickness
	Dose (mg)	15-20mcg/kg	10mcg/kg	Post auricular patch 5mcg/hr for 72hrs 0.4mg sc/im/iv antisialogue 20mg im/iv antispasmodic
	Onset (min)	1min	2-3min
	Duration (min)	30-50min	30-60min
P/kin	Vd (L/kg)
	CL (ml/kg/min)		>atro
	Renal	20%	80%	1%
	Hepatic	80% hydrolysis	20% bile	Mostly metabolised
	t1/2 (min)	2.3hrs	1.25hr
P/dyn	Sedation	+	0	+++
	Antisialogogue	+	++	+++
	↑ heart rate	+++	++	+
	Relax smooth muscle	++	++	+
	Mydriasis / Cycloplegia	+	0	+++
	Anti-nausea	+	0	+++
	↑ gastric acid secn	+	+	+
	Altered fetal HR	0	0	?

Low dose  high dose:

1. Salivary/bronchial secretions

2. Heart, eyes

3. GIT, GU

4. Gastric

Mild skin infections

Mainly use a topical preparation including some of the following

• Azoles
• Allylamines

Or over the counter stuff

• Tolnaftate (Tinactin)
• Clotrimazole
• Miconazole
• Terbinafine (Lamisil)

Severe skin infections

• Oral antifungal agents, mainly itraconazole

Tinea Capitis (ringworm of the scalp)

• Oral therapy with Griseofulvin
• Could also use azoles if Griseofulvin fails

Onychomycosis (infection of the nails)

• Griseofulvin for 6-12 months
• Or itraconazole and terbinafine for 3 months
• Topical preparations like Ciclopirox are easy to use, but have a low cure rate

Tinea Versicolor (sun spots)

• Topical ketoconazole for small spots
• For larger areas, use oral itraconazole or fluconazole for a short time

Chromomycosis (infections of the skin and sub-cutaneous)

• Surgical excision when possible
• In conjunction with itraconazole for 12-36 months
• When surgery is not possible, Amphotericin B may be necessary

Mycetoma (a tumor caused by filamentous bacteria or filamentous fungi)

• Surgical excision, maybe even amputation
• In combination with an Azole for 1 to 3 years

Zygomycosis (mucormycosis, phycomycosis) (opportunistic infections)

• Quickly initiate therapy with Amphotericin B
• (Azoles are not effective against mucormycosis)
• In diabetic patients, control the acidosis, then surgically debride the tissue

Aspergillosis

Allergic bronchopulmonary aspergillosis

• Desensitization protocols
• Along with oral corticosteroids

Aspergillomas

• Surgically excise
• Along with oral itraconazole
• Or IV amphotericin B

Invasive aspergillosis

• Amphotericin B, but the outlook is still poor

Candidiasis

Superficial candidiasis

• Creams or ointments containing an Azole or Nystatin

Oropharyngeal candidiasis

• Nystatin swish and swallow
• Or an Azole troche formulation

Esophageal candidiasis

• Treat with an oral Azole
• In AIDS pt’s, use Fluconazole, b/c the absorbtion of itraconazole and ketoconazole depends on gastric acid secretion, which may be depressed (achlorohydric) in a pt with AIDS

Vaginal Candidiasis

• One dose of 150mg of Fluconazole
• Or two doses of 200mg itraconazole given 8 hours apart
• Also vaginal creams and suppositories

Systemic Candidiasis

• Amphotericin B
• Removal of the artificial heart valve or indwelling catheter, if that is the cause

Cryptococcosis (CNS and disseminated infection)

• Treat with a combination of Amphotericin B and 5-fluorocytosine
• This combination allows for synergism and a reduction in the dose of Amp B

Blastomycosis (cutaneous, pulmonary and disseminated)

• For mild cases, treat with Itraconazole for at least 6 months
• For severe cases, treat with Amphotericin B for several weeks

Histoplasmosis (a disease of the reticuloendothelial system RES)

• Pulmonary, disseminated or ocular
• For mild cases, treat with Itraconazole
• For severe cases, treat with Amphotericin B

Coccidioidomycosis (cutaneous, pulmonary, ocular, disseminated, and Valley Fever)

• Amphotericin B for life-threatening infections
• Itraconazole or fluconazole for milder cases
• Itraconazole is primarily used, but Fluconazole has better BBB penetration, so
• Extended therapy with Fluconazole is indicated with CNS involvement
• Could require lifetime administration

Paracoccidioidomycosis (South American Blastomycosis)

• Mucocutaneous, pulmonary, lymphatic, and visceral
• Treat with Itraconazole for many months

Sporotrichosis (cutaneous and visceral)

• Cutaneous sporotrichosis, use Itraconazole
• Lymphatic sporotrichosis, use Itraconazole
• For systemic infection, treat with Amphotericin B

Unusual Opportunistic Organisims

• Rule of thumb, treat with Amphotericin B

Amphotericin B

• Used for systemic fungal infections
• Affinity for ergosterol
• Binds and disrupts cell membranes, causing leakage of low mw compounds
• IV 2-3 months - May want to premedicate with prostaglandin inhibitors

Nystatin

• Only effective against Candida albicans
• Same mechanism of action as Amphotericin B

Griseofulvin

• Used for severe skin, hair and nail infections
• Inhibits microtubule formation and formation of the mitotic spindle
• Accumulates in the stratum corneum, preventing fungal penetration
• Orally – 3 weeks to 12 months

Azoles (imidazoles and triazoles)

• Used primarily for mucocutaneous candidiasis and dermatophytosis
• Inhibits the synthesis of ergosterol
• * BLOCKS cytochrome p-450, causing other drug levels to INCREASE
• IV, orally, or as an ointment or cream

Allylamines (naftifine, terbinafine)

• Used primarily for dermatophytes
• Inhibit ergesterol synthesis (oxidation of squalene) - FUNGICIDAL
• Orally or as a topical treatment
• Oral form is given for 3 months for nail infections
• * Blocks CYP2D6 enzyme – causes less concern about drug interactions

5-fluorocytosine

• Used primarily in combination with Amphoteracin B or fluconazole to treat cryptococcosis
• Used alone to treat types of chromomycosis
• A nucleotide analoge
• Inhibits protein synthesis by blocking steps in DNA and RNA synthesis
• Orally

Morpholines (Amorolfine)

• Used to treat dermatophytoses
• Blocks steps in ergosterol synthesis
• Topical preparations

Ciclopirox

• Used to treat fungal infections of nails
• Has affinity for trivalent cations such as iron
• Inhibits the enzymes that use iron as a cofactor
• FUNGICIDAL
• Cream and nail lacquer (the only topical treatment available)

Echinocandins (caspofungin)

• Used to treat systemic aspergillosis and severe candidiasis
• Inhibits the synthesis of D-glucan, a component of the fungal cell wall
• IV administration

Production of the aqueous humor is stimulated by ß1-adrenergic receptors. It leaves the anterior chamber through the trabecular meshwork and the Canal of Schlemm. Drugs that are used in glaucoma cause miosis and increase drainage through the trabecular meshwork.

Closed-angle results from a dilated iris (mydriasis)

Open-angle is chronic

Treatment:

1. Muscarinic agonists (pilocarpine, carbachol)

2. AchE inhibitors (physostigmine, echothiophate)

3. Epinephrine

4. α2-agonists (brimonidine and apraclonidine)

5. ß1-adrenergic antagonists (timolol) – most popular

6. Prostaglandin agonists

7. Acetazolamide (carbonic anhydrase inhibitor)

8. Cannabinoids (marijuana)

Disease / Deficiency	Cause / Effect
Refsum's Disease	Inability to carry out alpha-oxidation of fatty acids (Treatment = NO diary products in diet)
Increased Dicarboxylic Acid (Lots of 8 Carbon Fatty Acids in blood)	No Beta-Oxidation ONLY omega-oxidation
Biotin Deficiency	No Fatty Acid Synthesis or 1-carbon transfers of amino acids No Odd Chain Fatty Acid total Synthesis (succinyl CoA) Increased Beta-Ox of fatty acids (no Malonyl CoA to inhibit)
No Leukotriene Synthesis (Lipoxygenase Pathway)	No Slow-reacting substances of Anaphylaxis (sustained constriction of bronchi smooth muscle) vs. too much synthesis=asthma
No B6 (PLP)	Hyperaminemia & No Glutamate Formation from Alanine & Ketoglutamate / Stuck in Methyl Cycle (no serine to cysteine or glycine) No Neurotransmitters (Serotonin, Melanonin, Epinephrine, Histimine) Not degrade some Neurotransmitters / No Heme Synthesis
No Folic Acid Or No Tetrahydrofolate OR B12	Methyl Trap Theory (Stuck with 5-Methyltetrahydrofolate) No Amino Acids to Succinyl CoA from Methylmalonyl CoA (only B12) Decreased DNA/RNA synthesis (mogoloblastic anemia) No Histidine to Ketoglutarate
No NADPH	No Fatty Acid Synthesis / Heme Synthesis No Cholesterol Synthesis / Bile Acids
No Tetrahydrobiopterin	No Phynlyalanine to Tyrosine (now essential amino acid) No Tryptophan to Neurotransmitters No Arginine to Nitric Oxide (neurotransmitter)
Essential Fatty Acid Deficiency	No Linoleic or Linolenic in Diet (also Arachidonic Acid?) "Scaley" dermititis, Mead Acid increase (body compensating)
Perturbants of AcCh	Bungarotoxin / Cobra Toxin = Antagonist Myasthenia Gravis = Autoimmune Disease (destroy receptor w/ Antibody)
Chronic Granulomatous	Lack ability to convert O2 to Superoxide (NADPH-oxidase)
Sickle Cell Hemoglobin	6th Position of Beta Chain (Glutamate to Valine switch) RBC lose resiliency / Resistence to Malaria!!
Thalessemia	Missing one of Beta Chains on Hemoglobin (not Alpha chain)
Osteogenesis Imperfecta	Defect in Type 1 Collagen (bones)
Scurvy	Decrease in Hydroxyproline or Hydroxylysine / Poor wound healing
Diabetes	Type 1 = Most common with children / cause Diabetes Ketoacidosis Type 2 = Adults / Make insufficient amount of insulin
I Cell Disease	Lysosome enzymes absent, unable to phosphorylate mannose (N-Linked Glycoprotein) Skeletal abnormalities, restricted joint movement
Dissacharide Deficiency	Not digest Lactose & sucrose (flatulence/diarhea since bacteria thrive)
Drug Induced Hemolytic Anemia	Glucose 6-Phosphate Dehydrogenase Deficiency (Anti-malarial drugs, aspirin may induce) Big to RBC
Vitamin D Rickets (Calcium Problem)	Type 1 = Defect in renal 1a-Hydroxylase Type 2 = Defect in Receptor for Vitamin D
Hypervitaminosis A	Greater then 7.5mg/day of Vitamin A
Defective Glucose 6 Phosphatase	Glycogen Build up / Lactic Acidemia Impaired Gluconeogenesis (Last Step in Liver Gluconeogenesis)
Lipiod Congenital Adrenal Hyperplasia	No StAR (Cholesterol transporter across mitochondria membrane)
Luft's Disease	Defective Coupling of Oxidative Phosphorylation
Atherosclerosis	High Cholesterol result in "scavenger" receptors to deposit cholesterol on artery walls

We don’t know the exact trigger of this disease, but we’ve found that there is a relative deficiency of brain Acetylcholine in Alzheimer’s patients’ autopsied brains. We can get acetylcholine to accumulate in the brain by giving some anticholinesterase agents that are relatively selective for the CNS cholinesterase. The two drugs are Tacrin (Cognex) and Donepezil (Aricept), and are widely seen in therapeutics. They are anticholinesterase agents intended to increase cholinergic transmission in the brain and hopefully increase memory. These drugs really aren’t that specific for brain cholinesterase though, and again there are systemic side effects.

Now we’ll talk about hypotension. One issue that led to a nobel prize was the discovery that on vascular smooth muscle there were muscarinic receptors. When acetylcholine was applied to these muscarinic receptors there was vasodilation! A substance derived from the endothelium was produced (not from the smooth muscle, but from the endothelium) which released a factor—Endothelium Dependent Releasing Factor (EDRF). EDRF turns out to be Nitric Oxide (NO). So the endothelium produces NO, which comes back to act on the smooth muscle for vasodilation. So cholinergic vasodilation, muscarinic mediated, caused by the production of nitric oxide. Turns out that dozens of other systems also utilize nitric oxide.

If a drug is administered to a patient, the drug concentration in the plasma will rise to a value and then decay away with time (see Brody fig.5-4, or handout fig.1). If we could monitor the drug concentration in the blood in real time, we’d see that it would rise to some value, the shape of the rise would depend on the way you administered the drug (via IV, it would rise very quickly; if given orally it would rise slower). The way that it dies away with time is the same no matter which way you administer the drug. This is called the elimination phase (the down-slope of the curve). Elimination means redistribution through the body, metabolism and excretion. We can talk about the total amount of the drug, or the plasma concentration—usually they’re proportional to each other.

There are two ways that a drug can disappear:

1.) ZERO ORDER KINETICS-- after a drug rises to its maximum, it just falls on a

straight line; eliminated at a constant rate. (see handout p. 2)

C(t): plasma drug concentration @ any time (t) after the drug is administered

C(t) = C₀ – k₀t C₀: peak concentration immediately after the drug is delivered

k₀: zero-order rate constant for elimination

t: time after drug administration @ t = 0

-Zero order kinetics occurs only rarely, usually when the elimination mechanisms

are saturated. A prime example of this is with alcohol.

2.) FIRST ORDER KINETICS-- a constant fraction (%) of the concentration is eliminated for a unit time. At each instant the rate of elimination is not constant, but is proportional to the concentration at that instant in time. The more drug present, the faster it goes out; the less drug present, the slower it goes out. So the rate is proportional to the concentration… this leads to exponential decay of the drug concentration. IMPORTANT: the rate is not constant, but always changing (decreasing) with time.

-First order kinetics occurs with most drugs

Equation for First Order Kinetics (p.2 handout, eq. 5-1 Brody)

C₀: peak concentration immediately after the drug is adminstered

e: the base of the natural logarithm (e = 2.718…)

C(t) = C₀e^-kt e^x: ‘exponential function’ sometimes written ‘exp x’

k: first-order rate constant for elimination

t: time after drug administration @ t = 0

Most important parameter associated with the drug disappearance curve is the half–life (t_½). Every drug has its own t_½, it must be given from the drug insert. It depends on the molecular structure and the mechanisms for elimination. So if we have an enzyme that will really crank on that molecule, it will be small. t_½ can vary from person to person, also can vary within a person depending on various conditions (those enzymes might be occupied with something else, ie. metabolizing food or another drug).

Another parameter of the drug disappearance curve is the pharmacologic half-life. That’s the time for half of the pharmacological response, not the plasma concentration. Whats the difference? If the pharmacological mechanism is used by binding to a receptor, the two are really the same because as the drug disappears from the blood the receptors are unbound and the response disappears. But there are other cases where a drug produces a long term effect. Some drugs will produce some covalent bonding, or may permanently damage some enzymes leaving long term effects (ie. LSD flashbacks).

The method of administration effects the maximum value, but not t ½ .

t_½ is independent of initial concentration, so if you change the initial concentration you’d still have the same pathway. (see handout p. 4, item 4).

-whatever concentration you start with, it will go to half of that value in time t_½ , it doesn’t matter what concentration you start with

The concentration at any time will be decreased by half in time t_½. (see handout p. 4, item 5)

The first order rate constant k is related to t_½ as follows (handout p. 4, item 6)

-see p. 4 for derivation

k = 0.69

t_½

PROBLEMS (handout p. 5)

• see handout for examples

• always keep track of time units; when t_½ units are in hours the answer will also be in hours, when t ½ units are in minutes the answer will be in minutes

• ln (e^x) = x

Question: If a dose were doubled, would the amount of time that the drug is active be doubled as well?

Answer: NO! This is the essence of first order kinetics… if the dose is doubled, the effect will last one half-life more.

** if you had zero-order kinetics however, doubling the dose would double the drug’s effects.

When prescribing a medication, practitioners must tell the patient to take repetitive doses of the drug in order to maintain the drug’s effects over days.

Lets say that after you take an initial dose C₀, you give a second dose before the first dose has completely disappeared. Clearly then the second peak (from the graph on handout p. 6—concentration of drug in plasma vs. time) will be higher than the first dose. This is called drug accumulation.

Why won’t the drug just keep accumulating in the plasma when a patient takes multiple doses?

We must first define another parameter; dosing interval (t_d) is the time in between doses. Since the peak drug concentration in the plasma rises further and further above C₀ with each administration, the drug accumulates due to the repetitive dosing. However, the peak concentration eventually reaches a maximal value that does not increase with further administration of the drug. This is called the plateau or maintenance state of the drug.

This happens because of first order kinetics, as the drug begins to accumulate the higher it gets the faster the decay. You finally reach a place where the amount of drug eliminated in one dosing interval just equals the dose.

*** ALWAYS ASKED ON EXAM ***

Definition of Maintenance State: the dose administered equals the amount eliminated in time t_d (one dosing interval).

(handout p. 8) Once we’re in the maintenance state, we can take a portion of the curve between C_max and C_min, and this is a piece of the drug disappearance curve. Thus, the equation is:

C(t) = C_max e ^-ktd

The amount eliminated in time t_d is the difference between C_max and C_min in the maintenance state:

C_max – C_min = C_max (1 – e^-ktd)

***IMPORTANT: Know this equation!!! (Maintenance State Equation)***

Dose = C_max (1 – e^-ktd); where k = 0.69

t_½

The maintenance state equation shows the relationship among 4 parametes: (1) the dose C₀, (2) the maximum accumulation C_max, (3) the half-life t_½, (4) the dosing interval t_d. If any three of these are known, the fourth can be found.

Special Case

When t_d is chosen to be equal to t_½, a simple relation results… in this case the maintenance state equation becomes:

Dose = ½ C_max or C_max = 2x Dose

This result can be reasoned out: if t_d = t_½, then after the interval t_d, C has fallen from C_max to ½ C_max. The dose must make up for this loss, so Dose = ½ C_max.

How long does it take to reach the maintenance state? The half time for rising, t ½, is equal to the old elimination t_½ that we saw before. This is called the Plateau Principle.

The Plateau Principle means that in one t_½, the concentration gets half way to the top (C_max), in 2 half lives it gets ¾ of the way (75%), in 3 half lives it gets 87.5% C_max, in 4 half lives it gets to 93.75%, etc.

The general rule is that 94% C_max is considered to be close enough for therapeutic purposes, so it takes 4 half lives (4 t_½) to reach the maintenance state.

Example: For tetracycline, where t_½ is 6 hours, the time to reach 94% of the maintenance level (assuming a constant repetitive dose) is 4 x 6 = 24 hrs.

But what if we don’t dare to wait 24 hours until an effective dose is reached? (see handout p. 13)

We could give one dose of 500 mg right away to get the patient right up there, then maintain it at 250mg each 6 hrs, or whatever the maintenance schedule is. This is the Loading (Priming) Dose.

Why not always do that? It can only be done with a high therapeutic index, when the drug is very safe. If the drug isn’t very safe, the patient may be adversely affected.

There’s another compromise method available if you don’t want to give one large priming dose. You can give two priming doses, that will get the concentration up fairly quickly, but in a safer manner.

The first loading dose (C_L) brings the amount of drug in the body to the level of C_L. At t_½ this amount has decayed to ½ C_L. So addition of a second dose C_L at this time now brings the total to ½ C_L + C_L = 3/2 C_L. When we know the peak maintenance level that we want, we can make that amount equal to 3/2 C_L, and solve for C_L.

1. Henderson-Hasselbalch:

for weak acid: log [A^-]/[AH] = pH – pKa

for weak base: log [B]/[BH⁺] = pH – pKa

2. Percent of drug in protonated form:

[AH] = 1 or [BH⁺] = 1 [Atotal] 1 + [A^-]/[AH] [Btotal] 1 + [B]/[BH⁺]

Three examples concerning the importance of pH:

1. Aspirin is readily absorbed in the acidic stomach, but not in the alkaline large intestine.

2. Antibiotics are not excreted in acidic urine, but be reabsorbed in the kidney… in alkaline urine, antibiotics are excreted.

3. An injection of local anesthetics into a low pH, infected gingival environment, you won’t get a nerve block (with the exception of benzocaine).

Many drugs can exist in either an ionized (charged) form or unionized (uncharged) form. These drugs are either weak acids or weak bases. These molecules can exist as either protonated or unprotonated forms. The difference between a weak acid and weak base is that a weak acid is known as a proton donor, while a weak base is called a proton acceptor.

Notation: AH = free acid (neutral proton donor; associated, protonated)

B = free base (neutral proton acceptor; dissociated, deprotonated)

1. = ionized acid (negatively charged; dissociated, deprotonated)

BH⁺= ionized base (positively charged; associated, protonated)

AH  B + H^{+ *If you add more protons, both equations will be driven to the left}

BH⁺ B + H⁺

(As we go through the subject, the weak acid and the weak base will be treated together, just so that we’ll understand both of them at the same time)

Don’t confuse weak acids/bases with strong acids/bases. Strong acids such as HCl (for example) are never found associated together, HCl is such a strong acid that its always dissociated. Weak acids, however, are partially in the AH form and the A^- form.

The proton concentration in solution is given by pH, which is equal to –log [H⁺].

An example of a weak acid that shows up a lot is a drug molecule having a carboxyl group: -COOH  -COO^- + H⁺

A typical weak base group is a drug molecule having an amino group:

-NH₃⁺  -NH₂ + H⁺

The first concept in talking about pharmacokinetics is that some forms permeate membranes easily, and some don’t. Neutral forms (AH and B) can go through membranes easily, whereas charged or ionized forms (A^- and BH⁺) cannot.

Why is this true? Ions/ charged molecules are very strongly hydrated; water sticks to them very strongly. So if they are in the blood, they won’t go through membranes of capillary walls because these are hydrophobic inside. If a molecule is strongly hydrated, it is thus hydrophilic. In the film, they called this a low partition coefficient. The reason why this happens is because water is a polar molecule, arranged in a tetrahedral formation. Water has a strong dipole (charge separation), but it is neutral as a whole. Because the charges are separated, the water molecule can be attracted to ions.

When a molecule has no charge associated to it, water is actually pushed away from it, making these molecules hydrophobic. Thus these molecules can go through membranes very easily and are called PERMEANT.

[A][H]/[AH] = Ka (acid dissociation constant); weak acid

[B][H+]/[BH+] = Ka; weak base


pKa = -logKa, where Ka is in molar units


Every drug, whether a weak acid or weak base, has its own pKa or Ka. This is a measure of the structure of the molecule; how strongly a weak acid wants to donate protons, or how strongly a weak base wants to accept protons. This is a structural parameter that we’re not expected to know.




THE USEFUL FORM OF THE HENDERSON-HASSELBALCH EQUATION:

for weak acid: log [A-]/[AH] = pH – pKa


for weak base: log [B]/[BH+] = pH – pKa


**How to remember the H-H equation: on the right side, we’ll always be talking about the pH relative to the pKa, (It’s always pH minus pKa). On the left, it’s the deprotonated form over the protonated form (the form with the H attached, is a little heavier and that’s why its on the bottom).


These equations are simply an algebraic rearrangement of Ka, which is just an expression of the mass action law.


BUT, these are very important in pharmacology BECAUSE if you have a drug and you know its pKa AND the pH of the body environment that the drug is in, you plug that information into the above equation to get the fraction of the drug that’s in the charged and uncharged forms. Remember, the uncharged form can transverse membranes while the charged form cannot. So in certain compartments where the drug is in the ionized form the drug is trapped and cannot go anywhere, whereas if the drug is in the uncharged form it can readily cross membranes and go all over the place.


We’ll be expected to know (more or less) the following ranges of body tissue pH:

*pH for blood = 7.4

*pH for stomach = 2

*pH for bowel = 8-9


So we need to know what percent of the drug is in each form (charged and uncharged). We can use the H-H equation for this. Usually however, what we need to know isn’t gained from the H-H equation, which only gives us the ratio [A-]/[AH]. What is more useful is something slightly different—which is the percent of total drug in form [A-] or in form [AH]. (Refer to page 5 of Cohen’s handout to see how we get this)


The fraction of total drug in the protonated form AH or BH+ is given by:


[AH] = 1 or [BH+] = 1

[Atotal] 1 + [A-]/[AH] [Btotal] 1 + [B]/[BH+]

*the equation for the protonated form is easier to remember. Thus, even if you’re asked for how much is in the deprotonated form, its just 1 minus the fraction of the protonated form. (see page 5 for the equations used to find the deprotonated form [A-] or [B], if you’d rather work it out that way).


Example: (handout p. 6)

A weak-acid drug has pKa = 5.0 and is in the intestine, where pH = 6.0. What percent of the drug is in the permeant (protonated) form?

(See calculations on p. 6)

The answer = 9.1% of the drug is in its protonated, permeant form.


This calculation only depends on the DIFFERENCE between pH and pKa!!!

So, if in the above example we had pH = 7.4 and pKa = 6.4, so that the difference is still 1, the answer will still be the same. Thus, its always the pH relative to the pKa that matters in all of these problems. It doesn’t matter at all what the pH is if we don’t know the pKa. (in the film that we saw, he was pretty sloppy with this concept, he should have specified if the drug was acidic or basic relative to the pKa that we were talking about, instead of only if the drug was ‘acidic’ or ‘basic’).


PERCENT OF DRUG IN PERMEANT OR IMPERMEANT FORM VS. pH:



When pH = pKa, HALF of the drug is in non-ionized (permeant) form [AH]

As pH increases with respect to pKa, free [H+] is below the value needed to keep half the sites protonated, so [AH] falls below 50% of the total drug (the equilibrium shifts to the right). Conversely, when pH is lower than pKa, free [H+] is high, more sites get protonated, so [AH] rises to more than 50% of total drug (the equilibrium shifts to the left)


pH = pKa + 1 = 9% pH = pKa – 1 = 91%

pH = pKa + 2 = 1% pH = pKa – 2 = 99%

pH = pKa + 3 = 0.1% pH = pKa – 3 = 99.9%

pH = pKa + 4 = 0.01% pH = pKa – 4 = 99.99%

pH = pKa + 5 = 0.001% pH = pKa – 5 = 99.999%

etc…


*most of the change (82%) occurs within 1 pH-unit on either side of pKa, and 98% of all change occurs within 2 pH-units on either side of pKa.


If you’re given a problem that says (for example), pKa=4.2, pH=5.8, ask yourself the diffence and the answer will be close; it’ll be within 1% - 9%. In a multiple choice exam, you can really narrow it down this way.


What if pH – pKa is not an integer? It’s the same procedure, using the same keys on your calculator (see top of handout page 8).


Check to see if your answer makes sense.


For a similar question with respect to the B form of the drug, see graph on p. 8 of handout.

-When pH goes above pKa, the proton concentration is dropping. So the equation shifts to the right. If we’re plotting %B, this will go up. So the curve will be opposite that of the A form.

**Don’t memorize this (graph that weak acids go down to the right, and weak bases go up to the right), because what if we’re asked to plot % of form [BH+], the graph won’t go the same.


To solve a problem, you’ve got to know three things:

1.

whether the drug is a weak acid or weak base
2.

pKa of the drug
3.

pH of the body fluid where the drug happens to be


A summary:

-At pH<>pKa, things deprotonate and go to the A- form or B form, here the B form is permeant and A- is not.

What happens when a drug is distributing between two compartments in the body (between the stomach and blood, or the bowel and blood, for example)?

Here, we look at how much of the drug is in the permeant form. If the drug is in the permeant form in the stomach it can get through the wall and into the blood. Once it gets into the blood, if it stays in the permeant form it will just shuttle back and forth—this is not absorption. If, however, the drug is converted to the impermeant form in the blood, it won’t be able to cross back over and will be trapped in the blood—this is absorption. The drug must be permeant in the stomach, and impermeant in the blood to be defined as well-absorbed.

Example :

If we have a weak acid, put it in the stomach (pH= 1.4), and the drug pK_a is 4.4, what percent is in each form?

-pH is less than pK_a (acidic) means an excess of protons, so most of the drug will be protonated.

-What % will be in AH form?

We are 4 pH units more acidic than pK_a, so that means that 99.9% is in the AH form (permeant) in the stomach. So it can pass into the plasma.

-Once the permeant form is in the blood, it will re-equilibrate (deprotonate) into the A^- form… how much?

-We can assume that [AH] comes to equilibrium across the membrane. ----The pH in the blood is 7.4, so our weak acid will deprotonate, immediately converting to the A^- form. In the deprotonated form, A^- is not able to cross back over the membrane and is thus stuck in the blood.

-We can calculate that the [A^-] is 1000% more prevalent in the blood than the [AH] form.

What if we had a weakly basic drug?

The reverse process would occur; BH⁺ would deprotonate to B, and B would be the permeant form. In blood, 99.9% would remain as the permeant form, and the drug would go back across the membrane and not be absorbed in any discernable amount. You can’t have absorption of a weakly basic drug in the stomach if its pK_a is much less than the pH. If you injected the drug into the blood, it would get excreted into the stomach!

The general rule is that drugs get trapped in the compartment that they are ionized. That way they’re impermeant. This translates into the fact that weak acid drugs accumulate in the more alkaline compartment, whereas the weak base drugs accumulate in the more acidic compartment.

•Flow determined by myocardial Oxygen requirement (myocardial metabolism rate)

•O₂ extraction is normally very high, so this is not important in increasing O₂ supply

•At rest there is pronounced basal tone in precapillary resistance vessels of heart

-This is NOT due to neural input

-Vessels are autoregulated… low O₂ in vessel triggers automatic vasodilation

•Catecholamines effects on coronary vessels:

-Indirect action of coronary vasodilation due to incr. O₂ demands of myocardium

-Direct action of decreasing flow to subendocardium

•this effect can be independent of changes in total coronary flow

•Diastole is the major time of coronary blood flow

-Systole only accounts for about 20-30% of coronary blood flow

-this percentage decreases with increased cardiac activity

•fixed artherosclerotic lesion + vasospasm around that lesion

•unstable angina that has high chance of MI

•O₂ demand > supply

•Usually occur at a given myocardial workload (SAME O₂ DEMAND)

•Calculation of workload:

-Double product: systole BP x HR = work load

-triple product: HR x BP x ejection fraction = workload

•Upon resting, pain subsides

•depression of the ST segment

•Treatment: cardiac work  CO  O₂ demand.

•angina at rest or early morning hours

•due to thrombus or coronary vasospasm occluding vessel (coronary artery injury) -> acute MI

•O₂ supply greatly decreased independent of myocardial demand

• rise in ST segment

•may be due to rise in catecholamines

•or increased number / affinity of alpha receptors in large coronary vessels

•Ergonovine maleate (weak -agonist) is used in diagnosis by inducing coronary spasm

•NE, Epi (-agonist), and methacholine (parasym. agonist) also induce variant attacks

•Beta blockers may aggregate the condition too

•Treatment: dilate coronary artery

Organic Nitrates (vasodilator):

• Nitroglycerin, Isosorbide dinitrate (ISDN), Pentaerythritol tetranitrate

•Oral admin. subject to significant First Pass metabolism

 So admin sublingually

•Effective w/in 2 min for 30 min

a/ Mechanism of Action (MOA)

•denitration of drug must occur freeing nitrite ion

-nitrite ion reacts with sulfhydryl groups which comprise a “nitrite receptor”

-subsequent release of Nitric Oxide results (Endothelial Derived Relaxing Factor)

•Nitric Oxide increases cGMP leading to vascular dilation

b/

Role in relief of Effort Angina

 Dilates large veins -->  preload (little effect on arteries)

•preload leads to  cardiac work (less left ventricular wall tension)

•plus  end diastolic P may blood flow to ischemic subendocardium

•does not increase the max rate x pressure achievable before angina

•does allow for increased work before reaching the maximal rate x pressure

•ie they do not increase O₂ supply, rather they decrease O₂ demand

c/

Role in relief of Variant Angina

•remember O₂ demand is not important here

 Direct coronary vasodilation of spastic segment is the main beneficial effect

d/

Other effects

•dilates bronchial, GI, biliary, genitourinary tracts

•may be of some use in esophageal achalasia

e/

Side effects (all but one related to vasodilatory effects)

•flushed appearance (vasodilations in face)

•pulsating headache (due to meningeal a. dilation)

•hypotension, orthostatic, syncope etc…

sympathetic reflexes can’t overcome the functional antagonism on the vessels

Other side effect

-Methemoglobinemia (nitrite oxides hemoglobin, antidote for cyanide poisoing)

-halitosis due to sublingula admin.

F/ Contraindication

Elevated intra-cranial pressure

G/ Tolerance

•Subsensitivity results from depletion of sulfhydryl groups in “nitrite receptor

•Dithiothreitol reduces disulfides and restores sensitivity

•Cross tolerance between the organic nitrates occurs

•Small intermittent doses help avoid tolerance development

H/

Dependence

•can be dangerous…. slowly wean patient from use

a/ Nitroglycerin

•diluted with lactose for safe handling

•active drug produces burning sensation under tongue

Low dose

•beneficial venodilation

High dose

•arterial + venous dilation

•decreased preload + afterload => usually beneficial in reducing cardiac work (O₂ demand)

•may cause paradoxical angina due to reflex tachycardia (induced by low BP at baroreceptors)

Dermal patch

•prolonged effects + avoid sudden pressure drops

•(-) Headaches, Hypotension, tachycardia, faintness, flushing, dizziness, and skin rashes

b/

Isosorbide dinitrate (ISDN)

•slower onset than nitro. but longer effects

•converted to isosorbide mononitrate (ISMN) by the liver

•potent vasodilator with longer plasma half life than parent drug

•oral administration of large doses are effective for longer periods

•Isosorbide mononitrate (ISMO) is approved oral drug for chronic stable angina

c/

Pentaerythritol tetranitrate

•not absorbed well sublingually

•absorbed from GI tract

•converted to active form, Pentaerththritol trinitrate

2/ Beta Blockers: (see Anti-Hypertension section)

Propanolol, Metoprolol, Atenolol, Pindolol, Nadolol, Labetalol

•Net effect:  myocardial O₂ consumption

•Mech:  TPR   SV

•Effort angina only ?

3/ Ca⁺⁺ Channel Blockers: (see anti-hypertensive section)

•Verapamil, Nifedipine, Diltiazem, Bepridil (last option)

•Mech: TPR ->  SV

•Net result: no change in heart size

4/ Combination Therapy of Angina

Propanolol and Organic Nitrates

•prophylactic use of propanolol, with symptom use of nitrates

•propanolol blocks reflex tachy associated with nitro

•nitro by reducing preload tends to diminish enlarging of the heart induced by propanolol

Organic Nitrates and Calcium Channel Blockers

•very effective in relieving variant and effort angina

5/ Anti-Thrombotic (anti-coagulant) Agents

Aspirin, Ticlopidine, Clopidogrel

-Use in patient who had an acute MI

-Rationale: reduce incidence of thromboembolic and mortality from recurrent infarction